Michael R. Lucey James Neuberger Abraham Shaked Liver Transplantation - Vademecum 2003

LANDES
BIOSCIENCE
V ad e me c u m
LANDES
BIOSCIENCE
V ad e me c u m
Table of contents
1. Liver Transplantation:
An Overview
2. The Allograft Immune
Response
9. Medical Management of the

Liver Transplant Patient
10. Pediatric Liver Transplantation
3. Assessment for Liver

Transplantation
Liver
Transplantation
4. Management on the Liver

Transplant Waiting List
5. The Liver Transplant
Operation
6. Immunosuppression after
Liver Transplantation
7. Graft Dysfunction
8. Recurrence of Disease after
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9 781570 596827
Michael R. Lucey
James Neuberger
Abraham Shaked
v a d e m e c u m
Michael R. Lucey, M.D., F.R.C.P.I.

University of Wisconsin School of Medicine
Madison, Wisconsin, U.S.A.
James Neuberger, D.M., F.R.C.P.
University of Birmingham
Birmingham, United Kingdom
Abraham Shaked, M.D., Ph.D.
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania, U.S.A.
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Contents
1. Liver Transplantation: An Overview ................................. 1
Michael R. Lucey
History ....................................................................................................... 1
The Donor Organ Shortage ........................................................................ 1
Outcome of Liver Transplantation .............................................................. 3
2. The Allograft Immune Response ....................................... 5

Peter Abt and Abraham Shaked
The Alloimmune response .......................................................................... 5
Recognition of Self and Non-Self ................................................................ 5
Recipient T- and B-cell Activation .............................................................. 5
Stages of Allograft Response ........................................................................ 8
Classification of Allograft Rejection .......................................................... 11
Mechanisms of Immunosuppressive Drug Action ..................................... 12
Tolerance .................................................................................................. 12
Glossary .................................................................................................... 14
3. Assessment for Liver Transplantation .............................. 17

Michael R. Lucey
Selection for Liver Transplantation ............................................................ 17
Assessment of Severity and Prognosis of Chronic Liver Disease ................. 17
Timing of Placement on the Waiting List ................................................. 19
Transplantation for Non-Life Threatening Disease .................................... 20
Allocation and Distribution of Donor livers .............................................. 20
Contraindications to Liver Transplantation ............................................... 20
Live liver donation .................................................................................... 20
Assessment of Medical, Surgical and Psychological Suitability ................... 22
Cardiac Assessment ................................................................................... 22
Pulmonary Assessment .............................................................................. 22
Renal Assessment ...................................................................................... 23
Endocrine Assessment ............................................................................... 25
Assessment for Primary Hepatic Malignancy ............................................. 25
Assessment for Infection ........................................................................... 26
Nutritional Assessment ............................................................................. 27
Bone Disease ............................................................................................. 27
Nutrition .................................................................................................. 27
Surgical Assessment .................................................................................. 28
Psychological assessment ........................................................................... 28
Specific Disorders ..................................................................................... 29
Retransplantation ..................................................................................... 34
4. Management on the Liver Transplant Waiting List ......... 36

James Neuberger
Introduction ............................................................................................. 36
Prevention of Complications of End-Stage Liver Disease .......................... 36
Cancer Development ................................................................................ 38
Vaccinations .............................................................................................. 40
Progression of Medical Complaints ........................................................... 41
Temporary Suspension from the Waiting List ........................................... 41
5. The Liver Transplant Operation...................................... 42

Michael Crawford and Abraham Shaked
Cadaveric Donors ..................................................................................... 42
The Cadaveric Donor Operation .............................................................. 42
Extended criteria donors ........................................................................... 46
The Recipient Operation .......................................................................... 48
Special Operative Problems ....................................................................... 54
Live Liver Donors ..................................................................................... 57
6. Immunosuppression after Liver Transplantation ............ 60

James Neuberger
Drugs and Other Agents Used in Immunosuppression ............................. 61
Types of Immunosuppression ................................................................... 61
Medications Used for Immunosuppression ............................................... 61
Principles of Immunosuppression ............................................................. 67
Side-Effects of Immunosuppression .......................................................... 71
Tailoring the Immunosuppression to the Individual .................................. 71
Retransplantation for Chronic Rejection, Late Acute Rejection
and Early Ductopenic Rejection ............................................................ 72
Co-Morbid Conditions ............................................................................. 72
Development of Lymphoma and Other Malignancy ................................. 72
7. Graft Dysfunction ........................................................... 74

Geoffrey H. Haydon
Introduction ............................................................................................. 74
Investigation of Graft Dysfunction ........................................................... 74
Primary graft non-function ....................................................................... 74
Immunological Complications .................................................................. 74
Graft Infection .......................................................................................... 78
Graft Ischemia .......................................................................................... 81
Biliary Complications ............................................................................... 83
Recurrence of Disease After Liver Transplantation .................................... 84
8. Recurrence of Disease after Liver Transplantation .......... 86

Lisa Forman and Geoffery Haydon
Hepatitis C Virus Infection ....................................................................... 86
Hepatitis B Virus Infection ....................................................................... 87
Hepatitis D virus Infection ....................................................................... 88
Hepatitis A Virus Infection ....................................................................... 88
Autoimmune Disease ................................................................................ 88
Metabolic Diseases .................................................................................... 90
Malignancy ............................................................................................... 92
9. Medical Management of the Liver Transplant Patient ..... 95

Anne Burke
Long Term Morbidity and Mortality of Liver Transplantation ................... 95
Medical Consequences of Immunosuppression ......................................... 95
Cardiovascular Disease .............................................................................. 95
Renal Insufficiency ................................................................................... 98
Osteoporosis and Osteopenia .................................................................... 99
Malignancy ............................................................................................. 100
Infections After Recovery from Liver Transplantation ............................. 101
Vaccinations ............................................................................................ 102
Common Causes of Morbidity in Liver Transplant Recipients ................ 102
Pregnancy and Reproductive Health ....................................................... 104
Lifestyle .................................................................................................. 106
10. Pediatric Liver Transplantation ..................................... 107

Elizabeth B. Rand and Kim M. Olthoff
Indications for Liver Transplantation in Children ................................... 107
Evaluation of Pediatric Candidates and Timing
of Liver Transplantation ....................................................................... 107
PELD ..................................................................................................... 109
Pre-Operative Management .................................................................... 110
Surgical Issues and Options .................................................................... 110
Early Post-Operative Management .......................................................... 111
Subsequent Management ........................................................................ 112
Index ............................................................................. 114
Editors
Michael R. Lucey M.D., F.R.C.P.I.
Professor of Medicine
Chief, Section of Gastroenterology and Hepatology
University of Wisconsin School of Medicine
Madison, Wisconsin, U.S.A.
James Neuberger, D.M., F.R.C.P.

Professor in Medicine
Liver Unit
Queen Elizabeth Hospital
Abraham Shaked, M.D., Ph.D.

Professor of Surgery
Chief, Division of Transplantation
University of Pennsylvania Medical Center
Department of Surgery
Contributors
Peter Abt, M.D.
University of Pennsylvania Health System
Geoffrey H. Haydon, M.R.C.P., M.D.

Liver Unit
Queen Elizabeth Hospital
Anne Burke, M.B., B.Ch., B.A.O.

Division of Gastroenterology
University of Pennsylvania Health System
Kim M. Olthoff, M.D.

Fred and Suzanne Biesecker Center for
Pediatric Liver Disease
University of Pennsylvania Health
System
Michael Crawford, M.D.

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

University of Pennsylvania School
of Medicine
Fred and Suzanne Biesecker Center
for Pediatric Liver Disease
Childrens Hospital of Philadelphia
Preface
The purpose of this volume is to provide a short, didactic handbook for
those clinicians (medical, surgical, nursing and others) who are involved in
the care and management of people who may, are or have undergone liver
transplantation. We are aware that there are several, large texts which
provide a comprehensive account of liver transplantation. This volume is
designed to complement and not replace them.
Liver transplantation has developed rapidly over the last two decades and
dogma is changing rapidly. This leads to controversy and debate which are
the essence of academic medicine. We are also aware that different transplant
programs have their own approach to managing patients. It is inevitable that
many views and arguments cannot be put in such a book as this one. Where
possible, we have tried to provide a consensus view. We have provided selected
references for further reading and electronic addresses to source material, for
the reader who wishes to probe deeper into any aspect of liver transplantation.
We are grateful to the authors who have contributed to this book. We
have tried to ensure a consistent style and hope the reader finds this useful
and helpful. Finally, if there are any errors or omissions, the editors would
be grateful if these could be identified, so that we may correct them in future
editions.
Michael R. Lucey
James Neuberger
Abraham Shaked
August 2002
Liver Transplantation: An Overview
CHAPTER 1

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

The source for donor livers in the western world is almost exclusively from
heart beating brain dead donors. Sophisticated schemes are required to identify
potential donors, retrieve their organs, and transport the organs to the location of
the potential recipient. At the same time, the number of potential recipients awaiting
liver transplant continues to grow at a furious pace, outstripping the modest increases
in donor numbers. This has meant that there are many more recipients for every
donor liver. Thus in the United States in 2000, there were over 17000 patients on
the waiting list, only 4579 cadaveric transplants done and 371 living related transplants. There were 1347 deaths on the waiting list. (See www.unos.org for current data)
Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked.
2003 Landes Bioscience.
The disparity between donor availability and recipient number has led to growing numbers of patients on the waiting list for liver transplant.
Innovative responses to the donor shortage have been introduced but while these
approaches may help relieve the situation, they are unlikely to ease the effects of the
organ shortage:
1. Non-heart beating donors. Non-heart beating donors are uncommon,
and the frequency of primary graft non-function and later, biliary strictures
are greater in these allografts.
2. Split liversthe division of a cadaveric organ between two recipients.
However, only some cadaveric donor livers are suitable for splitting.
3. Living donationthe harvesting of liver segments from living donors.
Many recipients lack a family member or friend who is suitable or willing
for living donation. Moreover, living segmental liver transplantation poses
real risks of morbidity and even mortality (1% or more) for the donor.
4. Use of marginal donors and extended use donor organs
Marginal donors: some donor livers are associated with a higher
probability of primary non-function (the so-called marginal donor).
Marginal organs include those from older or obese donors, or donors
who are unstable prior to organ retrieval. Other marginal grafts
include steatotic livers, in which histology demonstrates greater than
25% microvesicular or macrovesicular fat. These grafts are associated
with a higher incidence of primary non-function of the allograft.
Extended use organs from patients infected with present or past
viral hepatitis B or C and those with extrahepatic malignancy or
treated bacterial infection. Organs from virus-infected donors are
matched to a recipient already infected by the same virus, albeit
only after the recipient is apprised and has given consent. An example
would be putting an anti-hepatitis C positive liver into an antihepatitis C positive recipient, or an anti-HBcore positive liver into
an HBsAg positive recipient.
5. Xenotransplants: the use of genetically modified animals, such as pigs or
primates, is still a very long way from clinical use. While some of the
problems of hyperacute rejection may be overcome, problems, such as
chronic rejection, freedom from introducing infection (such as the porcine
endogenous retrovirus (PERVs) as well as physiological concerns make it
unlikely that this approach will provide a solution to the organ shortage
in the next decade.
6. Increasing organ donation: there are wide variations in the rates of organ
donationbetween 8 and 37 donors per million. Attempts to increase
organ donation by education have largely failed: the most successful model
in Spain is dependent on provision of a well-organized system of donor
co-ordinators and acceptance of older donors.
7. Future approaches may include stem cell transplantation and hepatocyte
transplantation.
Thus, it is unlikely that these methods will meet the needs of all potential recipients.
Table 1. Factors influencing the outcome of orthotopic liver transplantation

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

Liver transplantation has become the treatment of choice for many forms of lifethreatening liver disease because of the continuing lack of less radical therapies and
the gradual improvement in survival and quality of life after liver transplantation.
Five-year survival in excess of 75% is expected for most patients, and patients who
have survived more than 10 years after transplantation are commonplace in long
established programs. The success of liver transplantation has occurred despite unacceptably high early mortality and morbidity in a subset of recipients. In addition,
we now have to learn the best ways of managing the unwanted consequences of long
term immunosuppression and recurrence of the original disease in the long-term
survivor.
The outcome of liver transplantation is dependent on donor organ and recipient
factors. See Table 1. Donor factors, which reduce graft success, include donor age
and transplantation of a liver allograft from a female donor into a male recipient. It
is widely held that the fat content of the donor liver influences early graft function,
perhaps by facilitating the generation of reactive oxidative species.
Although the etiology of liver disease usually does not preclude liver transplantation, nevertheless, the cause of the underlying liver disease significantly affects the
outcome after liver transplantation.
The best outcomes are observed in patients with chronic cholestatic disorders and in chronic liver failure from cirrhosis of many causes.
The outcome is worse among patients transplanted for fulminant liver
failure and significantly worse in patients with malignant disease of the
liver.
Retransplantation carries a poorer outcome than primary grafting.
The outcome of liver transplantation is influenced by the severity of illness of
the recipient prior to surgery. Patient and graft survival are significantly impaired in
recipients requiring intensive care unit management or among patients with multisystem failure, prior to transplant. The allocation system currently in use in the
Table 2. Outcome of liver transplantation in the United States
Primary Diagnosis
N (94-95) 1 Year
Std Err N
Survival%
5 Year
Std
Survival% Err
Non-Cholestatic Cirrhosis 3520
86.2
0.6
10734 70.1
0.6
Cholestatic Liver Disease 939
89.4
1.1
3477
80.7
0.8
Biliary atresia
337
91.9
1.6
1549
82.1
1.2
Acute Hepatic Necrosis
392
77.5
2.2
1367
67.1
1.5
Metabolic Disease
274
88.7
978
79.9
1.5
Malignant Neoplasms
151
76.3
3.9
796
35.4
2.2
Overall
6271
87
0.5
20063 72.3
0.4
Based on The U.S. Scientific Registry of Transplant Recipients and The Organ
Procurement and Transplantation Network. Transplant Data 1988-1996. Reference 1
United States, Spain and Germany ensures that donor livers are offered preferentially to such high-risk candidates. Finally, center characteristics influence outcome
after liver transplantation, at least in the United States where it has been shown that
mortality rates are significantly higher in centers that perform 20 transplants or
fewer per annum, compared to centers which perform more than 20 annually.
Suggested Reading
1.
2.
3.
4.
The U.S. Scientific Registry of Transplant Recipients and The Organ Procurement
and Transplantation Network. Transplant Data 1988-1996. (See: www.unos.org)
Markmann J, Doyle HR, Morelli R, McMichael J, Doria C, Aldrighetti L et al.
Hepatic retransplantationAn analysis of risk factors associated with outcome.
Transplantation 1996; 61:1499-1505.
Edwards EB, Roberts JP, McBride MA, Schulak JA, Hunsicker LG. The effect of
the volume of procedures at transplantation centers on mortality after liver transplantation. N Engl J Med 1999; 341:2049-2053.
Trotter JF, Wachs M, Everson GT, Kam I. Medical progress: Adult to adult transplantation of the right hepatic lobe from a living donor. N Engl J Med 2002;
346:1074-1082.
The Allograft Immune Response
CHAPTER 2

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

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

Recipient T-cells are required for allograft rejection. The T-cell receptor is able to
recognize donor MHC antigens displayed on the surface of the antigen-presenting
Figure 1. Schematic structure of MHC class I and class II.
Figure 2. Antigen processing and presentation. The antigen presenting cell presents exogenous protein bound to class II molecules to CD4+ T-cells and also processes intracellular protein and presents it with MHC class I to CD8+ T-cells. The
T-cell receptors recognize peptide bound to MHC.
Table 1. Characteristics of MHC molecules

Common features of MHC Class I and II glycoproteins
allelic diversity
antigen presentation
Differing characteristics
Class I MHC molecules:
expressed on all nucleated cells
activate T-cells bearing the CD8 surface molecule (CD8+)
Class II MHC molecules:
expressed on dendritic cells, B-cells, and macrophages
activate T-cells bearing the CD4 antigen (CD4+)
cell. T-cell recognition is associated with the initation of complex intracellular signaling pathways that result in activation and proliferation of the T-cell (Fig. 3).
There are two classes of T-cells based on the surface expression of CD4 or CD8
molecules. CD4 and CD8 molecules bind to the same MHC on the antigen presenting cell as the T-cell receptor. CD4+ cells are known as helper cells and play an
important role in initiating and directing the immune response (Fig. 4). CD8+ cells
also known as cytotoxic T-cells are responsible for cell directed cytotoxicity.
Whether a T-cell, whose receptor has bound the MHC-peptide displayed on the
antigen presenting cell, becomes activated, depends on a receiving a second set of
signals (co-stimulation) from the antigen presenting cell. These costimulatory interactions act directly through cell surface receptor-ligand interactions and soluble
cytokines that are linked to intracellular signaling pathways (Fig. 4).
CD4+ T-cells are the dominant phenotype initiating acute cellular allograft rejection. Once activated the CD4+ T-cells undergo clonal expansion and differentiation. In doing so they secrete cytokines that attract other leukocytes to activate other
T-cells and facilitate the differentiation of B-cells to plasma and memory cells.
The pattern of cytokines elaborated by subsets of CD4+ and CD8+ stimulated
T-cells is important in directing the alloimmune response. CD4 bearing Th lymphocytes (T helper) cells have been stratified into two classes of Th cells depending
on the type of cytokines elaborated by the cells in question. The subdivision of Th
cells is called the Th1 and Th2 paradigm. Precursor CD4 cells producing interleukin-12
promote Th 1 cells, whereas precursor CD4 cells producing interleukin-4 (IL-4)
promote Th2 cells.Th1 cells secrete IFN-, IL-2, which promote cell-mediated cytotoxicity by activating macrophages and cytotoxic T cells. Th2 cells secrete IL-4
and IL-6, cytokines which promote allergic inflammation and stimulate B cells to
produce antibodies. Furthermore, cytokines from Th 1 cells inhibit Th2 cells whereas
cytokines from Th 2 cells inhibit Th1 cells. It appears in certain experimental situations that a Th 2 predominance is associated with the prolongation of graft survival
or even tolerance (Table 2).
While much attention has been given to T-cell activation, B-cells are also involved in the response. Donor antigen shed from the graft binds to surface Ig and is
then internalized by the B-cell. The antigen is processed and presented on the B-cell
Figure 3. T-cell receptor: The T-cell receptor (TCR) is composed of two subunits
and is associated with CD3 proteins. Transcriptional activity is initiated in the nucleus
via signaling pathways. (NFAT = nuclear factor of activated T-cells)
surface in conjunction with class II to recruit antigen specific T-cell help. The B-cell
undergoes clonal expansion and differentiation becoming a plasma cell capable of
producing soluble Ig (Fig. 5). Other B-cells will become memory cells.
Stages of Allograft Response

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

When first transplanted, the liver allograft has the immune phenotype of the
donor. Initially therefore, the liver allograft expresses the MHC molecules of the
donor, resulting in two pathways of antigen recognition. Whereas in the nontransplant setting, T cells recognize foreign (or non-self ) peptides bound to native
(or self ) MHC molecules, the MHC molecules in the allogeneic liver are non self,
and it is presumed that recipient T cells recognize intact donor MHC molecules as
non-self because their three-dimensional stoichiometry resembles a self MHC bound
to a foreign peptide, a concept referred to as molecular mimicry. This process is
called direct antigen recognition and is thought to be the main mechanism for the
immune response in acute cellular rejection. Later, there is migration of donor
dendritic cells into the host, and migration of recipient APCs into the donor liver.
This leads to a second pathway for alloimmune recognition, in which peptides derived
Figure 4. Cell surface proteins involved in T-cell activation. The T-cell receptor
complex, including CD3 and CD4 or CD8 bind to an APC displaying MHC and
peptide. Several costimulatory molecules such as CD28 are required for T-cell
activation.
Table 2. Th 1 and Th 2 paradigm

Differentiated by
Cytokines Produced
Function
Th1
IL-12
IL-2, IFN-
cell mediated cytotoxicity

suppresses Th2-cell
response
Th2
IL-4
IL-4, Il-5, IL-6
suppresses Th1-cell
response
promotes B-cell expansion
IL-10
from catabolism of the donor MHC molecules are presented by self MHC on recipient APCs.
It is unclear whether the non-immunologic injury incurred by the donor liver in
the process of organ retrieval, preservation and reperfusion contribute to the initiation
or maintenance of the alloimmune response. The period of cold preservation,
ischemia, and reperfusion leads to the differential expression of endothelial cell surface
molecules and cytokines. These include adhesion molecules, interleukins, and
10
Figure 5. Antibody structure. Heavy chains are in dark, light chains are white.
The antigen binding sites are composed of heavy and light chains.
chemokines which attract inflammatory cells. Oxygen radicals produced during ischemia and reperfusion directly harm the graft.
Helper T cells are thought to be the most important cells for initiating allograft
cellular rejection. They are responsible for the production of cytokines, such as
interleukin 2, which are necessary for clonal expansion of activated lymphocytes.
The cytokines act in an autocrine fashion on CD4 expressing surface molecules (Th
cells) and as a paracrine stimulus on other effector cells such as cytotoxic T cells
(CD8 cells), macrophages and B cells.
Leukocyte Migration into the Allograft

As part of the early evolution of the allograft immune response, recipient
leukocytes are recruited to the donor allograft. This involves the elaboration of a
series of soluble molecules as well as cell-to-cell interactions. Three main classes of
receptors are credited with leukocyte migration.
11
Selectins: primarily responsible for allowing the leukocyte to gently adhere to the endothelial surface
Integrins
Members of the immunoglobulin superfamily: responsible for
extravasation of leukocytes into the allograft.
Graft Destruction
CD8+ T-cells are the main effectors of graft destruction and cause cell death
through direct cell contact. When activated by membrane binding to the allograft
they release cytotoxic molecules termed perforin and granzyme. Perforins create holes
in the target cell membrane and granzymes disrupt intracellular processing. Cytotoxic
T-cells also have a cell surface protein termed Fas ligand which when bound to a
receptor protein called Fas, which is present on target cells, results in death of the
target cell by the process of apoptosis.
Macrophages which have been activated by CD4+ T-cells are capable of causing
tissue destruction through the release of cytotoxic cytokines or through direct cell
lysis. The role of NK cells in organ allograft rejection is unclear. B-cells secrete specific
antibody that binds to the allograft cell surface. The antibody induces tissue damage
through the activation of the complement system (Fig. 6).
Classification of Allograft Rejection

Allograft rejection is classified into three types based on the nature of the immune
response after transplantation:
1. Hyperacute rejection
2. Acute cellular rejection
3. Chronic ductopenic rejection.
Hyperacute Rejection
Hyperacute rejection is characterized by a rapid response of the host immune
system to the allograft. Within minutes to hours of the transplant, preformed
antibodies engage class I MHC or the ABO blood group antigens on the graft. The
antibodies facilitate complement mediated lysis of the endothelium and initiate an
inflammatory cell infiltrate. Hyperacute rejection is rarely observed in liver transplants,
even among those with a positive crossmatch.
Acute Cellular Rejection

Acute cellular rejection is due to an immune reaction mediated by recipient T
lymphocytes response to donor MHC antigens. Antibodies and cytokines also
contribute to the immunologic attack. The biliary epithelium and venous
endothelium express MHC class I and II molecules and are the focus of the acute
cellular rejection response. Hepatocytes which express few class I or II MHC antigens
are rarely the target of acute cellular rejection.
The principal clinical features of acute cellular rejection are:
1. Elevated liver transaminases and/or bilirubin
2. Lymphocytic infiltrates in the portal triads seen on biopsy
12
3. The development of graft dysfunction manifested by hyperbilirubinemia and

subsequent impaired liver synthetic function.
Acute cellular rejection is usually controlled with additional corticosteroid-based
immunosuppression with no significant impact on graft or patient survival.
Chronic Ductopenic Rejection

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

The rational design and use of drugs is based on an understanding of the immune
response to the donor organ. These agents can be divided by classes based on their
mechanism of action. The antimetabolites include azathioprine and mycophenolate
mofetil. Both interfere with purine synthesis and clonal expansion of T- and B-cells
(Fig. 7).
Cyclosporine and tacrolimus exert their action by inhibiting calcineurin, a protein responsible for promoting cytokine induced gene activation. By inhibiting IL2 production they prevent activation of lymphocytes. Rapamycin (Sirolimus), one
of the most recently approved antirejection drugs, is structurally similar to tacrolimus,
and appears to inhibit the T-cell response to IL-2.
Glucocorticoids bind to cytoplasmic receptors which are translocated to the
nucleus where they regulate gene transcription by binding to specific gene regulatory
regions. They interfere with many aspects of the immune system including the
production of IL-1, IL-2, and IFN-.
Antibodies recognize many surface antigen epitopes (polyclonal) or single cell
surface antigen epitopes (monoclonal). Antithymocyte globulin and thymoglobulin
are two polyclonal preparations of immunoglobulin to lymphocytes. OKT-3 is
directed against the CD3 receptor on T-cells. Basiliximab and daclizumab are two
monoclonal antibodies against the chain of the IL-2 receptor. They are used for
induction therapy and like the other antibodies result in depletion of the cells that
bear the cell surface protein which they bind.
Tolerance
The development of an immunologic state wherein the recipient is unresponsive
to donor alloantigen, but yet the immune system is capable of recognizing and
responding to other foreign proteins such as bacterial or tumor antigens without the
need for immunosuppression is known as tolerance.
Mechanisms of tolerance can be grouped into suppression, anergy, deletion, and
ignorance. Suppression involves the inhibition of donor reactive T and B-cell responses
by a suppressor cell population. While functional examples exist, it has been difficult
13
Figure 6. Antibody mediated damage to graft endothelium. Recipient antibody binds

to MHC on graft endothelium. Antibody initiates graft damage through antibody
dependent cellular cytotoxicity (ADCC) and activation of the complement system.
Figure 7. Mechanism of action of commonly used immunosuppresants. Cyclosporine

(CSA), tacrolimus (FK506), mycophenolate mofetil (MMF), azathioprine (AZA),
FK506 binding protein (FKBP).
identifying a suppressor cell. Anergy occurs when T-cells encounter peptide-MHC

complexes that they recognize, but the T-cell does not receive adequate co-stimulatory
signals. Deletion, the destruction of alloreactive T-cells, is likely to occur in the
thymus, and to a lesser extent in the periphery. Ignorance indicates that alloreactive
T-cells are present, but do not respond to stimuli.
14
Glossary
Acquired immunity: All immune processes utilizing immunological memory

(see below). Acquired immunity is the basis of vaccination.
Acute cellular rejection: Inflammation of the allograft elicited by genetic disparity
between the donor and recipient, primarily affecting interlobular bile ducts and
vascular endothelia, including portal veins and hepatic venules, and occasionally the
hepatic artery and its branches.
Allele: Alternative forms of the same gene
Allogeneic: Genetically dissimilar donor and recipient pair of the same species.
The converse is syngeneic.
Allotype: Antigenic determinants that differ among individuals of the same
species. Examples include different epitopes of the HLA system.
Anergy: Immunologic tolerance in which lymphocytes become functionally
unresponsive.
Antigen presenting cell (APC): Functional descriptor of specialized cells bearing MHC cell surface molecules, by which they present peptides which are the
product of intracellular degradation of exogenous proteins recognized as non-self.
Activated APCs also express co-stimulatory molecules. Macrophages and dendritic
cells are paradigmatic APCs.
Apoptosis: Also called programmed cell death. A specific form of cell death due
to enzymatic degradation of DNA, without inflammation.
B-cells: Lymphocytes capable of antibody production. Most arise from stem
cells in bone marrow. B lymphocytes produce antibodies as circulating proteins or as
stationary molecules. The latter, which constitute the B cell receptor, contain a
hydrophobic transgenic sequence which tethers the immune recognition segment
of the antibody to the cell surface membrane.
Cell mediated immunity: Immunologic response based on cellular elements of
the immune system.
CD antigen: Cell surface antigens, classified according to cluster of differentiation
(CD), in which individual molecules are assigned a CD number on the basis of their
reactivity with specific monoclonal antibodies
CD3: A complex of molecules on the cell surface of T cells, that in association
with the T cell receptor (TCR), activate intracellular signal transduction mechanisms
when the TCR binds an antigen. Blockade of CD3 by a monoclonal antibody
(Orthoclone OKT3) depletes the patient of T cells.
CD4: Cell surface molecule expressed by functionally distinct subset of T
lymphocytes. CD4 binds to an invariant part of the MHC class II molecule. CD4
bearing T cells usually act as T helper (Th) cells and recognize antigens processed by
APCs and presented in conjunction with MHC class II molecules.
CD8: Cell surface molecule expressed by functionally distinct subset of T
lymphocytes. CD8 binds to an invariant part of the MHC class I molecule. CD8
bearing T cells usually act as cytotoxic T lymphocytes (CTLs) and recognize antigens
processed by infected or injured nucleated cells and presented in conjunction with
MHC class I molecules.
15
CD28: The best characterized co-stimulatory molecule. Cell surface molecule

expressed by T lymphocytes, activated by binding of TCR and antigen ligand. CD
28 has two known ligands (variously named B7-1 or CD80 and B7-2 or CD86)
which are expressed on the cell surface of activated APCs.
CTLA-4: Cell surface molecule, structurally similar to CD28, which also binds
B7-1 and B7-2. In contrast to the CD28-B7 interaction, linkage of CTLA-4 and B7
leads to an inhibitory signal that terminates the inflammatory response.
Chemokine: Chemotactic cytokines that regulate leukocyte transit. Each type
of leukocyte bears chemokine receptors on its cell surface that guides it to chemokines
secreted in tissues.
Chronic ductopenic rejection: Defined by two histopathological features:
obliterative vasculopathy and bile duct loss
Clone: Genetically identical cells derived from a common ancestor.
Co-stimulatory signal: Non-antigen specific interaction between lymphocytes
and antigen presenting cells which uses cell surface molecules expressed on APCs to
bind to receptors on lymphocytes (e.g., CD 28 on lymphocytes and B7-1 on APC).
Co-stimulatory signals enhance the immune response by promoting lymphocyte
clonal expansion and cytokine production and are necessary for T cell activation.
Interaction of T lymphocyte and APC in the absence of co-stimulatory signals leads
to anergy or apoptosis of the T cell. A parallel receptor ligand interaction which is
inhibitory of the immune response is described through CTLA-4.
Cytokine: A large family of low molecular weight soluble proteins involved in
regulating cellular activity. Includes the chemokines (see above).
Cytotoxic T lymphocyte (CTL): T lymphocyte that kills its target upon
recognizing complexes of peptides and MHC complexes on the target cell membrane.
Cytotoxic T cells usually express the CD8 cell surface molecule.
Epitope: The structure within an antigen that is recognized by an antigen receptor
(antibody or T cell receptor).
Graft versus host disease (GVHD): Clinical syndrome caused by immune
reaction of allogeneic lymphocytes contained within allograft tissue reacting against
alloantigens in the recipient (usually in skin, liver, and gastrointestinal tract).
Haplotype: Closely linked alleles on the same chromosome, usually inherited as
a group and linked to inheritance of some phenotypic characteristic.
Helper T cell: T lymphocytes that secrete cytokines required for the immune
function of other cells in the immune system. MosT helper T cells express the cell
surface molecule CD 4.
Human leukocyte antigens (HLA): The major histocompatibility complexes
in humans.
Humoral immunity: Immunologic response involving antibodies.
Idiotype: An antigenic determinant within the binding site of an antibody that
is recognised by another antibody.
Immunologic memory: The ability of the immune system to recall an encounter with a specific antigen, and to generate a greater response in a subsequent exposure to the same alloantigen. Immunologic memory results from the generation of
16
memory T and B cells during the initial encounter with an alloantigen, and is the
characteristic feature of acquired immunity.
Innate immunity: All immunologic defenses that lack immunologic memory.
The characteristic feature is that the response remains unchanged however often a
specific immunogenic moiety (immunogen) is encountered. This contrasts with
acquired immunity (see above).
Isograft: Transplant between genetically identical members of the same species
such as inborn strain of animals or twins. Also known as a syngeneic transplant.
Major histocompatibility complexes: Histocompatibility antigens expressed
on cell surfaces which are the markers by which the immune system distinguishes
self from non-self. In humans, the MHC molecules are called HLA (see above).
Memory cells: Cells with lasting response to certain immunologic epitopes.
Natural killer (NK) cell: Lymphocytes that have an innate ability to kill infected
or damaged cells, without requiring interaction with MHC surface molecules.
T-cell: Lymphocyte which undergoes selection in the thymus. T cells are the
only cells essential to the acute cellular rejection response. T cells are distinguished
by their cell surface receptor (TCR). T cells are subdivided into categories: T helper
cells and T suppressor cells.
Tolerance: An immunologic state in the absence of immunosuppression wherein
the recipient is unresponsive to donor alloantigens, while retaining the capacity to
recognize and respond to other foreign proteins such as bacteria or tumor antigens.
Vaccination: The exposure of a nave host to a harmless version of a pathogenic
immunogen (an altered pathogen, or molecular mimic) which in turn generates
memory cells but not the pathologic consequences of the infection itself (the primary
immune response). The immune system is thus primed to deliver an enhanced
secondary immune response in the event that the host is exposed to the infectious
agent in the future.
Xenotransplantation: Transplantation across species. The graft is called a
xenograft.
Based on Delves and Roitt, New Engl J Med 2000; 343:37-49; and Sayegh and
Turka, New Engl J Med 1998; 338:1813-1821.
Suggested Reading
1.
2.
3.
4.
Delves PJ, Roitt IM. The immune system-the first of two parts. New Engl J Medicine 2000; 343:37-49. The immune system-the second of two parts. New Engl J
Med 2000; 343:108-117.
Sayegh MH, Turka LA. The role of T-cell co-stimulatory activation pathways in
transplant rejection. New Eng J Med 1998; 338(25):1813-1821.
Wiesner RH, Batts KP, Krom RA. Evolving concepts in the diagnosis, pathogenesis, and treatment of chronic hepatic allograft rejection. Liver Trans Surg 1999;
5:388-400.
Wiesner RH, Demetris AJ, Belle SH, Seaberg EC, Lake JR, Zetterman RK et al.
Acute hepatic allograft rejection: incidence, risk factors, and impact on outcome.
Hepatology 1998; 28:638-645.
Assessment for Liver Transplantation
17
CHAPTER 3

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

of Chronic Liver Disease
The severity of liver failure in patients with chronic liver disease can be assessed
by several models although the two models currently used are the Child-Pugh
classification and the MELD score (model for end-stage disease).
Child-Turcotte-Pugh Class (Table 1)

This scoring scheme is an empiric compilation of five features of end-stage liver
failure:
Ascites
Encephalopathy
18
Prothrombin time
Serum bilirubin
Serum albumin
It was developed originally as an instrument to predict outcome after portacaval
shunt surgery. Later Pugh modified it for a study of esophageal transection for bleeding
esophageal varices and modified the score for patients with cholestatic diseases. It
has been adopted as the most easily administered clinical tool to assess severity of
cirrhosis. Survival of cirrhotic patients declines with worsening Childs class. The
Childs class is useful for segregation of cirrhotic patients according to risk of dying.
It does not indicate prognosis for an individual patient with cirrhosis. Furthermore,
its origin as an empiric instrument for specific circumstances related to portal
hypertension make it less useful as a prognostic guide in many circumstances in
which liver transplantation is under consideration. These include patients with chronic
cholestatic diseases, liver tumors or fulminant liver failure. The Child-Pugh
classification has not been verified in childhood disorders.
Table 1. Child-Turcotte-Pugh classification

Variable
Encephalopathy
Ascites
Bilirubin (mg/dl)
Albumin (g/dl)
Prothrombin time (sec. prolonged)
(INR)
None
None
<2
>3.5
<4
<1.7
Points
1
Moderate
Slight
2-3
2.8-3.5
4-6
1.7-2.3
Severe
Moderate
>3
<2.8
>6
>2.3
Primary Biliary Cirrhosis/Primary Sclerosing Cholangitis

Bilirubin
1-4
4-10
>10
Scores are summed to determine Childs class: A = 5-6, B = 7-9 and C = 10-15.
MELD Score
The MELD score is based on the following three variables:
INR (International Normalized Ratio)
Serum bilirubin
Serum creatinine
To obtain the MELD score for any patient, access the Internet at: www.unos.org
or: www.mayo.edu/int-med/gi/model/mayomodl-5-unos.htm
There are other prognostic scoring schemes:
Primary biliary cirrhosis: sustained elevation of total bilirubin is the single
most influential factor in predicting outcome. Patient age, serum albumin,
prothrombin time and the presence of edema are minor influential factors.
The presence of cirrhosis is a weak prognostic factor.
Primary sclerosing cholangitis: patient age, serum bilirubin, albumin and
19
aspartate transaminase and a history of variceal hemorrhage have been

constructed into a prognostic instrument. Although the allocation priority scheme in the United States does not incorporate prognostic scoring
schemes specific to either primary biliary cirrhosis, or primary sclerosing
cholangitis, these scoring schemes allow transplant physicians to recognize patients with poor prognosis.
3
Table 2. Indications for consideration of liver transplantation in patients with
chronic liver disease
Recurrent gastroesophageal variceal hemorrhage
Refractory ascites
Spontaneous bacterial peritonitis
Severe hepatic encephalopathy
Hepatorenal syndrome
Profound non-responsive pruritus of cholestatic liver disease
Severe hepatic osteopathy
Hepatocellular carcinoma
Progressive rise in serum alpha-fetoprotein without mass
Refractory bacterial cholangitis
Severe coagulopathy due to liver failure
Severe sustained fatigue and weakness
Severe malnutrition
Hepatopulmonary syndrome
Timing of Placement on the Waiting List

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

Liver transplantation is also indicated for conditions which cause unacceptable
loss of quality of life:
Lethargy: is associated with chronic liver disease. However it is important
20
to exclude treatable causes such as depression, hypothyroidism, or unwanted effects of medication.

Pruritus: All therapeutic options are tried before transplantation, when
liver function is well maintained. Such therapies include cholestyramine,
cholestipol, rifampin, naltrexone, ursodeoxycholic acid, phenytoin, and
plasmapheresis.
Hepatic osteodystrophy: when progressive may be an indication for
transplantation.
Allocation and Distribution of Donor Livers

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

Absolute and relative contraindications to liver transplantation are shown in Tables
3 and 4.
21
Table 3. Absolute contraindications

Severe (uncontrolled) infection outside the hepatobiliary system
Metastatic cancer (except some neuroendocrine cancers)
Extra hepatic cancer (other than local skin cancer)
Cholangiocarcinoma
Advanced cardiopulmonary disease
AIDS
Severe pulmonary hypertension
Technical considerations (e.g., widespread intra-abdominal venous thrombosis)
Table 4. Relative contraindications

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

The use of live donors for liver transplantation was developed in response to the
inadequate donor organ supply. Live liver donation began with left lobe resection
from adults for transplantation into babies and small children. More recently, adult
to adult transplantation, in which the right lobe of a healthy adult is resected and
transplanted into an adult with severe liver disease, has been adopted by many
transplant programs in North America and Europe. Live liver donation places the
healthy living donor at risk and mandates that a careful selection process be applied
to the donor. The mortality for a donor of a hepatic right lobe is up to 2%. In brief,
a consensus has emerged that donors for adult to adult transplant must be:
Healthy
Of identical or compatible ABO type
Able to give informed consent and understand the risks of being a living
donor
Have sufficient body mass to provide a donor graft with a graft recipient
Graft to recipient weight ratio (GRWR) of at least 0.8, and preferably
1.0., whilst leaving at least 25% of the native liver remaining in the donor.
The selection of recipients to receive a donor partial hepatectomy is less well
defined. At the time of writing, there is an emerging consensus that adult to adult
live liver donation should be offered to patients who demonstrate increased urgency
without requiring ICU-based life support. Very ill unstable patients (i.e., patients
requiring ICU based life support) need of a full size graft. The very stable patient
who is not in danger of foreseeable death can wait safely and may get a cadaveric
organ. The patients most appropriate for receiving a graft from adult to adult living
liver donation are those who have recovered from an episode of decompensation,
22
those who manifest a gradual decline, and patients with newly diagnosed small
hepatocellular cancer.
Assessment of Medical, Surgical

and Psychological Suitability
All patients must undergo full history and examination. History of vaccination
and need for further vaccination is covered in Chapter 4.
Cardiac Assessment
A history of systemic hypertension, angina pectoris, myocardial infarction or age
greater than 45 years necessitates a cardiology evaluation. This includes:
Chest radiography (standard in all patients)
Stress cardiography
Echocardiography
In selected cases coronary angiography (selected patients)
However, the degree of abnormality that precludes transplantation has not been
established or agreed. The echocardiogram provides evidence of cardiac function
and an estimate of pulmonary artery pressure (see porto-pulmonary hypertension
below).
It is often difficult to interpret ejection fraction (EF) data in patients with endstage liver failure and ascites. These patients have low systemic vascular resistance,
and this lack of afterload means that even a cardiomyopathic heart can have an
apparently low normal EF. No absolute thresholds of EF have achieved consensus
for acceptance as a suitable candidate for liver transplantation. Similarly, there is no
consensus on how to interpret a prior history of coronary artery bypass grafting or
myocardial infarction, but many of these patients may be excluded from liver
transplantation.
A history of symptomatic peripheral vascular disease should lead to formal
evaluation of peripheral arterial flow. Significant claudication supported by flow
data will usually exclude the patient from transplantation.
Pulmonary Assessment
Clinical Evaluation
A history of dyspnea on moderate exertion, chronic cough or any degree of
hemoptysis are unequivocal warning signals of pulmonary disease.
If the peripheral oxygen saturation is low, arterial blood gases should be measured
both lying and standing, with and without oxygen. A low oxygen saturation, which
declines when the patient assumes a standing position (orthodeoxyia), suggests hepatopulmonary syndrome. This requires full pulmonary investigation such as bubble
echocardiography to assess vascular shunting.
Patients with symptomatic chronic obstructive pulmonary disease (COPD) or
other evidence of significant pulmonary disease need:
Formal spirometry and
Measurement of diffusion capacity
23
There are no absolute thresholds that determine that a patient is unsuitable for
surgery or postoperative recovery.
Patients should be strongly advised to stop smoking cigarettes and other tobacco
products whether or not there is manifest lung damage. However, most programs
do not exclude patients who are unable to stop tobacco use.
Porto-Pulmonary Hypertension
Idiopathic pulmonary hypertension associated with portal hypertension is called
porto-pulmonary hypertension. It is defined by high mean pulmonary artery pressure
(MPAP) (normal <25 mm/hg), high pulmonary vascular resistance (PVR) (normal
<120 dynes.centimeters -5) and normal pulmonary capillary wedge pressure (PCWP).
Evidence of pulmonary hypertension on echocardiography requires right heart
catheteriztion. Mild to moderate (MPAP <35 mm/Hg) poses no risk for
transplantation. Severe porto-pulmonary hypertension is associated with high intraand post-operative mortality. The utility of liver transplantation with simultaneous
continuous administration of prostacycline, or combined liver-lung transplantation
in patients with porto-pulmonary hypertension is unknown.
Hepatopulmonary Syndrome
Portal hypertension may also be associated with abnormal intrapulmonary shunts
that result in VQ mismatch and hypoxia. This is called hepatopulmonary syndrome.
Hepatopulmonary syndrome may gradually resolve after successful liver
transplantation, although the restoration of arterial partial pressure of oxygen (Pa
O2) to normal may take months.
Cystic Fibrosis
The colonization of the affected lungs by Burkholderia cepacia is an absolute
contraindication.
Renal Assessment
Many patients with acute or chronic liver failure have concomitant impairment
of renal function. The causes of renal failure in patients with serious liver disease
include:
Established parenchymal kidney injury either related to the cause of liver
disease (such as HCV infection) or independent of it.
The patient with end-stage liver failure is at risk for acute insults to the
kidney as a consequence of the acute decompensation such as:
A result of interventions and therapies which compromise the kidney

as due to over-use of diuretics or nephrotoxic drugs and contrast
medium
Hypotension
Hepatorenal failure. This is a complex disorder in which homeostatic

mechanisms in the splanchnic and renal vasculature act together to
produce a pre-renal type renal failure in which there is
vasoconstriction of the intrarenal arterioles, and avid retention of
sodium from the glomerular fitrate. Treatment is by correction of
24
intra-vascular volume contraction (usually with albumin) and

occasionally, glypressin, somatostatin, midodrine, TIPS.
The assessment of renal function:
Inspection of urine
Laboratory investigation of the urine for protein, blood and electrolytes
Measurement of serum creatinine.
Microscopy
Microscopy of the urine may reveal nephritic sediment (red cell casts, white cell
casts).
Low Urinary Sodium

Hepatorenal syndrome and prerenal uremia both produce avid retention of filtered
sodium and reduced urinary sodium. Urinary sodium is measured on a spot urine
and a level less than 10 mEq per ml is the standard threshold for recognizing sodium
retention. This result is confounded by recent exposure to loop diuretics.
Urinary Protein
Many patients with end-stage liver failure have peripheral edema and reduced
serum albumin concentrations. Hypoalbuminemia in cirrhotic patients is often
attributed to synthetic failure and it is easy to overlook renal protein loss. Diabetic
renal disease or glomerulonephrititis associated with chronic infection with hepatitis
B or C are common causes of nephrotic syndrome in liver patients. Spot urine
protein levels should be checked in all candidates for liver transplantation, and a
formal 24-hour collection made in anyone with detectable protein.
Glomerular Filtration
Serum creatinine is a inaccurate indicator of glomerular filtration in cirrhotic
patients, especially those with ascites or malnutrition. Formal measurement of
glomerular filtration rate is appropriate whenever there is concern that the full extent
of renal impairment might be masked. An elevated serum creatinine has been
repeatedly found to be an independent risk factor predicting a worse outcome after
liver transplantation.
There are many causes for lowered graft and patient survival in patients with
elevated serum creatinine prior to transplantation suggesting that serum creatinine
is acting as a surrogate for many high risk factors.
Combined Liver-Kidney Transplantation

There is controversy about the relative value of isolated orthotopic liver
transplantation in the face of established renal failure, compared with combined
liver kidney transplants. If the kidney failure is mainly due to hepatorenal syndrome,
then the patient should receive an orthotopic liver transplant only. If there is advanced
intrinsic kidney disease, serious consideration must be given to dual organ
replacement.
25
Endocrine Assessment
Diabetes
Many patients with end-stage liver failure are diabetic or have insulin resistance.
Retrospective analysis suggests that persons with diabetes mellitus requiring insulin
or hypoglycemic tablets therapy have a worse outcome after transplantation, as a
result of cardiac, renal or microvascular damage. The value of pancreas transplantation
in diabetic patients undergoing liver transplantation is controversial and probably
should be confined to centers studying combined transplants according to a
prospective protocol.
Sexual Endocrinology
Many women capable of menstruation experience amenorrhoea as a result of
end-stage liver failure. Specific investigation of ovarian failure is not necessary in
these circumstances. Menstrual periods are restored in 80% of these women within
three months of successful liver transplantation.
Male impotence is common in end stage liver failure. While liver transplantation
may restore male sexual function, the causes are often multifactorial (especially
diabetes, and drugs such as anti-hypertensives).
Thyroid Disease
Thyroid disease (hypo- or hyper-thyroidism) is associated with many chronic
liver diseases and thyroid function should be routinely checked in all, and corrected
where appropriate. In the sick patients, pseudo-hypothyroidism may be present but
does not require intervention.
Assessment for Primary Hepatic Malignancy

Primary Liver Cell Cancers
Hepatocellular Carcinoma
The development of liver cell cancer is suggested by the development of spaceoccupying lesions on liver imaging or a rising serum alpha-fetoprotein level.
All candidates for liver transplantation should undergo a careful evaluation for
cancer, including:
Measurement of serum alpha feto protein
Imaging of the liver parenchyma. The choice of cross sectional image of
the abdomen includes sonography plus Doppler studies, spiral CT or
MR imaging.
Analysis of the UNOS database up to 1996 shows a five year survival for all
patients undergoing liver transplantation for malignant neoplasms to be 35.4%
(n=796), compared with 72.3% for all liver transplants (n=20,063). In contrast,
acceptable outcomes occur when tumors meet the following criteria:
Small unifocal hepatocellular carcinomas, defined as less than 5 cm in
greatest diameter
26
Few multifocal hepatocellular carcinomas, defined as up to three tumors

whose greatest diameter is no more than 3 cm
Without evidence of vascular invasion or extrahepatic spread
Biopsy confirmation of a tumor is usually contra-indicated, as it is likely to spread
the tumor along the biopsy track.
Other Primary Liver Cancers

Slow growing tumors such as hepatoblastomas and neuroendocrine tumors are
occasionally considered appropriate for transplantation.
Cholangiocarcinoma
There is general agreement that patients with cholangiocarcinoma should not
receive liver transplantation, except within a defined research protocol (see discussion
page 36).
The detection of cholangiocarcinoma is often difficult.
Extrahepatic Malignancy Screening and Those with a Past

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

TB
Screening for tuberculosis includes chest radiograph and, in patients at risk,
placement of PPD (purified protein derivative). Candidates who are PPD positive
may be treated with antituberculosis monotherapy (e.g., Isoniazid for 6 months)
prior to transplantation or treatment may be postponed until after the transplant.
HIV
All patients should be screened for antibodies to human immunodeficiency virus
(HIV). The role of liver transplantation in HIV-infected patients with end-stage
liver failure is controversial.
27
Other Viruses
Antibodies to Hepatitis A, B and C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) are measured as baseline studies.
In the case of CMV, the viral status of the donor and recipient predict the risk of
CMV disease after transplant.
Nutritional Assessment
Protein and Calories
Many patients with end-stage liver failure are malnourished and malnutrition is
associated with a poor outcome after transplantation. Unfortunately, it is difficult to
restore nutritional well being in outpatients with liver failure. Many liver patients
are already on restricted diets: sodium restriction to diminish poorly controlled ascites, protein restriction to control recurrent hepatic encephalopathy, and fluid restriction in hyponatremic patients.
Most cirrhotic patients, even those with intermittent hepatic encephalopathy,
can tolerate 80 grams of protein per day.
Vitamins
People with chronic cholestasis and those on bile acid sequestrants (such as
cholestyramine) are at risk of malabsorption of fat-soluble vitamins.
Vitamin K should be used in patients with prolonged clotting,
Vitamin D levels (serum 25 hydroxycholecalciferol) should be measured
and replenished where needed,
Vitamin A replacement should be considered when there is the possibility
of deficiency.
Bone Disease
Patients with chronic liver disease may have many reasons for excessive bone
loss: chronic cholestasis, corticosteroids, chronic alcoholism, and postmenopausal
state in women.
Bone densitometry should be considered in:
Female candidates above the age of 45 years
Patients who have received corticosteroids for at least one year
Patients with a history of chronic cholestatic disorders
Treatment
Supplementation with Vitamin D and calcium as appropriate.

Add etidronate or palmidronate in patients shown to be osteoporotic.
Nutrition
Patients with cirrhosis from any cause tend to be malnourished. Malnutrition is
associated with a poor outcome after liver transplantation. Reasons for malnutrition
include:
Anorexia (common)
Inappropriate dietary advice. In particular, patients with end-stage liver
28
failure should be encouraged to ingest up to 2 grams/kg of protein per

day. The risk of hepatic encephalopathy from dietary protein has been
overstated.
Malabsorption
Associated pancreatitis
Associated celiac sprue (associated with autoimmune hepatitis and PBC)
Where there is evidence of malnutrition, candidates for transplantation should
have a formal assessment of their nutritional state. This should include:
Dietary assessment
Height, weight and body mass index (measured as weight(kg)/height(m2))
If there is evidence of malnutrition:
Assessment of possible malabsorption
Assessment of nutrition: measure mid-arm circumference and skin-fold
thickness
Give dietary advice: aim for calorie intake 35-50kcal/kg ideal body weight
and, unless hepatic encephalopathy is a clinically significant problem,
ensure the daily protein intake is at least 1.3-1.5g /kg ideal body weight.
If the patient cannot tolerate such an intake, consider nutritional
supplements.
Obese patients are at greater risk of morbidity and mortality after transplantation
and therefore should be advised to lose weight.
Surgical Assessment
There are few surgical contraindications to liver transplantation. Any prior surgery
in the right upper quadrant increases the risk of surgery and probable blood loss.
Extensive thrombosis of the portal venous system including the superior mesenteric
vein may preclude transplantation. Careful radiological assessment is mandatory in
these patients. Angiography remains the gold standard, but in many instances,
magnetic resonance (MR) scanning with gadolinium angiography has largely replaced
formal angiography, avoiding intravenous contrast in patients with marginal renal
function.
Psychological Assessment
All patients should be assessed for any psychological factors that might affect the
survival and quality of life after transplantation. The transplant evaluating team
must seek the opinion of psychiatric experts to assess prognosis of the psychiatric
disorder. The psychological assessment may be confounded by hepatic
encephalopathy. Patients with a combination of end stage liver failure, hepatic
encephalopathy and a history of significant psychiatric disorder present some of the
most difficult dilemmas which come before the transplant evaluating team.
Assessment for Patients with Alcoholic Liver Disease

and a History of Drug Addiction
More than 80% of transplant programs in North America and Europe include
assessment by a psychiatrist or addiction specialist in the evaluation of patients with
29
alcoholic liver disease. Assessment is directed to determining the likelihood that the
candidate will remain abstinent from addictive substances both before and after
transplant and will comply with all aspects of follow-up.
Although it remains controversial as an indicator of future abstinence, the great
majority of liver transplant programs in North America and Europe either require
or place a value on a period of abstinence in determining whether to place an alcoholic patient on the waiting list. Many programs will use an approach that also
assesses the patients acceptance of alcoholism, their social support to remain abstinent, and their use of behavior modifying programs such Alcoholics Anonymous.
Whether such assessments distinguish accurately future drinkers from abstainers
remains in doubt.
Many programs insist that the alcoholic or addicted candidate participate in
addiction therapy as a prerequisite to either placement on the transplant list, or to
reception of a donor liver. The degree of physical impairment due to liver failure
dictates the capacity of the candidate to acquiesce to required treatment. Furthermore,
there is no consensus on how best to manage a patient found to have returned to
alcohol use while waiting for transplantation. Many centers will recycle the patient
though alcoholism assessment and reconsider replacement on the list after achieving
a certain period of sobriety. This period is usually set arbitrarily at 6 months.
It remains uncertain whether the presence of a major psychotic disorder (bipolar
disease, unipolar depression, and schizophrenia) should preclude liver transplantation.
Candidates who carry a diagnosis of major psychosis are often functional on therapy.
Specific Disorders
Fulminant and Subfulminant Hepatic Failure (FHF, SHF)
Acute hepatic injury presents as a sudden increase in previously normal liver
transaminase. Acute hepatic injury in the absence of hepatic encephalopathy almost
always resolves.
FHF is defined as the development of acute hepatic encephalopathy (see Table
5) within 8 weeks of the onset of symptomatic hepatocellular disease in a previously
healthy person.
Sub-acute hepatic failure is also termed submassive hepatic necrosis, subfulminant
hepatic failure, subacute hepatic failure and late-onset hepatic failure. It is defined
by the development of acute hepatic encephalopathy within 9 to 26 weeks of the
onset of symptomatic hepatocellular disease in a previously healthy person. It is
characterized by a slow and fluctuating illness, with usually mild encephalopathy
and progressive ascites. Unlike FHF, the INR is rarely more than 3.0. These patients
usually die unless they are transplanted.
Cerebral edema, leading to increased intracranial pressure (ICP), is a common
feature of severe fulminant hepatic failure and may cause permanent cerebral injury
and death. The onset of cerebral edema may occur during surgery and in the first 48
hours post-transplantation. Fulminant hepatic failure and submassive hepatic necrosis
are always accompanied by severe coagulopathy.
The causes of fulminant hepatic failure are shown in Table 6.
30
Table 5. Clinical grades of acute hepatic encephalopathy

Grade
Mental State
Asterixis
Findings
Electroencephalogram
I.
Altered affect, subtle loss

of mental acuity, slurred
speech
Slight or none
Normal
II.
Accentuation of stage I,
drowsiness, Inappropriate
behavior, loss of sphincter
control
Easily elicited
Abnormal, generalized
slowing
III.
Sleepy but rousable,

marked confusion, can
answer simple
questions only
Present when
patient can
cooperate
Always abnormal
IV.
Coma
Cannot
cooperate
Always abnormal
IVa.
IVb.
Responds to pain
No response to pain
Acetaminophen toxicity is the most common cause of acute liver injury and
fulminant hepatic failure in Great Britain. Alcoholics, those on enzyme inducing
drugs and those who are malnourished, are at particular risk of acetaminopheninduced hepatic failure. Acetaminophen-induced liver injury in alcoholics is the
most common cause of fulminant hepatic failure in the US.
Acute viral hepatitis is an important cause of both fulminant and subfulminant
failure.
In many cases, the cause of FHF is not clear and there are no serological clues as
to the diagnosis. These patients are often classified as non-A non-B non C hepatitis
but a more accurate term is sero-negative hepatitis as there is usually no evidence for
a viral cause
The causes of subfulminant hepatic failure are similar to those for FHF, once the
causes of the most acute forms of acute hepatic injury such as acetaminophen-induced
liver injury have been omitted.
Ischemic hepatitis (also called shock liver) usually recovers with medical support.
Most patients with FHF have a small, shrinking liver. An enlarged liver is associated
with either venous-outflow obstruction or infiltration by tumor. In such cases, where
venous outflow obstruction has been excluded by imaging, a liver biopsy should be
considered.
31
Table 6. Causes of fulminant hepatic failure and subfulminant hepatic failure

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

and Subacute hepatic necrosis
In general, the deeper the coma, the worse the outcome. Paradoxically, rapid
onset of encephalopathy is a favorable prognostic sign, whereas delay in the onset of
encephalopathy after the onset of jaundice indicates a lack of spontaneous recovery
and is unfavorable prognostic factor. Consequently, most acetaminophen-induced
fulminant hepatic failure patients who experience grade III coma recover
spontaneously, while submassive hepatic necrosis has a particularly poor outcome.
32
Criteria for determining the prognosis of fulminant hepatic failure are shown
below (Table 7).
Table 7. Prognostic criteria for predicting requirement of liver transplantation in

patients with fulminant hepatic failure
Acetaminophen Toxicity:
pH <7.3 (irrespective of grade of encephalopathy)
or
Prothrombin time >50 seconds and serum creatinine >3.4 mg/dL (300 mol/L) in
Patients with grade III or IV encephalopathy:
Arterial blood lactate >3.5 mmol/l is associated with a high mortality.
All Other Causes:
Prothrombin time >50 seconds (irrespective of grade encephalopathy)
or
Any three of the following variables (irrespective of grade of encephalopathy):
Age <10 years or >40 years
Liver failure due to halothane or other drug idiosyncrasy or idiopathic
hepatitis
Duration of jaundice prior to encephalopathy >7 d
Prothrombin time >25 seconds
Serum bilirubin >17.5 mg/dL (300 mol/L)
Adapted from OGrady et al. Gastroenterology 1989; 97:439. The prothrombin
time thresholds have been reduced for application in the US due to differences in
laboratory methods to assay prothrombin time between Europe and US. In Europe,
prothrombin times should be multiplied by 2.
These criteria separate acetaminophen-induced FHF from all other causes. Druginduced hepatic failure, other than that caused by acetaminophen, has a poor
prognosis. Examples include hepatic failure due to phenytoin or halothane. HBVand HAV-induced hepatic failure have a better outcome than idiopathic (presumed
viral) fulminant hepatic failure. Patients younger than 2 years or older than 40 years
have a poor prognosis. Renal failure is also a poor prognostic factor. Some have
recommended serum factor V levels as an indicator of when to proceed to transplant.
A factor V level of less than 20% is a poor prognostic indicator. Acidosis is a valuable
prognostic factor, particularly in acetaminophen- induced fulminant hepatic failure.
Whilst listed and awaiting a suitable donor organ, the patient may deteriorate
(sepsis, cardiovascular or pulmonary failure, or cerebral edema) which may make
transplantation impossible. For this reason, human heterotopic auxiliary transplants,
live donor segmental liver transplantation, extracorporeal perfusion through human
or pig livers or artificial hepatocyte perfusion devices, and xenografts have been
attempted to sustain the patient until spontaneous recovery develops or a suitable
organ is found.
33
Chronic Hepatitis C
The problem of chronic hepatitis C relates to the recurrence after transplantation.
Strategies to reduce HCV RNA are currently being evaluated. This is discussed in
Chapter 8.
Hepatitis B Infection
HBV: Markers for active viral replication such as HBeAg and HBV DNA used
to be considered relative contraindications to liver transplantation. The advent of
anti-viral agents including lamivudine and postoperative management protocols using
HBIg has allowed successful transplantation in high-risk patients. Patients who have
circulating HBV DNA should receive treatment with lamivudine while awaiting
transplantation. Antibodies to hepatitis D should be measured in HBsAg positive
patients. Co-infection by hepatitis D ameliorates the severity of post-transplant
hepatitis B infection. Management of HBV after transplantation is discussed in
Chapter 8.
Hemochromatosis
Patients with hemochromatosis have a worse outcome after liver transplantation
than patients with other diagnoses. Some of this effect is due to failure to recognize
hemochromatosis during the pre-transplant evaluation. All candidates should have
serum iron, transferrin and transferrin saturation, and ferritin estimated. We recommend the measurement of the hemochromatosis gene test (HFE) in anyone with
iron saturation in excess of 45% or in anyone with a suggestive history for
hemochromatosis (personal or family history of diabetes, cirrhosis, and arthritis).
HFE is positive as a homozygous test for the major allele (C282Y) or heterozygous
for both the major and minor allele (H62D) in 80% or more of affected persons
depending on the ethnic diversity of the population in question. Diabetic candidates
for liver transplantation need particularly careful cardiac assessment.
Primary Sclerosing Cholangitis

Colitis and Colon Cancer
Those with PSC and inflammatory bowel disease (IBD) have a greater risk of
both cholangiocarcinoma and colon cancer than patients with IBD alone. Since the
colon cancer is likely to develop in the right colon, all patients should have a
colonoscopy to assess the presence and degree of colitis as well as exclude colon
cancer. Colectomy at the time of transplantation does not seem to add to the risks of
the procedure.
Cholangiocarcinoma
Because the tumor spreads early along the lymphatics and nerves, the detection
of cholangiocarcinoma is a contraindication for transplantation. Exclusion of
cholangiocarcinoma is difficult as the tumors are often not visualized on imaging,
whether by ultrasound, CT, MR or PET scanning. Bile cytology, while specific, is
not sensitive and ERCP is associated with a risk of inducing severe cholangitis and/
34
or pancreatitis. Serum markers, such as CEA and CA19-9 may help but have not
the specificity nor sensitivity required.
Non-Alcoholic Fatty Liver
Non-alcoholic steatohepatitis (NASH) and its variant non-alcoholic fatty liver

disorder (NAFLD) are terms used to describe an idiopathic clinico-pathological
spectrum of disorders characterized by macrovesicular and microvesicular deposition
within hepatocytes. NASH is associated with histologic appearances of inflammation
in the hepatic lobule often with Mallorys hyaline, in the absence of alcohol
consumption. NASH occurs in conjunction with insulin resistance, obesity, and
hyperlipidemia, although not all patients exhibit all of these elements of the syndrome.
NASH may progress to fibrosis within the liver and is thought to be an important
cause of cryptogenic cirrhosis. Some patients with cryptogenic cirrhosis thought to
be due to NASH progress to liver failure and are candidates for liver transplantation.
Celiac Sprue
Because of the association between celiac sprue and autoimmune disorders such
as autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis,
all caucasian candidates for orthotopic liver transplantation should be screened for
celiac disease by measurement of serum anti-endomysial antibodies. When positive,
a duodenal biopsy is mandatory.
Retransplantation
Early Retransplantation
Early retransplantation (usually defined as within the first 30 days) is required
for primary allograft non-function, hepatic artery thrombosis and massive
hemorrhagic necrosis. Such patients behave like those with fulminant hepatic failure,
and require emergency placement on the waiting list.
Late Retransplantation
Late retransplantation is required for management of graft failure due to recurrent
disease, vascular or biliary problems, or chronic ductopenic rejection. Survival is less
than that observed for primary graft recipients. Retransplantation on account of
recurrent viral hepatitis has a poor outcome due to aggressive recurrence of the
underlying disorder. Further attempts at rescue with second, third or fourth grafts
are associated with progressively poorer outcomes in mortality and morbidity.
Suggested Reading
1.
2.
3.
4.
Krowka MJ. Hepatopulmonary syndromes. Gut 2000; 46:1-4.

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

5.
6.
35
Trotter J F, Wachs M, Everson GT, Kam I. Adult-to-Adult transplantation of the

right hepatic lobe from a living donor. N Engl J Med 2002; 346:1074-1082.
Markmann JF, Markowitz JS, Yersiz H, Morrisey M, Farmer DG, Farmer DA et al.
Long-term survival after retransplantation of the liver. Ann Surg 1997; 226:408-418;
Discussion 418-420.
36
CHAPTER 4
Management on the Liver Transplant

Waiting List
4
James Neuberger
Introduction
Whilst awaiting liver transplantation, the patient should be closely monitored
for several reasons:
To ensure that the patient is receiving prophylaxis for complications of
the liver disease
To detect any new problems which may affect the success of the transplant
To ensure the patient is as fit as possible for the procedure
Prevention of Complications of End-Stage Liver Disease

The patient awaiting liver transplantation, like any other patient with end-stage
cirrhosis, is at risk of complications which may affect survival or the successful
outcome after transplantation (Table 1).
Variceal Hemorrhage
In portal hypertension due to cirrhosis, the threshold of portal hypertension
necessary for variceal hemorrhage is a transinusoidal gradient (portal pressure less
inferior vena caval pressure) of 12 mm Hg. The likelihood of a variceal hemorrhage
is predicted by:
The degree of portal hypertension
Severity of liver disease
Endoscopic appearances: size of varices, presence of red spots
History of previous variceal hemorrhage
The probability of bleeding or re-bleeding from esophageal varices can be reduced
by pharmacological or physical means. Prophylaxis is indicated in those patients
with cirrhosis who:
have had a previous variceal bleed
are at high risk (varices in a patient who is Childs 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
Management on the Liver Transplant Waiting List
37
Table 1. Potential complications in patients with cirrhosis awaiting liver

transplantation
-Variceal hemorrhage
-Development of hepatocellular carcinoma
-Development of portal vein thrombosis
-Renal failure and electrolyte disturbance
-Spontaneous bacterial peritonitis
-Encephalopathy
-Malnutrition
-Sepsis
-Osteopenia
overestimate the decline in pressure.

reduction in measured portal pressure to either less than 12 mm Hg or
25-50% below the initial portal pressure
About 30% of patients are unable to tolerate beta blockade in sufficient doses so
mechanical methods should be considered.
Long acting nitrates given in conjunction with non-selective beta receptor antagonists may have some additional efficacy.
Prophylactic sclerotherapy
Prophylactic band ligation
Transjugular intrahepatic porto-systemic shunt (TIPS)

Band ligation is preferable to sclerotherapy, as the latter is more likely to
cause esophageal ulceration or peri-esophageal abscess in the post-operative period. TIPS is effective in reducing portal pressure and preventing
variceal hemorrhage. However, there are potential problems:
The presence of the stent may complicate transplant surgery
Stent thrombosis and narrowing may occur. The benefits of

longterm anticoagulation as a means of preventing stent
occlusion are
uncertain
TIPS is associated with deterioration in hepatic function when

attempted in patients with severely compromised
hepatic function
(elevated serum bilirubin, renal failure or
marked coagulopathy)
Spontaneous Bacterial Peritonitis

Patients with ascites, which results from portal hypertension, are at risk of spontaneous bacterial peritonitis (SBP). The predictive factors for SBP are:
a previous episode of SBP
ascitic protein < 1 mg/dl
Antimicrobial therapy has been shown to be effective in reducing the probability
of developing SBP from Gram negative organisms but has no impact on the rarer
instances of SBP from Gram positive organisms. Furthermore, prophylaxis has not
been shown to affect mortality among patients with a history of SBP or who have
38
high-risk indicators for a first episode. There are many regimens for prophylaxis
against SBP:
Norfloxacin 400mg/day
Ciprofloxacin 250mg/day or 500 mg once per week
Co-amoxyclav one tablet/day
Trimethoprim/cotrimoxazole one tablet/day
Renal Function and Electrolyte Balance
Patients with end-stage liver failure are at risk of renal failure, occurring
spontaneously (hepatorenal failure) or due to iatrogenic intervention. Patients with
ascites are at greatest risk, because the factors leading to ascites development (portal
hypertension, splanchnic vasodilation, and peripheral vasodilatation) are also the
factors promoting renal impairment through the development of intrarenal
vasoconstriction and renal sodium retention.
Renal function should be monitored carefully and any episode of renal impairment
should be investigated fully.
Care must be taken to avoid precipitating renal impairment by:
Avoidance of nephrotoxic drugs (such as gentamicin)
Avoidance of non-steroidal anti-inflammatory agents
Avoidance of intravenous contrast material
Monitoring the use of diuretics very closely and discontinue if serum urea
>8mmol/l, serum creatinine > 150mol/l or serum sodium<120mmol/l
Avoidance of hypovolemia: in particular, reduce diuretics when patient
likely to become dehydrated (as in hot weather).
Hyponatremia, due to impaired free water clearance, often exacerbated by
diuretics, is common in end-stage liver failure. When the serum sodium concentration
is less than 120 mmol/L, there is a high risk of central pontine myelinolysis during
or soon after liver transplantation. Treatment of hyponatremia includes withdrawal
of diuretics, restriction of water intake, and in rare cases dialysis. Many programs
will attempt to restore the serum sodium concentration to greater than 120 mmol/
L before starting the procedure.
Cancer Development
Hepatocellular Carcinoma (HCC)
HCC may be the indication for liver transplant or may develop during the waiting
period. Follow-up of transplant candidates will differ:
Follow-up of Patients with Known HCC

In patients known to have HCC, it is important to monitor the growth of the
tumor since during this time transplantation may no longer be indicated. Features
indicating transplantation may no longer be appropriate include:
More than three detectable nodules
Tumor diameter greater than 5 cm
Spread of tumor outside the liver
Invasion of the portal vein or hepatic artery by tumor. This may be
39
recognized as clot formation and a presumption drawn that the clot is

malignant.
The serum alpha feto protein (AFP) level is a poor guide to the size of the cancer
but the rate of rise is a reasonable guide to the rate of growth. The frequency of
repeat imaging of the tumor will depend on the size and location of the tumor: for
example, a large tumor close to the margin of the liver will require more frequent
monitoring than a small 1 cm tumor in the right lobe. As an approximate guide, we
suggest the following follow-up schedule:
Serum AFP every month
Liver ultrasound or CT every 3 months
Chest x-ray every 6 months.
The role of ablative therapy (radiofrequency ablation, cryotherapy,
chemoembolization, alcohol injection) in this situation is uncertain.
Follow-Up of Patients Without a Known HCC (the At-Risk Group)

The main risk factors for the development of HCC include the presence and
duration of cirrhosis, male sex and chronic viral infection. There are no established
guidelines regarding the best screening protocol for at-risk patients.
Serum AFP measurement: There are many causes of an elevated serum
AFP. Elevations of serum AFP, often in the range of 100-500 ng/ml are
particularly common among patients infected by HCV. Sustained,
progressively rising serum AFP levels demand a full assessment for HCC.
In the absence of rising levels, repeat levels every 3-6 months are appropriate
for cirrhotic patients awaiting liver transplantation.
Imaging of the abdomen (sonography or CT scanning) should be done
every 6 months whilst awaiting a liver transplant.
Cholangiocarcinoma
In general, the known presence of cholangiocarcinoma is a contra-indication for
liver transplantation. However, such cancers are very difficult to detect using either
serological tests (such as CA19-9 or CEA) or imaging techniques (such as ultrasound,
CT or MRI scanning). There is little evidence to suggest that assessment by serological
or imaging is of value although the development of progressively dilated bile ducts
may herald the onset of a cholangiocarcinoma.
Other Cancers
Patients awaiting liver transplantation are susceptible to the development of extrahepatic malignancy. It remains uncertain whether the presence of cirrhosis or which
of the diseases predisposing to cirrhosis are associated with a greater probability of
developing cancer. The most common extrahepatic cancers to bear in mind are
colon cancer in patients with ulcerative colitis. These patients should have full
colonoscopy every year while awaiting liver transplantation.
Annual mammography and cervical screening (Pap smears) should be maintained in women of 40 years or more who are awaiting transplantation. Annual
40
Table 2. Immunizations in adults awaiting liver transplantation

Vaccine
Type of Vaccine
Dose Regimen
Comment
Tetanus-diphtheria
Toxoid vaccine
3 doses in nave
patients at 0, 4
weeks and 6-12
months
Persistent immunity
up to 10 years
Poliomyelitis
Trivalent
Nave: 3 doses at
inactivated whole 0, 4 weeks and
virus vaccine (IPV) 6-12 months
Booster every
10 years
Influenza
Trivalent split or
subunit vaccine
One dose.
Annual booster
prior to flu season
Hepatitis B
Recombinant or
plasma-derived
subunit vaccine
3 doses at 0, 4
weeks and 6
months
Monitor anti-HBs;
if <10 IU/L repeat
booster dose
Hepatitis A
Inactivated whole- 2 doses, at 0 and

virus vaccine
3-6 months
Persistent immunity
up to 10 years.
Pneumococcus
23-valent
polysaccharide
vaccine
One dose.
Persistent immunity
up to 6 years
H influenzae type b Polysaccharide

conjugate vaccine
One dose
Complete
immunization > 6
weeks prior to Tpx
Varicella
Live-attenuated
vaccine
2 doses 6 weeks
apart
Complete
immunization 4
weeks prior to Tpx
Mumps-measlesrubella (MMR)
Live-attenuated
vaccine
One dose
Complete rubella
immunization 4
weeks prior to Tpx
Adapted from Stark K, Gunther M, Schonfeld, Tullius SG, Bienzle U.

Immunizations in solid-organ transplant recipients. Lancet 2002; 359: 957-965
Tpx indicates transplantation
prostatic specific antigen (PSA) levels should be measured in men over 45 years who
are on the waiting list for liver transplantation.
Vaccinations
Most candidates for liver transplantation will have been vaccinated against or
exposed to many of the viral pathogens which might prove harmful after liver
transplantation. It is appropriate therefore to assess the immunity to potential viral
pathogens as part of the transplant evaluation. Serologic markers to CMV, EBV,
41
HSV, varicella, HBV, HCV and HAV are checked as a routine measure. Patients
without immunity to the viruses listed in Table 2 should be vaccinated if time permits.
Candidates for liver transplantation should receive annual influenza immunization.
Progression of Medical Complaints

Hypertension
Patients with systemic hypertension will need monitoring to ensure that the
blood pressure is optimally controlled. If there is any cardiac abnormality on screening,
then it may be helpful to repeat the ECG and echocardiograph at 6 monthly intervals.
Diabetes Mellitus
Patients with established diabetes mellitus will need careful monitoring to ensure
that the blood sugar is within acceptable limits; when normoglycemia cannot be
maintained by dietary methods or with oral hypoglycemic agents, then insulin should
be instituted.
Alcoholism and Other Addictions

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

Patients may be suspended from the waiting list for several reasons and returned
to the active list when the temporary problem is resolved. Temporary events leading
to suspension from the list include:
Intercurrent infections
Variceal bleeding
Alcohol use by alcoholics
Suggested Reading
1.
2.
3.
4.
5.
Runyon BA. Management of adult patients with ascites caused by cirrhosis.

Hepatology 1998; 27:264-272.
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F et al. Liver
transplantation for the treatment of small hepatocellular carcinomas in patients
with cirrhosis New Eng J Med 1996; 334:693-699.
Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999; 353:1253-1257.
Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. New Eng J Med
2001; 345:669-681.
Stark K, Gunther M, Schonfeld, Tullius SG, Bienzle U. Immunizations in solidorgan transplant recipients. Lancet 2002; 359:957-959.
42
CHAPTER 5
The Liver Transplant Operation

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

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

The patient is positioned supine on the table, muscle relaxation given, gastric
tube placed, and prepped from neck to groins. An incision is made from sternal
notch to symphysis pubis. The round ligament is divided and falciform ligament
taken down towards suprahepatic inferior vena cava (IVC). A median sternotomy is
performed and retractors are placed. (see Fig. 1)
The falciform dissection is continued to the IVC, the left triangular ligament is
taken down. The gastrohepatic ligament is incised; any accessory or replaced left
hepatic artery is identified and preserved.
A full mobilization of the right colon and small intestine is performed beginning
at the appendix, mobilizing the right colon and small bowel up and to the left,
passing behind the second and third parts of the duodenum. The superior mesenteric
artery limits this dissection.
The infrahepatic IVC is thus exposed and the upper border of the renal veins are
defined as they enter it.
43
Table 1. Donor information

ABO
Donor age and sex
Donor size (height and weight)
Cause of death
Time in hospital
Hospital course, including history of arrest, and stability of blood
pressure and requirement of inotropes
Pulmonary status
Results of virus screening for hepatitis, HIV etc.
Pertinent past medical history (tumors, infections etc.)
Previous surgical history
Previous drug and alcohol history
Results of electrolytes and liver function studies
Results of relevant pre-operative imaging
Table 2. Donor definitions

Extended Criteria
Livers which are less than perfect due to previous

donor history or current condition of donor
Brain Dead or Heart-Beating

Donors
Heart still beating, brain death

declared by clinical or investigational findings
Non-heart beating donors
Fail brain death criteria, procurement occurs after

cardiac death has been declared
-Controlled
Support is withdrawn and death is declared
-Non-Controlled
Cardiac arrest occurs despite continued support
Table 3. Pre-operative management of the donor

Problem
Management
Aim
Hypotension
Transfusion, dopamine,
levo-thyroxine,
Epinephrine
Beta blockers or other
anti-hypertensives
Diuresis and oxygen
delivery
Dextrose replacement
Maintenance of good perfusion to

donor organs
Hypertension
Hypoxia
Diabetes
insipidus
Acidosis
Severe
instability
Prevent acute hypertensive injury to

donor organ.
Maintain adequate oxygenation of
donor organs
Avoid hypernatremia
Bicarbonate replacement Avoid end organ acidosis

Urgent procurement
Minimize time of organ injury
44
Figure 1. Donor setup.
The ligament of Treitz is taken down and the inferior mesenteric vein (IMV) is
exposed and isolated. The aorta is then dissected just above its bifurcation, umbilical
tapes are placed around it for control later.
The bowel is returned and the common bile duct (CBD) is dissected just above
the duodenum in the hepatoduodenal ligament. It is ligated distally and incised
above the tie. The gallbladder is incised and emptied, then flushed with normal
saline until the effluent at the incised CBD is clear.
The supraceliac aorta is exposed by incising the right crus of the diaphragm.
Umbilical tape is placed around the aorta.
Heparin 30,000 units are given. The distal IMV is ligated and the proximal IMV
is cannulated, with the cannula passed into the portal vein. The distal aorta is ligated
and the proximal aorta incised and cannulated with a large bore infusion catheter.
The inferior vena cava is exposed within the pericardium. The right pleura is
opened to allow blood to pool in the right chest.
In a coordinated fashion, the IVC (or right atrium) is cut, the supraceliac aorta is
clamped and the infusion of preservation solution into the IMV and aorta is begun.
Ice is quickly placed over the liver and other intra-abdominal organs.
Suction catheters are placed in the chest to take the warm blood coming out of
the IVC away from the liver. Infusion of preservation solution continues until the
effluent from the IVC is clear (usually around 4-5L total).
The IVC is completely transected in the chest and the posterior pericardium is
opened from side to side exposing the esophagus and thoracic aorta.
45
Figure 2. Donor porta-hepatis.
The diaphragm is divided sagitally in front of the esophagus well to the left of
the suprahepatic IVC. The right diaphragm is then divided, well lateral to the right
coronary ligament, and continued towards the infrahepatic IVC.
The IVC is transected above the renal veins and a suction catheter placed at this
point.
The CBD is completely transected and the peritoneum above the duodenum is
incised to allow the duodenum to peel downwards. The right gastric artery is ligated
and divided. The gastroduodenal artery (GDA) is exposed and followed to its origin
from the hepatic artery. It is then ligated and divided away from the hepatic artery.
(see Fig. 2)
The hepatic artery is followed proximally on its left side, dividing the lymphatic
and nervous tissue that overlies it here. The coronary vein will be seen and can be
divided. It usually lies over the origin of the splenic artery, which can be dissected
for a centimeter or two and then transected, once the celiac axis is clearly identified.
The dissection is continued proximally along the left side of the celiac to the aorta.
The length of supraceliac aorta is exposed on its left side by division of the crus
of the diaphragm. The supraceliac aorta is transected at the level of the clamp and
the aorta just to the left of the celiac incised and continued superiorly to the point of
transection.
The duodenum is now further mobilized away from the porta hepatis. And the
tissue lateral to the portal vein is dissected toward the portal vein (PV) taking care to
look for a replaced right hepatic artery. With the anterior surface of the vein exposed,
46
the pancreas is split at the neck to expose the portal vein origin. The superior mesenteric and splenic veins are then transected. The portal vein segment is passed beneath the duodenum to lie with the other hepatic structures. If there is no replaced
right hepatic artery, the nerves and lymphatic tissue lying behind the portal vein are
divided all the way to the aorta between the celiac and SMA. If there is a replaced
right hepatic artery, then it is preserved and the SMA is included in the aortic patch.
The aortic patch is completed around the celiac origin and lifted up with the other
portal structures.
Cutting across the right adrenal gland and dividing the hepato-pulmonary
ligament completes the donor hepatectomy. The liver is surrounded by University
of Wisconsin (UW) solution in a bag and then stored in ice for transportation.
The back table dissection is carried out with the liver sitting in UW solution
surrounded by ice. The coronary ligaments are first taken down exposing the
suprahepatic IVC. The diaphragm is carefully dissected off the IVC, ligating any
phrenic veins. The infrahepatic cava is dissected free, after dividing the diaphragm
between the aorta and IVC. The right adrenal vein and any other external branches
are ligated and the adrenal gland removed.
The portal vein is dissected towards the liver with ligation of any small branches
along its course until the bifurcation is seen. The PV is then cannulated with
intravenous tubing, secured and tested for leaks.
The artery is then dissected in segments from aorta towards splenic, and then
splenic towards GDA. Small branches are ligated. The splenic is left open for blowout
on reperfusion. It is leak tested, an aortic patch is created (1-2mm brim) and the
liver is covered by UW solution until required for implant.
Extended Criteria Donors

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

This is a special group of extended criteria donors. These are donors for whom
recovery is hopeless, and are on life support, but fail to fulfill the criteria of brain
death. The donor is brought to the operating room and prepped and draped.
Perfusion lines are primed with University of Wisconsin Solution. Heparin (300
unit/kg) and intravenous hydrocortisone 1000 mg are administered, and then life
support is withdrawn. A physician from the donors treating team pronounces the
patient deceased according to clinical or electrical evidence. (If pronouncement does
not occur within 1 hour after withdrawal of life support, then the procurement is
abandoned and the donor is returned to the intensive care unit.) Following the
47
Table 4. Extended criteria donors

Age >70 years
Prolonged pre-mortal hospital stay
Hemodynamic instability or requirement for large doses of inotropes
Pre-mortal cardiac arrest
Alcohol or drug dependency
Elevated liver function tests or serum sodium
Fatty liver
Hepatitis infected liver
History of malignancy
Non-heart beating donor
declaration of death, a mandatory wait period, determined by local policy (usually

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

The initial preparation is as for whole organ procurement.
Prior to cannulation and perfusion attention is turned to the portahepatis. The
left hepatic artery is identified and dissected free near its origin and followed up to
the umbilical fissure. The left portal vein is now dissected and small caudate branches
of the portal vein are ligated and divided.
The liver bridge between segment VI and III is divided (if present) where it
crosses the umbilical fissure. This exposes the fissure with multiple small portal vein
branches that cross between the umbilical vein and segment IV here. These are
ligated and divided. After division of these branches, the left hepatic duct is identified lying above the artery and divided. (see Fig. 3)
The left hepatic vein is dissected free of the middle hepatic vein over a short
distance.
Parenchymal dissection can now begin just to the right of the falciform ligament. This is best done using electrocautery with ligation of any major structures
crossing between the left lateral segment and segment IV.
This dissection is continued until the entire left segment is freed and the caudate
lobe is exposed near the insertion of the gastrohepatic ligament.
48
Figure 3. Split donor technique.
The cannulas are then placed and the organs perfused and dissected as per whole
organ. The left lateral segment is removed by dividing the relevant vessels. The left
hepatic artery can be taken at its origin, or the aortic patch and common hepatic
artery can be kept with the left lateral segment by dividing the right hepatic artery at
its origin.
The Recipient Operation

The patient is positioned supine on the operating table with arms extended to
90 degrees. A large bore peripheral cannula, arterial line and a Swan Ganz catheter
are generally used for intra-operative management and fluid replacement. If
percutaneous bypass is to be used, then the right internal jugular vein is cannulated
with the large bore cannula at this time.
A nasogastric tube and a Foley catheter are placed and a warming blanket or
device is set up. The patient is prepped and draped from neck to groins leaving
particularly the left groin exposed for cannulation for bypass.
A bilateral subcostal incision with a midline upper extension is made, the round
ligament is divided, and the falciform ligament is taken down towards the suprahepatic IVC.
Subcostal retractors are placed and the dissection continues until the right and
left hepatic veins are exposed. The left triangular ligament is taken down and the left
49

Figure 4. Incision.
Figure 5. Recipient porta

hepatis.
lateral segment retracted medially. The gastrohepatic ligament is incised and continued cephalad, ligating any vessels crossing it.
Attention is turned to the porta hepatis, any adhesions are taken down and inferior retractors are placed. The peritoneum is scored level with the lower border of
the caudate lobe. The cystic duct and artery are ligated and divided freeing the right
50
Figure 6. Recipient setup with bypass lines.
edge of the hepatoduodenal ligament. The dissection is deepened stepwise until the
hepatic arteries and common bile duct (CBD) are exposed. These are ligated and
divided.
Dissection continues through the neural and lymphatic tissue until the portal
vein is exposed. The portal vein is dissected carefully, ligating any small tributaries.
Once sufficient length has been dissected on all sides, the remainder of the hepatoduodenal ligament tissue can be divided. (see Fig. 5)
The left femoral vein is now cannulated using Seldinger technique and secured
in place. Air in the lines is expelled and the patient is placed on systemic venous
bypass.
The portal vein is isolated with umbilical tape and a snugger. The assistant
controls the vessel with a large Debakey forceps. The distal portal vein is ligated near
its bifurcation, and incised just below this.
The bypass cannula is inserted to the level of the portal vein origin and secured
with the umbilical tape snugger. The snugger is secured to the bypass tubing with
further tape, and the portal vein transection is completed. The portal system is added
to the circuit placing the patient on portal venous bypass. (see Fig. 6) The dissection
of the infrahepatic IVC is begun by scoring the overlying peritoneum and extending this line along the left side of the IVC up to the level of the phrenic vein, while
retracting the liver and caudate lobe to the right so that the posterior aspect can be
freed.
51
Figure 7. Caval anastomosis.
The right triangular and coronary ligaments are taken down with the liver retracted to the left, exposing the right posterior aspect of the IVC. The right adrenal
vein is ligated and divided. The infrahepatic IVC is clamped below the level of the
right adrenal vein stump. The suprahepatic IVC is clamped in a manner to ensure
that a good posterior length is available.
The liver is dissected off the IVC inferiorly ligating any caudate tributaries until
a suitable length for anastamosis has been obtained. The infrahepatic IVC is
transected. The hepatic veins are the transected and the suprahepatic IVC is transected
below the hepatics.
The liver is removed and careful hemostasis is obtained. The diaphragmatic peritoneum corresponding to the bare area of the liver can be oversewn if desired for
hemostasis.
The supra hepatic IVC is prepared for anastamosis by dividing the caval bridge
between the middle and left hepatic veins and the dividing between this and the
IVC. The bridge between the right hepatic vein and IVC is likewise divided. The
IVC is the checked at both ends for holes or tributaries. There are usually one or two
phrenic veins which require over-sewing (knots tied on the outside.)
The donor liver is delivered to the table and re-checked for IVC integrity. The
posterior wall of the suprahepatic caval anastamosis is completed from the inside
running from patients left to right, using an everting or lipping technique. The
52
Figure 8. Vascular anastamosis.
same suture is continued along the front wall around half way from right to left and
then the remaining front wall is sutured from left to right and tied to the original
suture. (see Fig. 7)
The cannula in the donor portal vein is flushed with 700-1000 cc of cold Ringers
lactate solution while surgical attention is turned to the infrahepatic IVC. This
anastamosis is performed as described for the suprahepatic above.
The portal bypass line is clamped and the cannula removed from the recipient
portal vein with a clamp placed.
The donor portal vein is measured up for length with the recipient vein. The
anastamosis is performed in the manner described for the IVC except 5 or 6/0 prolenes
are used and the following suture is placed rather than pulled taut. Prior to tying,
the vessel is temporarily opened to flush out any clot. A growth factor or air knot of
30-50% the diameter of the portal vein is used for the final tie. This slack is taken up
by expansion of the vein upon reperfusion.
53
Figure 9. Bile duct.
The liver is now ready for reperfusion. The suprahepatic caval clamp is first
removed and the suprahepatic anastamosis and cava is checked for leaks. The infrahepatic clamp is released with warning given to the anesthesia team. When the
anesthesia team are ready, the portal clamp is released and the liver reperfused. The
femoral vein cannula can be clamped and removed once the patient is hemodynamically stable.
The recipient hepatic artery is dissected toward the celiac, beyond the level of
the GDA where it is clamped. The GDA is ligated distally and divided well away
from the hepatic artery. A branch patch is created using the distal hepatic artery and
GDA. The lumen can be gently dilated using a mosquito forceps. The anastomosis
is performed patch to patch using 6/0 prolene. (see Fig. 8) The vessel is allowed to
blow out any clot via the open donor splenic artery prior to opening up to the liver.
The donor splenic artery is then ligated. The entire operative bed is checked in a
systematic manner for hemostasis.
The donor gallbladder is dissected fundus down until it is suspended by the
cystic duct. The cystic duct can be dissected all the way to the common bile duct
(CBD). The donor CBD is divided at the level of the cystic duct junction. The
recipient bile duct and its blood supply are mobilized over a length of around 2 cm,
and then divided just below the tie. The bile duct anastamosis is performed using 5/
0 interrupted sutures (knots outside). A T-tube is optional.
A hemostatic check is made and the abdomen irrigated well. Three suction drains
are placed: 1) along the right border of IVC to suprahepatic caval area; 2) abutting
the porta hepatis and bile duct anastamotic area; and 3) along the left side of the
IVC to the suprahepatic area. The wound is closed in a careful manner to prevent
ascitic leak and hernias.
54
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 dense
and have large venous collaterals running through them.
The incision remains the same with special care when entering the abdomen, so
as not to damage bowel stuck to previous incisions. The incision is gradually deepened
and continued into the peritoneal space using careful electrocautery dissection to
separate the abdominal contents from the wound. The round ligament is divided.
The liver surface is sought and abdominal contents are dissected down and off
the anterior surface of the liver. Once the incision edges and anterior surface of the
liver are clear, subcostal retractors are placed. The left lobe of the liver should be
mobilized in the normal fashion and the gastrohepatic ligament divided. This helps
define the left edge of the porta hepatis.
The key to this surgery is to start the dissection toward the porta hepatis from
the sides, taking down adhesions from the inferior surface of the liver until the
normal anatomy is clear. This is done by staying in the plane right next to the liver,
and if in doubt venturing a little into the liver rather than away from it. An argon
beam coagulator is invaluable in this surgery for drying up the bleeding liver surface.
Coming across the gallbladder fossa following prior cholecystectomy is usually difficult
because the duodenum may be firmly adhered in this region. When dissecting from
the right, the plane of dissection continues across the gallbladder fossa and then
should leave the liver surface and continue between the porta hepatis and the falciform
ligament.
The duodenum and other adhesive elements are gently dissected down off the
porta hepatis. From either side the epiploic foramen can be gently probed digitally
and reconstituted.
The remainder of the operation is as for the nave abdomen except that care is
taken to ensure hemostasis of all the previously adhered abdominal contents.
Retransplantation
The retransplant of the liver begins as described above for previous surgery. The
operation is essentially as for the primary graft except for the following potential
deviations.
In the dissection of the porta hepatis; the hepatic artery from the previous
transplant is likely to be folded and redundant and is found to lie more superficial
than expected. Great care is taken when dissecting the portal vein to avoid close
dissection of the previous anastamosis, lest it be inadvertently disrupted until proximal control is gained.
The native suprahepatic IVC may be significantly shortened and weakened by
the previous anastamosis here, and if an attempt were made to replace the cava, as
described above, there can be significant risk for loss of integrity of the suprahepatic
anastamosis. Therefore many surgeons elect to sew in the new liver with a piggy
back (end to side) technique. This of course preserves the first graft IVC.
55
Figure 10. Portal thrombectomy.
The arterial anastomosis should be made more proximally than the original and
may necessitate using a splenic artery branch patch. The portal venous anastomosis
is rarely a concern, since the original anastomosis can be preserved if needed for
extra length. The bile duct reconstruction frequently requires a Roux-en-Y hepaticojejunostomy.
Portal vein Thrombosis

Portal vein thrombosis leads to larger and higher pressure collateral vessels, and
extra care is required during the initial dissection. Most portal vein thromboses are
partial and can either be ignored or removed.
The technique for thrombectomy is as follows: The portal vein is controlled
proximally by the assistant with a large forceps and ligated near the bifurcation. A
longitudinal incision is made in the anterior wall. 5/0 prolene stay sutures are placed
on either side. A plane is developed between the vein wall and the thrombus using a
carotid dissector. The distal end of the thrombus is grasped and delivered out of the
vein. Gentle upwards traction is placed on the thrombus while the portal vein wall is
peeled off it proximally. (see Fig. 10) The controlling forcep will need to be released
briefly to deliver the proximal thrombus (which usually extends at least to the portal
vein origin). Now a large Fogarty balloon catheter is passed proximally to sweep the
portal vein of any further, loosely adherent thrombus. The portal vein is opened and
flushed to determine flow and bypass proceeds in the usual manner.
In the unusual circumstance that the portal vein is completely thrombosed and
cannot be cleared using the method above or if the flow is poor, a jump graft using
donor iliac vein to superior mesenteric vein may be required.
56
Table 5. Selection criteria for right lobe donors

Test
Phase 1
Over the
phone &
Local doctor
Ideal
Age
History
Young adult
No significant
illnesses or
previous
abdominal surgery
Blood group
ABO identical
Liver function tests Normal
BUN Creatinine Normal
Exclude
<18, >50 y old
Significant
morbidities, previous
cholecystectomy is a
relative contra-indication
ABO incompatible
Abnormal
Significantly abnormal
renal function
Meet with transplant surgeon and briefing of procedures, risks, and benefits
Phase 2
Transplant
Center
Imaging
(Volumetric MRI
or CT scan)
Further labs
Psychosocial
evaluation
Phase 3
Transplant
Center
Liver Biopsy
(center variability
on its use)
Celiac and
Superior
mesenteric
angiography and
portal venography
No pathology
identified. Suitable
volume for
donation (donated
segment >1% of
weight of
recipient). No
steatosis.
HIV, Hepatitis
virology negative
Stable with good
social supports
Pathology identified in
liver, steatosis,
donor segment <0.8% of
body weight of recipient,
remnant <0.7% of
donor weight.
Normal liver
Fibrosis, hepatitis,
significant steatosis >10%
Normal anatomy,
or replaced left
hepatic artery,
completely
replaced right
hepatic artery
ERC or MRC
Normal biliary
(center variability anatomy.
on their use)
Positive HIV or hepatitis

serology
Drug or alcohol
dependency, no social
support. Marginal if
significant psychiatric
history.
Accessory right hepatic

from SMA in the present
of normal right.
Large segment four duct

draining to right hepatic
duct well above the
bifurcation
Previous TIPS Procedure

A perfectly placed TIPS (Trans-jugular intra-hepatic porto-systemic shunt) is
intrahepatic in its course and does not present any particular problem. However, the
TIPS can extend into the extrahepatic portal vein or back up into the right atrium.
For extension into the portal vein, the vein is transected short on the recipient
below the shunt. If this cannot be done then a jump graft to the SMV may be
required.
57
The TIPS extending into the IVC or the right atrium is a more dangerous problem. It is essential that the suprahepatic clamp be placed above the end of the shunt.
This is achieved by more aggressive dissection of the diaphragm off the cava here
and by pinching off the right atrium with the suprahepatic clamp. A useful technique is to place a smaller clamp on as high as possible and then placing a larger
clamp outside and thereby above the first clamp.
Live Liver Donors

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

With the patient positioned supine and a nasogastric tube and Foley catheter in
place, a subcostal incision, with vertical upper extension, is made. The falciform
ligament is taken down and the suprahepatic IVC is exposed with dissection of the
right hepatic vein insertion.
Any adhesions around the gallbladder or porta hepatis are taken down and a
fundus down cholecystectomy is performed. After a limited exploratory dissection
of the porta hepatis, a cholangiogram is performed via the cystic duct. It is helpful to
have dissected some way up into the porta hepatis, taking down the hilar plate to
expose the confluence of the hepatic ducts, which is marked with a forceps for
confirmation on the cholangiogram. If a segment IV duct is joining the right hepatic
duct, then an assessment needs to be made whether to proceed, as this portion of the
right hepatic duct will need to remain with the donor.
All of the porta hepatis dissection should be limited to the right side of the
common bile duct. Attention is turned to the right hepatic artery, which is identified
as it passes beneath the common hepatic duct. It is dissected well up into the liver to
facilitate the dissection of the hepatic duct and portal vein. The right hepatic duct is
dissected and transected several millimeters from the confluence, the donor side is
suture ligated. It is more common than not to have two hepatic ducts on the donor
side, and these are marked with prolene sutures to aid identification later. Retracting
the common bile duct and the hepatic artery to the patients left exposes the right
portal vein. Dissection of the right portal vein continues up towards the right lobe
of the liver working on both sides of the hepatic artery until the bifurcation of the
portal vein is clearly seen. Now the posterior portal vein is dissected and caudate
branches of the vein are ligated and divided. Approximately 2 cm of right portal
58
Figure 11. Right lobe vascular
anastamosis.
Figure 12. Hepatico-jejunostomy.
vein should be freed on all sides in this manner until a right angle forceps can be
safely passed around the right portal vein.
The right triangular and coronary ligaments are taken down exposing the right
posterolateral aspect of the inferior vena cava (IVC). The liver is returned to its
anatomical position and the peritoneum overlying the anterior surface of the infrahepatic IVC is dissected and freed. Dissection is continued up towards the liver. The
caudate lobe is elevated off the cava and small tributaries from the caudate lobe are
ligated and divided. Small tributaries from the right lobe are likewise ligated and
divided. Larger tributaries (> 5 mm) are preserved for re-implantation. In such a
manner, the entire anterior and right lateral surfaces of the cava are exposed up to
the level of the right hepatic vein which is now dissected working both from above
and below until it can be isolated with a vessel loop.
59
The caudate process between the right portal vein and the IVC is scored. The
line of resection is marked on the surface of the liver. This line runs from between
the middle and right hepatic veins to the left side of the gallbladder fossa, and then
down the inferior surface of the liver to the IVC.
Parenchymal dissection is undertaken using the technique preferred by the
operating team. During this dissection it is usual to encounter two significant middle
hepatic vein tributaries; one from segment V and one from segment VIII. When
these are large some centers re-implant one or other of these into the recipient cava
using a venous conduit.
Once completed the two parts of the liver with their respective blood supplies
should be left until the recipient hepatectomy is completed. A completion
cholangiogram can be performed to exclude stricture or leak at the sight of the
oversewn right hepatic stump. The liver segment is removed by clamping vessels
(inflow before outflow) on the remnant side and dividing the vessels. The graft is
immediately placed on ice and flushed via the portal vein and hepatic artery with
preservation solution.
The donor ends of the vessels are oversewn and the wound is closed with drains
to the cut surface of the liver.
The Live Donor Right Lobe Recipient Operation

The hepatectomy is undertaken as for the whole organ recipient except that the
bile duct and the vessels are left especially long and the inferior vena cava is left in
place by ligating caudate lobe tributaries. The left and middle hepatic veins are over
sewn. The right hepatic vein opening can be extended into the IVC inferiorly for a
wide-open anastamosis.
The segment is sewn in beginning with the right hepatic vein which lies best if
sewn up-to-down instead of left-to-right (this is not tied down until after flushing
the liver). The hepatic arterial anastomosis is completed, usually using the hepatic
artery bifurcation as a patch. The liver is flushed through the portal vein and the
hepatic vein is tied down. The portal venous anastomosis is carried out as usual, and
the liver is reperfused with portal and arterial blood. The type of bile duct anastomosis
is determined by the donor anatomy. A duct to duct anastomosis is usually possible,
although a Roux-en-Y hepaticojejunostomy may be required for biliary
reconstruction.
Hemostasis is obtained, drains are placed and the abdomen is closed as usual.
60
CHAPTER 6
Immunosuppression after Liver

Transplantation
James Neuberger
The purpose of immunosuppression is to prevent the bodys immune system

destroying or damaging the graft. Since currently available drugs are not specific for
graft alloantigens, the clinician must maintain a balance between underimmunosuppression, leading to graft rejection, and over-immunosuppression, leading
to the consequences of immunodeficiency such as sepsis and malignancy. The clinician
should also be aware of, and attempt to minimize, the unwanted effects of longterm use of these agents.
In the early days of liver transplantation, the protocols for liver allograft recipients
were derived by extrapolation from renal transplantation. It has become clear, however,
that different approaches need to be adopted: for example, in liver allograft recipients,
tolerance may develop and those strategies that aim to abolish early acute rejection
may inhibit the development of tolerance. While acute rejection is associated with a
poor outcome in renal transplantation, there is no evidence that acute cellular
rejection, which is reversed by short periods of increased immunosuppression (socalled reversible acute cellular rejection), has any untoward effect on liver graft
survival.
There have been comparatively few studies on which to base a rational approach
to immunosuppression: the success of liver transplantation has meant that to
demonstrate significant improvement in graft survival or a reduction in the
immunosuppressive-related morbidity, a large number, of patients needs to be
followed for long periods of time. In the present climate, this is usually difficult.
Furthermore, the introduction of newer agents, or improved formulations of existing
drugs, means that the conclusions of randomized trials may be superseded before
results are available.
Most centers have adopted a common approach to the principles of
immunosuppression but differ significantly in the details. Therefore, in this Chapter,
the principles of immunosuppression will be outlined together with a description of
the consequences of over-immunosuppression. Details of those drugs that are
currently available and those shortly to be licensed will be described.
Immunosuppression after Liver Transplantation
61
Table 1. Physical methods of immunosuppression

Types of physical immunosuppression include:
Blood transfusion
Removal of lymphocytes:
Leucophoresis
UV or total body irradiation
Thoracic duct drainage
Thymectomy, splenectomy
Plasmaphoresis
Photophoresis after lymphocyte priming
Drugs and Other Agents Used in Immunosuppression

The drugs and other agents and procedures used for immunosuppression are
shown in Table 1 and details of those drugs and agents licensed for
immunosuppression are shown in Tables 2 to 13.
Types of Immunosuppression
Immunosuppression may be physical or pharmacological. Physical methods, as
shown in Table 1, are rarely used in liver transplantation.
Medications Used for Immunosuppression

Purine Analogues
Azathioprine has been used for many years in transplantation (see Table 3). It is
metabolized by thiopurine methyltransferase to the active component 6mercaptopurine (6-MP), an analogue of the natural purines hypoxanthine and
adenine. 6-MP is then metabolized to thioinosine monophosphate which inhibits
synthesis of DNA precursor molecules and interferes with nucleic acid synthesis
during clonal expansion of lymphocytes. People who have low levels of thiopurine
methyltransferase are more susceptible to the side effects of azathioprine but may
tolerate 6-MP.
The rationale for long-term use of azathioprine is not well established although
several studies have suggested an increased probability of chronic rejection in patients
not taking azathioprine. Following the introduction of azathioprine (usually at a
dose of 1-2 mg/kg/day), the white count should be monitored twice monthly for 3
months: if the white count falls below 4.0 x 10.9/l, the dose should be halved; if the
white count falls below 3.0 x 10.9/l, azathioprine should be discontinued. Venoocclusive disease and hepatitis are the most serious forms of liver dysfunction
associated with azathioprine and usually develops within the first 6 months.
IMPDH Inhibitors (Table 4)

Mycophenolate mofetil acts by inhibition of inosine monophosphate
dehydrogenase, it is colloquially referred to as MMF.
62
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 activation
Corticosteroids
Immunophilin-binding drugs
Calcineurin-inhibitors:
Cyclosporin
Tacrolimus
TOR inhibitors: Sirolimus (formerly known as
rapamycin)
Inhibitors of de novo nucleotide synthesis
Purine synthesis inhibitors (IMPDH inhibition)
Mycophenolate mofetil
Mizoribine
Pyrimidine synthesis inhibitors ((DHODH inhibition)
Leflunomide
Brequinar
Antimetabolites
Azathioprine
Cyclophosphamide
Inhibition of lymphocyte activation/trafficcking/interaction
Inhibition of trafficking
FTY720
Inhibition of interactions
Antibodies to ICAM-1
Antibodies to IL2-R
CTLA-4 Ig
Table 3. Immunosuppressive drugs: Azathioprine

Drug name
Azathioprine
Mechanism of action
Anti-metabolite; metabolised to 6mercaptopurine and then active agent interferes

with DNA and RNA synthesis so inhibits T and
B lymphocyte differentiation and proliferation
Leukopenia (significant 15%)
Nausea and vomiting
Hepatotoxicity (especially venoocclusive disease)
Pancreatitis
Pneumonitis
Megaloblastosis
1-2 mg/kg/day
Allopurinol (avoid) ACE inhibitors
Used as a second-line drug
Side-effects
Doseage
Drug interactions
Notes
63
Table 4. Immunosuppressive drugs: Mycophenolate mofetil

Drug name
Mycophenolate mofetil
Mechanism of action
Prevents T and B cell proliferation by inhibition of

de novo purine synthesis by inhibition of
monophosphate dehydroge-
inosine
nase (IMPDH)
Side-effects
Diarrhea (15%) Leucopenia (5%) anemia,

thrombocytopenia, Rarely GI
hemorrhage and
perforation hematuria,
hypertension,
hyperglycemia,
disturbances of electrolytes and
blood lipids, peripheral
edema, dyspnea, cough,
dizziness, insomnia, tremor.
Hypersensitivity
reactions
Dosage
1 to 2g/day in divided doses
Drug interactions
May compete with drugs that undergo active renal

tubular secretion
Probenecid
Acyclovir
Some antacids and cholestyramine reduce

tion
absorp-
Table 5. Equivalence of corticosteroids

Prednisolone/Prednisone
Betamethasone
Cortisone acetate
Deflazacort
Dexamethasone
Hydrocortisone
Methylprednisolone
Triamcinolone
5 mg
750 g
25 mg
6 mg
750 g
20 mg
4 mg
4 mg
(Derived from the British National Formulary, 2000)
Notes
alternative to
calcineurin-inhibitor sparing
Teratogenic in animals. Used as

azathioprine or in
protocols
Glucocorticoids
These agents have both anti-inflammatory and immunosuppressive effects. The
glucocorticoids bind to the glucocorticoid receptor and the complex then translocates to the nucleus where, after binding to DNA, protein synthesis is affected.
64
Table 6. Immunosuppressive drugs: Corticosteroids

Drug name
Prednisolone/prednisone
Mechanism of action
Anti-inflammatory; stimulates migration of T cells

from intravascular tissue to lymph nodes; inhibits
production of T cell lymphokines
Side-effects
Increased tendency to diabetes mellitus

Osteoporosis
Impaired wound healing and increased skin
bruising
Sodium and fluid retention, potassium depletion
Hypertension
Muscular weakness, myopathy and muscle wasting
Aseptic necrosis especially of femoral head
Cataracts, glaucoma, raised intra-ocular pressure
Cushingoid facies
Retardation of growth
Headaches, pseudotumor cerebri
Mood change (euphoria, hypomanic psychosis,
depression)
Weight gain
May increase risk of peptic ulceration or retard
ulcer healing
Dosage
Maintenance up to 20 mg/day; treatment of

rejection 200 mg/day for 3 dats or 3 days
Drug interactions
NSAIDs
Notes
Other forms of steroidssee Table 5
Among the intra-nuclear functions altered by glucocorticoids is synthesis of nuclear

factor kappa B (NF-B), resulting in apoptosis of lymphocytes. There are many
different glucocorticoids used in transplantation and the potency on a weight for
weight basis varies and is summarised in Table 5.
There is increasing evidence that corticosteroids can be withdrawn by three
months or earlier in most liver transplant recipients. In contrast, some centers maintain corticosteroids in patients grafted for autoimmune hepatitis to prevent recurrent disease in the allograft (see Table 6).
Calcineurin Binding Drugs (Tables 7 and 8)

Both cyclosporin and tacrolimus bind to immunophilins which are widely
distributed intracellular proline isomerases. Cyclosporin binds to cyclophilin and
tacrolimus to the FK-binding protein which results in inhibition of calcineurin which
inhibits activation of transcription factors such as NFATc, a transcriptional factor
responsible for the calcium activation of cytokine genes during the immune response.
65
Table 7. Immunosuppressive drugs: Cyclosporin

Drug Name
Cyclosporin
Mechanism of action
Binds to immunophilins (cyclophilin). Inhibition of T

cells; suppresses T-cell activation by inhibiting synthesis
and release of IL-2 and other lymphokines
Side-effects
Renal impairment (30-40%); hepatotoxicity (10%);

hypertension (30%); gum hypertrophy (10%);
hirsutism (40%); tremor (40%)
Convulsions (3%)
Headaches (40%)
Hyperkalemia
Hyperuricemia
Gout
Dosage
Adjust to maintain trough whole blood levels (measured

by RIA) between 100-250 ng/ml (target levels vary
between centers and according to time after
transplantation and graft function)
Drug interactions
See Table 8
Notes
Several formulations available: as they have different

absorption profiles the different formulations may not
be interchangeable
Other down-stream effects are thought to relate some of the side effects of this class
of drugs including diabetes and renal impairment.
Tacrolimus is well absorbed from the upper GI tract. Consequently, there is
rarely an indication to give tacrolimus intravenously. The starting dose is 0.1 mg/kg/day in
two divided doses: target levels for the first three months lie between 10 and 15 ng/ml
(trough whole blood levels measured by RIA) and between 5 and 10 ng/ml thereafter.
Cyclosporin is fat soluble, and absorption is variable from the gut, especially in
the early post-operative period when bile production and flow may be compromised.
The microemulsion form is absorbed in a more consistent fashion and there is rarely
a need to administer cyclosporin intravenously. The starting dose is 8 mg/kg/day
and the dose adjusted to trough whole blood levels between 150 and 200 ng/ml for
the first three months and 100-150 ng/ml thereafter. However, measurement of
blood levels taken 2 hours post dose (otherwise called C-2) may provide a better
assessment of drug monitoring.
Tacrolimus and cyclosporin are metabolized by oxidation through the cytochrome
P450 system. The liver is the main site of metabolism, although minor metabolism
occurs in the gut. Drugs which induce or inhibit cytochromes P450, such as
erythromycin, ketoconazole or rifampicin, interact with tacrolimus and cyclosporin
and may affect drug levels. Drug interactions are listed in Table 9.
66
Table 8. Immunosuppressive drugs: Tacrolimus
Drug Name
Tacrolimus
Mechanism of action
Binds to FK-binding protein 12; inhibits

synthesis and release of IL-2
Side-effects
Diabetes mellitus
Hypertension
Headaches
Tremor
Convulsions
Nephrotoxicity
Renal impairment
Myocardial hypertrophy
Dosage
Target
Maintain trough whole blood levels

measured by RIA between 5-15 ng/ml.
levels vary between centres, time after
transplantation and renal and hepatic
function
Drug interactions
See Table 8
Notes
Not licencsed for use in pregnancy

(although no evidence of increased
teratogenicity compared with cyclosporin
Calcineurin inhibitors (cyclosporin and tacrolimus) are the current mainstays of

maintenance immunosuppression. Both agents are associated with significant side
effects in the long term. There are several studies comparing the two drugs and these
suggest that tacrolimus may be superior. For both drugs, target levels have been
derived from clinical experience although the dose should be adjusted in the light of
complications (such as renal impairment or symptoms such as headaches or tremors) and liver function.
TOR Inhibitors (Table 10)

Sirolimus (previously known as rapamycin) inhibits lymphocyte proliferation
mediated by cytokines such as IL-2 and IL-4. Sirolimus, like tacrolimus, binds to
the immunophilin called FK binding protein (FKBP) but it does not inhibit the
calcineurin pathway. The Sirolimus-immunophilin complex interacts with a protein
kinase called TOR (target of rapamycin) that is integral to a signal transduction
pathway regulating the synthesis of proteins required for cell-cycle progression in
both lymphoid and non-lymphoid cells.
Sirolimus is poorly absorbed from the gut. It is widely distributed in many tissues.
The liver is the principal organ of metabolism, via the cytochome P450 3A4 system.
The half-life is approximately 50-70 hours in healthy subjects and renal transplant
recipients and is considerably lengthened in patients with chronic liver dysfunction.
The most frequently reported adverse effects in subjects receiving Sirolimus are mild
67
Table 9. Drugs which affect levels and toxicity of the calcineurin inhibitors and
Sirolimus
Increase levels (usually by inhibition Bromocryptine
of cytochrome P450 3A4 or reduced Cimetidine
clearance)
Cisapride
Clarithromycin
Danazol
Diltiazem
Erythromycin
Fluconazole
Grapefruit juice
Itraconazole
Ketoconazole
Methylprednisolone
Metoclopramide
Nicardepine
Statins (HMG CoA reductase inhibitors)
Verapamil
Protease inhibitors
Decrease levels (usually induction
of cytochrome P450 3A4)
Barbiturates
Carbamazepine
Phenytoin
Rifampicin
St. Johns wort (Hypericum)
Increase toxicity
Amphotericin B
Cimetidine
Gentamicin
NSAIDs
Ranitidine
Tobramycin
Vancomycin
Decrease toxicity
dose-related thrombocytopenia and leukopenia, and hyperlipidemia, affecting both

serum triglycerides and cholesterrol. Among the other effects reported include nausea,
vomiting, hypertension, elevations in serum creatinine, elevations in liver-associated
enzymes and acne. Isolated cases of interstitial pneumonitis or hepatic arterial thrombosis have also been observed in patients receiving Sirolimus.
Immunosuppressive Antibodies (Tables 11, 12 and 13)

Antibodies may be mono- or polyclonal. Some preparations react with epitopes
expressed by all lymphocytes whereas others recognize epitopes expressed by subsets
of lymphocytes only. All are profoundly immunosuppressive. Some centers use
polyclonal antibodies to lymphocytes (e.g., ALG, Thymoglobulin) for induction
(see Table 9).
68
Table 10. Immunosuppressive drugs: Sirolimus

Drug name
Sirolimus (AKA rapamycin)
Mechanism of action
Inhibits T cell activation
Side-effects
Hyperlipidemia (40%)
Hypercholesterolaemia (40%)
Thrombocytopenia
Gastrointestinal disturbances
Interstitial pneumonitis
Hepatic artery thrombosis
May impair wound healing
Dosage
2 mg/day
Should be taken 4 hours after
cyclosporin
Monitoring of drug levels is not required
in most patients (except in children,
renal or hepatic impairment, with
concurrent administration of enzyme
inducers/inhibitors of CYP 3A4 or if
cyclosporine discontinued)
Drug interactions
As for calcineurin inhibitors
Notes
Anti-proliferative in vitro. May be

effective in reducing malignant cell
proliferation and in intimal call
proliferation
Principles of Immunosuppression
The management of immunosuppression can be considered in five phases:
Induction
Maintenance
Treatment of acute rejection
Treatment of chronic rejection
Withdrawal of immunosuppression
Induction of Immunosuppression
There is no consensus for the optimal method for induction of
immunosuppression. Some centers use mono- or polyclonal antibodies, in
combination with other immunosuppressive agents. Other centers use intra-operative
corticosteroids.
Maintenance of Immunosuppression
Currently most centers use a combination of corticosteroids, azathioprine and a
calcineurin inhibitor although some use monotherapy (calcineurin inhibitor alone)
or dual therapy (calcineurin inhibitor with azathioprine or mycophenolate) but there
69
Table 11. Immunosuppressive drugs: Polyclonal antibody preparations

Drug name
Anti-thymocyte globulin (ATG), Antilymphocyte globulin (ATGAM)
Mechanism of action
Polyclonal antibodies raised in mammals

against human lymphocytes or
lymphocyte subsets.
Side-effects
Hypersensitivity; anaphylaxis; headache,

dizziness, muscle pain, lymphopenia,
leukopenia, thrombocytopenia (usually
transient); nephrotoxicity
Dosage
Different preparations vary in their

activity. See manufacturers instructions
Drug interactions
Notes
Test for sensitivity before administration

of first dose. Increases the risk of CMV.
Use CMV prophylaxis in selected
patients
Table 12. Immunosuppressive drugs: Monoclonal antibodies to T lymphocytes

Drug name
Mechanism of action
Side-effects
Dosage
Drug interactions
Notes
Anti-CD3
Binds to and blocks the CD3 receptor on T cells
and prevents signal transduction
Treatment is associated with a cytokine release
reaction (shake and bake syndrome) which may
be severe. Pre-treatment with methylprednisolone
may prevent the syndrome. Other side-effects
include profound lymphopenia, seizures,
encephalopathy, aseptic meningitis, cerebral
edema, and anaphylactic responses (such as
wheezing, rigors and hypertension).
5 mg/day intravenously for 10-14 days
Avoid the concomitant use of NSAIDs and
cyclosporin (increased CNS side-effects),
corticosteroids (increased risk of psychosis)
Muromonab-CD3 is a monoclonal antibody ;
should be avoided in patients with anti-murine
antibody titres >1:1000; uncompensated fluid
overload or patients with heart failure or with a
history of seizures. Avoid in pregnancy or breast
feeding.
70
Table 13. Immunosuppressive drugs: Antibodies to IL-2 receptor

Drug name
receptor)
Mechanism of action
Basiliximab; daclizumab (antibodies to IL-2

These bind to and block the alpha unit of the IL-2
receptor on activated T cells and so inhibits IL-2
binding and inhibits IL-2 activation
Side-effects
Anaphylaxis
Dosage
See below
Drug interactions
None known
Notes
There are two preparations: Basiliximab is a

chimeric monoclonal antibody and is given at a
dose of 20 mg within 2 hours of surgery and at 4
days (children below 15 years have a smaller dose)
Daclizumab is a humanized monoclonal antibody:
the dose is 1 mg/kg/dose for 5 doses, the first within
24 hours of transplantation
The initial dose required for liver transplants may be
greater than for other solid organ recipients due to
loss of antibody in ascites drained at laparotomy,
and in ascitic or pleural fluid drained during the
peri-operative period.
are few data to define the optimal regime. The introduction into clinical practice of
newer drugs such as Sirolimus will allow the clinician to tailor the immunosuppressive
regime more closely to the patient.
Treatment of Acute Rejection

Acute rejection should, whenever possible, be confirmed prior to treatment using histology obtained either by liver biopsy; fine needle aspiration biopsy is used
occasionally. Although many serological markers in blood and bile have been
described, none has been shown to be of adequate sensitivity and specificity to confirm rejection. It is rarely possible to distinguish reliably between rejection and infection without histology.
The mainstay of immunosuppression for early acute rejection is high dose corticosteroids: regimes vary between centers and there are no good data to demonstrate
superiority of any one regime. Typical regimes are:
Prednisolone 200 mg/day for 3 days
Methyl prednisolone 0.5-1 g/day for 3 days
The rate of reduction of corticosteroid pulses to maintenance steroids varies from
center to center.
71
Treatment of Chronic Rejection

Chronic rejection of the liver allograft has many names: chronic ductopenic
rejection, vanishing bile duct syndrome, chronic rejection. Chronic ductopenic
rejection may lead to loss of the graft. It is treated by increased immunosuppression,
including conversion to tacrolimus from cyclosporin or switching to Sirolimus.
Withdrawal of Immunosuppression
The observation that some patients have maintained long-term good graft function after discontinuing immunosuppression has led some centers to embark on
carefully controlled trials of withdrawal of all immunosuppression in long-term (>5
years) survivors with good graft function, or in subjects with major impediments to
continued use of immunosuppressant, such as malignant disease. These studies have
demonstrated that it is possible to withdraw all immunosuppression in about 20%
of carefully selected patients. The remainder required maintenance immunosuppressants or their reintroduction if they had been stopped. The usual reason for
failure to withdraw immunospressants was late onset acute cellular rejection, which
was then controlled by adjusted phamacotherapy. Those recipients grafted for nonautoimmune diseases, without episodes of acute rejection and with a good HLA
match are more likely to be able to withdraw immunosuppression.
Side-Effects of Immunosuppression
The side-effects of immunosuppression may be due either to
The effect of immunosuppression itself (especially infection and
malignancy)
The effects of individual drugs
These are discussed in detail in Chapter 9.
Tailoring the Immunosuppression to the Individual

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

Currently available immunosuppressants will not only reduce the risk of rejection
but will predispose the patient to infection. The balance between over- and underimmunosuppression is even more difficult to maintain in the presence of active
sepsis. The general approach is to reduce the immunosuppression but the onset of
graft rejection may not only herald the need for high-dose immunosuppression but
hepatic impairment is associated with a further reduction in the host defences against
infection. In the presence of bacterial infection, early detection and vigorous treatment
with appropriate antimicrobials is clearly required; depending on liver function,
72
steroids should be reduced initially. Remember, however, in maintaining the balance between rejection and infection, with rejection the graft will be lost but with
infection the patient will be lost.
Intercurrent Viral Infection

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

immunosuppression, most centers use prophylactic treatment with Isoniazid 100
mg/day in those at risk. Isoniazid should be given with pyridoxine. Treatment should
be for at least one year.
The interaction between the immunosuppression and recurrent viral disease,
such as HCV or HBV, is discussed in Chapter 8.
Retransplantation for Chronic Rejection, Late Acute

Rejection and Early Ductopenic Rejection
These are associated with an increased risk of developing graft loss and therefore
many centers are using a combination of corticosteroids, tacrolimus and
mycophenolate or Sirolimus.
Co-Morbid Conditions
Pregnancy and Breast Feeding
See Chapter 9: if the recipient is likely to become pregnant after transplantation,
consideration should be given to the appropriate choice of drugs.
Diabetes Mellitus
The tendency of calcineurin inhibitors to induce diabetes mellitus is controversial.
Tacrolimus may be more diabetogenic than cyclosporin. Most transplant programs
do not switch from tacrolimus to cyclosporin, on account of diabetes mellitus. Those
diabetics given corticosteroids may have an increased requirement for insulin or oral agents.
Renal Impairment
Renal impairment may occur following transplantation for many reasons (such
as IgA nephropathy, HCV associated glomerulonephritis, diabetic nephropathy or
associated with the inappropriate prescription of non-steroidal anti-inflammatory
drugs or nephrotoxic drugs such as gentamicin). In the presence of peri-operative
renal failure, some centers avoid the use calcineurin inhibitors. If renal impairment
develops in associated with calcineurin inhibitor use, most centers will reduce or
discontinue the calcineurin inhibitor (see Chapter 9).
73
Development of Lymphoma and Other Malignancy

This is discussed in Chapter 7. Lymphoma post transplantation may be associated with EBV infection. Treatment is with aggressive therapy of the lymphoma and
a reduction in the immunosuppressive regime; some centers discontinue all immunosuppression during chemotherapy.
Suggested Reading
1.
2.
3.
Micromedex Information System; http://www.micromedex.com; info@mdx.com

Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B et al. Defining the outcome of immunosuppression withdrawal after liver transplantation.
Hepatology 1998; 27:926-933.
Jain A, Kashyap R, Marsh W, Rohal S, Khanna A, Fung JJ. Reasons for long-term
use of steroid in primary adult liver transplantation under tacrolimus. Transplantation 2001; 71(8):1102-1106.
74
CHAPTER 7
Graft Dysfunction
Geoffrey H. Haydon
Introduction
The causes of graft dysfunction occurring after liver transplantation may be
classified either according to the time period post-transplantation (Table 1) or to the
etiology of the graft dysfunction. It should be emphasised that any of these conditions
may become evident at any time after liver transplantation, and Table 1 lists the
most common times for presentation.
Investigation of Graft Dysfunction

The general diagnostic approach is outlined in Table 2. Investigation of each of
the complications above is considered under the appropriate heading.
Primary graft non-function

Primary graft non-function is defined as failure of the graft to function in the
first post operative week. It is manifested by:
Failure to regain consciousness
Sustained elevations in transaminases
Increasing coagulopathy
Acidosis
Poor bile production
Primary graft non-function may be due to:
Massive hemorrhagic necrosis
Ischemia/reperfusion injury
Idiopathic
It may be difficult to distinguish non-function which will not recover, from early
poor function wherein graft function will return to normal after a period of systematic
support. The value of agents such as prostaglandins and n-acetyl cysteine in these
circumstances is uncertain.
Immunological Complications
Acute Cellular Rejection (ACR)
-Definition:
Inflammation of the allograft elicited by genetic disparity between the
75
Graft Dysfunction
Table 1. Etiology of graft dysfunction more than one-month post transplantation.

Time Period Post-OLT
Diagnosis
1-6 months
Acute cellular rejection

Opportunistic infection
-Viral: CMV; EBV (HSV, VZV less common)
Vascular
-Hepatic artery thrombosis
Recurrent viral hepatitis
Biliary tract abnormalities
6-12 months

Chronic ductopenic rejection
>12 months

Recurrent autoimmune disease (PSC; PBC; AICAH)
Steatohepatitis
Table 2. Graft dysfunction according to pathogenesis

Immunological complications: acute cellular rejection; chronic ductopenic
rejection
Primary viral infection: CMV; HSV; EBV
Graft ischemia: hepatic artery thrombosis
Biliary complications: biliary leaks; bile duct strictures; choledocholithiasis and
cholangitis
Recurrent disease: viral hepatitis (HCV; HBV); PBC; PSC; AICAH, NASH
donor and recipient, primarily affecting interlobular bile ducts and vascular endothelia, including portal veins and hepatic venules, and occasionally the hepatic artery and its branches.
-Incidence:
Occurs in 20% to 80% of grafts.
-Timing:
First occurs between 5 and 30 days post-transplantation; 80% of ACR
occurs in the first 10 weeks post-transplantation. ACR may still occur
thereafter.
-Clinical Findings:
Usually asymptomatic, although in late or severe cases, fever and hepatomegaly occur. When bile is collected, it is noted to be pale and watery.
76
Table 3. Banff criteria grade of histologic injury

Subjective Grade
Criteria
Indeterminate
Portal inflammatory infiltrate that fails to meet criteria for the

diagnosis of acute rejection
Rejection infiltrate in a minority of the triads, that is generally
mild and confined within the portal spaces
Rejection infiltrate expanding most or all of the triads
As above for moderate, with spillover into periportal areas
and moderate to severe perivenular inflammation that extends
into hepatic parenchyma and is associated with perivenular
hepatocyte necrosis
Mild
Moderate
Severe
Banff grading of acute liver allograft rejection. Global assessment of rejection

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

-Definition:
Chronic ductopenic rejection is defined by two histopathological features:
obliterative vasculopathy and bile duct loss (Table 4). It is also called chronic
rejection and chronic vanishing bile duct syndrome.
-Incidence:
Most programs report less than 5% of grafts develop chronic ductopenic
rejection.
Graft Dysfunction
77
Table 4. Reported risk factors for chronic ductopenic rejection

Highly Probable:
-Retransplantation for chronic rejection
-Late acute rejection episodes
-Steroid-nonresponsive acute cellular rejection
Controversial Associations:
-Underlying liver disease
-AICAH
-PBC
-PSC
-Positive lymphocytotoxic cross-match
-CMV infection
-Recipient age
-Donor/recipient of different ethnic origins
-Male donor allograft into female recipient
-Cyclosporin based immunosuppression (compared with tacrolimus
regimes)
Table 5. Histological features and grading of chronic ductopenic rejection

Bile duct loss*, without centrilobular cholestasis, perivenular sclerosis, or
hepatocyte ballooning or necrosis and dropout
Bile duct loss*, with one of the following four findings:
-centrilobular cholestasis
-perivenular sclerosis
-hepatocellular ballooning
-hepatocyte necrosis and drop-out
Bile duct loss*, with at least two of the four following findings:
-centrilobular cholestasis
-perivenular sclerosis
-hepatocellular ballooning
-centrilobular necrosis and drop-out
*Bile duct loss: >50% of triads
-Timing:
Chronic ductopenic rejection may occur at any time after liver transplantation, but is usually seen in the first postoperative year.
-Clinical Findings:
As with ACR, most patients are free of symptoms. Some have generalized
systemic symptoms or complain of increasing jaundice and cholestatic
symptoms.
Risk factors for chronic ductopenic rejections are shown in Table 4.
-Investigations:
Liver chemistry tests usually demonstrate a relentless rise in markers of
cholestasis. Liver biopsy is essential to make the diagnosis of chronic
ductopenic rejection. Special cytokeratin stains to identify biliary epithelia
are useful when assessing bile duct loss. Vascular lesions may be absent on
78
Table 6. Differential diagnosis of cholestatic liver disease in the transplanted

liver
Biliary obstruction
Viral hepatitis (viral cholestatic hepatitis)
Sepsis
Drug hepatotoxicity
Recurrent primary biliary cirrhosis
Recurrent primary sclerosing cholangitis
needle biopsy specimens (Table 5).

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

In a small number of liver transplant recipients a syndrome resembling autoimmune hepatitis Develops. It is characterised by biochemical hepatitis, autoantibodies and histologic appearances of inflammatory hepatitis. The hepatitis usually
responds to reintroduction or increased doses of corticosteroids.
Graft Infection
Infection is a major cause of morbidity and mortality post-transplantation; there
is also a complex interplay between the immune system and infectious agents.
CMV Disease
-Timing:
Commonly within 2-3 months, and rarely within the first month of transplantation
-Clinical Presentation:
Triad: fever; leukopenia; thrombocytopenia
May present as: hepatitis; pneumonitis; GI tract infection (esophagitis,
gastritis, duodenititis, and colitis)
-Diagnosis of CMV Disease:
Abnormal liver chemistry tests
CMV PCR positive when there is active viremia or shedding of virus
(specificity 50-60%)
Typical CMV inclusion bodies demonstrated on liver biopsy. May also be
seen in rectal or duodenal biopsies
Graft Dysfunction
79
CMV PCR of liver biopsy

-Risk Factors for CMV Infection:
The respective serological status of the donor and recipient is most important and must be documented: seronegative recipients of a graft from
a seropositive donor have the highest risk of infection
Infection may be transmitted by the graft; blood products; reactivation of
previous infection or superinfection by a CMV variant
Patients with septic biliary complications (including hepatic artery
thrombosis)
Patients transplanted for fulminant hepatic failure
Recipients treated with muromab OKT3 or thymoglobulin. The risk of
CMV in recipients of monoclonals directed against the IL-2 receptor
remains uncertain
-Prophylaxis against CMV Infection:
Ganciclovir and acyclovir are highly effective against CMV reactivation;
re-infection or new disease
Studies comparing the two drugs suggest that ganciclovir produces a more
significant reduction in infection than acyclovir
Individual programs determine policy regarding prophylactic regimes
against CMV. Prophylaxis may be restricted to high risk patients, but are
not essential for all recipients
-Treatment of CMV Graft Infection
Immunosuppression should be reduced (azathioprine usually stopped)
A 14 day course of intravenous ganciclovir (10 mg/kg/day IV in 2 doses)
is most effective. Many programs follow this with 6 weeks oral ganciclovir.
Second line therapy: Foscarnet 60 mg/kg every 8 hours for 14 days (avoid
in renal failure); CMV Ig
Third line therapy: Cidofovir 5 mg/kg once weekly for 2 weeks, followed
by 5mg/kg every 2 weeks (also avoid in renal failure).
EBV Hepatitis (Table 7)

-Timing:
No specific timing after liver transplantation.
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:
80
Table 7. Clinical and histological features of EBV related graft dysfunction

Disease/
disorder
Clinical features Histology
Therapy
Outcome
Post-transplant Fatigue, fever,

Mild increase in Acyclovir
infectious
rash, sore throat, portal infiltrates
mononucleosis lymphadenopathy
(IM)
Self-limited
disease/
resolved
Polyclonal B- Similar to acute

cell hyperplasia IM with severe
hepatitis, bone
marrow failure
and ARDS
Decreased
immunosuppression;
treat with
acyclovir or
ganciclovir
Responds to
antiviral
treatment/
resolves
Polyclonal
Nodal and extra- Polymorphic
proliferation B- nodal lympholymphocytic
cell lymphoma cytic proliferation infiltrate
in patients treated
with immunosuppressive
medication
Withdraw
immunosuppression; treat
with acyclovir,
ganciclovir or
anti-B cell
monoclonal Ab
Most progress
to lymphoma
and have a
low survival
rate
Monoclonal
polymorphic
B-cell
lymphoma
Withdraw
Aggressive
immunosupdisease with
pression; treat survival rate
with chemoof less than
therapy; radio- 1 year
therapy or
surgical resection
Prominent
portal
lymphocyte
and (plasma
cell) infiltrate
Nodal and extra- Polymorphic to

nodal lymphomonomorphic
cytic proliferation lymphocytic
in patients treated proliferation
with immunodepending on
suppressive
the stage of
medications
disease
None is necessary
-Treatment of EBV hepatitis:
A decrease in the immunosuppressive therapy will result in resolution of
both symptoms and histopathological findings
-Outcome of EBV infection after liver transplantation:
Excellent prognosis
Post-Transplant Lymphoproliferative Disorders (PTLD) (Table 7)

Malignancies occur in solid organ transplant recipients with a frequency 101000 times that of the normal population. After skin cancer, lymphoma has the
second highest incidence in the immunosuppressed patient. The association of EBV
with post-transplant lymphoproliferative disorders has been well described and the
presence of EBV-specific proteins and fragments of EBV genome demonstrated
consistently in PTLD. There are three clinical disorders of differing presentations
and prognosis, which may involve graft dysfunction in PTLD.
Polyclonal B-cell Hyperplasia
Graft Dysfunction
81
As for infectious mononucleosis.

-Subpopulation:
Young patients in second to fourth decade, who are profoundly immunosuppressed
-Histology:
Polyclonal B-cell lymphoproliferation
-Treatment:
Acyclovir
-Outcome:
Usually excellent response to acyclovir
Polymorphic B-cell Lymphoma
Patients present with infectious mononucleosis-like symptoms and then
develop a rapidly disseminated lymphoproliferation involving the liver,
spleen and other visceral organs
-Histology:
Polymorphic B-cell lymphoproliferation
-Treatment:
Immediately withdraw immunosuppression and initiate anti-viral therapy
-Outcome:
Usually fatal
Monoclonal Polymorphic B-cell Lymphoma
Usually older patients more than 5 years post-transplant. Prominent
extranodal masses develop in the central nervous system, gastrointestinal
tract and liver
-Histology:
Non-Hodgkins lymphoma with a monomorphic pattern and monoclonal
immunoglobulin expression
-Treatment:
Withdraw immunosuppression. Surgical resection of masses with adjuvant
radiotherapy and chemotherapy
-Outcome:
Aggressive disease with high mortality at 1 year
Graft Ischemia
Hepatic Artery Thrombosis (HAT)
Hepatic artery thrombosis is one of the principal causes of morbidity and

graft loss following liver transplantation
-Presentation (Table 8)
-Incidence:
This has been described as high as 10%; technical aspects of the arterial
anastomosis are important particularly for early thrombosis, but with
82
Table 8. Presentation of hepatic artery thrombosis (HAT)

Clinical Presentation
Acute graft failure
Massive rise in liver enzymes (particularly transaminases). This is a feature of HAT
presenting immediately after transplantation.
Unexplained septicaemia
Biliary tract problems
-Leaks
-Abscess
-Breakdown of biliary anastomosis
Liver abscess (may be sterile, also called a biloma)
improvement in surgical technique it is likely that the incidence is falling.

It is a recognized component of the small sized graft syndrome in recipients of adult to adult right lobe grafts
-Timing:
It is most common within the first month after transplantation, but may
occur at any time
-Clinical Sequelae:
Graft necrosis
Intrahepatic abscesses. Also called bilomas
Infarction of the bile ducts with bile leakage and gram negative sepsis.
-Diagnosis of hepatic artery thrombosis:
Doppler sonography (sensitivity for diagnosis of hepatic artery thrombosis:
60-92%)
Confirmed by arteriography (CT, MR or arteriograms)
-Risk Factors:
Technical aspects of the arterial anastomosis
Raised hematocrit
Low donor/recipient age ratio
Procoagulant syndromes
Smoking
CMV infection (followed by rapid procoagulant response)
Adult to adult right lobe transplantation
-Treatment:
Early thrombosis is an indication for urgent regrafting
Patients with late thrombosis may survive with conservative therapy and
satisfactory graft function
There are anecdotal reports of a good response to thombectomy and
thrombolytic therapy
Graft Dysfunction
83
Hepatic Artery Stenosis

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

This can occur in up to 3% of recipients; the diagnosis is often suggested by the
subsequent development of gastroesophageal varices or other signs of portal
hypertension. Treatment is usually management of the complications of portal
hypertension. Thrombectomy or angioplasty are rarely feasible.
Biliary Complications
Biliary tract complications are the most frequent late complication of liver
transplantation with an incidence of 15-20%. Biliary leaks occur at T-tube withdrawal
in up to 30 % of patients who have a biliary drainage tube placed at time of transplant.
Among the important factors which have been implicated in the pathogenesis of
biliary strictures or leaks are:
The arterial supply to the biliary tree: biliary epithelial cells are particularly
susceptible to interruption of their arterial blood supply; so that if this is
compromised by even relative ischemia, bile duct necrosis will follow
Bile composition: the composition of bile is altered following
transplantation, predisposing to supersaturation with cholesterol and stone
formation
Denervation of the liver may inhibit or alter the composition of bile.
Biliary complications have been recorded in up to 20% of recipients of living
donor adult to adult right lobe grafts
-Early biliary complications:
These can be recognized by the appearance of bile in surgical drains and
the measurement of drain fluid bilirubin, in patients without T-tubes
-Late biliary complications:
Biliary leak following withdrawal of peroperative biliary drainage tube
(often referred to as a T-tube)
Biliary strictures (see below)
Ascending cholangitis
Increasing cholestasis
The biliary cast syndrome
-Investigations:
When the patient is septic, a full sepsis screen is undertaken
Increasing cholestasis is investigated by ultrasound (or CT) and collections
drained under ultrasound guidance
The integrity of the biliary tree can be assessed by T-tube cholangiography,
endoscopic retrograde cholangiography or by magnetic resonance
cholangiopancreatography. Biliary leaks may resolve if stented by ERC
84
If these investigations are normal, a liver biopsy is necessary to exclude

chronic ductopenic rejection
Biliary Leaks
These occur because of ischemic necrosis at the anastomosis or following removal
of a T-tube.
Bile Duct Strictures
These are usually classified as anastomotic or non-anastomotic;

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

biliary tree. May be more common with non-heart beating donors. In
addition to strictures the extrahepatic and ultimately the intrahepatic biliary
trees are clogged with cast material/sludge. Cholesterol is the main
component of biliary cast matter
Presents with intractable pruritus
Managed by serial removal of biliary cast material/sludge by ERC or by
percutaneous cholangiography
May require retransplantation
Recurrence of Disease After Liver Transplantation

Recurrence of disease following liver transplantation remains a problem for the
long-term survivor in several indications and may affect graft function and survival.
It does however, provide useful information about the pathogenesis of the underlying
disease process. Recurrent disease is described in Chapter 8.
Suggested Reading
1.
2.
3.
4.
Demetris AJ, Batts KP, Dhillon AP et al. Banff scheme for grading liver allograft
rejection: an international consensus document. Hepatology 1997; 25:658-663.
Dousset B, Conti F, Cherruau B et al. Is acute rejection deleterious to long-term
liver allograft rejection? J Hepatol 1998; 29:660-668.
Demetris AJ, Seaberg E, Batts KP et al. Reliability and predictive value of the
NIDDK transplantation database nomenclature and grading system for cellular
rejection of liver allografts. Hepatology 1995; 21:408-416.
Demetris A, Adams D, Bellamy C et al Update of the International Banff Schema
Graft Dysfunction
5.
6.
85
for Liver Allograft Rejection: Working recommendations for the histopathologic

staging and reporting of chronic rejection. An International Panel. Hepatology
2000; 31:792-799.
Wiesner RH, Demetris AJ, Belle SH, Seaberg EC, Lake JR, Zetterman RK et al.
Acute hepatic allograft rejection: Incidence, risk factors, and impact on outcome.
Hepatology 1998; 28:638-645.
Heneghan MA, Portmann BC, Norris SM, Williams R, Paolo Muiesan P, Mohamed
Rela M et al. Graft dysfunction mimicking autoimmune hepatitis following liver
transplantation in adults. Hepatology 2001; 34:464-470.
86
CHAPTER 8
Recurrence of Disease after Liver

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

Graft infection with hepatitis C virus (HCV) is universal
100 % of patients have persistence of HCV RNA after transplantation
Serum HCV RNA levels decrease during surgery, both when the recipient
native liver is removed and when the donor organ is reperfused. Afterwards
the concentrations of circulating HCV RNA increases as early as day 3
post-transplantation and the levels at 1-3 months are greater than pretransplant levels.
An acute hepatitic syndrome occurs in many HCV infected patients in
the first 4 months post-OLT. It may be difficult to distinguish HCV
recurrence from acute cellular rejection or a combination of the two.
Chronic hepatitis is found in 50% of patients at 2 years and 70% at 4
years.
The prevalence of hepatic cirrhosis in graft recipients at 5 years is at least
10%
Up to 10 % of HCV infected recipients develop a cholestatic syndrome
associated with ballooning degeneration of hepatocytes, which has been
called fibrosing cholestatic hepatitis. It occurs in the first year and is
associated with very high circulating HCV RNA levels. It has a poor
prognosis.
Investigation of HCV after liver transplantation:
Biochemical profile
HCV RNA levels in serum
Liver biopsy
Many factors have been associated the severity of recurrent disease (See Table 1).
Recurrence of Disease after Liver Transplantation
87
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
MHC donor/ recipient match
Ethnicity
Recipient of a live donor hepatic graft
Treatment of Recurrent HCV

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

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

The early experience of liver transplantation for chronic HBV infection
highlighted a significant adverse effect of infection on graft and patient
survival. Aggressive re-infection and progression to cirrhosis and sub-acute
88
graft failure were almost universal; the overall outcome was inferior to
other etiologies. HBV infection presenting as FHF had a better prognosis
for post transplant hepatitis on account of the low level of pre-transplant
HBV DNA.
-Investigation of Recurrence:
Biochemical profile
HBsAg and Anti-HBs titer
HBV DNA
Liver biopsy
- Risk Factors for Recurrent HBV Hepatitis:
Evidence of active viral replication as shown by pre-transplant serum HBV
DNA levels and/or HBeAg status
The role of vaccination against HBV in this population is controversial.
Prophylaxis against infection
All candidates who are actively replicating HBV should receive lamivudine
pre-transplant as discussed in Chapter 5
Post transplant: patients should receive hepatitis B immunoglobulin
(HBIg). Many centers combine HBIg with lamivudine. The dose, mode
of administration and duration of treatment with HBIg is uncertain. Some
centers titrate the dose of HBIg to maintain levels of circulating anti-HBs
> 100 IU/ml. The main side effect of i.v. HBIg is severe back and chest
pain
Post transplant Treatment of Recurrent HBV Graft Hepatitis
Lamivudine has allowed effective transplantation of patients who
are HBV DNA positive, although re-infection has occurred in a
minority of patients following the emergence of lamivudine
resistance (YMDD mutations)
Other strategies being evaluated include the use of other antiviral
drugs, such as adefovir, tenofavir and entecavir, and HBV
vaccination
Hepatitis D Virus Infection

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

Anecdotal reports of patients transplanted for fulminant HAV show
infection of the graft may occur, but it is of little clinical significance
Autoimmune Disease
Primary Biliary Cirrhosis
Following transplantation, anti-mitochondrial antibodies remain positive
in 72-100% of cases; however, the persistence of these antibodies does
not indicate recurrent disease
89
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.
Biochemical markers, such as serum alkaline phosphatase have a low
sensitivity and specificity
Serum IgM levels fall immediately after transplantation; they rise again in
some patients with recurrence
Histologically, there is overlap between PBC recurrence, chronic rejection
and chronic HCV infection in the graft
Granulomatous destruction of bile ducts is considered pathognomonic
-Risk Factors:
There are suggestions that the type of immunosuppression may influence
the incidence of disease prevalence. In particular, there may be an increased
susceptibility to recurrence with tacrolimus immunosuppression
-Treatment of Recurrent PBC
The same principles may apply as pre-transplantation; ursodeoxycholic
acid is usually prescribed, albeit without definitive data on its effect
-Prognosis:
Long-term follow up data are awaited
There seems to be little adverse effect on graft function and the majority
of patients are asymptomatic.
Primary Sclerosing Cholangitis

Most patients transplanted for PSC have a choledochojejunostomy with a Roux
loop. Differentiation of recurrent PSC from secondary sclerosing cholangitis may
be difficult in the transplant setting. Causes of non-anastomotic biliary strictures
are discussed in Chapter 7.
Possibly 20% of graft recipients
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:
Autoimmune Hepatitis (AIH)

The distinction between graft hepatitis and recurrent AIH is difficult; there are
no unequivocal criteria for the diagnosis of recurrent AIH. Therefore, the literature
on this topic is confusing.
-Incidence and Prevalence
90
There is graft recurrence of AIH in between 10 and 60% of recipients

De novo graft AIH also occurs in a small proportion of patients
Acute rejection in patients transplanted for AIH occurs in upwards of
80% of individuals, but its prognostic significance is uncertain
-Risk Factors
Low maintenance immunosuppressive regimes
Absence of azathioprine
The role of HLA matching is conflicting
-Treatment of Recurrent AIH
Many programs maintain long-term corticosteroid therapy in low doses
(<10 mg per day)
Prevention of recurrent AIH is possible if patients are maintained on a
small dose of prednisolone after transplantation (5-10 mg), although
immunosuppression should be tapered to the minimum tolerated regimen
for each patient. This requires close supervision and regular liver biopsies.
-Prognosis:
Metabolic Diseases
Recurrence of the original disease, both hepatic and extrahepatic, depends on
both the location of the primary metabolic defect and its target organs.
Transplantation cures the patient for those metabolic diseases in which the primary
defect resides in the hepatocyte itself. These include metabolic disorders in which
the liver is damaged, and those disorders in which liver function remains intact but
which are associated with severe damage to other organs (See Table 2). In the latter
group, the recipient explanted liver may be perfectly healthy except for the single
metabolic defect. Occasionally these explants have then been used to provide a liver
graft to another recipient in whom the metabolic defect will is not of immediate
concern. This has been called the domino procedure.
Other metabolic diseases are associated with a more generalized metabolic defect
and the original disease may recur. Examples include hemochromatosis, NiemannPick disease, Gauchers disease, cystic fibrosis, and protoporphyria.
Hemochromatosis
Defect in hemochromatosis is dysregulation of iron absorption in the
enterocyte
Hepatic iron reaccumulation occurs after transplant, but long-term followup is needed to establish the rate and risk for hepatic iron reaccumulation
in allograft
There have been no reports of graft failure attributed to iron overload
Patient survival after transplant in patients with hemochromatosis is less
than for other forms of cirrhosis. This phenomonon appears to be related
to cardiac and infectious complications and may also be related to lack of
pre-transplant diagnosis and treatment. Several reports have suggested
that iron depletion prior to transplant can improve postoperative sur-
91
Table 2. Metabolic diseases cured by liver transplantation

Associated with Liver Damage:
Wilsons disease
1-anti-trypsin disease
tyrosinemia
Crigler-Najjar syndrome
Bylers disease
Not associated with liver damage:
primary oxaluria
amyloidosis
primary hypercholesterolemia
vival.
Clinical approach:
Monitor serum ferritin and iron saturation in these patients on an annual
basis
Consider venesection if there is evidence of excessive iron overload.
There have been several reports of patients who inadvertently received livers
from donors with hemochromatosis. In the short term, these recipients have shown
a progressive and rapid reduction in hepatic iron concentration over time.
Wilsons Disease
Liver transplantation does not always completely reverse the nervous system
complications associated with WD but significant improvements are often
seen.
Liver transplantation does not fully correct copper kinetic measurements
to normal, although it does result in normalization of serum copper and
ceruloplasmin.
Transplantation converts the response to one similar to that found in a
heterozygote for WD.
Despite incomplete metabolic normalization, transplantation effectively
cures the patient as the heterozygote state is not associated with clinical
disease.
Amyloidosis
Transthyretin amyloidosis is a group of hereditary, often fatal, systemic
disorders caused by mutant TTR.
Familial amyloidotic polyneuropathy is the commonest hereditary form
and is a systemic disease that most seriously affects the heart, kidneys and eyes.
Although hepatic amyloidosis is common, clinically significant liver failure
is rare
Liver transplantation replaces mutated with donor wild-type TTR and
halts amyloid production and further systemic amyloid deposition. After
transplant, improvement in extrahepatic symptoms may occur, especially
in gastrointestinal disturbances. Liver transplant may prevent further de-
92
cline and the onset of new complications

Survival after transplantation is determined by disease duration, hereditary
and geographic factors, nutritional status, gastrointestinal and cardiac
involvement. 5-year survival of 75% has been reported
Alcoholic Liver Disease (ALD)
Survival rates after liver transplantation are similar among alcoholics and nonalcoholics, at least in the short and intermediate term. Long term follow-up data are
needed.
-Incidence:
Up to 30% adult recipients are affected by alcohol addiction
A return to alcohol use within 5 years of transplantation is seen in up to
50% of those grafted for ALD
A return to alcohol consumption is usually seen in the first year
Drinking to excess is reported in up to 10% of alcoholic liver transplant
recipients within 5 years
Graft injury, due to alcohol excess, is rare
Other medical problems, such as infection, pancreatitis, alcohol withdrawal
occur in in these recipients who relapse to abusive drinking
-Risk Factors:
It is difficult to identify those patients who are at risk of relapse
The period of abstinence prior to transplant is an insensitive prognostic
indicator for alcoholic relapse
-Therapy:
The efficacy of alcoholism therapy in post transplant patients is unproven
but all such patients should be offered support and therapy
Malignancy
Hepatocellular Carcinoma
Liver transplantation is potentially curative in a subset of patients with HCC
with a small tumor burden
Incidence
Initial series described a very high tumor recurrence rate, but the majority
of included patients with advanced HCC. Recurrence is negligible if the
criteria outlined in Chapter 3 are met and survival is excellent with a 4year survival rate of 75%, and rate of recurrence-free survival of 83%
Tumor recurrence is usually observed in the liver and less frequently the
lungs. Recurrence has been observed at the site of prior liver biopsy
suggesting seeding of tumor along biopsy site tract
Therapy of HCC after liver transplantation is ineffective, and the prognosis
is poor
Cholangiocarcinoma
The majority of studies have reported poor survival after transplantation with
one, two, and five-year survival ranging from 53-72%, 32-48%, and 17-25%
93
respectively. The main explanation for poor survival is a high incidence of tumor
recurrence. Tumor recurrence occurs early; 85% of recurrences occur within 2 years
of transplant. Recurrence is most common in the allograft, followed by lung.
Metastatic Neuroendocrine Tumors

There has been little experience with liver transplantation in secondary hepatic
tumors. In contrast to many other carcinomas, neuroendocrine tumors generally
behave less aggressively and have a slower growth rate and patients with such tumors
are more likely to benefit from liver transplantation. Reports have been confined to
small numbers of patients and short follow-up,
Despite overall good medium-term survival, tumor recurrence is common (most
commonly in liver, followed by bone) and recurrence free 5-year survival does not
exceed 24%. Despite this, transplantation offers relief of symptoms from the
neuroendocrine tumors.
Cryptogenic Cirrhosis
It is clear that many cases of cryptogenic cirrhosis are due to clandestine
NASH.
Recurrence of NASH has been recorded among patients transplanted for
NASH
No data are available about the long term consequences of NAFLD or
NASH in liver allografts, nor are there data on strategies to prevent fat
accumulation
Suggested Readings
1.
2.
3.
4.
5.
6.
7.
8.
Perrillo R, Rakela J, Dienstag J et al. Multicenter study of lamivudine for hepatitis

B after liver transplantation. Hepatology 1999; 29:1581-1586.
Samuel D, Muller R, Alexander G et al. Liver transplantation in European patients
with the hepatitis B surface antigen. N Engl J Med 1993; 329:1842-1847.
Ottobrelli A, Marzano A, Smedlie A et al. Patterns of hepatitis Delta virus reinfection and disease in liver transplantation. Gastroenterology 1991;
101:1649-1655.
Feray C, Caccamo L, Alexander GJM et al. European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. Gastroenterology 1999; 117:619-625.
Ratziu V, Samuel D, Sebagh M et al. Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J
Hepatology 1999; 30:131-141.
Forman LM, Lewis JD, Berlin JA, Feldman HA, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation
Gastroenterology 2002; 122:889-896.
Harrison RF, Davies MH, Neuberger JM et al. Fibrous and obliterative cholangitis
in liver allografts: Evidence for recurrent primary sclerosing cholangitis. Hepatology
1994; 20:356-361.
Garcia RFL, Garcia CE, McMaster P, Neuberger J. Transplantation for primary
biliary cirrhosis: Retrospective analysis of 400 patients in a single center
Hepatology 2001; 33:22-27.
94
9.
10.
11.
12.
13.
14.
15.
Brandhagen DJ, Alvarez W, Therneau TM et al. Iron overload in cirrhosis-HFE

genotypes and outcome after liver transplantation. Hepatology 2000; 31:456-460.
Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilsons disease: Indications and outcome. Hepatology 1994; 19:583-587.
Suhr OB, Herlenius G, Friman S et al. Liver transplantation for hereditary
transthyretin amyloidosis. Liver Transplantation 2000; 6:263-276.
Lucey MR, Carr K, Beresford TP et al. Alcohol use after liver transplantation in
alcoholics: a clinical cohort follow-up study. Hepatology 1997; 25:1223-1227.
Mazzaferro V, Regalia E, Doci R et al. Liver transplantation for the treatment of
small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;
334:693-699.
Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: An
analysis of 103 patients. Transplantation 1998; 66:1307-1312.
Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH et
al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease.
Liver Transplantation 2001: 7;608-614.
Management of the Liver Transplant Patient
95
CHAPTER 9
Medical Management of the Liver

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

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

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

Many of the adverse health effects seen in liver transplant recipients are direct or
indirect consequences of immunosuppression.
Systemic Hypertension
Epidemiology: Systemic hypertension is defined as diastolic pressure > 90 mmHg
or systolic pressure > 140 mmHg. Systemic hypertension occurs in 40-80% of liver
transplant recipients. It typically occurs within a few weeks of transplantation and is
largely due to the use of calcineurin inhibitors.
Pathogenesis: The molecular mechanism underlying calcineurin inhibitor-induced
hypertension is not fully understood but renal vasoconstriction is the predominant
96
Table 1. Cause of death in liver transplant recipients after the first year
Cause of death
% of all causes of death
Graft failure
CVD
Infection
De novo malignancy
Other
40%
18%
15%
8%
19%
Adapted from Abbasouglu O, Levy MF, Brkic B, Testa G, Jeyarahaj DR, Goldstein
RM et al. Ten years of liver transplantation. Transplantation 1997;
64(12):1801-1807.
Table 2. Causes of morbidity in liver transplant recipients after the first year (not
age-adjusted)
Disease
Prevalence post
transplant
Rate in US
population
Hypertension (BP > 140/90)

Hypercholesterolemia (>240mg%)
HDL < 35mg%
Diabetes mellitus
Obesity (BMI > 30)
Skin cancer (BCC and SCC)
Other Cancers
Renal Impairment
Symptomatic Fractures
41-81%
20-66%
52%
21-32%
39-43%
10%
2%
77%-80%
10%
15.7%
14.9%
12%
3.7%
16.1%
0.3%
0.4%
4%
.04%
abnormality seen. Corticosteroids add to the risk of hypertension. A history of hypertension prior to the development of liver disease is an important additional risk
factor.
Clinical Management:
Drug therapy: Drug therapy should be introduced early
Weight loss: Patients should be encouraged to lose weight if more than
15% above their ideal body weight
Sodium restriction: patients should be advised to restrict sodium intake
to 2-4 g per day
Other measures: stop smoking and reduce alcohol intake and increase
exercise
Choice of drugs:
Calcium channel blockers
Nifedipine and drugs of a similar class are preferred. Nifedipine is associated with development of peripheral oedema.
Verapamil and diltiazem may inhibit cyp 450 drug metabolism of
calcineurin inhibitors, and levels should be monitored
Angiotensin converting enzyme (ACE) inhibitors and angiotensin II (ATII)
antagonists may also be used. ACE inhibitors and ATII antagonists may
97
confer additional benefit by preventing left ventricular hypertrophy, a

risk factor for cardiovascular disease. Initial concerns regarding worsening
of renal function seem unfounded and these drugs are as effective and as
well tolerated as calcium channel blockers. Patients should be monitored
for hyperkalemia and hypomagnesemia.
Other drugs: Diuretics should be used to control peripheral edema or as
second-line antihypertensives. The centrally acting sympatholytics such
as clonidine are considered third-line agents against post-transplant
hypertension.
Hyperlipidemia
Epidemiology: See Table 1. Sirolimus causes a dose-dependant increase in
triglycerides rather than in cholesterol.
Pathogenesis: The mechanism whereby serum cholesterol levels are increased
after liver transplantation is unclear.
Review immunosuppression
Dietary modification: rarely successful in isolation in the post-liver
transplant setting.
HMG CoA-reductase inhibitors (statins).
Diabetes Mellitus
Diabetes mellitus is seen in 20-30% of liver transplant recipients. This arises
from a combination of pre-liver transplant diabetes (13% in one study) and true
post-liver transplant diabetes. This compares to less than 4% in the general population.
Pathogenesis:
Corticosteroids increase insulin resistance.
Calcineurin inhibitors: The calcineurin inhibitors increase insulin
resistance, injure pancreatic islet cells and impair insulin secretion.
Tacrolimus and cyclosporin are associated with an increased incidence of
diabetes. The effect may be transient.
Chronic hepatitis C infection may potentiate the risk or severity of diabetes
mellitus.
General: diabetic liver allograft recipients should be managed in the same
way as diabetic patients in the general population, with lifestyle
modification and drug therapy as needed.
Modification of immunosuppressive protocol: where possible,
corticosteroids should be withdrawn, and calcineurin inhibitor dose
minimised. A conversion from tacrolimus to cyclosporin, Sirolimus or
mycophenolate mofetil may be of help.
Obesity
Prevalence: Up to 40% of patients are obese (>20% above ideal body weight)
within 1 year of transplantation. Weight tends to increase for at least 2 years following
98
transplantation and weight gains of 20%-30% above pre-operative weight are not
uncommon.
General: as in the general population, management of weight gain is to
reduce caloric intake and to increase exercise.
Renal Insufficiency
Epidemiology: Prior to liver transplantation, renal insufficiency may go

unrecognized in many cirrhotic patients. Poor muscle mass and impaired hepatic
synthesis of creatinine may lead to an underestimation of glomerular filtration rate
based on serum creatinine levels. Several liver diseases, including chronic viral
hepatitis, autoimmune hepatitis, primary biliary cirrhosis are associated with
glomerulonephritis. Early onset of chronic renal failure in patients transplanted for
chronic hepatitis C infection may be due to cryoglobulinemia-associated
glomerulonephritis.
Key facts are:
The majority of recipients demonstrate decreased renal function within
months of liver transplantation.
Serum creatinine concentrations > 1.6 mg/dl (140 mmol/l) are found in
over 75% of liver transplant recipients after 3 years of follow up.
The progression to end-stage renal failure is predicted by significant renal
impairment as early as one year after liver transplantation.
Between 4% and 10% of liver allograft recipients develop end-stage kidney
failure by 10 years. Post liver transplant diabetes mellitus, hypertension
and viral hepatitis may all increase the risk of progression to end-stage
renal disease. Mortality has been shown to be higher in post-liver transplant
patients whose renal failure progresses to the point of requiring dialysis.
Pathogenesis: Post liver transplant renal insufficiency is a direct consequence of
calcineurin inhibition. Acute elevation of serum creatinine is frequently the result of
calcineurin inhibitor toxicity and responds to dose reduction. Chronic elevations in
serum creatinine rarely return to normal levels after reduction of calcineurin inhibitor
doses. Kidney biopsy in liver transplant recipients with sustained reduction in GFR
shows interstitial fibrosis and patchy glomerular loss and hypertrophy of unaffected
glomeruli.
Clinical Management: The goals of therapy are to
Minimize the use of calcineurin inhibitors. If renal failure persists despite
reducing calcineurin inhibition, consider switching to alternative
immunosuppressive therapy.
Avoid other nephrotoxic drugs
Control hypertension
Control diabetes mellitus
Renal transplantation is appropriate in established renal failure arising after liver
transplantation.
99
Osteoporosis and Osteopenia

Prevalence: Chronic liver disease is associated with osteopenia due to low bone
turnover.
Risk factors:
Chronic cholestasis
Female gender
Older age
Cessation of menses
Cigarette smoking
Poor dietary calcium intake
Alcoholism
Calcineurin inhibitors
Maternal history of fracture
Key facts are:
Bone turnover is greatly increased after transplantation due to excessive
osteoclastic activity. Cyclosporin and tacrolimus increase osteoclastic
activity and bone turnover. Corticosteroids reduce new bone formation.
Bone loss increases rapidly over the first 3 months following liver
transplantation. Z-scores (number of standard deviations from the normal
mean), a marker of bone mineral density, commonly reach -2 standard
deviationsthe range for osteoporosis. Each standard deviation decrease
in bone mineral density is associated with a 1.5 2.8 fold increase in the
risk of hip fracture in post-menopausal women.
Atraumatic vertebral fractures have been reported in up to 30% of liver
transplant recipients within the first 6 months of transplant. Bone density
tends to improve over the first post-liver transplant year approaching pretransplant levels, but remains below that of the general population.
Clinical Management: Spontaneous fractures are a late sign of bone loss, therefore,
management focuses on screening and prevention.
Patients should be screened pre-transplant for osteopenia by (dual energy x-ray
absorption) DEXA scan, or early post-transplant
Medication:
Those with osteopenia z-scores between -1 and -2 should be treated with
calcium (1g per day) and vitamin D (400 iU/ day) supplementation.
Those with z-scores less that -2 should receive bisphosphonates in addition
to the calcium and vitamin D supplementation.
Other measures:
Weight bearing exercise (e.g., walking) and strength training in conjunction
with calcium and vitamin D supplementation decrease the rate of bone
loss in post-menopausal women.
It is advisable to recheck bone mineral density 1 year after transplantation. In
patients with z-scores greater than -1, repeat DEXA can be deferred for about 5
years.
100
Malignancy
The risk of malignancy is increased in liver transplant recipients.
Post-Transplant Lymphoproliferative Disorder

PTLD is discussed in Chapter 7.
Skin Cancer
Prevalance: skin cancer is the most common cancer after liver transplantation. It
tends to behave more aggressively than in the non-transplant patient. Over 5% of
cases are metastatic. This compares to <1% for the general population. The relative
risks of individual immunosuppressive medicines either alone or in combination
remain unknown.
The prevalance of Kaposis sarcoma is also increased in solid-organ transplant
recipients although less strikingly than in the HIV-positive population. Human herpes
virus-8 (HHV-8) has been implicated in Kaposis sarcoma in both immunosuppressed
and immunocompetent individuals.
The increase in non-melanomatous skin cancer seen in liver transplant recipients
seems to be largely due to increased prevalence and activity of human papilloma
virus (HPV) in the immune-suppressed host.
Education is key. All transplant recipients should be informed of their
increased risk of skin cancer.
Avoidance of sun: They should be educated in sun-protective practices,
including minimising sun exposure between 10:00 and 16:00, the use of
protective clothing and broad brimmed hats, and the use of sun-screen
and lip-balm with a sun protection factor of 15 or higher.
Self-examination: Patients should be encouraged to examine their skin.
They should also have a formal skin inspection at least annually and should
any suspicious lesions be seen, these should be referred to a dermatologist
for further evaluation.
Oral Cancer
Oral cancer is associated with smokeless tobacco, alcohol consumption
and sun exposure.
Both EBV and HPV are associated with hairy leukoplakia, which can be
seen as feathery appearing plaques on the tongue or buccal mucosa.
Macroscopically they are indistinguishable from pre-malignant leukoplakia
and should be biopsied.
Erythroplakia a red hyperplastic area of mucosa is a pre-malignant
condition
Carcinoma of the Uterine Cervix

Prevalence: The prevalence of cervical intraepithelial neoplasia in transplant recipients is approximately 5-fold that of immunocompetent controls. 75-93% of
cervical cancers or carcinomas in-situ are associated with HPV.
101
Clinical Management: all female liver transplant recipients over the age of 18
years who are sexually active should undergo annual cervical smear cytology tests.
Patients with cervical dysplasia or carcinoma in situ should be referred to a
gynecologist. The role of reduced immunosuppression as part of a treatment plan
for cervical carcinoma in situ or cervical carcinoma is uncertain
Other Cancers
Liver and other transplant recipients are at increased risk of cancer of the vulva
and perineum, anal cancer, hepatobiliary tumours and colon cancer. Routine screening
is important, and physicians should maintain a high index of suspicion for cancer
development in liver transplant recipients.
Infections After Recovery from Liver Transplantation

Infection accounts for 15-20% of deaths in long-term liver transplant survivors.
Viral infections: viral infection with CMV, EBV, HPV-6, VZV and
parvovirus B19 tend to occur within 3 months of transplant, but may
occur later. Patients seronegative for varicella zoster, who are exposed to
varicella should receive immunoglobulin. The development of primary
Varicella zoster infection should be considered a medical emergency in
the post-transplant patient and intravenous acyclovir (10 mg/kd) should
be started immediately
Tuberculosis
Tuberculosis occurs in <1% of patients at any time after liver transplantation.
The risk of disseminated tubercular disease (25%) and of death (20%) is much
greater among solid organ recipients than for the general population.
Diagnosis is made by a combination of staining for acid fast bacilli, culture of
the organism, histopathology and tuberculin skin testing.
Treatment with standard therapy is problematic.
Isoniazid: There is a high rate of hepatic dysfunction (33%) particularly
with Isoniazid use
Rifampicin induces cytochrome P450 3a, and thereby greatly accelerates
metabolism of cyclosporin and tacrolimus. Despite careful monitoring of
levels, rejection is a common occurrence (30-50%) in liver transplant
recipients receiving rifampicin in conjunction with cyclosporin.
Conversely, there is a risk of cyclosporin or tacrolimus toxicity when the
dose of rifampicin is reduced or withdrawn
Other drugs: Due to the high toxicity with conventional therapy, an
alternative approach using ethambutol and ofloxacin as maintenance
therapy has been suggested. Although promising, this regimen has not
yet been widely tested
Vaccinations
Immunosuppressed patients should not be given live or attenuated vaccines (Table
3) See also Table 2, Chapter 4.
102
Table 3. Live and attenuated vaccines

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

in Liver Transplant Recipients
Insomnia
Early post-operative insomnia is related to corticosteroids and/or calcineurin

inhibitor. Patients frequently feel hyperalert and have difficulty achieving a sufficiently relaxed state in which to sleep. Postoperative pain, especially right posterior
rib pain (which can last several months), and adjustment to the transplant compound the problem. Most patients respond to reassurance and analgesia. Relaxation
exercises and good sleep practices may also help.
Lassitude
Tiredness is a common complaint after liver transplantation and may have many
contributing factors including medications. Recurrence of chronic hepatitis C is
often associated with lassitude. Lassitude may be a manifestation of depression.
Cosmetic Concerns
Hirsutism: may be due to cyclosporin and exacerbated by nifedepine or corticosteroids. Treatment is switching to tacrolimus.
Gum hypertrophy: may be caused by poor dental hygiene and cyclosporin and is
exacerbated by nifedepine.
Acne: Corticosteroids can cause acne. Fortunately this tends to improve with
dose reduction and with time.
Cutaneous warts: are more common in transplant recipients, affecting 25%90% of recipients. They tend to be quite exuberant and difficult to treat. Flat warts
may become the site of future squamous cell carcinoma.
Musculoskeletal Pain
Back pain particularly over the right posterior ribs can persist for many months
post-liver transplant. Its persistence and severity surprises many patients and
103
reassurance is in order. Simple analgesia can be used. Other more focal, severe or
persistent musculoskeletal pains should raise the suspicion for osteoporosis with
secondary fracture, especially of the vertebrae, osteonecrosis particularly of the hip
joints and osteomyelitis or abscess.
Seizures
New seizures occur most commonly within the first post-operative week and are
related to intraoperative metabolic changes, calcineurin inhibitor toxicity, central
pontine myelinolysis, intracranial bleed or infection. Seizures occurring in the later
weeks following liver transplant are less likely to be due to electrolyte disturbance or
central pontine myelinolysis and drug toxicity and infection are more of a concern.
Investigations: neurological examination for focal deficits, biochemical testing
for electrolyte disturbances, including hypomagnesemia and cyclosporin or tacrolimus
levels, blood count and coagulation profile to check for coagulopathy or infection,
computed tomography (CT) or magnetic resonance imaging (MRI) of the head for
space-occupying lesions and an examination of the CSF to rule out bacterial or
opportunistic infection in the immunocompromised host. Both cyclosporin and
tacrolimus can cause diffuse white matter changes which are seen on MRI more
readily than on CT.
Management focuses on correction of underlying metabolic or infectious problems
and the use of anticonvulsant agents. Consideration must be given to the risk of
interactions between immunosuppressive agents and anticonvulsants.
Headache
Headache and tremor are common complaints. Milder headaches, often associated
with tremulousness, are usually due to calcineurin inhibitor toxicity. An exacerbation
of previously existing migraine headaches may also occur due to cyclosporin or
tacrolimus.
Evaluation consists of examination to rule out focal neurological deficits, screening
for cyclosporin or tacrolimus toxicity or metabolic disturbances, and CT or MRI to
rule out space occupying lesions.
Treatment: simple analgesia and where possible reduction in the calcineurin
inhibitor doses. Where headaches are severe, narcotic analgesia may be required.
Anti-depressants, calcium channel blockers and -blockers have also been used with
varying success. Migraine may respond to sumatriptan, although systemic
hypertension may limit its use.
Fine Tremor
Fine tremor is common in the liver transplant recipient. It is related to calcineurin
inhibitor use and may respond to lowering of the dose.
Psychiatric disturbances such as short-term anxiety, depression or adjustment
disorders are common after liver transplant. Less commonly they represent an atypical
presentation of an organic syndrome for example, drug toxicity or infection. Liver
transplant recipients with a history of addiction should be monitored for evidence
of relapse. Prompt referral to substance abuse services may be helpful.
104
Pregnancy and Reproductive Health
Menstrual function: Recovery of menstrual function in pre-menopausal females

and of andrological function in males occurs after liver transplantation. Menses
typically resume within a few months of transplantation.
Preconception management: Most centers advise waiting 1-2 years after liver
transplantation before becoming pregnant. Barrier or oral contraception should be
considered during this period. The 1-2 year delay allows for the patients to fully
recover from the transplant, for opportunistic infection prophylaxis to be discontinued
and for immunosuppression to be reduced.
Conception should be planned when graft function is stable and good. Some
immunosuppressant drugs are teratogenic (see Chapter 6). The immunosuppressive
regime may be modified to avoid these drugs. Due to the increased prevalence of
both maternal and fetal complications, these are high-risk pregnancies and should
be closely monitored by both the transplant and obstetrical teams.
Pregnancy: Data from the National Transplant Pregnancy Registry (NTPR),
record 2017 pregnancies in 732 women or fathered by 603 men who were recipients
of solid organ transplants (See Armenti VT, Wilson GA, Radomski JS, Moritz MJ,
McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy
Registry (NTPR): outcomes of pregnancy after transplantation. Clinical Transplants
1999;111-119.) No pattern of congenital anomaly has been noted. Of the 175 offspring studied all of whom are children of female kidney transplant recipients, 76%
were live born, 14% suffered spontaneous abortion and 10% were still-born, ectopic
pregnancies or electively aborted. There was no significant developmental delay in
84% of the children, but 3 children (1.7%) had major disabilities. In 72 female liver
transplant recipients, 119 pregnancies were associated with 91 (76%) live births.
This compares with the general population wherein 10% of pregnancies are lost
before 20 weeks with late fetal loss of approximately 0.5%. It is likely that there is
underreporting of early pregnancy loss in the NTPR. 37% of live born children
were premature (<37 weeks gestation) and 32% were low birth weight (<2500g).
Regarding the health of the expectant mother, the risk of acute cellular rejection
in the pregnant liver transplant recipient seems to be increased, either occurring
during pregnancy or within 3 months of delivery. Acute cellular rejection was
associated with poorer fetal outcome and increased risk of recurrent rejection. 33%
of pregnant liver transplant recipients will develop hypertension, and 10-15% diabetes
mellitus. Hypertension, diabetes and infections should be meticulously managed.
Consideration should be given to stress dose steroids for mothers requiring caesarean
section.
Breast feeding: most immunosuppressive drugs are secreted in breast milk.
Consequently breast feeding should be avoided.
Lifestyle
Liver allograft recipients should be encouraged to return to a normal healthy
lifestyle, with appropriate health maintenance (see Table 5)
105
Table 5. Routine health screening of liver transplant recipients

Routine Health Screening of Liver Transplant Recipients
Disease
OLT pat
US pop
Hypertension
Every visit
Every 2 years if previously

normotensive
Renal Insufficiency Serum creatinine every visit
No recommendations
Hypercholesterolemia
At 6 months, 1 year, 2 years

and if normal every 3-5 years
thereafter.
Every 5 years in men aged

35-65 years and in women
aged 45-65 years
Diabetes mellitus
Gluc >160 on routine labs

are grounds for a formal oral
glucose tolerance test
Screening in the
asymptomatic general
population is not
recommended.
Cigarettes
Counselling on smoking
cessation
Counselling on smoking
cessation
Osteoporosis
DEXA pre-OLT (or post-OLT)
DEXA in early postmenopausal women
Breast Cancer
Self-breast exam monthly

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

Annual clinical breast exam
age 40-69, possibly longer
Mammography 50-69
Cervical cancer
Papanicolaou smear every

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

years (assuming prior smears
were normal) until age 65
Colon cancer
As for general population

annual colonoscopy for those
with history of IBD
Flexible sigmoidoscopy ever

3-5 years age 50-70 years
old, begin earlier in those at
higher risk
Prostate Cancer
Annual digital rectal exam

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

+/- prostatic specific antigen
after age 50
Skin cancer
Monthly self-exam. Annual

physician provided skin exam
Not recommended
Dental care
Routine oral hygiene (brushing

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

(brushing and flossing of
teeth)
Oral cancer
Annual exam by dentist
Not recommended
106
Selected Reading
1.
2.
3.
4.
5.
6.
Abbasouglu O, Levy MF, Brkic B, Testa G, Jeyarahaj DR, Goldstein RM et al. Ten
years of liver transplantation. Transplantation 1997; 64(12):1801-1807.
Midtvedt K, Neumayer HH. Management strategies for posttransplant hypertension. Transplantation 2000; 70(11):SS64-SS69.
Feller RB, McDonald JA, Sherbon KJ, McCaughan GW. Evidence of continuing
bone recovery at a mean of 7 years after liver transplantation. Liver Transplantation and Surgery 1999; 5(5):407-413.
Otley CC, Pittelkow MR. Skin cancer in liver transplant recipients. Liver Transplantation 2000; 6(3):253-262.
Meyers BR, Papanicolaou GA, Sheiner P, EMRe S, Miller C. Tuberculosis in orthotopic liver transplant patients: increased toxicity of recommended agents; cure of
disseminated infection with nonconventional regimens. Transplantation 2000;
69(1):64-69.
Armenti VT, Wilson GA, Radomski JS, Moritz MJ, McGrory CH, Coscia LA.
Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes
of pregnancy after transplantation. Clinical Transplants 1999:111-119.
Pediatric Liver Transplantation
107
CHAPTER 10

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

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

of Liver Transplantation
Children with acute or chronic liver disease will often come to transplantation
for indications similar to those seen in adults, including fulminant liver failure,
complications of cirrhosis, portal hypertension, variceal bleeding, encephalopathy.
Health care providers for children should be aware of the consequences of liver
disease that are specific to the pediatric population and indicate the need for early
listing for transplantation:
-Growth and nutrition:
Growth failure is a significant complication of liver disease
Liver Transplantation, edited by Michael Lucey, James Neuberger and Abraham Shaked.
10
108
Table 1. Primary diagnosis of 395 children undergoing liver transplantation

Primary Diagnosis
Number of
Patients
Percentage
Biliary atresia
Metabolic diseases (all types)
Alpha-1-antitrypsin deficiency
Tyrosinemia
Wilson disease
Glycogen storage disease
Cystic fibrosis
Other
Fulminant hepatic failure
Cryptogenic cirrhosis
Familial cholestatic syndromes
(Alagille syndrome, Byler
syndrome, etc.)
Chronic active hepatitis
(infectious, autoimmune)
Primary sclerosing cholangitis
Neonatal hepatitis
Biliary obstruction
Tumors
Miscellaneous
187
78
46
12
9
5
4
2
21
17
16
47
19
12
3
2
1
1
<1
5
4
4
10
9
8
3
11
13
2
2
<1
3
3
Data were compiled from published and personal series.
10
Children with otherwise compensated cirrhosis may have poor weight
gain and/or linear growth often followed by declining school performance
or cognitive development.
If malnutrition cannot be reversed with supplemental tube feedings or
other interventions, liver transplantation should be performed as soon as
possible.
Due to the serious nature of growth failure and resulting developmental
and cognitive delay in children, these findings qualify a child for higher
UNOS listing status for transplantation.
-Hepatic encephalopathy:
Encephalopathy must be evaluated in an age-appropriate manner and
therefore experience in assessing pediatric cognitive skills and
developmental milestones is of critical importance.
Ammonia levels correlate very poorly with degree of encephalopathy.
-Metabolic Diseases:
Metabolic diseases causing primary hepatic injury are as a group, a common
indication for liver transplantation in childhood. Children may also benefit
from special exceptions to standard listing criteria in these cases if additional
end organ or malignant risks are involved. Diseases in this category include
tyrosinemia, cystic fibrosis and alpha-1-antitrypsin deficiency, for example.
109
Tyrosinemia is a disorder of tyrosine metabolism caused by deficiency of

fumarylacetoacetate hydrolase (FAH). The enzyme defect results in injury
to multiple organs via the generation of abnormal metabolites. In the
liver, the primary site of tyrosine metabolism, the block of tyrosine catabolism produces a large variety of toxic intermediates that result in a
range of phenotypes extending from neonatal fulminant hepatic failure
to chronic relapsing liver disease. In all forms of disease, there is a sharply
increased rate of hepatocellular carcinoma, estimated at 13 37% in
various studies, occurring even as young as 2 years of age. Medical therapy
comprised of dietary restrictions and supplements designed to redirect
the formation of toxic intermediates has been very successful in stabilizing
liver function, however development of hepatocellular carcinoma is still a
problem. Liver transplantation restores liver function, reduces extrahepatic
organ injury, and normalizes the hepatocellular cancer risk to that of the
general transplant population.
Metabolic diseases with primarily extrahepatic manifestations may be cured
by liver transplantation despite otherwise normal hepatic function. These
diseases are accepted indications for liver transplantation and area eligible
for exception status within the UNOS system. Children with urea cycle
defects, Crigler-Najjar syndrome type I, or primary hyperoxaluria, for
example, have automatic exceptions to standard listing practices.
Inborn errors of the urea cycle (for example ornithine transcarbamylase
deficiency) lead to recurrent hyperammonemia and irreversible brain
injury, despite aggressive medical therapy. Liver transplantation is curative;
standard listing criteria are inappropriate, as all other hepatic functions
are normal.
Crigler-Najjar syndrome: CNS injury from unconjugated
hyperbilirubinemia is virtually unavoidable in Crigler-Najjar syndrome
type I despite medical therapies.
Primary hyperoxyluria is an inborn error producing oxylate crystals
throughout the body that ultimately causes renal failure and cardiac
arrhythmia. Early liver transplantation can prevent renal failure and
preclude the need for combined renal and hepatic transplantation.
PELD
The MELD system used for allocation of livers to adults in the United States has
been modified for children; the following variables are assessed:
Age at listing
Albumin
Bilirubin
INR
Growth failure (based on gender, height and weight)
The score for an individual patient can be calculated on the UNOS website
(www.unos.org). In addition to this scoring system, UNOS policy has several
10
110
advantages for pediatric recipients. The pediatric advantages were granted in response to concern that the small number of children waiting for liver transplant
would be overwhelmed by the huge number of adults with equivalent higher scores,
causing increases in deaths and lengthy waiting times. Lengthy waiting time has a
disproportionate negative effect on young infants and children due to the impact of
chronic liver disease on physical, cognitive and social development. For these reasons,
pediatric donors (donors under 18 years of age) are offered to pediatric recipients at
an equivalent status or score before potential adult recipients. Furthermore, standard
UNOS exceptions exist for specific metabolic diseases, and additional exceptions
may be granted by the regional review boards of UNOS on request.
Pre-Operative Management
10
Medical therapy to correct metabolic abnormalities, coagulopathy, ascites,

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

donors for infants and young children limited the application of
transplantation to pediatric patients. Although the death rate on the waiting
list remains significant for children, the risk of dying whilst waiting for a
liver allograft has considerably improved for pediatric patients as shown
in data in Table 2.
Innovative surgical techniques including reduced-size liver grafts, split
and living related grafts has resulted in dramatic improvements in organ
procurement for even very small infants and waiting times and deaths
have been proportionately reduced. The surgical aspects of these forms of
transplant operation are discussed in Chapter 5.
Biliary atresia
111
Table 2. Deaths awaiting OLT in 1990, 1995 and 1999

Age of candidate:
< 1 year
1-5 years
6-10 years
11-17 years
1990
1995
1999
268/34/540
337/45/359
548/54/234
265/17/197
389/23/132
425/22/92
100/7/212
208/5/51.6
254/7/48
161/18/455
287/14/110
454/22/80
Data are shown as Patients listed/Deaths/Death rate per 1000 patient years at risk.
(Adapted from the UNOS web-site: www.unos.org)
- Biliary atresia is the result of an inflammatory/obliterative process of the

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

The immediate post-operative management of pediatric liver graft recipients is
directed toward continued support of liver function, critical care issues and detection of early surgical complications.
Vascular problems: small children and infants are particularly at risk for
vascular thromboses so the routine includes frequent Doppler ultrasound
to evaluate flow. Pediatric recipients are routinely treated with intravenous Dextran to prevent thromboses in the peri-operative period and
10
112
then receive oral aspirin for 1 year after transplantation.

Bile leaks: Reduced size, living related or split liver grafts have increased
risk of bile leak and/or bleeding from the cut surface.
Nutrition: Feeding can be difficult in small children and infants with
midline liver placement and short term trans-pyloric tube feeding may be
needed.
Immunosuppression: in general immunosuppressive management is
similar to that in adults, although the arguments for restricting
corticosteroids is even greater. Drug dosages need be considered for the
childs weight.
Subsequent Management
10
This is similar to that of adult recipients in terms of monitoring for and

management of changes in liver function, rejection, late biliary complications and
infections, but there are a few important exceptions.
Nutrition is again of utmost importance in recovery and rehabilitation,
though a standard formula can generally replace the specialized feedings
used pre-transplant. Very young children and infants who received tube
feedings pre-transplant often have delayed oral-motor development and
may require feeding therapy in order to accept oral feedings.
Occupational or physical therapy may be necessary for children and infants
with a lifetime history of chronic liver disease. Older children generally
recover very quickly and are eager to return to school and normal activities,
often much faster than their adult counterparts return to work.
Infections: Prophylaxis and surveillance for viral infections, particularly
in those young children who did not have primary infections with EBV
and CMV pre-transplant, is an ongoing issue.
- EBV nave children undergoing liver transplant are at high risk of developing chronic EBV infection and post transplant lymphoproliferative disease if the primary EBV infection occurs on immunosuppression. The
use of new quantitative PCR analysis for EBV has improved the monitoring for EBV activity. PTLD is discussed in Chapter 7. In addition to the
standard reduction or elimination of immune suppression and addition
of ganciclovir or acyclovir antiviral therapy.
- CMV negative children will often receive CMV positive grafts (especially if they receive a partial graft from an adult donor) and are at risk of
CMV infection.
- Exposure to other childhood viral illnesses is an ongoing issue for these
children; varicella exposure for example is a frequent occurrence. Children should be vaccinated for varicella prior to transplant, however the
vaccine is less effective if given under 1 year of age. Varicella antibody
negative children should receive varicella immune globulin within 48
hours of known exposure (ideally within 12-24 hours) and are treated
with intravenous acyclovir if clinical chicken pox develops. Even after an
episode of clinical infection most of these children will not develop anti-
113
bodies and they are therefore at risk for repeated infection with subsequent exposures.
- Live vaccine administration to immunosuppressed transplant recipients
is controversial, with standard recommendations against immunization.
Even in those centers where MMR and/or varicella immunizations are
given post transplant, reduced response to vaccination is observed.
Compliance: Compliance with medical therapy is a major issue with teenage liver graft recipients especially those transplanted in infancy or early
childhood. Many of these teenagers do not remember their transplant
experience and are entering a time of personality turbulence, testing of
limits, and have acquired a general sense of invulnerability that extends
from the usual adolescent risk taking (experimentation with drugs of abuse,
exploration of sexuality) to failure to take medications. The response to
this behavior must be tailored to the individual child and family and
must take into account the social and cultural background. Parents, social
workers, school guidance counselors and other resources are important
partners in the effort to sustain delivery of medical care through
adolescence.
The adolescent patient: Children entering adolescence experience a variety of
endocrinologic, physical and psychosocial changes. In most cases these young adults
will be best served at a pediatric center but care should be transitioned to an adult
transplant center when medically and psychosocially appropriate.
Suggested Reading
1.
2.
3.
4.
5.
6.
7.
8.
Kogan-Liberman D, EMRe S, Shneider BL. Recent advances in pediatric liver

transplantation. Current Gastro Reports 2002; 4(1):84-97.
Emre S. Living-donor liver transplantation in children. Pediatric Transplantation
2002; 6(1):43-46.
Bucuvalas JC, Ryckman FC. Long-term outcome after liver transplantation in children. Pediatric Transplantation 2002; 6(1):30-36.
Shneider BL. Pediatric liver transplantation in metabolic disease: Clinical decision
making. Pediatric Transplantation 2002; 6(1):25-29.
McDiarmid SV. Management of the pediatric liver transplant patient. Liver Transplantation 2001; 7(11suppl 1):S77-S86.
Emond JC, Whitington PF, Thistlewaite JR et al. Transplantation of two patients
with one liver: analysis of a preliminary experience with split-liver grafting. Annals of Surgery 1990; 212(1):14-22.
McDiarmid SV, Gornbein JA, Desilva PJ et al. Factors affecting growth after pediatric liver transplantation. Transplantation 1999; 67(3):404-411.
Gloss JA, Shackleton CR, McDiarmid SV et al. Long-term results of pediatric liver
transplantation: An analysis of 569 patients. Annals of Surgery 1998;
228(3):411-420.
10
114
Index
Acetaminophen 30-33
Acne 67, 102
Acute cellular rejection (ACR) 5, 8,
11, 12, 14, 16, 47, 60, 71, 74-77,
86, 104
Acyclovir 63, 79, 81, 101, 112
Addiction 28, 29, 41, 92, 103
Alcoholism 27, 29, 41, 92, 99
Alloimmune response 5, 7, 9
Alpha feto protein (AFP) 25, 39
Alpha-1-antitrypsin deficiency 108,
109
Amyloidosis 90, 91
Anergy 12-15
Angina pectoris 22
Angiotensin converting enzyme (ACE)
63, 96
Angiotensin II 96
Antibody dependent cellular cytotoxicity (ADCC) 13
Antigen presenting cells 5, 15
Apoptosis 11, 14, 15, 64
Argon beam coagulatorargon beam
coagulator 54
Autoimmune hepatitis 28, 34, 64, 78,
89, 93, 98
Azathioprine (AZA) 12, 13, 61, 63,
68, 72, 79, 90
B
B-cells 5-8, 11, 12, 14
Basiliximab 12, 71
Biliary atresia 4, 109, 110, 111
Biliary cast syndrome 83, 84
Biliary leaks 74, 83, 84
Bone densitometry 27
Breast feeding 72, 104
Burkholderia cepacia 23
C
Calcineurin 12, 63, 64, 66, 68, 69, 72,
86, 95-98, 102, 103
Calcium 27, 64, 96, 97, 99, 103
CBD 44, 45, 50, 53
CD antigen 14
CD28 9, 15
CD3 8, 9, 12, 14, 68
Celiac sprue 28, 34
Central pontine myelinolysis 38, 103
Cerebral edema 29, 32
Cervical cancer 100
Cervical carcinoma 101
Chemoembolization 39
Chemokine 10, 15
Child-Pugh classification 17, 18
Cholangiocarcinoma 20, 26, 33, 39,
92
Cholangiogram 57, 59, 111
Cholestipol 20
Cholestyramine 20, 27, 63
Chronic ductopenic rejection (COPD)
11, 12, 15, 22, 34, 71, 74, 76-79,
84
Chronic obstructive pulmonary disease
22
Ciprofloxacin 38
Cirrhosis 3, 4, 18, 19, 27, 30, 33, 34,
36, 39, 41, 79, 86-88, 90, 93, 98,
107-109, 111
Co-amoxyclav 38
Co-stimulation 7
Coagulopathy 19, 29, 37, 74, 103,
110
Colon cancer 26, 33, 39, 101
Common bile duct 44, 50, 53, 57
Complement 11, 13
Cotrimoxazole 38
Creatinine 18, 24, 33, 38, 57, 67, 98
Crigler-Najjar syndrome 90, 107, 109
Cryoglobulinemia 98
Cryotherapy 39
Cryptogenic cirrhosis 34, 93, 109
CSA 13
CTLA-4 15, 63
Cutaneous warts 102
Cyclosporin 12, 13, 63-69, 71, 72, 76,
97, 99, 101-103
Cyclosporine 69
Cystic duct 49, 53, 57
Cystic fibrosis 23, 90, 107-109
Cytokine 7, 9-12, 15, 64, 66, 68
Cytomegalovirus (CMV) 27, 30, 40,
68, 72, 74, 76, 78, 79, 82, 86,
101, 110, 112
Cytotoxic T lymphocyte CTL) 14, 15
Daclizumab 12, 71
Deletion 12, 13
DEXA scan 99
Diabetes insipidus 42
Diabetes mellitus 25, 65, 67, 72, 95,
97, 98, 104
Diltiazem 66, 96
Direct antigen recognition 8
Diuretics 23, 24, 38, 97
Halothane 30, 32, 33

Headache 64-68, 103
Hemochromatosis 33, 90, 91
Hemochromatosis gene test 33
Hemorrhagic necrosis 34, 74
Heparin 44, 46
Hepatic artery stenosis 83
Hepatic artery thrombosis (HAT) 34,
69, 74, 79, 81-83
Hepatic osteodystrophy 20
Hepatitis A virus (HAV) 32, 41, 88
Hepatitis B immunoglobulin (HBIg)
33, 88
Hepatitis B virus (HBV)
32, 33, 41, 72, 74, 87, 88,
110
Hepatitis C virus (HCV) 2, 23, 30,
33, 39, 41, 72, 74, 86, 87, 89,
93, 97, 98, 102
Hepatitis D virus (HDV) 33, 78, 88,
93
Hepatoblastomas 26
Hepatocellular cancer 20, 21, 109
Hepatopulmonary syndrome 19, 23,
34
Herpes simplex virus 27
Heterotopic auxiliary transplants 32
HFE 33
HHV-8 100
Hirsutism 64, 102
HMG CoA-reductase inhibitors 97
HPV 100, 101
HPV-6 101
HSV 27, 41, 74
Human herpes virus-8 100
Human immunodeficiency virus (HIV)
20, 26, 42, 57, 100
Human papilloma virus 100
Hydrocortisone 46, 62
Hyperacute rejection 2, 11
Hyperhomocysteinemia 95
Hyperkalemia 64, 97
Hyperlipidemia 34, 67, 69, 95, 97
Hypertension 18, 20, 22, 23, 36-38,
41, 42, 63-65, 67, 68, 83, 95-98,
103, 104, 107, 111
Hypoalbuminemia 24
Hypomagnesemia 97, 103
E
Ebstein-Barr virus 27
EBV 27, 40, 73, 74, 79, 80, 81, 100,
101, 110, 112
Etidronate 27
Extended criteria donors 46
Extended use organs 2
Extracorporeal perfusion 32
F
Factor V 32
FAH 109
Fas 11
Fibrosing cholestatic hepatitis 86
FK506 13
FK506 binding protein 13
FKBP 13, 66
Foscarnet 79
Fulminant hepatic failure 20, 29-33,
34, 79, 109
Fumarylacetoacetate hydrolase 109
G
Gadolinium angiography 28
Gallbladder 44, 53, 54, 57, 59
Ganciclovir 79, 81, 112
Gentamicin 38, 66, 72
Glomerulonephritis 72, 98
Glucocorticoids 12, 63, 64
Glypressin 23
Graft versus host disease (GVHD) 15
Granzymes 11
Gum hypertrophy 64, 102
Index
115
Index
116
Hyponatremia 38
Index
IBD 33
Immunoglobulin superfamily 11
Impotence 25
Inflammatory bowel disease 33
Innate immunity 16
Insomnia 63, 102
Insulin resistance 25, 34, 97
Integrins 11
Interferon 87
Interleukin-2 (IL-2) 7, 9, 12, 64, 66,
67, 71, 79
Interleukin-4 (IL-4) 7, 9, 66
Interleukin-6 (IL-6) 7, 9
Ischemic hepatitis 30
Isoniazid 26, 30, 72, 101
K
Kasai procedure 111
Kidney transplantation 24
L
Lamivudine 33, 88, 93
Lassitude 102
Lethargy 19
Live donor right lobe recipient
operation 59
Live liver donation 20, 21
Living donation 2, 57
Lymphoma 30, 73, 80, 81
M
Macrophages 5-7, 10, 11, 14
Magnetic resonance (MR) 25, 28, 33,
39, 41, 57, 82, 83, 89, 93, 103,
110, 113
Major histocompatibility complex
(MHC) 5-9, 11, 13-16, 86
Malabsorption 27, 28
Mammography 26, 39
Marginal donors 2
MELD score 17, 18
Menstruation 25
Midodrine 23
Molecular mimicry 8
Musculoskeletal pain 102, 103
Mycophenolate 12, 13, 68, 72, 97
Mycophenolate mofetil 12, 13, 97
Myocardial infarction 22
N
Nadalol 36
Naltrexone 20
NASH 34, 74, 93
Nephrotic syndrome 24
Neuroendocrine tumors 26, 93
Niemann-Pick disease 90
Nifedipine 96
NK cells 11
Non-alcoholic fatty liver disorder
(NAFLD) 34, 93
Non-alcoholic steatohepatitis 34
Non-heart beating donors 2, 42, 84
Non-heart-beating donors 46
Non-steroidal anti-inflammatory agents
38
Norfloxacin 38
O
Obesity 34, 95, 97
OKT-3 12
Oral cancer 100
Ornithine transcarbamylase deficiency
107, 109
Orthoclone 14
Osteopenia 36, 99
Osteoporosis 65, 99, 103
P
Palmidronate 27
Pancreatitis 28, 34, 63, 92
Pap smears 39
Parvovirus B19 101
PELD 20, 109
Perforins 11
Peritonitis 19, 36, 37
Phenytoin 20, 32, 66
Plasmapheresis 20
Porcine endogenous retrovirus (PERVs)
2
Portal hypertension 18, 23, 36-38, 83,
107, 111
117
Index
R
Radiofrequency ablation 39
Rapamycin 12, 63, 66, 69
Renal function 23, 24, 28, 57, 97, 98
Retransplantation 3, 4, 34, 35, 54, 72,
76, 83, 84, 86
Ribavirin 87
Rifampicin 65, 66, 101
Rifampin 20
Right lobe living donor operation 57
Roux-en-Y hepatico-jejunostomy 55
S
Seizures 68, 103
Selectins 11
Sirolimus 12, 63, 66, 67, 69-72, 97
Skin cancer 20, 80, 97, 100
Somatostatin 23
Split liver grafts 47, 112
Spontaneous bacterial peritonitis (SBP)
19, 36, 37, 38
Statins 66, 97
Steatosis 57
Stent thrombosis 37
Steroid resistant rejection 76
Subacute hepatic necrosis 31
Subfulminant hepatic failure 29, 30
Suppression 3, 12, 16, 20, 60, 61, 63,
66, 68, 70-73, 76, 78, 79, 81, 86,

89, 90, 95, 97, 101, 104, 112
T
T helper 7, 14-16
T-cell receptor 5-9
T-cells 5-8, 11-13
T-tube 53, 83, 84
Tacrolimus 12, 13, 63-67, 71-73, 76,
89, 97, 99, 101-103
Target of rapamycin (TOR) 63, 66
TCR 8, 14, 15, 16
Th lymphocytes 7
Th1 and Th2 paradigm 7
Th2 paradigm 7
Thyroid disease 25
Tobacco products 23
Tolerance 7, 12, 14, 16, 30, 60, 87,
104
Transjugular intrahepatic portosystemic shunt (TIPS) 23, 37,
56, 57
Tremor 63, 64, 66, 67, 103
Trimethoprim 38
Tuberculosis 26, 72, 101
Tyrosinemia 30, 90, 108, 109
U
Ulcerative colitis 26, 39
UNOS 20, 25, 108-110
Ursodeoxycholic acid 20, 89
V
Vaccinations 40, 101, 103, 110
Vanishing bile duct syndrome 12, 71,
76
Variceal hemorrhage 19, 36, 37, 41,
111
Varicella zoster 101
Verapamil 66, 96
Vertebral fractures 99
Vitamin A 27
Vitamin D 27, 99, 110
Vitamin K 27
VZV 74, 101
X
Xenotransplants 2
Index
Portal vein thrombosis 36, 55, 83

Portal venous bypass 50
Porto-pulmonary hypertension 22, 23
Post-transplant lymphoproliferative
disorders (PTLD) 80, 100, 112
PPD 26
Pregnancy 30, 67, 68, 72, 104
Primary biliary cirrhosis 18, 19, 34,
79, 88, 98
Primary graft non-function 2, 74
Primary hyperoxaluria 109
Primary sclerosing cholangitis 19, 33,
34, 79, 89, 109
Propranolol 36
Prostatic specific antigen 26, 40
Protoporphyria 90
PSA 26, 40
Psychological assessment 28
Purified protein derivative 26
LANDES
BIOSCIENCE
V ad e me c u m
LANDES
BIOSCIENCE
V ad e me c u m
Table of contents
1. Liver Transplantation:
An Overview
2. The Allograft Immune
Response
9. Medical Management of the

Liver Transplant Patient
10. Pediatric Liver Transplantation
3. Assessment for Liver

Transplantation
Liver
Transplantation
4. Management on the Liver

Transplant Waiting List
5. The Liver Transplant
Operation
6. Immunosuppression after
7. Graft Dysfunction
8. Recurrence of Disease after
The Vademecum series includes subjects generally not covered in other handbook
series, especially many technology-driven topics that reflect the increasing
influence of technology in clinical medicine.
The name chosen for this comprehensive medical handbook series is
Vademecum, a Latin word that roughly means to carry along. In the Middle
Ages, traveling clerics carried pocket-sized books, excerpts of the carefully
transcribed canons, known as Vademecum. In the 19th century a medical publisher
in Germany, Samuel Karger, called a series of portable medical books
Vademecum.
The Landes Bioscience Vademecum books are intended to be used both in the
training of physicians and the care of patients, by medical students, medical house
staff and practicing physicians. We hope you will find them a valuable resource.
I SBN 1- 57059- 682- 4
All titles available at
www.landesbioscience.com
9 781570 596827
Michael R. Lucey
James Neuberger
Abraham Shaked

Michael R. Lucey James Neuberger Abraham Shaked Liver Transplantation - Vademecum 2003

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LANDES

9. Medical Management of the

3. Assessment for Liver

4. Management on the Liver

I SBN 1- 57059- 682- 4

All titles available at

Michael R. Lucey, M.D., F.R.C.P.I.

Library of Congress Cataloging-in-Publication Data

2. The Allograft Immune Response ....................................... 5

3. Assessment for Liver Transplantation .............................. 17

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

5. The Liver Transplant Operation...................................... 42

6. Immunosuppression after Liver Transplantation ............ 60

7. Graft Dysfunction ........................................................... 74

8. Recurrence of Disease after Liver Transplantation .......... 86

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

10. Pediatric Liver Transplantation ..................................... 107

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

James Neuberger, D.M., F.R.C.P.

Abraham Shaked, M.D., Ph.D.

Geoffrey H. Haydon, M.R.C.P., M.D.

Anne Burke, M.B., B.Ch., B.A.O.

Kim M. Olthoff, M.D.

Michael Crawford, M.D.

Elizabeth B. Rand, M.D.

Liver Transplantation: An Overview

Liver Transplantation: An Overview

The Donor Organ Shortage

Liver Transplantation: An Overview

Table 1. Factors influencing the outcome of orthotopic liver transplantation

Outcome of Liver Transplantation

Table 2. Outcome of liver transplantation in the United States

Cholestatic Liver Disease 939

Acute Hepatic Necrosis

The Allograft Immune Response

The Allograft Immune Response

Recognition of Self and Non-Self

Recipient T- and B-Cell Activation

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

The Allograft Immune Response

Table 1. Characteristics of MHC molecules

Stages of Allograft Response

Antigen Presentation and Allorecognition

The Allograft Immune Response

Table 2. Th 1 and Th 2 paradigm

cell mediated cytotoxicity

IL-4, Il-5, IL-6

Leukocyte Migration into the Allograft

The Allograft Immune Response

Classification of Allograft Rejection

Acute Cellular Rejection

3. The development of graft dysfunction manifested by hyperbilirubinemia and

Chronic Ductopenic Rejection

Mechanisms of Immunosuppressive Drug Action

The Allograft Immune Response

Figure 6. Antibody mediated damage to graft endothelium. Recipient antibody binds

Figure 7. Mechanism of action of commonly used immunosuppresants. Cyclosporine

identifying a suppressor cell. Anergy occurs when T-cells encounter peptide-MHC

Acquired immunity: All immune processes utilizing immunological memory

The Allograft Immune Response

CD28: The best characterized co-stimulatory molecule. Cell surface molecule

Assessment for Liver Transplantation

Assessment for Liver Transplantation

Assessment of Severity and Prognosis