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Friday 12 October 2007

Ethanol is the most widely used and abused agent throughout the world. There are 15 to 20 million alcoholics in the United States; approximately 100,000 deaths in the United States are attributed to alcohol abuse per year, with an economic cost of $100 to $130 billion.

Ethanol is ingested in alcoholic beverages such as beer, wine, and distilled spirits. A blood alcohol concentration of 80 to 100 mg/dL is the legal definition for driving under the influence of alcohol in many states. Approximately 3 ounces (44 ml) of ethanol are required to produce this blood alcohol level in a 70-kg person. This is equivalent to 12 ounces of fortified wine, 8 bottles of beer (12 ounces each), or 6 ounces of 100-proof whiskey. In occasional drinkers, a blood alcohol level of 200 mg/dL produces inebriation, with coma, death, and respiratory arrest at 300 to 400 mg/dL.

Habitual drinkers can tolerate blood alcohol levels up to 700 mg/dL. This metabolic tolerance is partially explained by a fivefold to tenfold induction of the cytochrome P-450 xenobiotic-metabolizing enzyme CYP2E1. Such induction increases the metabolism of ethanol as well as that of other drugs and chemicals, including cocaine and acetaminophen. Although no specific receptor for ethanol has been identified, chronic use results in psychologic and physical dependence. The biologic basis for ethanol addiction is unknown, although genetic factors may be involved.

Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase in the gastric mucosa and liver, and by cytochrome P-450 (CYP2E1) and catalase in the liver. Acetaldehyde is converted to acetic acid by aldehyde dehydrogenase.

There are genetic polymorphisms in aldehyde dehydrogenase that affect ethanol metabolism; approximately 50% of Chinese, Vietnamese, and Japanese people have reduced activity of this enzyme due to a point mutation that converts glutamine to lysine at amino acid 487.

These ethnic groups also rapidly convert ethanol to acetaldehyde, which builds up and triggers a facial flushing syndrome. Women have lower levels of gastric alcohol dehydrogenase activity than men do; therefore, they may develop higher blood alcohol levels than men after drinking the same quantity of ethanol.

The metabolism of ethanol is directly responsible for most of its toxic effects. In addition to its acute action as a central nervous system depressant, chronic ethanol use can cause a wide range of systemic effects.

Some of these chronic effects can be attributed to specific vitamin deficiencies; for example, damage to the peripheral and central nervous systems is related to thiamine deficiency, whereas other systemic effects result from direct toxicity. The effects of ethanol on various organ systems are discussed next.


Ethanol can cause fatty change, acute alcoholic hepatitis, and cirrhosis. Fatty change is an acute, reversible manifestation of ethanol ingestion. In chronic alcoholism, fat accumulation can cause massive enlargement of the liver.

The biochemical mechanisms responsible for fat accumulation in hepatocytes are the following:

- Catabolism of fat by peripheral tissues is increased, and there is increased delivery of free fatty acids to the liver.
- Metabolism of ethanol in the cytosol and of its derivative, acetaldehyde, in the mitochondria converts the oxidized form of nicotinamide adenine dinucleotide (NAD+) to the reduced form (NADH); an excess of NADH over NAD stimulates lipid biosynthesis.
- Oxidation of fatty acids by mitochondria is decreased.
- Acetaldehyde forms adducts with tubulin and impairs function of microtubules, resulting in decreased transport of lipoproteins from the liver.

Acute alcoholic hepatitis is another potentially reversible form of liver injury. Although fatty change is asymptomatic except for liver enlargement, alcoholic hepatitis can produce fever, liver tenderness, and jaundice. On histologic examination, there are focal areas of hepatocyte necrosis and cell injury manifest by fat accumulation and alcoholic hyalin, or Mallory bodies. Neutrophils accumulate around foci of necrosis.

Ethanol and its metabolites are directly toxic to hepatocytes; this toxicity is believed to be mediated by glutathione depletion, mitochondrial injury, altered metabolism of methionine, and cytokine release from Kupffer cells.

Hepatocellular necrosis, as well as fibrosis, begins around the central vein, suggesting that hypoxia may contribute to this injury. With chronic ethanol use, 10% to 15% of alcoholics develop irreversible liver damage, or alcoholic cirrhosis. This is characterized by a hard, shrunken liver with formation of micronodules of regenerating hepatocytes surrounded by dense bands of collagen.

Alcoholic cirrhosis is a serious, potentially fatal disease accompanied by weakness, muscle wasting, ascites, gastrointestinal hemorrhage, and coma. Perisinusoidal fibrosis occurs initially, with deposition of collagen by perisinusoidal stellate cells (Ito cells) in the spaces of Disse.

Stimulation of collagen synthesis by Ito cells may be caused by direct toxic effect of ethanol or its metabolites, or it may be mediated by cytokines. Patients with cirrhosis have depleted liver stores of α-tocopherol, which increases their vulnerability to oxidative injury.

Nervous System. The acute depressive effects and addiction produced by ethanol are hypothesized to be related to fluidization of membrane phospholipids and altered signal transduction. A deficiency of thiamine is common in chronic alcoholics. Chronic thiamine deficiency contributes to degeneration of nerve cells, reactive gliosis, and atrophy of the cerebellum and peripheral nerves. It produces the ataxia, disturbed cognition, ophthalmoplegia, and nystagmus characteristic of Wernicke syndrome. Some alcoholics with poor nutrition develop the severe memory loss characteristic of Korsakoff syndrome; this is believed to result from a combination of toxicity and thiamine deficiency.

Cardiovascular System. Chronic ethanol abuse can cause cardiomyopathy, a degenerative disease of the heart muscle, resulting in dilation of the heart.

The exact mechanism responsible for myocardial injury and altered contractility is unknown, although it is most likely due to direct toxicity rather than thiamine deficiency. Hypertension is also more common in chronic alcoholics, secondary to the vasopressor effects of ethanol triggered by increased release of catecholamines. Paradoxically, moderate consumers (one to two drinks per day) show a protective effect of ethanol on the cardiovascular system. At this level of consumption, drinkers show increased levels of high-density lipoprotein and decreased platelet aggregation.

Gastrointestinal Tract. Acute gastritis is a direct toxic effect of ethanol use. Chronic users are vulnerable to acute and chronic pancreatitis, which may lead to destruction of pancreatic acini and islets. Pancreatic acinar destruction leads to impaired intestinal absorption of nutrients and contributes to vitamin deficiencies.

Skeletal Muscle. Direct ethanol toxicity can also injure skeletal muscles, leading to muscle weakness, pain, and breakdown of myoglobin.

Reproductive System. Chronic ethanol use leads to testicular atrophy and decreased fertility in both men and women. Women who drink alcohol also have an increased risk of spontaneous abortion. The mechanisms responsible for these adverse reproductive effects are unknown.

Fetal Alcohol Syndrome. A tragic consequence of maternal ethanol consumption at levels of only one drink per day is the fetal alcohol syndrome, first recognized in 1968. This syndrome is characterized by growth and developmental defects, including microcephaly; facial dysmorphology; and malformations of the brain, cardiovascular system, and genitourinary system.

Affected infants show growth retardation, microcephaly, atrial septal defect, short palpebral fissures, maxillary hypoplasia, and several other minor anomalies. This is the most common type of preventable mental retardation in the United States, and it affects at least 1200 children per year.

The pathogenesis of fetal alcohol syndrome is not entirely clear. It is hypothesized that acetaldehyde, a metabolite of ethanol, crosses the placenta and damages the fetal brain.

Ethanol and Cancer. Use of alcoholic beverages is associated with an increased incidence of cancer of the oral cavity, pharynx, esophagus, liver, and possibly the breast. Although ethanol is not a direct-acting carcinogen, one of its metabolites, acetaldehyde, may act as a tumor promoter.18 Ethanol inhibits the detoxification of chemical carcinogens such as nitrosamines, which have been associated with tumors of the upper gastrointestinal tract. Heavy alcohol use synergizes with chronic hepatitis B or C infection in predisposing to the development of hepatocellular carcinoma.

Two other chemicals, methanol and ethylene glycol, may be ingested accidentally or used as inexpensive substitutes for ethanol. They are metabolized by alcohol dehydrogenase, but more slowly than ethanol, resulting in initial symptoms of intoxication, followed by toxic effects after several hours or days.

Methanol is metabolized to formaldehyde and formic acid, resulting in metabolic acidosis, dizziness, vomiting, blurred vision or blindness, and respiratory depression. Methanol has been proposed as a gasoline additive or substitute, but there is concern that chronic inhalation of methanol-containing fumes may cause central nervous system depression.

The lethal dose of ethylene glycol is only 1.4 mL/kg; it is metabolized by alcohol dehydrogenase to aldehydes, glycolate, oxalate, and lactate. If a person survives the initial toxicity, acute renal failure may occur several days later because of obstruction of the kidney tubules by calcium oxalate crystals. Acute methanol or ethylene glycol poisoning is treated by administration of ethanol, which slows the production of toxic metabolites.

Susceptibility (Examples)

- The ADH2 (ADH1B) Arg47His polymorphism (MIM.103720) has been associated with alcoholism in numerous studies of several populations in Asia and Europe.

- Data from South and Southeast Asia confirm that there is a low frequency of this allele in the region between eastern and western Asia. The distribution suggests that the derived allele increased in frequency independently in western and eastern Asia after humans had spread across Eurasia. (17847010)


- Li H, Mukherjee N, Soundararajan U, Tarnok Z, Barta C, Khaliq S, Mohyuddin A, Kajuna SL, Mehdi SQ, Kidd JR, Kidd KK. Geographically separate increases in the frequency of the derived ADH1B*47His allele in eastern and western Asia. Am J Hum Genet. 2007 Oct;81(4):842-6. PMID: 17847010