Two kinds of epithelial cells, hepatocytes and cho-langiocytes, are present in the liver[1-3]. While hepatocytes initially secrete bile into the bile canaliculus[4], cholangiocytes modify bile of canalicular origin by a series of coordinated spontaneous and hormone/peptide regulated secretion/reabsorption of water and electrolytes before it reaches the small intestine[3,5-7]. For more information on the mechanisms of bile formation we refer to recent reviews[4,5]. The human biliary system is divided into extrahepatic bile ducts and intrahepatic bile ducts, the latter further sub-divided into large and small bile ducts[2,3,8]. The intrahepatic bile ducts represent that part of the biliary tree proximal to the confluence of the hepatic ducts[9]extending from the canals of Hering to the large extrahepatic ducts[2,3,8]. In human liver, a study by Ludwig classified the intrahepatic bile duct system upon duct diameter[8], small bile ductules (< 15 mm), interlobular ducts (15-100 mm), septal ducts (100-300 mm), area ducts (300-400 mm), segmental ducts (400-800 mm) and hepatic ducts (> 800 mm)[8] (Table 1). Small ductules are lined by 4-5 cholangiocytes, have a basement membrane, tight junctions between cells and microvilli projecting into the bile duct lumen[10,11]. Cholangiocytes are progressively larger and more columnar in shape in larger bile ducts (lined by 10-12 cholangiocytes)[10,11].
In rats, morphological studies in liver sections and small and large intrahepatic bile duct units (IBDU) have shown[2,12-14] that the intrahepatic biliary tree is divided into: (1) small ducts (< 15 mm in external diameter) lined by small cholangiocytes (approximately 8 mm in diameter)[12,13]; and (2) and large ducts (> 15 mm in diameter) lined by large cholangiocytes (approximately 15 mm in diameter)[12,13] (Figure 1, Table 1). Specifically, we have shown[12] that the rat intrahepatic biliary epithelium is formed by ducts of different sizes (5 to 200 mm in external diameter) and cholangiocytes of different cell areas (3 to 80 mm2). Furthermore, a direct relationship exists between cholangiocyte area and external duct diameter, a finding that demonstrates that small ducts are lined by small cholangiocytes, whereas larger ducts are lined by larger cholangiocytes[12-14]. The fact that small and large ducts are lined by small and large cholangiocytes, respectively, is important since it allows for the assignment of the secretory, apoptotic and proliferative functions (achieved in isolated small and large cholangiocytes) within the different portions of the intrahepatic biliary epithelium. Recently, Masyuk et al[15] have reconstructed the intrahepatic biliary epithelium that resembles a tree, with the common and hepatic ducts corresponding to the trunk, the intrahepatic bile ducts corresponding to the large branches and the small ducts corresponding to the smallest tree limbs of a tree.
Studies by Phillips et al[16] have shown that no major ultrastructural differences exist among cholangiocytes lining small and large bile ducts. However, in support of the concept that the intrahepatic biliary epithelium is morphologically heterogeneous, electron microscopic studies by Benedetti et al[14] in rat liver sections and IBDU have demonstrated that large bile ducts are lined by 8-15 cholangiocytes and small ducts by 4-5 cholangiocytes. The studies also showed that small and large cholangiocytes have a multilobulated nucleus, numerous vesicles at the subapical region, tight junctions, high density of microvilli and lysosomes and a few mitochondria[14]. Other studies have shown the presence of microvilli and cilia in the apical plasma membrane of cholangiocytes[17,18], cilia that play an important role in the regulation of cholangiocyte functions[19,20]. While large cholangiocytes are columnar in shape, small cholangiocytes have a cuboidal shape[14]. Abundant Golgi apparatus was observed between the apical pole and the nucleus[14]. Rough endoplasmic reticulum was inconspicuous in the smallest ducts and increased only slightly in the largest[14]. While large cholangiocytes display a small nucleus and conspicuous cytoplasm, small cholangiocytes possess a high nucleus/cytoplasm ratio[14]. Cholangiocytes have distinct apical and basolateral membranes[14,17,18].Coated pits have also been observed on the apical and basolateral membranes of cholangiocytes, a finding suggesting receptor-mediated endocytosis at both domains of cholangiocytes[21]. Functional tight junctions are located between adjacent cholangiocytes in proximity to the apical domain[17].
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