Immunosuppression, Liver Injury and Post-transplant HCV Recurrence

S. Ciesek; H. Wedemeyer

Disclosures

J Viral Hepat. 2012;19(1):1-8. 

In This Article

HCV Recurrence After Liver Transplantation

Chronic infection with HCV is a major cause of end-stage liver disease and a leading indication for orthotopic liver transplantation (OLT) worldwide. However, re-infection of the graft by HCV particles present in the blood stream is almost universal and at least 25% of patients will develop liver cirrhosis after transplantation within 5–10 years.[17,18] Once cirrhosis is established, transplanted patients show an accelerated natural history with decompensation rates of as high as 40% after 12 months.[19] To date, there is no safe and effective way to prevent HCV recurrence. Moreover, patients with recurrent hepatitis can develop a severe cholestatic hepatitis C syndrome characterized by jaundice shortly after transplantation in the absence of biliary obstruction, particular high HCV RNA levels and a very high risk for liver failure.[18] Subsequently, graft loss caused by recurrent HCV infection is the most important reason to consider re-transplantation. Some data suggest that the outcome of hepatitis C after liver transplantation has worsened during the last decades.[20] Across different countries and transplantation programs, the 5-year post-transplantation survival rate for hepatitis C patients is significantly lower as compared to patients who underwent liver transplantation for other chronic liver diseases. Factors being associated with graft loss in HCV-infected patients included an older donor age, steatosis of the donor organ, specific immunosuppressive regimens (discussed later), female sex, a high necroinflammatory activity in the allograft 1 year after transplantation and high HCV viral loads (Table 1).[21–23] In addition, several additional factors have been discussed to influence the long-term outcome of graft hepatitis C such as herpes virus infections,[24] the degree of human leucocyte antigen (HLA) matching[25] or the IL28b genotype of the donor and the recipient.[26,27]

Cellular immune responses by both T cells and NK cells are thought to play a major role in the pathogenesis of chronic hepatitis C after transplantation. HCV-specific T-cell responses have been linked with improved histological and clinical outcomes[28,29] and are also associated with spontaneous HCV clearance after liver transplantation.[30] Genotypes of killer cell immunoglobulin-like receptors and their donor HLA ligands which determine NK cell activities may also play an important role in the recurrence and progression of hepatitis C in liver transplant recipients.[31] An interesting study from Japan showed that adoptive immunotherapy 3 days after liver transplantation with activated lymphocytes extracted from the liver allograft perfusate can result in markedly reduced HCV RNA titres of the recipient confirming the importance of immune cells to control HCV infection after liver transplantation.[32]

In general, HCV RNA levels are higher after OLT than before and high virus titres are associated with a worse long-term outcome of these patients.[33] More specifically, serum HCV RNA levels increase rapidly from the second-week post-transplantation and peak by the fourth postoperative month. HCV RNA levels at 1 year after liver transplantation are 10- to 20-fold higher than pretransplant levels.[34] Viral quasispecies composition differs after liver transplantation as compared to pretransplant sera[35] and may also be involved in the long-term outcome of graft hepatitis.[36] However, detailed mechanisms of how high viral loads and distinct viral compositions contribute to the accelerated disease progression in graft hepatitis C are still poorly defined.

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