Expression of Bcl-2 familial proteins is reduced in small bile duct lesions of primary biliary cirrhosis.

In primary biliary cirrhosis, biliary epithelial cell death by apoptosis results in progressive bile duct loss. We examined immunohistochemically 4 apoptosis-regulating bcl-2 familial proteins (bcl-2, mcl-1, bcl-X, and bax) in the biliary epithelium in 19 cases of primary biliary cirrhosis. Ten cases of chronic hepatitis C, 9 cases of extrahepatic biliary obstruction, and 10 cases of normal liver were used as a control. Bcl-2 and mcl-1 are inhibitors of apoptosis, bcl-X, probably bcl-XL in biliary epithelial cells, an inhibitor, and bax, a promoter of apoptosis. First, we clarified the distribution of bcl-2 familial proteins on the intrahepatic biliary tree in normal livers. Bcl-2 was detected in the interlobular bile ducts and bile ductules, but not in the large and septal bile ducts in all cases examined. Mcl-1, bcl-X, and bax were diffusely detectable at the any level of the intrahepatic biliary tree, with a staining pattern that was diffuse and cytoplasmic. This distribution pattern was preserved in extrahepatic biliary obstruction. Bcl-2 expression was lost or markedly reduced in the damaged interlobular bile ducts in primary biliary cirrhosis, whereas the reduction was only focal or mild in the bile ducts with hepatitis-associated damage in chronic hepatitis C. Expression levels of mcl-1, bcl-X, and bax were similarly reduced to that of bcl-2 in these 2 diseases. These findings suggest that bax is not important as a proapoptotic factor in the damaged bile ducts and that downregulation of bcl-2 and mcl-1, and probably that of bcl-XL, leads to a decrease in the threshold of apoptosis and increase in the vulnerability to apoptotic stimuli in these bile ducts, followed by the progressive apoptotic loss of interlobular bile ducts, in primary biliary cirrhosis.