Research opportunities on alcohol and liver damage†
Potential conflict of interest: Nothing to report.
Alcohol abuse contributes significantly to liver-related morbidity 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+ 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.
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Alcohol metabolism, energy intake, and pharmacokinetic studies (using miniature biosensors).
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Role of alcohol in changing the hepatocyte redox state and gene activation.
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Interactions between ethanol metabolism, medications, and xenobiotics in ALD.
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Ethanol's effects on energy balance and its interactions with obesity, diabetes, and the metabolic syndrome.
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Alcohol metabolism and fatty liver.
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Differences and similarities between alcoholic and nonalcoholic steatohepatitis.
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Interactions between alcohol and its metabolism and nutritional status in ALD.
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Alcohol's effects on folic acid and methionine metabolism, hypomethylation, and epigenetics.
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Effects of alcohol on stem cell differentiation and the microenvironment.
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The effect of alcohol on liver regeneration and liver transplantation.
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Genetic vulnerability to ALD in humans and animal models.
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Use of genomics, proteomics, and metabolomics technologies to develop signature biomarkers for susceptibility to ALD and its response to treatment.
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Use of liver imaging and biotechnology to further understanding of ALD.
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Application of systems biology in elucidation of the pathophysiology of ALD.
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Mechanisms of progression of liver fibrosis, cirrhosis, and hepatocellular carcinoma in ALD.
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Role of abnormal cytokine metabolism, hepatic macrophage function, endotoxin, Kupffer and hepatic stellate cell activation, proinflammatory cytokines, and prostaglandins in ALD.
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Role of adaptive and innate immune suppression by ethanol in ALD.
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Effects of different levels of ethanol consumption on the course and outcome of hepatitis C and HCV/HIV coinfection.
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New treatment modalities for ALD and HCV-infected patients who consume alcohol.
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Effectiveness of S-adenosylmethionine, betaine, or milk thistle for the treatment of both ethanol- and HCV-induced liver diseases.
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Effects of cannabinoid receptor antagonists on the liver and PPAR signaling cascades.
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Special population studies to understand the difference in risk factors of ALD in women, diabetics, obese individuals, Hispanics, and African Americans.
NIAAA is an active participant in the NIH-wide “Action Plan for Liver Disease Research,” contributing to efforts in 8 of the 16 topic areas outlined in the Action Plan. In Fiscal Year 2003, NIAAA ranked fourth among the 27 NIH Institutes and Centers in funding for liver disease research, with a budget of $34.5 million, representing approximately 9% of the total liver-disease related budget for the NIH. Currently, NIAAA supports several program announcements related to liver disease, including “Mechanisms of Alcohol-Induced Tissue Injury” (PA-05-074) and “Mechanisms of Alcoholic and Nonalcoholic Fatty Liver (Steatosis)” (PA-05-119). Further information is available at: http://www.niaaa.nih.gov.
