Hepatitis C Information Central

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 HepatitisHepatitis 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 HepatitisHepatitis 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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