Hepatotoxicity hepatic fibrosis/cirrhosis

Hepatic Fibrosis/Cirrhosis Fibrosis usually results from chronic inflammation which can be the result of continuous exposure to a variety of hepatotoxic chemicals such as organic arscnicals, vinyl chloride, or high doses of vitamin A (Zimmerman, 1999), chronic ethanol ingestion and nonalcoholic fatty liver disease. Fibrosis usually occurs around the portal area, in the space of Disse, and around the central veins. This results in loss of liver architecture and function. The hepatocytes are replaced with fibrous material and thus there is hepatocyte loss. Periportal fibrosis may lead to portal hypertension. 

Other additional studies or pertinent information which lend support to this MRL Hepatic effects (hepatotoxicity, necrosis, fibrosis, hemosiderosis, ascites, cirrhosis, degeneration) have been observed in rats (Bedell et al. 1982), guinea pigs (Wilson 1976), dogs (Wilson 1976), and pigs (Wilson 1976) subchronically exposed to 4.2-30 mg/kg/day 1,2-dimethylhydrazine by the oral route. 

Low et al. (2004) have proposed a model to explain thioacetamide-induced hepatotox-icity and cirrhosis in rat livers. The pathways of thioacetamide-induced liver fibrosis were found to be initiated by thioacetamide S-oxide derived from the biotransformation of thioacetamide by the microsomal flavin-adenine nucleotide containing monooxygenase and cytochrome P450 systems and involve oxidative stress and depletion of succinyl-CoA, thus affecting heme and iron metabolism. Karabay et al. (2005) observed such hepatic damage in rats with elevation of total nitrite level in livers and decrease in arginase activity. The authors have reported that nitrosative stress was essentially the critical factor in thioacetamide-induced hepatic failure in rats. 

Liver Methotrexate causes hepatotoxicity, fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequent, usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have occurred these latter lesions often are not preceded by symptoms or abnormal liver function tests (see Precautions). For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the RA population. 

Hepatic - Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal it generally occurs after prolonged use (generally 2 years or more) and after a total dose of at least 1.5 g. 

Hepatic Effects. Carbon tetrachloride has been known for many years to be a powerful hepatotoxic agent in humans and in animals. The principal clinical signs of liver injury in humans who inhale carbon tetrachloride are a swollen and tender liver, elevated levels of hepatic enzyme (aspartate aminotransferase) in the serum, elevated serum bilirubin levels and the appearance of jaundice, and decreased serum levels of proteins such as albumin and fibrinogen (Ashe and Sailer 1942 McGuire 1932 New et al. 1962 Norwood et al. 1950 Straus 1954). In cases of acute lethal exposures, autopsy generally reveals marked liver necrosis with pronounced steatosis (Jennings 1955 Markham 1967 Smetana 1939), and repeated or chronic exposures leads in some cases to fibrosis or cirrhosis (McDermott and Hardy 1963). 

The hepatotoxic pyrrolizidine alkaloids (PAs) present in coltsfoot pose the greatest concern regarding use of coltsfoot, (see also Chapter 18 for additional discussion of the pyrrolizidine alkaloids). Hepatic venoocclusive disease is characteristic of PA intoxication. The specific histologic findings are described in Section 17.5, but generally include endothelial edema, sclerosis and occlusion of the small vessels, necrosis, progressive fibrosis, and eventually cirrhosis (Roulet et al., 1988). PAs are not hepatotoxic themselves, but are converted... 

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