Comparison of histopathology in acute allograft rejection and recurrent hepatitis C infection after liver transplantation

Abstract

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 F .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.

Early recurrence of hepatitis C virus infection after liver transplantation

“…It has been well documented that HCV RNA can be detected in the peripheral blood within a few days after transplantation, often reaching the titers much higher than the pretransplantation levels 5, 6. Histopathologic features of recurrent HCV infection, although perhaps initially very subtle, may become evident within the first week after LT. Liver biopsy, despite sometimes inconclusive and ambiguous findings, remains the gold standard for the assessment and evaluation of recurrent HCV‐associated hepatitis 7, 8. The severity of the recurrent viral hepatitis and the disease progression are highly variable.…”

Cytokine profile of liver- and blood-derived nonspecific T cells after liver transplantation: T helper cells type 1/0 lymphokines dominate in recurrent hepatitis C virus infection and rejection

“…4,7,15 Both are associated with lymphocytic infiltration of the portal tracts and variable degrees of bile-duct injury. During the first few months after OLT when immunosuppression is maximal, classic features of hepatitis C may be absent or modified.…”

“…Diagnoses and differentiation between rejection and recurrent HCV infection were made by liver histological evaluation, 15,16 abnormal liver enzyme levels, positivity for antibodies to HCV by second-generation enzyme-linked immunosorbent assay, and detection of HCV RNA in serum. The histological criteria of Ishak et al 17 were used to grade the inflammatory activity (hepatitis activity index) and stage the degree of fibrosis.…”

Recurrent diseases following liver transplantation

“…Differentiating AAR from early recurrence of HCV infection remains one of the most challenging issues both clinically and histologically [2,[17][18][19][20]. With time, rHCV infection is histologically indistinguishable from an HCV-associated hepatitis in the nontransplant setting [18,19,21].…”