Chronic alcohol consumption induces liver fibrosis (scarring) by stimulating the fat-storing cells of the liver to differentiate into collagen-producing stellate cells. It is believed this leads to irreversible cirrhosis. Alcoholic liver fibrosis may occur indirectly through acetaldehyde-protein adducts that can enhance collagen synthesis by stellate cells in vitro. Products of lipid peroxidation also increase collagen synthesis which may lead to fibrosis.

Although there are a variety of biomechanical mechanisms through which alcohol or alcohol-metabolites may cause liver damage, the problem is more complex. Hereditary variations in enzymes may explain why only a small proportion of alcoholics develop serious liver disease. Although generic variants, polymorphisms in alcohol dehydrogenase (ADH), CYP2E1 isozyme, and aldehyde dehydrogenase (ALDH) result in various rates of alcohol metabolism among different ethnic groups, no single alcohol dehydrogenase allele has been causally linked to alcoholic liver injury.

Aldehyde dehydrogenase polymorphisms may also play a role in the development of alcoholic liver injury. ALDHY, an allele which is present in about half of all Chinese and Japanese, encodes an enzyme that is completely nonreactive toward acetaldehyde. ALDHY homozygotic individuals (those who have two copies of this allele) generally have an aversion to alcohol because of the accumulation of acetaldehyde. However, chronic drinkers who are ALDHY heterozygotes (those who have one copy of the ALDHY allele) do not have an alcohol aversion and develop liver injury more frequently and at lower cumulative doses than people with normal aldehyde dehydrogenase.

Finally, gender also may play a role in the development of alcohol-induced liver damage. Some evidence indicates that women are more susceptible than men to the cumulative effects of alcohol on the liver, even though women drink less than men. Compared with men, women who have alcoholic liver injuries remain at higher risk of disease progression even with abstinence. This curious gender difference suggests that gastric alcohol dehydrogenase may be a causative factor. alcohol dehydrogenase is present at high levels in the liver in both men and women, but differences in gastrointestinal alcohol dehydrogenase between men and women may affect its bioavailability. Women have lower levels of gastric alcohol dehydrogenase activity than men so their livers receive more concentrated levels of alcohol from the gut, thereby placing women at greater risk for liver damage. Although this is an interesting concept, other investigators have found no such gender differences in gastric alcohol dehydrogenase activity, and some researchers question the significance of the stomach in the first-pass metabolism of alcohol.

Gender differences in alcohol-induced liver injury may be related to gender differences in the metabolism of fatty acids rather than alcohol itself. The accumulation of nonmetabolized fatty acids in the liver through alcohol inhibition of the oxidation of fatty acids by hepatic mitochondria has long been known to be part of the alcoholic disease process. It is believed the infiltration of fat impairs intracellular functioning and causes cell injury (NIAAA).