A lcohol abuse contributes significantly to liver-related mor- bidity and mortality in the United States. The effects of alcohol on the liver include fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis (alcoholic liver disease or ALD). As many as 900,000 people in the United States suffer from cirrhosis, and some 26,000 of these die each year. Current estimates are that 40% to 90% of people with cirrhosis have a history of alcohol abuse.
The risk for liver disease from alcohol is related to the extent and amount a person drinks. Other factors that contribute to the outcome in ALD include infection with hepatitis C virus (HCV), iron overload (hemochromatosis), obesity, diabetes, genetic variations in alcohol-metabolizing enzymes, and female sex. In addition, excessive alcohol consumption impairs the absorption and use of nutrients such as vitamins, proteins, and amino acids, contributing to the malnutrition and liver injury found in many alcoholics. Moreover, the normal metabolism of other nutrients such as lipids can be impaired by alcohol metabolism in the liver, thus contributing to the formation of reactive oxygen species (ROS), causing oxidative stress and depletion of glutathione, factors that exacerbate liver injury. Alcohol also interferes with the folate cycle, which results in DNA hypomethylation and may predispose to cancer.
Understanding alcohol metabolism is important in elucidating the mechanisms by which alcohol injures the liver. The major pathway of oxidative metabolism of ethanol in the liver involves alcohol dehydrogenase, which produces acetaldehyde, which can form stable acetaldehyde-protein adducts that are immunogenic and can induce inflammatory injury. In addition, the resulting increase in NADH/ NAD Ο© ratio (redox state) produces ROS via the mitochondrial electron transport chain, and it may influence acetylation of histones and gene activation. The upregulation of cytochrome CYP2E1 by chronic ethanol use plays a key role in the pathogenesis of ALD and alters the metabolism of other compounds such as acetaminophen and environmental pro-carcinogens. Ethanol also depletes mitochondrial glutathione, which reduces mitochondrial antioxidant capacity and predisposes to apoptosis and cell death.
Understanding the interactions between ethanol consumption, the hepatic metabolism of ethanol, its effects on gene activation, and the interactions of alcohol with other risk factors for liver disease is far from complete. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) supports basic and clinical research in areas including but not limited to the following:
β’ Alcohol metabolism, energy intake, and pharmacokinetic studies (using miniature biosensors).
β’ Role of alcohol in changing the hepatocyte redox state and gene activation.
β’ Interactions between ethanol metabolism, medications, and xenobiotics in ALD.
β’ Ethanol's effects on energy balance and its interactions with obesity, diabetes, and the metabolic syndrome.
β’ Alcohol metabolism and fatty liver.