Excessive ethanol consumption causes more than 60% of chronic liver disease in Western countries and accounts for 40% to 50% of deaths due to cirrhosis. Among the most important adverse effects of chronic alcohol consumption are the overlapping forms of alcohol-related fatty liver disease already discussed: (1) hepatic steatosis, (2) alcoholic hepatitis, and (3) fibrosis and cirrhosis, collectively referred to as alcoholic liver disease (
Fig. 16.18
Between 90% and 100% of heavy drinkers develop fatty liver (i.e., hepatic steatosis), and of those, 10% to 35% develop alcoholic hepatitis, whereas only 8% to 20% of chronic alcoholics develop cirrhosis. Steatosis, alcoholic hepatitis, and fibrosis may develop sequentially or independently, so they do not necessarily represent a sequential continuum of changes. Hepatocellular carcinoma arises in 10% to 20% of patients with alcoholic cirrhosis.
Short-term ingestion of as much as 80 g of ethanol per day (5–6 beers or 8–9 ounces of 80-proof liquor) generally produces mild reversible hepatic changes, such as fatty liver. Chronic intake of 40 to 80 g/day is considered a borderline risk factor for severe injury. For reasons that may relate to decreased gastric metabolism of ethanol and differences in body composition, women are more susceptible than men to hepatic injury. It seems that how often and what one drinks may affect the risk for liver disease development. For example, binge drinking causes more http://ebooksmedicine.net
Fig. 16.18 Alcoholic liver disease. The interrelationships among hepatic steatosis, alcoholic hepatitis, and alcoholic cirrhosis are shown and key morphologic features are listed. As discussed in the text, steatosis, alcoholic hepatitis, and steatofibrosis may all develop independently and not along a continuum.
liver injury than that associated with steady, lower-level consumption. Since not everyone who drinks gets all the listed complications, individual, possibly genetic, risk factors must exist, but no reliable markers of susceptibility are known. In the absence of a clear understanding of the factors that influence liver damage, it is difficult to state what constitutes a safe level of alcohol consumption.
Hepatocellular steatosis is caused by alcohol through several mechanisms. First, metabolism of ethanol by alcohol dehydrogenase and acetaldehyde dehydrogenase generates large amounts of nicotinamide-adenine dinucleotide (NADH), which increases shunting of substrates away from catabolism and toward lipid biosynthesis. Second, ethanol impairs the assembly and secretion of lipoproteins. The net effect is to cause the accumulation of intracellular lipids.
The cause of alcoholic hepatitis is uncertain, but it may stem from one or more of the following toxic byproducts of ethanol and its metabolites:
Acetaldehyde (a major metabolite of ethanol) induces lipid peroxidation and acetaldehyde-protein adduct formation, which may disrupt cytoskeleton and membrane function.
Alcohol directly affects mitochondrial function and membrane fluidity.
Reactive oxygen species generated during oxidation of ethanol by the microsomal ethanol oxidizing system react with and damage membranes and proteins. Reactive oxygen species also are produced by neutrophils, which infiltrate areas of hepatocyte necrosis.