Evolution of hepatitis C virus in liver allografts.

1. Hepatitis C virus (HCV) RNA+ liver allograft recipients invariably reinfect the liver allograft within hours after transplantation, and the majority (>70%) develop chronic hepatitis. The rate at which these patients experience progression to cirrhosis and the overall percentage are significantly increased in comparison with HCV infection in the nontransplant setting. 2. Core needle biopsy evaluation is used to establish the diagnosis of recurrent HCV, which can be difficult to distinguish from acute cellular rejection and other causes of allograft dysfunction. In the vast majority of cases, however, distinguishing recurrent HCV from other posttransplant syndromes is reliably achieved by a careful examination of hematoxylin and eosin-stained sections and correlation with clinical and serological data. 3. Recurrent HCV often coexists with other causes of liver allograft dysfunction, and the determination of the most important cause of injury and whether other causes of injury are present is important. Included are residual changes of preservation/reperfusion injury, biliary sludging/structuring, acute cellular and chronic rejection, and autoimmune hepatitis. 4. The complex interplay between immunosuppression management, viral replication, and the recipient immune system results in distinct patterns of recurrent chronic HCV in the liver allograft: (1) conventional or usual acute and chronic HCV, which resembles that seen in the general population with HCV; (2) fibrosing cholestatic hepatitis; and (3) plasma cell-rich HCV, which might represent a variant of, or overlap with, autoimmune hepatitis and rejection. 5. The variable but usually hastened histopathological progression toward cirrhosis in HCV+ allografts is similar to that seen in the nontransplant setting, but in allografts, the overall severity of lymphocytic inflammation is less, and ductular reactions, stellate cell activation, and subsinusoidal fibrosis are accentuated. Hepatic stressors and causes of an impaired ability of hepatocytes to replicate include persistently high levels of viral replication, HCV-specific CD4+ T responses, advanced donor age, high levels or rapid withdrawal of immunosuppression, and coexistent liver damage from preservation/reperfusion injury, biliary structuring, or coexistent cytomegalovirus or herpes 6 viral infection. 6. Immunological effector mechanisms involved in the rejection and control of HCV replication/HCV elimination show significant overlap. Patients with very high levels of HCV RNA rarely show significant clinically significant acute or chronic rejection, whereas their occurrence is frequently associated with very low levels or clearance of HCV RNA. Studying the evolution from recurrent HCV to acute rejection in patients treated with interferon and/or weaned from immunosuppression might provide valuable insights into the relationship between these 2 processes as well as liver allograft acceptance.