Randomized controlled trial of total immunosuppression withdrawal in liver transplant recipients: role of ursodeoxycholic acid.

BACKGROUND: Total immunosuppression withdrawal (TIW) without causing rejection has been reported in stable liver recipients. The role of ursodeoxycholic acid (UDCA) and patient characteristics that predict the success of this tolerance are unclear. There are two goals, to determine: 1) whether TIW is frequently associated with rejection; and 2) whether UDCA decreases the risk of liver disease (both rejection and recurrence) after TIW. METHODS: Twenty-six liver recipients who had been free of rejection while on immunosuppressive agents for a minimum of 2 years were randomized to receive either (15 mg/kg) of UDCA (n=14) or identical placebo (n=12) followed by sequential withdrawal of their immunosuppressive regimen over several months. Endpoints were defined as biochemical and histological evidence of rejection, graft dysfunction without rejection, recurrence of pretransplant disease, or 6 months without immunosuppression and no rejection or dysfunction on repeat liver biopsy. RESULTS: Rejection occurred in 6 of 14 (43%) of the UDCA group and 9 of 12 (75%) of those receiving placebo (P=0.09). Degree of rejection was mild, moderate, and severe in 73%, 20%, and 7% of patients respectively. All responded to rescue therapy and none developed chronic rejection. Nine of the remaining 11 patients (eight of the UDCA recipients and three of controls) who did not develop rejection developed graft dysfunction which responded to reintroduction of immunosuppressive agents in each case. Disease recurrence was most common in patients with underlying immune-mediated disorders of the liver. One year after withdrawal only two patients were free of immunosuppression, 80% were able to discontinue prednisone therapy (steroid free), and 50% were able to reduce their dose of cyclosporine. Age, underlying cause of liver disease, and regimen of immunosuppression were favorable predictors. CONCLUSIONS: The results of this study suggest that TIW: 1) is frequently associated with subsequent rejection, 2) increases the risk of underlying disease recurrence, and 3) is not facilitated by UDCA use and responds properly to the reintroduction of immunosuppressive therapy.

Are chronic hepatitis C viral infections more benign in patients with hemophilia?

BACKGROUND AND AIMS: Cirrhosis is associated with thromboses of the intrahepatic vasculature. This raises the possibility that HCV infections in hemophiliacs may differ from those in non-hemophiliacs METHODS: Liver biopsy findings from 12 hemophiliacs and 20 age- and gender-matched, non-hemophiliac controls with chronic hepatitis C viral (HCV) infections were compared for inflammatory activity and fibrosis. RESULTS: The mean ages of hemophiliacs and controls were 35.0 +/- 3.0 yr and 39.6 +/- 5.6 yr, respectively (P= 0.2). Serum aspartate aminotransferase (AST) levels were lower (44 +/- 13 vs 70 +/- 43 U/L) and the duration of the partial thromboplastin (PTT) time longer (49.2 +/- 16.9 vs 31.2 +/- 1.2 s.) in hemophiliacs than in controls (P < 0.02 and <0.001, respectively). Six of the seven hemophiliac patients (86%) and 8/17 controls (46%) were infected with genotypes 1a or 1b with the remainder being infected with 2b, 3a, or 3b. Histological activity and fibrosis scores were significantly lower in hemophiliacs than in controls (1.9 +/- 0.6 vs 3.6 +/- 2.7 and 0.3 +/- 0.2 vs 1.5 +/- 1.5, P < 0.05 and P < 0.01, respectively). None of the hemophiliacs had histological evidence of advanced disease (bridging fibrosis and/or cirrhosis) as compared to 7/20 (30%) controls (P < 0.05). CONCLUSION: HCV infections in hemophiliacs may be less severe than in HCV infected patients without hemophilia.