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Alcohol-induced liver disease (ALD) is a major cause of illness and death in the United States. Fatty liver, the most common form of ALD, is reversible with abstinence. More serious ALD includes alcoholic hepatitis, characterized by persistent inflammation of the liver, and cirrhosis, characterized by progressive scarring of liver tissue. Either condition can be fatal, and treatment options are limited. During the past 5 years, research has significantly increased our understanding of the mechanisms by which alcohol consumption damages the liver. This Alcohol Alert highlights recent research on the mechanisms and treatment of ALD, updating a previous Alcohol Alert on ALD published in 1993 and available from the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Approximately 10 to 35 percent of heavy drinkers develop alcoholic hepatitis, and 10 to 20 percent develop cirrhosis (1). In the United States, cirrhosis is the seventh leading cause of death among young and middle-age adults. Approximately 10,000 to 24,000 deaths from cirrhosis may be attributable to alcohol consumption each year (2).
Normal liver function is essential to life. Alcohol-induced liver damage disrupts the body's metabolism, eventually impairing the function of other organs. Multiple physiological mechanisms, discussed in the following sections, interact to influence the progression of ALD. Medications that affect these mechanisms may help prevent some of the medical complications of ALD or reduce the severity of the illness.
Alcohol Metabolism. Most of the alcohol a person drinks is eventually broken down by the liver. However, some products generated during alcohol metabolism (e.g., acetaldehyde) are more toxic than alcohol itself. In addition, a group of metabolic products called free radicals can damage liver cells and promote inflammation, impairing vital functions such as energy production. The body's natural defenses against free radicals (e.g., antioxidants) can be inhibited by alcohol consumption, leading to increased liver damage (3).
The Inflammatory Response. Inflammation is the body's response to local tissue damage or infection. Inflammation prevents the spread of injury and mobilizes the defense mechanisms of the immune system. One such defense mechanism is the generation of free radicals that can destroy disease-causing microorganisms. Long-term alcohol consumption prolongs the inflammatory process, leading to excessive production of free radicals, which can destroy healthy liver tissue.
Bacteria that live in the human intestine play a key role in the initiation of ALD. Alcohol consumption increases the passage of a noxious bacterial product called endotoxin through the intestinal wall into the bloodstream. Upon reaching the liver, endotoxin activates specialized cells (i.e., Kupffer cells) that monitor the blood for signs of infection. These cells respond to the presence of endotoxin by releasing substances called cytokines that regulate the inflammatory process (4-6).
Cytokines. Cytokines are produced by cells of the liver and immune system in response to infection or cell damage. Alcohol consumption increases cytokine levels, and cytokines in humans produce symptoms similar to those of alcoholic hepatitis (7). Recent studies implicate cytokines in scar formation and in the depletion of oxygen within liver cells, processes that are associated with cirrhosis (7). Each of the disease mechanisms described above contributes to the death of liver cells. The presence of damaged cells triggers the body's defensive responses, including the release of additional cytokines, resulting in a vicious cycle of inflammation, cell death, and scarring.
Scar Formation. Normal scar formation is part of the wound-healing process. Alcohol-induced cell death and inflammation can result in scarring that distorts the liver's internal structure and impairs its function. This scarring is the hallmark of cirrhosis. The process by which cirrhosis develops involves the interaction of certain cytokines and specialized liver cells (i.e., stellate cells). In the normal liver, stellate cells function as storage depots for vitamin A. Upon activation by cytokines, stellate cells proliferate, lose their vitamin A stores, and begin to produce scar tissue. In addition, activated stellate cells constrict blood vessels, impeding the delivery of oxygen to liver cells (6,8).
Acetaldehyde may activate stellate cells directly, promoting liver scarring in the absence of inflammation (9,10). This finding is consistent with the observation that heavy drinkers can develop cirrhosis insidiously, without preexisting hepatitis.
Factors That Influence Vulnerability to ALD
Susceptibility to ALD differs considerably among individuals, so that even among people drinking similar amounts of alcohol, only some develop cirrhosis. Understanding the mechanisms of these differences may help clinicians identify and treat patients at increased risk for advanced liver damage.
Genetic Factors. Structural or functional variability in any of the cell types and biochemical substances discussed above could influence a person's susceptibility to ALD. Researchers are seeking genetic factors that may underlie this variability. Results of this research may provide the basis for future gene-based therapies.
Dietary Factors. Nutritional factors influence the progression of ALD (11). For example, a high-fat, low-carbohydrate diet promotes liver damage in alcohol-fed rats (12,13), and high amounts of polyunsaturated fats may promote the development of cirrhosis in animals (14,15).
Gender. Women develop ALD after consuming lower levels of alcohol over a shorter period of time compared with men (16). In addition, women have a higher incidence of alcoholic hepatitis and a higher mortality rate from cirrhosis than men (17). The mechanisms that underlie gender-related differences are unknown.
Hepatitis C. Many patients with ALD are infected with hepatitis C virus (HCV), which causes a chronic, potentially fatal liver disease (18,19). The presence of HCV may increase a person's susceptibility to ALD and influence the severity of alcoholic cirrhosis. For example, alcohol-dependent patients infected with HCV develop liver injury at a younger age and after consuming a lower cumulative dose of alcohol than do those without HCV (20). Patients with HCV are often treated with an antiviral substance called interferon. However, interferon is less effective in patients with chronic HCV who are heavy drinkers, compared with those who are not (21).
Abstinence is the cornerstone of ALD therapy. With abstinence, fatty liver and alcoholic hepatitis are frequently reversible, and survival is improved among patients with ALD, including those with cirrhosis (1). For terminally ill patients, liver transplantation remains the only effective treatment. Research has established the effectiveness of liver transplantation in patients with alcoholic cirrhosis (1). More recently, Belle and colleagues (22) summarized followup medical data on all persons who received liver transplants in the United States between 1988 and 1995. Deaths among these subjects were not alcohol related. That is, alcohol-dependent patients died from the same conditions that caused deaths among patients without alcoholism (e.g., infection, cancer, or heart disease). Recurrences of liver disease among alcohol-dependent patients are rare (23).
Hepatitis C infection in patients with ALD does not appear to affect survival after liver transplantation, despite the continued presence of the virus in the bloodstream (24).
Medication Interactions. Chronic alcohol consumption may increase the adverse side effects of medications used to treat conditions other than ALD. In particular, excessive use of the widely used pain killer acetaminophen has been associated with liver damage in people drinking heavily (25).
Prospects for Future Treatment
The multiple mechanisms of ALD development provide several potential targets for medical intervention. Some promising lines of inquiry are summarized below.
The role of endotoxin in the inflammatory response suggests the possibility of inhibiting ALD development at its earliest stages. For example, suppression of endotoxin-producing intestinal bacteria reduced signs of liver damage in alcohol-fed rats (4,26).
An adequate daily supply of total carbohydrates is important in treating ALD (13,27). In addition, researchers are investigating certain nutritional supplements for patients with ALD. One such supplement is polyunsaturated lecithin (PUL), a mixture of fatty substances extracted from soybeans. PUL protected against liver scarring in alcohol-fed baboons (9,28). Another dietary factor, S-adenosyl-l-methionine (SAM), can reduce liver cell damage in animals that is induced by alcohol or other toxic substances (29). The safety and effectiveness of these supplements for treating human ALD are under investigation.
Finally, an important goal of ALD research is to develop medications that can moderate the toxic effects of inflammatory cytokines while sparing their essential defensive functions. In one study, administration of antibodies designed to recognize and inactivate key inflammatory cytokines markedly decreased liver injury in rats (30).
Alcohol and the Liver: Research Update--A Commentary by
NIAAA Director Enoch Gordis, M.D.
Serious alcoholic liver disease (ALD) is a major public health problem. These conditions--including alcoholic hepatitis and cirrhosis--can be progressive and fatal, especially if the patient continues to consume alcohol. Efforts to decrease the prevalence of ALD have therefore focused on prevention, by attempting to reduce alcohol consumption in the general population and in alcohol-dependent patients.
In recent years, scientists have made significant progress in understanding the biological and environmental factors that combine with the effects of alcohol to damage the liver. For example, many patients with ALD are infected with a nonalcoholic liver disease called hepatitis C. Heavy drinking increases the severity of hepatitis C and complicates its treatment. Researchers are studying the mechanisms by which these diseases interact. This and other studies on ALD may lead to the development of medications to interrupt liver disease processes such as liver inflammation and scarring. Prevention remains the key approach to the problem of ALD, but research provides hope that at least some effects of ALD may be reversible even after the disease has become established.
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1These authors defined "heavy drinking" as the daily consumption of five to six standard drinks, each drink equivalent to approximately 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of distilled spirits.
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