Bile duct proliferation

In chronic studies rats fed 1000 ppm MOCA in a standard diet for 2 years developed lung tumors there were 2 5 adenomatoses and 48 adenocarcinomas in 88 rats. Accompanying liver changes included hepatocytomegaly, necrosis, bile duct proliferation, and fibrosis. In 88 control animals, there were two lung adenomatoses. MOCA in a low-protein diet caused lung tumors in rats of both sexes, liver tumors in males, and malignant mammary tumors in females. 

In one-, four- and 13-week studies, the effects of coumarin treatment were compared in male Sprague-Dawley rats, CD-I mice and Syrian hamsters. Rats were fed 0-0.75% coumarin for one and four weeks and 0.5% coumarin for 13 weeks. Mice and hamsters were fed 0-0.5 and 0-1.0% coumarin, respectively, for one, four or 13 weeks. In the rat, coumarin caused dose-related hepatotoxic effects which included vacuolar degeneration, apoptosis and bile duct proliferation and increases in serum bilirubin content and both serum and hepatic y-glutamyltranspeptidase activity. A sustained stimulation of hepatocyte replicative DNA synthesis was observed in rats treated for four and 13 weeks. Levels of total hepatic glutathione were increased approximately twofold, and there were statistically significant decreases in microsomal cytochrome P450 content and ethylmorphine 7V-demethylase activity. These effects were reduced or not observed in mice and hamsters (Lake Grasso, 1996). 

Ethionine is a hepatotoxic analogue of methionine causing fatty liver (accumulation of triglycerides). Chronic exposure causes cirrhosis, bile duct proliferation, and heptatocellular carcinoma. It forms S-adenosyl ethionine, which traps adenosyl leading to ATP depletion, which reduces triglyceride export from the liver. It also leads to ethylated bases in DNA. 

A 49-year-old woman developed jaundice after taking pioglitazone 30 mg/day for 6 weeks, and after 3 weeks the alanine transaminase was 131 U/l and aspartate transaminase 79 U/l (106). Tests for viral hepatitis were negative. A liver biopsy showed marked portal edema, patchy chronic inflammation, a cellular infiltrate, and marked bile duct proliferation. There was no fibrosis. The laboratory results worsened after pioglitazone was withdrawn, and 1 month after withdrawal the bilirubin reached a peak of 585 pmol/1. Over the next 8 weeks the symptoms and laboratory tests improved, and after 6 months her condition was the same as when she had started to take pioglitazone. 

A dose-related trend towards portal sclerosis and bile duct proliferation was observed in rats given doses of from 0.3 to 6.2 mg/kg/day triphenyltin hydroxide for 52 and 104 weeks there was no corresponding increase in liver weight (Tennekes et al. 1989a). The dose-related trend was stronger in females (p<0.0005) than in males (p<0.005). In mice this same compound was associated with a 35%-40% increase in liver weight and nodular hyperplasia at doses of 15.2 mg/kg/day for males and 20.2 mg/kg/day for females but not at lower doses (Tennekes et al. 1989b). 

Gn pig (NS) 35 wk 2 or 4x/wk (GO) Hepatic 0.75 (moderate to marked fibrosis, parenchymal fatty metamorphosis, slight bile duct proliferation, hypertrophy, atrophy) Ashburn et al. 1948... 

TCDD. Necrosis, peripheral fibrosis, and bile duct proliferation were observed in rabbits acutely exposed to 2,3,7,8-TCDD on the ear surface (Kimbrough et al. 1977). Increased liver/body weight ratio and hepatocellular hypertrophy were seen in HRS/J hairless mice topically exposed to 0.0025 g... 

Fig. 22.5 Numerous multinuclear giant cells (centre of picture) as well as bile duct proliferation (arrow) in so-called giant-cell hepatitis (HE)...

A disease of epidemic proportions affected more than 1,000 persons in India in 1974. The patients suffered from jaundice and ascites. Histological examination revealed centroacinar necrosis, inflammatory mesenchymal reactions and bile-duct proliferation fibrosis and septal formation, sometimes ultimately cirrhosis, were determined. Mortality was 10%. The cause was thought to be the additive effect of several unidentified mycotoxins (B.N. Tandon et al., 1977). 

In NRH, the liver is interspersed with numerous diffuse nodes, which are 1-3 mm in size (occasionally up to 3 cm) and yellow to yellowish brown in colour with blurred boundaries they consist of hyperplastic hepato-cytes. No fibroses or perinodal connective tissue septa are evident. The multilayered, disordered trabeculae do not have a lobular structure. (66, 69) CD 8" cytotoxic T cells infiltrate the acinus. The nodes lack central veins and bile duct proliferations. The intemodular parenchyma becomes atrophied due to pressure. It is possible by means of reticulin staining to demonstrate the nodes with the irregular trabeculae, whereas the altered vessels are best shown using elastica staining. The liver surface is smooth. (78) In the course of disease, presinusoidal, and later sinusoidal, portal hypertension with hepato-splenomegaly and oesophageal varices are usually observed. (64, 65, 67) (s. fig. 36.4)... 

Bile-duct adenomas are rare. Usually, they are solitary and < 2 cm in size. This type of adenoma is more often detected in men than in women (3 1) and it occurs in patients mainly over the age of 50. It is nearly always localized beneath the liver capsule. This adenoma has the form of a firm, whitish node and consists of bile-duct proliferations. It contains biliary acini and tubules which are lined with a layer of cuboid epithelium within loose fibrous, partially hyaline stroma. There is evidence of mononuclear inflammatory cells and, occasionally, lymph follicles. It is discussed that such biliary adenomas are peribiliary gland hamartomas. (162) There are no clinical or biochemical abnormalities, nor is there any tendency towards malignant degeneration. (161,163)... 

In female rats josamycin caused bile duct proliferation at a high dose of 1460 mg/kg (3). 

A previously healthy 46-year-old man developed acute fulminant hepatitis following treatment with rabepra-zole, citalopram hydrobromide, terbinafine, and a multivitamin formulation (41). Liver biopsy showed submassive centrilobular necrosis and intrahepatic cholestasis with florid bile duct proliferation. 

Hruban RH, Sturm PD, Slebos RJ, et al. Can K-ras codon 12 mutations be used to distinguish benign bile duct proliferations from metastases in the liver A molecular analysis of 101 liver lesions from 93 patients. Am J Pathol. 1997 151 943-949. 

Hepatic effects such as elevated liver enzyme levels, nodular hepatic hyperplasia, fatty changes, necrosis, fibrosis, and bile duct proliferation were observed in rats and dogs following chronic exposure to MBOCA (Stula et al. 1975, 1977). Chronic exposures to high levels of MBOCA at hazardous waste sites may induce similar adverse hepatic effects. 

In rats orally administered riddelliine at doses up to 10 mg/kg and in mice administered riddelliine at doses up to 25 mg/kg 5 days a week for 13 weeks, dose-related hepatopathy and intravascular macrophage accumulation in rats and hepatocytomegaly in mice were observed. Some animals were given a 14-week recovery period after treatment, and during that time, hepatic foci of cellular alteration in male rats and bile duct proliferation in female rats and male and female mice increased in severity (Chan et al. 1994). 

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