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Recurrent hepatitis C infection after orthotopic liver transplantation (OLT) is frequent and may occur as early as a few weeks postoperatively. Early histopathological features of recurrent hepatitis C virus (HCV) infection may be modified by immunosuppressive therapy and can be difficult to differentiate from acute allograft rejection (AAR). Thus, we retrospectively compared histopathological features of liver biopsy specimens from two carefully selected patient groups: one with unequivocal recurrent hepatitis C, the other with unequivocal AAR. Index biopsy specimens obtained at the time of the appearance of liver test abnormalities after OLT and all serial liver biopsy specimens (2 to 13 per patient) were assessed under code and scored semiquantitatively for 44 histopathological variables. The index biopsy specimens from patients with recurrent HCV infection and AAR index biopsies (AAR-Ib) differed significantly (P < .05) for 11 features (10 features were statistically associated with AAR and 1 with early recurrence of HCV infection). Statistically significant features associated with AAR included bile duct injury with overlapping nuclei, lymphocytic infiltrates and necrosis, endothelialitis, portal inflammatory infiltrates containing eosinophils and polymorphonuclear leukocytes, hepatocyte mitoses, and zone 3 canalicular cholestasis. In contrast, the only statistically significant feature associated with early recurrent HCV was sinusoidal dilatation. Stepwise discriminant analysis showed that the presence of eosinophils in the portal inflammatory infiltrate, bile duct necrosis, and bile duct lymphocytic infiltrates were independently associated with AAR. However, serial biopsy specimens from patients with recurrent HCV infection showed statistically significant progression in scores for portal inflammation, portal lymphoid aggregates, and lobular inflammation. We conclude that (1) multiple histopathological features are associated with AAR; (2) early recurrent HCV infection is characterized by elevated alanine aminotransferase levels, positive HCV RNA by polymerase chain reaction (PCR), and absence of diagnostic histopathological features; and (3) serial biopsies are needed to demonstrate progression of histopathological features of recurrent hepatitis C. (Liver Transpl Surg 1997 Jul;3(4):398-406)

IntroductionObeticholic acid (OCA) is a potent and selective farnesoid X receptor (FXR) agonist under investigation for treatment of primary biliary cholangitis (PBC) and other chronic liver diseases. POISE was a double-blind, placebo-controlled, randomised Phase 3 study examining the efficacy of OCA in PBC. The objective of this post-hoc analysis was to assess the efficacy of OCA in the subset of patients with cirrhosis who were at higher risk of progression to liver-related outcomes or death.MethodWe randomised and dosed 216 patients 1:1:1 with placebo (PBO) (n=73), OCA 5–10 mg (n=70, titrated to 10 mg after 6 months based on response and tolerability) or OCA 10 mg (n=73). Inclusion criteria included PBC diagnosis, ALP≥1.67x ULN and/or total bilirubin (BILI) >ULN to <2x ULN, stable UDCA dose or intolerance to UDCA. Patients were considered to have cirrhosis if they met one of the following criteria: biopsy-proven cirrhosis, transient elastography of ≥16.9 kPa, or history of cirrhosis. The primary composite endpoint was an ALP<1.67x ULN with ≥15% reduction in ALP and BILI ≤ULN after 12 months.ResultsCirrhosis was present in approximately 17% of patients in POISE: PBO, n=13; OCA 5–10 mg, n=13; OCA 10 mg, n=10. At month 12, 54% (p<0.05) of patients in the OCA 5–10 mg group and 40% (p=0.06) in the OCA 10 mg group met the primary composite endpoint compared to 8% of PBO patients with cirrhosis. The table shows significant differences in ALP and BILI between PBO and both OCA groups after 12 months. BILI increased on PBO; however, it remained stable in both OCA groups after 12 months of treatment. Pruritus was the most common adverse event in patients with cirrhosis, affecting 23%, 69%, and 80% of patients in the PBO, OCA 5–10 mg, and OCA 10 mg groups, respectively.ConclusionIn this post-hoc analysis, no additional safety concerns due to OCA were observed in the subgroup of OCA-treated patients with cirrhosis, and OCA treatment resulted in significant improvements in biochemical markers associated with disease progression. The percentage of patients achieving the primary composite endpoint on OCA was comparable in patients with cirrhosis and non-cirrhotic patients. These results suggest that OCA may play a beneficial role in preservation of the functional capacity of residual liver tissue in cirrhotic patients.Disclosure of InterestJ Vierling: None Declared, G. Hirschfield: None Declared, D. Jones: None Declared, R. Groszmann: None Declared, K. Kowdley: None Declared, R. Pencek Conflict with: Intercept Pharmaceuticals, Inc., Conflict with: Intercept Pharmaceuticals, Inc., T. Marmon Conflict with: Intercept Pharmaceuticals, Inc., Conflict with: Intercept Pharmaceuticals, Inc., L. MacConell Conflict with: Intercept Pharmaceuticals, Inc., Conflict with: Intercept Pharmaceuticals, Inc.[Figure]