National Institute on Alcohol Abuse and Alcoholism No. 19 PH 329 January 1993

Alcohol and the Liver

Alcoholic liver disease is one of the most serious medical consequences of chronic alcohol use. Moreover, chronic excessive alcohol use is the single most important cause of illness and death from liver disease (alcoholic hepatitis and cirrhosis) in the United States (1).

The Normal Liver

Normal liver function is essential to life. The liver is the largest organ of the body, located in the upper right section of the abdomen. It filters circulating blood, removing and destroying toxic substances; it secretes bile into the small intestine to help digest and absorb fats; and it is involved in many of the metabolic systems of the body. Digested food substances are carried from the intestine directly to the liver for further processing. The liver stores vitamins; synthesizes cholesterol; metabolizes or stores sugars; processes fats; and assembles amino acids into various proteins, some for use within the liver and some for export. The liver controls blood fluidity and regulates blood-clotting mechanisms. It also converts the products of protein metabolism into urea for excretion by the kidneys.

Alcoholic Liver Disease

The three alcohol-induced liver conditions are fatty liver, alcoholic hepatitis, and cirrhosis.

Some degree of fat deposition usually occurs in the liver after short-term excessive use of alcohol. However, fatty liver rarely causes illness (2).

In some heavy drinkers, alcohol consumption leads to severe alcoholic hepatitis, an inflammation of the liver characterized by fever, jaundice, and abdominal pain (3). Severe alcoholic hepatitis can be confused with many serious abdominal conditions, such as cholecystitis (inflammation of the gall bladder), appendicitis, and pancreatitis. It is important to be aware of this potential confusion because some of these other conditions require surgery, and surgery is contraindicated in patients with alcoholic hepatitis. These patients have a high death rate following surgery.

The most advanced form of alcoholic liver injury is alcoholic cirrhosis. This condition is marked by progressive development of scar tissue that chokes off blood vessels and distorts the normal architecture of the liver (2).

A patient may have only one of the three alcohol-induced conditions or any combination of them. Traditionally, they have been considered sequentially related, progressing from fatty liver to alcoholic hepatitis to cirrhosis. However, some studies have demonstrated that alcoholics may progress to cirrhosis without passing through any visible stage resembling hepatitis. Thus, alcoholic cirrhosis can appear insidiously, with little warning (4).

Fatty liver is reversible with abstinence. Alcoholic hepatitis may be fatal but can be reversible with abstinence (5). While alcoholic cirrhosis is often progressive and fatal, it can stabilize with abstinence (3).

Complications of advanced liver disease include severe bleeding from distended veins in the esophagus, brain disorders (hepatic encephalopathy), accumulation of fluid in the abdomen (ascites), and kidney failure (6).

Not all liver disease that may occur in alcoholics is caused by alcohol. In addition, when alcohol-induced liver disease does occur, it may be accompanied by other conditions, not related to alcohol, that also can cause liver failure. These include nonalcoholic hepatitis and exposure to drugs and occupational chemicals (see below).

Extent of the Problem

Alcohol-related cirrhosis is know n to be underreported. However, about 44 percent of all deaths caused by cirrhosis in North America are reportedly alcohol related (7).

Up to 100 percent of heavy drinkers show evidence of fatty liver, an estimated 10 to 35 percent develop alcoholic hepatitis, and 10 to 20 percent develop cirrhosis (1).

Daily drinkers are at a higher risk of developing alcoholic cirrhosis than are binge drinkers (8). In general, patients with alcoholic cirrhosis have been drinking heavily for 10 to 20 years (8-10).

Mortality from cirrhosis in the United States varies significantly with gender, race, and age. In 1988, the highest mortality from cirrhosis occurred in nonwhite males, followed by white males, nonwhite females, and white females (11). Most of the deaths from alcoholic cirrhosis occur in people ages 40-65 (11). Thus, alcoholic cirrhosis kills people in what should be their most productive years.

How Does Alcohol Damage the Liver?

Currently we do not know how alcohol causes cirrhosis. However, there are many mechanisms by which alcohol injures the liver. Many of these mechanisms are poorly understood, in part because no simple animal model has been developed for cirrhosis. In addition, there is considerable variation among individuals in susceptibility to alcoholic liver disease, so that among people drinking similar amounts, only some develop cirrhosis.

Diet. Before the 1970's, alcoholic cirrhosis was believed to arise from nutritional deficiencies common among heavy drinkers. Overwhelming evidence subsequently proved that alcohol itself is toxic to the liver, even when nutrition is adequate. Today, it is believed that nutritional effects and direct alcohol toxicity interact in such complex ways that the influence of the two cannot be separated (12).

Genetics. Genetic differences might explain why some heavy drinkers develop cirrhosis while others do not. The scar tissue that forms in the cirrhotic liver is composed of the protein collagen. It has been suggested that stimulation of collagen synthesis resulting from activation of the collagen gene may promote liver scarring (13). In that case, it might be speculated that differences in genes for collagen among individual drinkers may be associated with differences in the development of alcoholic cirrhosis.

Free radicals and acetaldehyde. Much of the cell damage that occurs during liver degeneration is believed to be caused by free radicals, highly reactive molecular fragments, liberated during alcohol metabolism. The damage caused by free radicals can include the destruction of essential components of cell membranes. The cell's natural defenses against free radicals include the natural chemicals glutathione (GSH) and vitamin E.

The function of GSH and vitamin E is impaired in alcoholics. For example, chronic alcohol ingestion decreased GSH levels in baboons and humans (14). Similarly, chronic alcohol feeding significantly increased damage caused by free radicals in liver cells of rats maintained on a diet low in vitamin E (15).

Acetaldehyde, the primary metabolic product of alcohol in the liver, appears to be a key generator of free radicals. Because of its reactivity, acetaldehyde can promote membrane damage and can stimulate the synthesis of collagen to form scar tissue (16-18).

Nonalcoholic hepatitis. The increased prevalence of hepatitis C viral infection in alcoholics might explain some of the variation in individual susceptibility to alcoholic liver disease (19). In addition, chronic hepatitis C infection is significantly correlated with the severity of alcoholic cirrhosis (20) and may influence the progression of alcoholic liver disease in some patients (21,22).

The immune system. The immune system responds or contributes to liver cell damage in alcohol-induced liver disease in complex ways, although a causal relationship is unclear. Acetaldehyde has been shown to attach chemically to liver proteins. The altered proteins may then trigger various immune responses (23). Cellular toxins are released, causing cell damage; certain proteins are deposited along the liver's small blood-carrying channels; and specific white blood cells are activated (24-27).

Liver metabolism. Chronic alcohol administration has been found to increase the rate of oxygen metabolism by the liver. In addition, a series of studies by Israel and colleagues (28) demonstrated similarities in the effects of alcohol and thyroid hormone on liver cells. They called these effects the "liver hypermetabolic state." As a result of these studies, propylthio-uracil, a drug used to treat excessive production of thyroid hormone, has been tested for the treatment of alcoholic liver disease (see Treatment below).

Gender. Current evidence suggests that women may be more susceptible than men to alcoholic liver disease; more research is necessary to validate this hypothesis (8,19).

Environmental factors. Chronic alcohol consumption markedly increases the liver toxicity of various industrial solvents, anesthetics, medications, and vitamins (29,30). For example, acetaminophen (Tylenol and others), a widely used over-the-counter pain reliever, is generally safe when taken in recommended doses. However, excessive use of acetaminophen has been associated with liver toxicity in people drinking heavily (30-32). Alcohol also enhances the toxicity of excess vitamin A, so care must be taken when treating an alcoholic with a vitamin A deficiency (33).

Treatment

Alcoholic hepatitis. Mortality from alcoholic hepatitis during the early weeks of treatment is very high. Although the evidence is inconsistent, corticosteroid therapy may improve survival during the early stages of the disease in patients with severe alcoholic hepatitis (34-38). Supplemental amino acids may improve a patient's nutrition but not the chances of survival or progression to cirrhosis (39).

Orrego and colleagues (40) reported that the drug propylthiouracil (PTU) improved survival of patients with all types of alcoholic liver disease. However, other studies have demonstrated no benefit from this therapy in patients with alcoholic hepatitis (41,42).

Abstinence is the cornerstone of therapy for patients with prolonged alcoholic hepatitis. Also important are careful control of diet with correction of vitamin deficiencies, and management of medical complications (38).

If the patient with alcoholic hepatitis lives to leave the hospital, abstinence is essential for long-term survival. Alexander and coworkers (43) found that more than 80 percent of those who abstained or markedly reduced their drinking were alive 7 years later, whereas only 50 percent who continued to drink were alive 7 years later.

Alcoholic cirrhosis. Treatment for cirrhosis is directed at symptoms and complications, with abstinence a requirement. For terminally ill patients, liver transplantation is the only effective treatment. This procedure in alcoholic cirrhotic patients has demonstrated success and survival rates equal to those for nonalcoholic cirrhotic patients (44).

Future directions in cirrhosis therapy are suggested by a study showing that lecithin protects against the development of alcohol-induced liver scarring in baboons (45). This therapy has not yet been studied in humans.

Alcohol and the Liver--A Commentary by
NIAAA Director Enoch Gordis, M.D.

Abstinence from alcohol is the single most important component of treatmen t for alcoholic liver disease. Continued drinking will worsen the condition of patients with this disease and greatly increase their risk for death. Physicians who treat alcoholic liver disease, no matter how competently, and who do not address their patients' drinking are practicing bad medicine, akin to treating an iron-deficiency anemia and disregarding the colon cancer that is causing it.

Because many alcohol abusers and most alcoholics require some form of treatment to remain abstinent, simply giving advice to "quit" drinking often is not sufficient. Physicians who choose not to manage their patients' alcohol problems may refer these patients to specialized alcohol treatment providers for evaluation and appropriate treatment. In referring a patient to appropriate alcohol treatment, physicians should keep informed of their patients' progress, as relapse may further complicate management of the alcoholic liver disease.

References

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ACKNOWLEDGMENT: The National Institute on Alcohol Abuse and Alcoholism wishes to acknowledge the valuable contributions of Marcus A. Rothschild, M.D., editor of Alcohol: Clinical and Experimental Research, to the development of this Alcohol Alert.

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