The amount of fatty acid in the liver depends on the balance between the processes of delivery and removal. Fatty liver develops in every individual who consumes more than 60 g/d of alcohol. Many mechanisms of ethanol-induced fatty liver have been proposed. Increased hepatic levels of glycerol 3-phosphate (3-GP) following ethanol ingestion are related to an increase in the ratio of nicotinamide adenine dinucleotide, reduced form, (NADH) to nicotinamide adenine dinucleotide (NAD) in the liver. Increasing concentration of 3-GP results in enhanced esterification of fatty acids.
An increased level of free fatty acids also has been incriminated in the pathogenesis of fatty liver. Large amounts of alcohol enhance lipolysis because of the direct stimulatory effect on the adrenal and pituitary axis. In addition, chronic ingestion of ethanol inhibits the oxidation of fatty acids in the liver and the release of very low-density lipoprotein (VLDL) into the blood. All of these mechanisms favor steatosis. Centrilobular localization of steatosis results from decreased energy stores from relative hypoxia and a shift in lipid metabolism, along with a shift in the redox reaction caused by the preferential oxidation of alcohol in the central zone.
Advancement in the understanding of the pathogenesis of alcoholic steatosis provided some novel insights, including the role of peroxisome proliferator-activated receptor alpha, which is crucial for the regulation of hepatic fatty acid metabolism. Its blockade, in animal models, along with ethanol consumption, contributes to the development of alcoholic fatty liver. In addition, induction of adiponectin, a hormone secreted by adipocytes, has been implicated in the protective action of saturated fat against the development of alcoholic fatty liver in mice.
Recent developments in the understanding of the pathogenesis of fatty liver provided the findings described below.
The role of the early growth response-1 (EGr-1) transcription factor is thought to be essential for ethanol-induced fatty liver injury in mice. Hepatocyte death by apoptosis occurs in alcoholic fatty liver and has been demonstrated in rats and mice after ethanol feeding. This may be related to mitochondrial proteins that regulate apoptosis and necrosis and that are shown to be induced in mouse fatty liver models.
Serum leptin, a cytokine-type peptide hormone mainly produced by adipocytes, may play an important role in the pathogenesis of steatosis. Steatosis occurs with decreased leptin action, whether due to leptin deficiency or resistance. In a recent study in patients with alcoholic liver disease, serum leptin was noted to be independently correlated with the grade of steatosis.
Recent data from both animal studies and clinical studies support the role of proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the early stage of fatty liver as well as alcoholic steatohepatitis.
Frequency
United States
Approximately 15.3 million people in United States abuse or depend on alcohol. Fatty liver develops in 90-100% of patients with heavy alcohol use.
International
One observational study from northern Italy demonstrated prevalence rates of steatosis in 46.4% of heavy drinkers (>60 g/d of alcohol) and in 94.5% of obese heavy drinkers.
Mortality/Morbidity
Simple steatosis rarely is fatal. With complete abstinence, histologic changes can return to normal within 2-4 weeks.
Continued alcohol consumption may result in more advanced forms of liver disease, either alcoholic hepatitis or cirrhosis.
A study from Denmark, which used the Danish National Registry, noted an increase in mortality among patients with a hospital discharge diagnosis of alcoholic fatty liver, which remained increased after censoring patients upon a diagnosis of cirrhosis.
Race
Very little data are available on racial differences in the incidence of alcoholic fatty liver. However, overall differences in alcoholic liver disease have been noted in various studies.
One study of 42,862 US adults showed differences in drinking patterns among different races. Whites were the most likely to drink, but blacks had the highest volume of intake and frequency of heavy drinking.
Another study showed a higher rate of cirrhosis among blacks.
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Women develop more severe alcoholic liver disease (ALD) more quickly and at lower doses of alcohol than men.
Increased susceptibility of females possibly is related to ----dependent differences in the hepatic metabolism of alcohol, cytokine production, and the gastric metabolism of alcohol.
Age
The liver handles alcohol differently with age, and alcohol toxicity increases with age because of increased organ susceptibility. This is thought to be related to a mitochondrial transport defect with age as well as decreased function of the smooth endoplasmic reticulum and metabolism of CYP2E1-dependent microsomal ethanol oxidation.
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