Bile duct lesions

Dibutyltin dichloride induced acute pancreatitis and bile duct lesions in rats, depending on dose (6 and 8 mg/kg body weight intravenously) and time (1-24 weeks) (Merkord Hennighausen, 1989 Merkord et al., 1997, 1999 Sparmann et al., 2001). The lesions in the pancreas developed into a pancreatic fibrosis, and the lesions in the liver into liver cirrhosis. A single intravenous administration of dibutyltin dichloride at 4 mg/kg body weight induced a mild interstitial pancreatitis after 2 days (Merkord et al., 2001). Repeated administration of dibutyltin dichloride (4 mg/kg body weight intravenously) to rats at intervals of 3 weeks induced acute interstitial pancreatitis and, after 9-12 weeks, a pancreatic fibrosis and liver lesions (intrahepatic bile duct hyperplasia) (Merkord et al, 2001). 

Immunocomplexes It has also been suggested that complement activation with subsequent bile-duct lesions and an increased synthesis of immunoglobulins is evoked by immunocomplexes. They are even considered to be responsible for the formation of granulomas. However, they are certainly not the primary aetiological factors. 

Harrison, R.F., Hiibscher, S.G. The spectrum of bile duct lesions in end-stage primary sclerosing cholangitis. Histopathology 1991 19 321-327... 

Sale G, Storb R, Kolb H. Histopathology of hepatic acute graft-versus-host disease in the dog. A double blind study confirms the specificity of smaU bile duct lesions. Transplantation 1978 26 103-6. 

Leonard, T. B., D. A. Neptnn, and J. A. Popp. 1984. Serum gamma glutamyl transferase as a specific indicator of bile duct lesions in the rat liver. American Journal of Pathology 116 262-269. 

Centrilobular hepatic necrosis by single doses of coumarin (1,2-benzopyrone, ds-o-coumarinic acid lactone) have been reported in the rat (Lake 1984, Lake et al. 1989, Fentem et al. 1992), whereas chronic administration resulted in bile duct lesions (Hagan etal. 1967, Cohen 1979, Evans etal. 1989). The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives (Lake etal. 1994). Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, non of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin 0-deethylase activities, whereas one or both mixed function oxidases appeared to be induced by treatment with 3,4-dimethylcoumarin, 4-methylcoumarin, 3-methyloctahydrocoumarin and 4-methyloctahydrocoumarin. These results provides an evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. 

A wide spectrum of hepatic lesions has been reported in AIDS (H4), but it is not known whether the changes are related to the presence of HIV-1. Therefore, sections from livers of autopsied patients with AIDS were examined for the presence of HIV-1 antigen p 24 (core) and gp 41 (envelope) by the avidin-biotin-peroxidase complex methods using monoclonal antibodies. The most common histologic abnormalities were steatosis, portal inflammation, Kupffer cell hyperplasia, and focal hepatocellular and bile duct damage. Immunoreactivity for HIV-1 antigens was demonstrated in 80% of cases. 

The rate of resectability is only 15-20% for proximal bile duct carcinomas but up to 70% for distal lesions. In addition, there is little benefit to preoperative decompression of the biliary tree in patients having obstructive jaundice (65,66). However, this procedure is frequently practiced. For proximal cancers, local excision is often possible. In particular, hepatic resection is indicated for upper bile duct cancers with quadrate lobe invasion or unilateral intrahepatic ductal or vascular involvement, and distal and midductal lesions may require pancreatoduodenectomy. Also, biliary-enteric continuity... 

Coumarin was tested by oral administration in two early studies in rats (Hagan etal, 1967 Bar Griepentrog, 1967 Griepentrog, 1973) and found to produce bile duct carcinomas at high levels of exposure in the latter study (lARC, 1976). However, in a re-evaluation by other pathologists of the slides from the Bar and Griepentrog (1967) study, these lesions were deemed to be non-neoplastic cholangiofibrosis and not bile duct carcinomas (Cohen, 1979 Evans et al, 1989). 

Liver changes in rats, mice, and hamsters appear to be secondary to the injury to the bile ducts presumably caused by either the di- or tributyltin compounds (Barnes and Magee 1958 Jang et al. 1986). These animals have common bile-duct systems. In rabbits and guinea pigs that have separate bile duct systems hepatic lesions were not observed, suggesting that bile duct structure may influence susceptability to hepatic damage. 

It should be noted that the cerebral edema produced by triethyltin can be regarded as a specific effect. However, the lesions of the bile ducts in rats and mice previously described for dibutyltin compounds appear to be a more species-specific effect. 

Liver is the target organ for aflatoxins, and aflatoxicosis leads to proliferation of the bile duct, centrilobular necrosis and fatty infiltration of the liver, hepatomas and hepatic lesions. The susceptibility of animals to AFB] varies with species [reviewed in Eaton and Groopman, 72]. In addition to the liver, AFB] also affects other organs and tissues, such as the lungs and the entire respiratory system [73-75]. 

Cholangiodestmctive cholestasis is caused by bile duct obstruction which may be intrahepatic or extrahepatic. Bile duct injury may lead to sloughing of epithelial cells into the lumen, cell edema, and inflammation, which may contribute to obstruction (Treinen-Moslen, 2001 Plumlee, 2004). Chronic lesions associated with cholangiodestmctive cholestasis typically include bile duct prohferation and periductular fibrosis. Vanishing bile duct syndrome, characterized by a loss of bile ducts, has been seen in chronic cholestatic disease in humans (Zimmerman, 1999 Treinen-Moslen, 2001) and has been produced experimentally in dogs (Uchida, 1989). 

The Increase In AP activity is stimulated by bile acids. A rise in bile acids, which is considered to be the most sensitive and earliest marker of cholestasis, precedes any elevation in AP. The latter derives from enzyme synthesis with increased secretion into the blood. Under pathological conditions, bile duct AP is formed, which is a sensitive marker for hepatobiliary diseases, cholestasis and space-occupying lesions of the liver. The sensitivity is 80-100% in cholestatic diseases. AP activity is usually higher in obstructive jaundice and cholangitis than in intrahepatic obstructions, and it is highest in the vanishing bile duct disease or in complete obstruction. (13, 39, 41) (s. tabs. 5.9 13.2-13.4)... 

Occasionally, ductopenia (= vanishing bile duct syndrome) is observed. This condition is given when more than half of the portal fields in a large biopsy specimen fail to feature a bile duct. The irregular distribution of the lesions can make it very difficult to form a diagnosis based on just one biopsy specimen. The safest way is to carry out several biopsies (e. g. with the help of laparoscopy) and to make an assessment based on more than 20 portal areas. (8, 31, 93, 118, 128) (s. tabs. 29.3 29.10)... 

Leukotrienes can form in hepatocytes, Kupffer cells and masto-cytes. Their release, induced by endotoxins for example, correlates with the increase in AP, LAP and y-GT. Leukotrienes have a marked inflammatory effect. Enhanced production together with reduced secretion of leukotrienes into the bile can result in severe lesions of the bile ducts. (203)... 

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