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Home » Biology Articles » Anatomy & Physiology » Heterogeneity of the intrahepatic biliary epithelium » Heterogeneity in chlorangiopathies

Heterogeneity in chlorangiopathies
- Heterogeneity of the intrahepatic biliary epithelium

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[134]. 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[136]. 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[137].
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[54]. 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[140]. 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[140]. 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[141]. The pathogenesis of biliary atresia is unknown but infections or toxic agents combined with genetic/immunologic susceptibility have been proposed[3, 142, 143].

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