Bile Duct Hyperplasia

Bile duct hyperplasia (BDH) is a relatively common toxicologic pathology that occurs in both rodent and non-rodent species. Two distinct processes can lead to chemical-mediated BDH: cholestasis and oval cell proliferation. The pathogenesis involving cholestasis is exemplified by a-naphthylisothiocyanate (ANIT; Lopez and Mazzanti, 1955; Desmet et al., 1968; Kossor et al., 1998). A single oral dose of ANIT leads to a rapid decrease in biliary function within 24 hr, measurable as decreased biliary taurocholate transport and decreased elimination of erythritol from systemic circulation, a compound normally excreted via the bile. Biliary epithelial cell necrosis ensues ~48 hr after exposure to ANIT, leading to sloughing of epithelial cell debris into bile ducts, causing complete obstruction of many ducts. A compensatory proliferative response 4-7 days after treatment with ANIT increases the number of bile ducts and biliary epithelial cells per bile duct, resulting in BDH (Lopez and Mazzanti, 1955; Desmet et al., 1968; Kossor et al., 1998).

BDH pathogenesis involving oval cell proliferation is less clearly defined, in large part because of the complex biology of oval cells. Oval cells are thought to be progenitor cells that can differentiate into both parenchymal (i.e., hepatocytes) and non-parenhymal (i.e., biliary epithelial) hepatic epithelial cell types (Germain et al., 1988; Yasui et al., 1997). Under normal conditions in the mammalian liver oval cells occur at low abundance, but under pathological conditions they can become a prominent feature, particularly following severe liver injury. Oval cells are recognizable by the ovoid shape of their nuclei, a large nuclear:cytoplasm ratio, and basophilia using H&E stain (Dabeva and Shafritz, 1993). Their proliferation can be induced with compounds such as acetylaminofluorene (Park and

Suh, 1999; Bisgaard et al., 2002), in transgenic mice that overexpress SV40 large T antigen (Montag et al., 1993) or ErbB-2 (Kiguchi et al., 2001), and by genetic disruption of genes such as Tg737 (Richards et al., 1996). In each of these models, oval cells proliferate around the portal triad and expand into the periportal region. Under severe conditions basophilic oval cells delineate periportal regions. Concurrent with oval cell proliferation in these models is the proliferation of bile ducts, and proliferation of biliary epithelial cells per bile duct. Progression of these lesions to cholangiocarcinoma can occur in animals that live sufficiently long.

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