Chronic cholestatic liver diseases (cholangiopathies), which target intrahepatic and extrahepatic bile ducts, are characterized by the coexistence of cholangiocyte growth/apoptosis, inflammation and fibrosis[3,128]. Cholangiopathies differentially target the biliary epithelium with heterogeneous proliferative and apoptotic responses of different sized ducts[3,47,50,129-131]. Primary biliary cirrhosis is characterized by the selective proliferation/loss of small interlobular bile ducts[3,132]. Some studies demonstrated that damage of interlobular bile ducts is immune mediated[3,133]. The origin of primary sclerosing cholangitis (PSC), which is associated with inflammation and fibrosis of bile ducts, originates from multiple factors including autoimmune, bacterial, congenital, drug, or viral agents[3,73]. PSC affects mainly extrahepatic and interlobular or septal bile ducts although smaller bile ducts can be affected[3,73]. Patients with small duct PSC seem to have a good prognosis in terms of survival and development of cholangiocarcinoma. Cholangiocarcinoma occurs frequently in patients with PSC and targets mainly the major bile duct bifurcation[3,135]. Peripheral cholangiocarcinoma occur within the liver rather than within large bile ducts may arise from small bile ducts[3,135]. Mutations in the CFTR gene are responsible for causing the human biliary disease, cystic fibrosis, due to defective transport of water and chloride presumably by large cholangiocytes expressing CFTR. Our previous studies in rodent liver has shown that CFTR is expressed principally in large cholangiocytes and in bile ducts greater than 15 mM diameter[12,13] but in studies of human liver of cystic fibrosis patients, CFTR was expressed in both large and small ducts.
Defective chloride transport and chloridemediated bile secretion by large cholangiocytes may be respon-sible for the reduced fluidity and alkalinity of bile, leading to bile duct damage. Ca2+-dependent Cl- cha-nnels[138,139] (presumably expressed by both small and large cholangiocytes) may be able to secrete bile, thus compensating for loss of CFTR functional activity of CFTR in large cholangiocytes. In polycystic kidney liver disease (PKLD), the genetic defect results in the growth of multiple epithelial cysts within the renal, liver parenchyma and intrahepatic bile ducts. The disease targets presumably large bile ducts since the cystic ductal cells also secrete Cl- and HCO3- (as normal large cholangiocytes)[2,3,54,71,73] but the secretion is diminished, likely due to reduced Cl-/HCO3- exchanger activity in cystic ductal cells as compared with normal cholangiocytes. Biliary atresia, which is the most common reason of cholestasis in infants and children, is a destructive, inflammatory process of the extrahepatic bile ducts but as the disease progresses smaller intrahepatic bile ducts are also involved. The pathogenesis of biliary atresia is unknown but infections or toxic agents combined with genetic/immunologic susceptibility have been proposed[3, 142, 143].