Hepatotoxicity fatty liver

Hazle JD, Narayana PA, Dunsford HA. 1991. In wVoNMR, biochemical, and histologic evaluation of alcohol-induced fatty liver in rat and a comparison with CCh hepatotoxicity. Magn Reson Med 19 124-135. 

Liver disease is the most common medical complication of alcohol abuse an estimated 15-30% of chronic heavy drinkers eventually develop severe liver disease. Alcoholic fatty liver, a reversible condition, may progress to alcoholic hepatitis and finally to cirrhosis and liver failure. In the United States, chronic alcohol abuse is the leading cause of liver cirrhosis and of the need for liver transplantation. The risk of developing liver disease is related both to the average amount of daily consumption and to the duration of alcohol abuse. Women appear to be more susceptible to alcohol hepatotoxicity than men. Concurrent infection with hepatitis or C virus increases the risk of severe liver disease. 

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. 

Toxic effects to the liver are studied under the topic of hepatotoxicity, and substances that are toxic to the liver are called hepatotoxins. Much is known about hepatotoxicity from the many cases of liver toxicity that are a manifestation of chronic alcoholism.6 Liver injury from excessive alcohol ingestion initially hampers the ability of the organ to remove lipids, resulting in their accumulation in the liver (fatty liver). The liver eventually loses its ability to perform its metabolic functions and accumulates scar tissue, a condition known as cirrhosis. Inability to synthesize clotting factors can cause fatal hemorrhage in the liver. 

Hazle JD, Narayana PA, Dunsford HA (1991) In vivo NMR, biochemical, and histologic evaluation of alcohol-induced fatty liver in rat and a comparison with CC14 hepatotoxic-ity. Magnetic Resonance in Medicine 19 124-135 Hockings PD, Busza AL, Byrne J et al. (2003a) Validation of MRI measurement of cardiac output in the dog The effects of dobutamine and minoxidil. Toxicology Mechanisms Methods 13 39-43... 

Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004 24 3-20. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003 37 917-923. Wanless IR, Lentz JS. Eatty liver hepatitis (steatohepatitis) and obesity an autopsy study with analysis of risk factors. Hepatology 1990 12 1106-1110. Zimmerman HJ. Hepatotoxicity. The adverse effects of drugs and other chemicals in the liver, 2nd edn. Philadelphia Lippincott Williams Wilkins, 1999. Mason P. Cystic fibrosis - the disease. Hosptal Pharmacist 2005 12 201-207. Tolman KG, Eonseca V, Tan MH, et al. Narrative review hepatobiliary disease in type 2 diabetes mellitus. Ann Intern Med 2004 141 946-956. 

Chalasani N (2005) Statins and hepatotoxicity focus on patients with fatty liver. Hepatology 41 690-695. 

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. 

Comparable reports have prompted a questionnaire investigation of 770 patients with type 2 diabetes at the start of acarbose therapy (51). Patients with one or more susceptibility factors for liver damage underwent ultrasonography and autoantibody assays. There was silent hver disease in 13% and 20 patients had a fatty liver without hepatic disease. In 15% of these patients there were slight reversible changes in transaminase activity after acarbose. This supports the supposition that severe hepatotoxic reactions to acarbose are idiosyncratic. 

Donthamsetty S, Bhave VS, Mitra MS, LatendresseJR, Mehendale HM. Nonalcoholic fatty liver sensitizes rats to carbon tetrachloride hepatotoxicity. Hepatology. 2007 45(2) 391-403. 

Ethionine is a hepatotoxic analogue of the amino acid methionine (figure 7,4 E). Ethionine is an antimetabolite which has similar chemical and physical properties to the naturally occurring amino acid. After acute doses ethionine causes fatty liver but prolonged administration results in liver cirrhosis and hepatic carcinoma. Some of the toxic effects may be reversed by the administration of methionine. The effects may be produced in a variety of species, athough there are differences in response. The rat also shows a sex difference in susceptibility, the female animal showing the toxic response rather than the... 

Carbon tetrachloride. A hepatotoxic solvent which causes centrilobular necrosis and fatty liver liver cirrhosis and tumours and kidney... 

Given the multiple metabolic functions performed by the liver, it should not be surprising that the hepatotoxic effects of xenobiotics are so different several different morphological patterns of xenobiotic-induced hepatotoxicity can be observed (Plaa 1991 Batt and Ferrari 1995 Zimmerman 1999 Plaa and Charbonneau 2001 Kaplowitz 2002 Kaplowitz and DeLeve 2003 Lee 2003). For example, in acute toxicity, cell degeneration leads to necrosis (cell death), and this may or may not be accompanied by steatosis (an accumulation of lipids and fatty liver where hepatic lipid content is >5%). Necrosis may affect small groups of hepatocytes (i.e., focal... 

An 82-year-old man with fatty liver who regularly used laxatives (herbal and nonherbal) over the course of the prior 20 years developed hepatotoxicity with elevated levels of liver enzymes after the commercial herbal laxative that he had been taking changed formulas to include an extract of boldo as one of the ingredients in a multi-ingredient product. Liver enzymes returned to normal after cessation of the herbal laxative (Piscaglia et al. 2005). 

There are two isomers of triehloroethane, namely methyl chloroform and 1,1,2-trichloroethane. Animal hepatotoxicity to 1,1,2-trichloroethane is documented in the literature with potentiation of toxieity in association with acetone, isopropyl aleohol and ethanol. Hepatotoxicity, with steatosis, necrosis, elevated serum enzymes, and increased liver weight have been observed in animal models exposed to 1000 ppm of methyl chloroform. Human studies eonsist of ease reports documenting hepatotoxicity, with elevated serum transaminases and fatty liver disease related to 1,1,1-triehloroethane exposure. Epidemiologic evidence suggests little hepatotoxieity related to this agent at exposure levels <350 ppm. ... 

Cederbaum AI (2010) Role of CYP2E1 in ethanol-induced oxidant stress, fatty liver and hepatotoxic-... 

Liver Hepatotoxic events occasionally have been reported when ezetimibe is used in conjunction with a statin, as in the case of a 70-year-old woman who developed fulminant hepatic failure, necessitating liver transplantation 10 weeks after switching from simvastatin to simvastatin 4- ezetimibe[25]. A study with 32 subjects with nonalcoholic fatty liver disease pathology showed that ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA c [26]. 

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