Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by an immune-mediated destruction of intrahepatic small bile ducts. Apoptosis, a unique pattern of cell death, has been suggested to be responsible for the biliary destruction in PBC. To address this issue, we attempted to detect the apoptosis of biliary epithelial cells by in situ nick-end labeling and by the expression of apoptosis-related proteins using immunohistochemistry in patients with various hepatobiliary diseases, including PBC. The data was noteworthy for several reasons. First, apoptosis was occasionally detected on biliary cells in all liver specimens; however, the positive rate was high in PBC and relatively low in other livers. Strong expression of CD95 was frequently observed in the epithelial cells of the injured bile ducts of PBC, which accompanied high intensity CD95 ligand-expressing mononuclear cells. Perforin and granzyme B immunoreactivities were occasionally found on the bile ducts in control liver diseases as well as PBC, but granzyme B-positive biliary cells were prominent in PBC. In contrast, Lewis Y expression, as detected using BM-1 antibody, was consistently present in the injured bile ducts of PBC. These data suggest that apoptosis, via the perforin/granzyme B pathway, may be associated with the degrading fraction of cell cycle regulation in the small-sized biliary tree under physiological and pathological liver conditions. Moreover, enhanced apoptosis, mediated by CD95/CD95 ligand interaction, may contribute to the bile duct injury and loss observed in PBC.