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Table of contents
1. Liver Transplantation:
An Overview
2. The Allograft Immune
Response
Liver
Transplantation
www.landesbioscience.com
9 781570 596827
Michael R. Lucey
James Neuberger
Abraham Shaked
v a d e m e c u m
Liver Transplantation
LANDES
BIOSCIENCE
GEORGETOWN, TEXAS
U.S.A.
VADEMECUM
Liver Transplantation
LANDES BIOSCIENCE
Georgetown, Texas U.S.A.
Copyright 2003 Landes Bioscience
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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
Vaccinations .............................................................................................. 40
Progression of Medical Complaints ........................................................... 41
Temporary Suspension from the Waiting List ........................................... 41
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.
Contributors
Peter Abt, M.D.
Department of Surgery
University of Pennsylvania Health System
Philadelphia, Pennsylvania, U.S.A.
Preface
The purpose of this volume is to provide a short, didactic handbook for
those clinicians (medical, surgical, nursing and others) who are involved in
the care and management of people who may, are or have undergone liver
transplantation. We are aware that there are several, large texts which
provide a comprehensive account of liver transplantation. This volume is
designed to complement and not replace them.
Liver transplantation has developed rapidly over the last two decades and
dogma is changing rapidly. This leads to controversy and debate which are
the essence of academic medicine. We are also aware that different transplant
programs have their own approach to managing patients. It is inevitable that
many views and arguments cannot be put in such a book as this one. Where
possible, we have tried to provide a consensus view. We have provided selected
references for further reading and electronic addresses to source material, for
the reader who wishes to probe deeper into any aspect of liver transplantation.
We are grateful to the authors who have contributed to this book. We
have tried to ensure a consistent style and hope the reader finds this useful
and helpful. Finally, if there are any errors or omissions, the editors would
be grateful if these could be identified, so that we may correct them in future
editions.
Michael R. Lucey
James Neuberger
Abraham Shaked
August 2002
CHAPTER 1
Liver Transplantation
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.
Liver Transplantation
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
89.4
1.1
3477
80.7
0.8
Biliary atresia
337
91.9
1.6
1549
82.1
1.2
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.
CHAPTER 2
Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked.
2003 Landes Bioscience.
Liver Transplantation
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.
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
Liver Transplantation
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.
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.
Cytokines Produced
Function
Th1
IL-12
IL-2, IFN-
Th2
IL-4
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
Liver Transplantation
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.
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).
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.
12
Liver Transplantation
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
14
Liver Transplantation
Glossary
15
16
Liver Transplantation
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.
17
CHAPTER 3
18
Liver Transplantation
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.
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
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
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
20
Liver Transplantation
21
22
Liver Transplantation
those who manifest a gradual decline, and patients with newly diagnosed small
hepatocellular cancer.
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:
Hypotension
24
Liver Transplantation
Microscopy
Microscopy of the urine may reveal nephritic sediment (red cell casts, white cell
casts).
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.
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.
26
Liver 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.
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
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
Liver Transplantation
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.
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
Liver Transplantation
Mental State
Asterixis
Findings
Electroencephalogram
I.
Slight or none
Normal
II.
Accentuation of stage I,
drowsiness, Inappropriate
behavior, loss of sphincter
control
Easily elicited
Abnormal, generalized
slowing
III.
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
32
Liver Transplantation
Criteria for determining the prognosis of fulminant hepatic failure are shown
below (Table 7).
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.
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
Liver Transplantation
or pancreatitis. Serum markers, such as CEA and CA19-9 may help but have not
the specificity nor sensitivity required.
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.
35
36
Liver Transplantation
CHAPTER 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
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
Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked.
2003 Landes Bioscience.
37
Prophylactic sclerotherapy
38
Liver Transplantation
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
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:
39
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
Liver Transplantation
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
Persistent immunity
up to 10 years.
Pneumococcus
23-valent
polysaccharide
vaccine
One dose.
Persistent immunity
up to 6 years
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
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.
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.
Suggested Reading
1.
2.
3.
4.
5.
42
Liver Transplantation
CHAPTER 5
Donor Selection
The cadaveric liver transplant begins with a donor offer from an Organ
Procurement Organization (OPO) coordinator. The information in Table 1 should
be obtained from the coordinator in each case.
The surgeon determines, based upon the donor and relevant recipient factors,
the suitability of the donor for liver procurement. Donor suitability can sometimes
only be determined intra-operatively or with a liver biopsy.
43
-Controlled
-Non-Controlled
Management
Aim
Hypotension
Transfusion, dopamine,
levo-thyroxine,
Epinephrine
Beta blockers or other
anti-hypertensives
Diuresis and oxygen
delivery
Dextrose replacement
Hypertension
Hypoxia
Diabetes
insipidus
Acidosis
Severe
instability
44
Liver Transplantation
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
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
Liver Transplantation
the pancreas is split at the neck to expose the portal vein origin. The superior mesenteric and splenic veins are then transected. The portal vein segment is passed beneath the duodenum to lie with the other hepatic structures. If there is no replaced
right hepatic artery, the nerves and lymphatic tissue lying behind the portal vein are
divided all the way to the aorta between the celiac and SMA. If there is a replaced
right hepatic artery, then it is preserved and the SMA is included in the aortic patch.
The aortic patch is completed around the celiac origin and lifted up with the other
portal structures.
Cutting across the right adrenal gland and dividing the hepato-pulmonary
ligament completes the donor hepatectomy. The liver is surrounded by University
of Wisconsin (UW) solution in a bag and then stored in ice for transportation.
The back table dissection is carried out with the liver sitting in UW solution
surrounded by ice. The coronary ligaments are first taken down exposing the
suprahepatic IVC. The diaphragm is carefully dissected off the IVC, ligating any
phrenic veins. The infrahepatic cava is dissected free, after dividing the diaphragm
between the aorta and IVC. The right adrenal vein and any other external branches
are ligated and the adrenal gland removed.
The portal vein is dissected towards the liver with ligation of any small branches
along its course until the bifurcation is seen. The PV is then cannulated with
intravenous tubing, secured and tested for leaks.
The artery is then dissected in segments from aorta towards splenic, and then
splenic towards GDA. Small branches are ligated. The splenic is left open for blowout
on reperfusion. It is leak tested, an aortic patch is created (1-2mm brim) and the
liver is covered by UW solution until required for implant.
47
48
Liver Transplantation
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.
49
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
Liver Transplantation
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
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
Liver Transplantation
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
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
Liver Transplantation
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
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.
56
Liver Transplantation
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)
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.
58
Liver Transplantation
Figure 11. Right lobe vascular
anastamosis.
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.
60
Liver Transplantation
CHAPTER 6
Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked.
2003 Landes Bioscience.
61
Types of Immunosuppression
Immunosuppression may be physical or pharmacological. Physical methods, as
shown in Table 1, are rarely used in liver transplantation.
62
Liver Transplantation
Azathioprine
Mechanism of action
Side-effects
Doseage
Drug interactions
Notes
63
Mycophenolate mofetil
Mechanism of action
inosine
nase (IMPDH)
Side-effects
Dosage
Drug interactions
absorp-
5 mg
750 g
25 mg
6 mg
750 g
20 mg
4 mg
4 mg
Notes
alternative to
calcineurin-inhibitor sparing
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
Liver Transplantation
Prednisolone/prednisone
Mechanism of action
Side-effects
Dosage
Drug interactions
NSAIDs
Notes
65
Cyclosporin
Mechanism of action
Side-effects
Dosage
Drug interactions
See Table 8
Notes
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
Liver Transplantation
Drug Name
Tacrolimus
Mechanism of action
Side-effects
Diabetes mellitus
Hypertension
Headaches
Tremor
Convulsions
Nephrotoxicity
Renal impairment
Myocardial hypertrophy
Dosage
Target
Drug interactions
See Table 8
Notes
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
68
Liver Transplantation
Mechanism of action
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
Notes
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
Mechanism of action
Side-effects
Dosage
Drug interactions
Notes
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
Liver Transplantation
Side-effects
Anaphylaxis
Dosage
See below
Drug interactions
None known
Notes
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.
71
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.
72
Liver Transplantation
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.
Tuberculosis
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
Suggested Reading
1.
2.
3.
74
Liver Transplantation
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.
Immunological Complications
Acute Cellular Rejection (ACR)
-Definition:
Inflammation of the allograft elicited by genetic disparity between the
Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked.
2003 Landes Bioscience.
75
Graft Dysfunction
Diagnosis
1-6 months
6-12 months
>12 months
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
Liver Transplantation
Criteria
Indeterminate
Mild
Moderate
Severe
-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.
Graft Dysfunction
77
-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
Liver Transplantation
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
80
Liver Transplantation
Therapy
Outcome
Self-limited
disease/
resolved
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
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
Graft Dysfunction
81
Graft Ischemia
Hepatic Artery Thrombosis (HAT)
82
Liver Transplantation
Graft Dysfunction
83
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
Liver Transplantation
Biliary Leaks
These occur because of ischemic necrosis at the anastomosis or following removal
of a T-tube.
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
86
Liver Transplantation
CHAPTER 8
87
88
Liver Transplantation
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
Autoimmune Disease
Primary Biliary Cirrhosis
-Incidence and Prevalence:
Following transplantation, anti-mitochondrial antibodies remain positive
in 72-100% of cases; however, the persistence of these antibodies does
not indicate recurrent disease
89
90
Liver Transplantation
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
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
Liver Transplantation
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.
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
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2.
3.
4.
5.
6.
7.
8.
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Liver Transplantation
9.
10.
11.
12.
13.
14.
15.
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CHAPTER 9
Systemic Hypertension
Epidemiology: Systemic hypertension is defined as diastolic pressure > 90 mmHg
or systolic pressure > 140 mmHg. Systemic hypertension occurs in 40-80% of liver
transplant recipients. It typically occurs within a few weeks of transplantation and is
largely due to the use of calcineurin inhibitors.
Pathogenesis: The molecular mechanism underlying calcineurin inhibitor-induced
hypertension is not fully understood but renal vasoconstriction is the predominant
Liver Transplantation, edited by Michael R. Lucey, James Neuberger and Abraham Shaked.
2003 Landes Bioscience.
96
Liver Transplantation
Table 1. Cause of death in liver transplant recipients after the first year
Cause 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
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
Hyperlipidemia
Epidemiology: See Table 1. Sirolimus causes a dose-dependant increase in
triglycerides rather than in cholesterol.
Pathogenesis: The mechanism whereby serum cholesterol levels are increased
after liver transplantation is unclear.
Clinical Management:
Review immunosuppression
Dietary modification: rarely successful in isolation in the post-liver
transplant setting.
HMG CoA-reductase inhibitors (statins).
Diabetes Mellitus
Diabetes mellitus is seen in 20-30% of liver transplant recipients. This arises
from a combination of pre-liver transplant diabetes (13% in one study) and true
post-liver transplant diabetes. This compares to less than 4% in the general population.
Pathogenesis:
Corticosteroids increase insulin resistance.
Calcineurin inhibitors: The calcineurin inhibitors increase insulin
resistance, injure pancreatic islet cells and impair insulin secretion.
Tacrolimus and cyclosporin are associated with an increased incidence of
diabetes. The effect may be transient.
Chronic hepatitis C infection may potentiate the risk or severity of diabetes
mellitus.
Clinical Management:
General: diabetic liver allograft recipients should be managed in the same
way as diabetic patients in the general population, with lifestyle
modification and drug therapy as needed.
Modification of immunosuppressive protocol: where possible,
corticosteroids should be withdrawn, and calcineurin inhibitor dose
minimised. A conversion from tacrolimus to cyclosporin, Sirolimus or
mycophenolate mofetil may be of help.
Obesity
Prevalence: Up to 40% of patients are obese (>20% above ideal body weight)
within 1 year of transplantation. Weight tends to increase for at least 2 years following
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Liver Transplantation
transplantation and weight gains of 20%-30% above pre-operative weight are not
uncommon.
Clinical Management:
General: as in the general population, management of weight gain is to
reduce caloric intake and to increase exercise.
Renal Insufficiency
99
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Liver Transplantation
Malignancy
The risk of malignancy is increased in liver transplant recipients.
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.
Clinical Management:
Education is key. All transplant recipients should be informed of their
increased risk of skin cancer.
Avoidance of sun: They should be educated in sun-protective practices,
including minimising sun exposure between 10:00 and 16:00, the use of
protective clothing and broad brimmed hats, and the use of sun-screen
and lip-balm with a sun protection factor of 15 or higher.
Self-examination: Patients should be encouraged to examine their skin.
They should also have a formal skin inspection at least annually and should
any suspicious lesions be seen, these should be referred to a dermatologist
for further evaluation.
Oral Cancer
Oral cancer is associated with smokeless tobacco, alcohol consumption
and sun exposure.
Both EBV and HPV are associated with hairy leukoplakia, which can be
seen as feathery appearing plaques on the tongue or buccal mucosa.
Macroscopically they are indistinguishable from pre-malignant leukoplakia
and should be biopsied.
Erythroplakia a red hyperplastic area of mucosa is a pre-malignant
condition
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.
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
Liver Transplantation
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
Liver Transplantation
Lifestyle
Liver allograft recipients should be encouraged to return to a normal healthy
lifestyle, with appropriate health maintenance (see Table 5)
105
OLT pat
US pop
Hypertension
Every visit
No recommendations
Hypercholesterolemia
Diabetes mellitus
Screening in the
asymptomatic general
population is not
recommended.
Cigarettes
Counselling on smoking
cessation
Counselling on smoking
cessation
Osteoporosis
Breast Cancer
Cervical cancer
Colon cancer
Prostate Cancer
Skin cancer
Not recommended
Dental care
Oral cancer
Not recommended
106
Liver Transplantation
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.
107
CHAPTER 10
Liver Transplantation, edited by Michael Lucey, James Neuberger and Abraham Shaked.
2003 Landes Bioscience.
10
108
Liver Transplantation
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
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
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
Liver Transplantation
advantages for pediatric recipients. The pediatric advantages were granted in response to concern that the small number of children waiting for liver transplant
would be overwhelmed by the huge number of adults with equivalent higher scores,
causing increases in deaths and lengthy waiting times. Lengthy waiting time has a
disproportionate negative effect on young infants and children due to the impact of
chronic liver disease on physical, cognitive and social development. For these reasons,
pediatric donors (donors under 18 years of age) are offered to pediatric recipients at
an equivalent status or score before potential adult recipients. Furthermore, standard
UNOS exceptions exist for specific metabolic diseases, and additional exceptions
may be granted by the regional review boards of UNOS on request.
Pre-Operative Management
10
111
< 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)
10
112
Liver Transplantation
Subsequent Management
10
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.
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
Liver Transplantation
CD3 8, 9, 12, 14, 68
Celiac sprue 28, 34
Central pontine myelinolysis 38, 103
Cerebral edema 29, 32
Cervical cancer 100
Cervical carcinoma 101
Chemoembolization 39
Chemokine 10, 15
Child-Pugh classification 17, 18
Cholangiocarcinoma 20, 26, 33, 39,
92
Cholangiogram 57, 59, 111
Cholestipol 20
Cholestyramine 20, 27, 63
Chronic ductopenic rejection (COPD)
11, 12, 15, 22, 34, 71, 74, 76-79,
84
Chronic obstructive pulmonary disease
22
Ciprofloxacin 38
Cirrhosis 3, 4, 18, 19, 27, 30, 33, 34,
36, 39, 41, 79, 86-88, 90, 93, 98,
107-109, 111
Co-amoxyclav 38
Co-stimulation 7
Coagulopathy 19, 29, 37, 74, 103,
110
Colon cancer 26, 33, 39, 101
Common bile duct 44, 50, 53, 57
Complement 11, 13
Cotrimoxazole 38
Creatinine 18, 24, 33, 38, 57, 67, 98
Crigler-Najjar syndrome 90, 107, 109
Cryoglobulinemia 98
Cryotherapy 39
Cryptogenic cirrhosis 34, 93, 109
CSA 13
CTLA-4 15, 63
Cutaneous warts 102
Cyclosporin 12, 13, 63-69, 71, 72, 76,
97, 99, 101-103
Cyclosporine 69
Cystic duct 49, 53, 57
Cystic fibrosis 23, 90, 107-109
Cytokine 7, 9-12, 15, 64, 66, 68
Cytomegalovirus (CMV) 27, 30, 40,
68, 72, 74, 76, 78, 79, 82, 86,
101, 110, 112
Cytotoxic T lymphocyte CTL) 14, 15
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
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
Liver Transplantation
Musculoskeletal pain 102, 103
Mycophenolate 12, 13, 68, 72, 97
Mycophenolate mofetil 12, 13, 97
Myocardial infarction 22
N
Nadalol 36
Naltrexone 20
NASH 34, 74, 93
Nephrotic syndrome 24
Neuroendocrine tumors 26, 93
Niemann-Pick disease 90
Nifedipine 96
NK cells 11
Non-alcoholic fatty liver disorder
(NAFLD) 34, 93
Non-alcoholic steatohepatitis 34
Non-heart beating donors 2, 42, 84
Non-heart-beating donors 46
Non-steroidal anti-inflammatory agents
38
Norfloxacin 38
O
Obesity 34, 95, 97
OKT-3 12
Oral cancer 100
Ornithine transcarbamylase deficiency
107, 109
Orthoclone 14
Osteopenia 36, 99
Osteoporosis 65, 99, 103
P
Palmidronate 27
Pancreatitis 28, 34, 63, 92
Pap smears 39
Parvovirus B19 101
PELD 20, 109
Perforins 11
Peritonitis 19, 36, 37
Phenytoin 20, 32, 66
Plasmapheresis 20
Porcine endogenous retrovirus (PERVs)
2
Portal hypertension 18, 23, 36-38, 83,
107, 111
117
Index
R
Radiofrequency ablation 39
Rapamycin 12, 63, 66, 69
Renal function 23, 24, 28, 57, 97, 98
Retransplantation 3, 4, 34, 35, 54, 72,
76, 83, 84, 86
Ribavirin 87
Rifampicin 65, 66, 101
Rifampin 20
Right lobe living donor operation 57
Roux-en-Y hepatico-jejunostomy 55
S
Seizures 68, 103
Selectins 11
Sirolimus 12, 63, 66, 67, 69-72, 97
Skin cancer 20, 80, 97, 100
Somatostatin 23
Split liver grafts 47, 112
Spontaneous bacterial peritonitis (SBP)
19, 36, 37, 38
Statins 66, 97
Steatosis 57
Stent thrombosis 37
Steroid resistant rejection 76
Subacute hepatic necrosis 31
Subfulminant hepatic failure 29, 30
Suppression 3, 12, 16, 20, 60, 61, 63,
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
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
Liver
Transplantation
www.landesbioscience.com
9 781570 596827
Michael R. Lucey
James Neuberger
Abraham Shaked