Cell Cycle Arrest in Fibrosing Cholestatic Hepatitis – C (FCH-C)
NT Beaubier, JH Lefkowitch. Columbia University Medical Center, New York, NY
Background: FCH is an uncommon but severe form of post-transplantation liver injury associated with marked hepatic reinfection by either hepatitis B virus (HBV) or hepatitis C virus (HCV) in the setting of immunosuppression. FCH-C shows cytopathic hepatocellular injury and portal/periportal fibrosis associated with a prominent ductular reaction (DR). DR in FCH is likely due to progenitor cell activation due to severe hepatocellular injury and impaired regeneration. The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21), an effector of cell cycle arrest when induced by p53, is known to be expressed in liver parenchyma following various insults including toxins, viruses and steatohepatitis. We investigated the possible role of cell cycle arrest in cases of FCH-C after liver transplantation.
Design: 13 liver biopsies (bxs) showing FCH-C and 7 control bxs with cholestasis and DR due to large bile duct obstruction (LBDO) were immunostained for p21, a marker of cell cycle arrest, for p53, an inducer of p21, and for Ki-67, a marker of dividing cells. All three proteins have nuclear expression; the samples were therefore graded according to the percentage of positive nuclei. Cytokeratin 7 (CK7) immunostain was also applied in order to assess the DR.
Results: p21 was highly expressed in the parenchyma of the FCH-C cases: 10 of 13 cases showed p21 expression in >60% of hepatocytes while only 1 case of LBDO had > 60% expression (p = 0.0072, Fisher's exact test). p53 was also more highly expressed in FCH-C (p = 0.0012). The FCH-C bxs showed a much lower level of Ki-67 positivity (1-20% of cells). There was no statistical difference between the DR of FCH-C and LBDO as assessed by CK7 immunohistochemistry (p = 0.64), thus making LBDO an appropriate control. These data are consistent with ongoing parenchymal attempts at cell division in FCH-C being ineffective because of large numbers of cells in replicative arrest.
Conclusions: In FCH-C the extensive cholestatic liver parenchymal damage and HCV replication are associated with widespread cell cycle arrest as measured by p21 expression (also supported by the elevated levels of p53 expression, the upstream inducer of p21.) The p53-p21 pathway therefore may represent a final common pathway for several types of liver injury, including FCH-C, in which hepatic regeneration is impaired.
Category: Liver & Pancreas
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 243, Tuesday Morning