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Vol. 4, Issue 5, Suppl 1, pp. S65-S67, September
1998
HEPATITIS B AND C
Hepatitis B and C: An Overview
Henry C. Bodenheimer Jr
From the Division of Liver Diseases, Mount Sinai Medical
Center, New York, NY.
Introduction
A typical clinical problem faced by transplantation surgeons is
the evaluation of elevated aminotransferase values in a patient
after transplantation. This may be a particular challenge when
occurring in a patient undergoing liver transplantation for
hepatitis C or B. A liver biopsy is often included in the
evaluation of such a patient, and the differentiation of changes of
viral hepatitis from allograft rejection is both important and
difficult. This is a most serious issue, because the therapy for
each disorder may be diametrically opposed to the treatment of the
other.
The most critical issue facing the clinician in using
information on liver disease when deciding the origin of liver
injury in a patient after transplantation is the specificity of the
pathological findings. The pathologist needs to define features of
injury that more likely suggest recurrent hepatitis or acute
rejection.
Acute hepatitis in the patient posttransplantation is recognized
by predominant involvement of the parenchymal hepatocytes with
diffuse necroinflammatory changes. Activation of sinusoidal lining
cells and the finding of eosinophilic degeneration of hepatocytes
is characteristic. Endophlebitis of central veins may be observed
but is usually less than that seen in cellular rejection.
Cholestasis is mild, and portal vein endophlebitis is absent.
Chronic hepatitis is recognized by the presence of portal
inflammation and fibrosis. Lobular and periportal inflammation may
be prominent, in addition to fibrous septa formation. The degree of
inflammatory activity within the septa may vary. Hepatitis C is
characterized by lymphoid aggregates, and bile duct injury may be
seen.1 Ground- glass cells are helpful diagnostic clues
in distinguishing hepatitis B.2 Cholestasis is a feature
of severe disease.3
Acute liver allograft rejection is characterized by inflammation
and edema of the portal tracts. Eosinophils are present, and there
is inflammatory injury to the endothelium of the portal and central
veins. Biliary epithelium may be damaged. When rejection is severe,
parenchymal inflammation and necrosis may be seen.
Chronic liver allograft rejection is characterized by bile duct
loss. A finding of fewer than 5 bile ducts per 20 portal tracts is
diagnostic of duct loss. Cholestasis is common. Portal tracts may
be mildly inflamed, but eosinophils are absent. There may be
obliteration of small hepatic artery branches by lipid-filled
macrophages. Mild to moderate portal and/or central fibrosis may be
seen.4,5
Managing Posttransplantation Viral Hepatitis Hepatitis
B
Hepatitis B is a major cause of liver failure and hepatocellular
carcinoma worldwide. In the United States, nearly 200
transplantation procedures are performed each year on patients with
this condition. The appropriateness of transplantation in hepatitis
B is dependent on effective therapy to control hepatitis B
recurrence in the allograft. The lack of disease control with
short-term prophylactic hepatitis B immunoglobulin (HBIG) is well
documented.6 Presently, several options are available that show
promise in control of posttransplantation hepatitis B. The most
widely used therapy is HBIG. Other antiviral agents, including
lamivudine and famciclovir, are being evaluated for efficacy of
disease control.
Several critical questions remain the focus of clinical
research, the results of which will guide our care of patients in
the future. Four issues are highlighted here for further
consideration. First, should patients undergoing transplantation
for hepatitis B receive unique immunosuppression? Specifically,
should corticosteroid use be avoided or curtailed? Second, does
alteration of hepatitis B replication with antiviral administration
pretransplantation alter results? Third, what is the optimal
regimen for the use of HBIG after transplantation? Finally,
exciting new research may help define whether antivirals or
adoptive immunotransfer will be effective in controlling hepatitis
B infection after transplantation.
Hepatitis B viral replication is stimulated by the presence of
corticosteroids. This may occur directly by gene
regulation7 and indirectly by blunting immune control of
hepatitis B viral infection. The potential risks of the limitation
of steroid use may include enhanced rejection and must be weighed
against the potential for greater control of hepatitis
B.8
Different levels of pretransplantation hepatitis B viral
replication have been associated with variable graft and patient
survival after transplantation.6 The presence of antiviral agents
capable of altering hepatitis B virus (HBV)-DNA levels9
raises the question of whether pharmacologically altered states of
pretransplantation viral replication will have a long-term benefit
in control of the disease.
Experience with interferon administered pretransplantation
suggests that a treatment-associated decline in HBV DNA does not
alter the rate of posttransplantation HBV
recurrence.10
HBIG has been shown to be markedly effective in controlling the
recurrence of HBV when used as a prophylactic agent.11
There is a clear benefit in long-term HBIG administration compared
with short-term or no prophylactic treatment. The effects of
thimerisol-free formulations or multiple monoclonal antibody
products need consideration.
Adoptive transfer of immunity by bone marrow transplantation may
enhance the development of an immune chimera with properties of
both donor and recipient.
Donor bone marrow may supply antibody to hepatitis B and result
in control or elimination of disease.12 The feasibility
of bone marrow/liver transplantation has been explored. The
application of this technique in hepatitis B patients is
intriguing.
Managing Posttransplantation Viral Hepatitis Hepatitis
C
Hepatitis C virus currently infects nearly 4 million Americans
and contributes to the need for liver transplantation in about 20%
of the nearly 4000 transplants performed annually in the United
States. After an initial decrease in viral titer immediately after
surgery,13 immunosuppression administration is
associated with a marked increase in viral titer.14
About 10% of patients develop severe recurrent hepatitis C, which
leads to death or re-transplantation within 2 years.15
Approximately 50% will have a moderately active chronic hepatitis
with a course that may be truncated compared with the
pretransplantation natural history. The remaining patients have
mild disease.
Severe critical questions remain concerning the management of
patients with hepatitis C infection undergoing transplantation.
First, should patients preferentially receive either cyclosporine
or tacrolimus-based immunosuppression regimens? Second, is
interferon effective in controlling clinically significant
recurrent hepatitis C after transplantation, and does it
precipitate rejection? Third, does ribavirin have a role in the
control of hepatitis C in patients with transplants?
The proper balance of immunosuppression is designed to lessen
organ rejection while allowing the body's immune defenses to
continue to control infection. Hepatitis C viral replication is
enhanced following transplantation and immunosuppression. More
potent immunosuppression may lead to greater viral load and more
rapid liver injury as immunosuppression is then lowered with time.
Can modulation of immunosuppression alter the natural history of
posttransplantation recurrent hepatitis C?
Interferon is the most widely used agent in the treatment of
hepatitis C infection. The drug, however, has not been widely used
following transplantation. Since the agent enhances HLA expression
and stimulates cellular immunity, there is a concern that graft
rejection may be triggered.16,17 Of course, any use of
interferon in this setting would depend on proven efficacy. The
experience in treating established recurrent hepatitis C with
interferon has been disappointing.18-21
The use of ribavirin alone has not been found to be an effective
antiviral therapy in immunocompetent patients.22 Early
data have shown some control of viral replication and improvement
in histological status when a combination regimen of ribavirin and
interferon is used.23 This approach remains
investigational.24
Patients with hepatitis C make up a substantial proportion of
those who receive liver transplants. Because the infection persists
after transplantation,25 these individuals are at risk
for progressive hepatitis and may be in need of re-transplantation.
Should patients with recurrent hepatitis C, at a time of severe
organ shortage and suboptimal antiviral therapy, be offered
re-transplantation? This problem has the potential for growing to
involve a substantial proportion of future transplants. In our
experience,26 among 262 patients who received
transplants for hepatitis C, 14 (5.3%) had a second transplant for
recurrent disease. Patients with severe hepatic failure due to
recurrent hepatitis C are at risk for an unacceptable mortality
rate at re-transplantation. However, of the 10 patients who
received another transplant when end-stage disease was apparent,
but before any evidence of sepsis, 8 remain well.26
Thus, the timing of surgery may be a crucial factor in defining the
success of re-transplantation.
Footnotes
Address reprint requests to Henry C. Bodenheimer, Jr, MD,
Division of Liver DiseasesBox 1633, Mount Sinai Medical Center, One
Gustave L. Levy Place, New York, NY 10029.
References
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