Alcoholic Fatty Liver

Background: Pathologic changes observed in patients with alcohol-induced liver disease can be divided into the following 3 groups: alcoholic fatty liver (simple steatosis), alcoholic hepatitis, and alcohol-related cirrhosis. Alcoholic fatty liver is an early and reversible consequence of excessive alcohol consumption.

Pathophysiology: 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 direct stimulatory effect on the adrenal and pituitary axis. In addition, chronic ingestion of ethanol inhibits oxidation of fatty acids in the liver and 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.

Recent advancement in the understanding of the pathogenesis of alcoholic steatosis has 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. Another recent finding is the role of early growth response-1 transcription factor (EGr-1), which is thought to be essential for ethanol-induced fatty liver injury in mice. Hepatocyte death by apoptosis occurs in the 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.

Frequency:

• In the US: 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.

• Internationally: 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.

• Recently, 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.

Sex:

• 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 sex-dependent differences in the hepatic metabolism of alcohol, cytokine production, and the gastric metabolism of alcohol.

Treatment
Medical Care:

• No specific medical treatment is needed for patients with alcoholic fatty liver. Steatosis usually resolves within 2 weeks of discontinuing alcohol.

• Abstinence and adequate diet are the mainstays in therapy for alcohol-induced steatosis.

• Bed rest has no proven benefit.

• Anabolic steroids may be detrimental.

• Management of patients with alcoholism and fatty liver often requires recognition and treatment of alcohol withdrawal.

• These patients may have deficiencies of vitamins, minerals, and trace elements. Adequate replacement of these deficiencies should be a part of management.
• Although alcohol-induced hyperhomocysteinemia (which has been associated with endoplasmic reticulum stress leading to apoptosis and up-regulation of lipid synthesis) and its correction by betaine have been studied in animal models, no definite role of the use of betaine in alcoholic fatty liver in humans is available.

Consultations:

• Offer alcohol rehabilitation to all patients, with an understanding of the addictive problem of alcoholism.

• Counsel patients on the detrimental effects of alcohol on the current liver problem and the likely progression to a more advanced form of liver disease with continued alcohol use.

Diet:

• No specific dietary restrictions are needed in patients with simple steatosis.

• Protein-calorie malnutrition is a common finding for patients with ALD and is associated with major complications observed with cirrhosis. Consequently, recognizing and understanding the significance of malnutrition in these patients is very important.