Exploring Alcohol’s Effects on Liver Function JACQUELYN J. MAHER, M.D. A large proportion of heavy drinkers develop serious alcoholic liver disease. Susceptibility to alcoholic hepatitis and cirrhosis appears to be influenced by heredity, gender, diet, and co-occurring liver illness. Most alcoholic liver damage is attributed to alcohol metabolism. Liver injury may be caused by direct toxicity of metabolic by-products of alcohol as well as by inflammation induced by these by- products. Exposure of liver cells to bacterial toxins may contribute to liver disease. Escalating liver injury can lead to fibrosis and, ultimately, to cirrhosis. Increased understanding of the mechanisms of liver injury has led to innovative treatments for alcoholic liver disease, including the use of corticosteroids, antioxidants, antibiotics, and certain polyunsaturated fats. KEY WORDS: heavy AOD use; alcoholic liver cirrhosis; alcoholic hepatitis; ethanol metabolism; biochemical mechanism; toxic drug effect; inflammation; drug therapy; hereditary factors; gender differences; diet; risk factors; endotoxin; fibrosis; free radicals; etiology; literature review n association between liver As alcohol is broken down in the intake that can be achieved by con- disease and heavy alcohol liver, a number of potentially danger- suming approximately 72 ounces (oz) A consumption was recognized ous by-products are generated, such as of beer, 1 liter of wine, or 8 oz dis- more than 200 years ago (Smart and acetaldehyde and highly reactive tilled spirits (i.e., 5–6 standard Mann 1992). Long-term heavy alco- molecules called free radicals. Per- drinks1) daily for 20 years. For wom- hol use is the most prevalent single haps more so than alcohol itself, these en, the threshold dose is one-fourth to cause of illness and death from liver products contribute to alcohol-induced one-half that amount. In this article, disease in the United States (National liver damage. the phrase “heavy drinking” refers to Center for Health Statistics 1994). The liver is one of the largest or- this daily intake. gans in the body; it has not only con- The liver is particularly susceptible to Heavy long-term alcohol consump- siderable reserves but also the ability alcohol-related injury because it is the tion clearly plays a major role in the to regenerate itself. Consequently, primary site of alcohol metabolism. development of alcohol-related liver symptoms of liver damage may not damage. Yet, no more than one-half of appear until damage to the organ is heavy drinkers develop alcoholic hep- JACQUELYN J. MAHER, M.D., is associ- quite extensive. Epidemiological atitis or cirrhosis (French et al. 1993). ate professor of medicine, University studies suggest that a threshold dose of California, San Francisco, This finding suggests that other fac- of alcohol must be consumed for tors—heredity, environment, or both— California. serious liver injury to become appar- interact to influence the course of liver ent (Mezey et al. 1988). For men, this disease. This article examines some This work was funded by grants from dose amounts to 600 kilograms (kg) types of liver injury and their potential the National Institute on Alcohol taken chronically over many years, an Abuse and Alcoholism (NIAAA) mechanisms, discusses factors that may (AA00215 and AA07810) and the place people at increased risk for such 1One standard drink is defined as 12 fluid Alcoholic Beverage Medical ounces (oz) of beer, 5 fluid oz of wine, or 1.5 injury, and provides a brief description Research Foundation. fluid oz of distilled spirits. of different treatment approaches. VOL. 21, NO. 1, 1997 5 TYPES OF ALCOHOL-INDUCED related, progressing from fatty liver to pp. 93–96), detoxify harmful sub- LIVER DAMAGE alcoholic hepatitis to cirrhosis. How- stances that enter the body. The ever, heavy drinkers may develop MEOS oxidizes alcohol to acetalde- Alcohol-related liver damage can be alcoholic cirrhosis without first devel- hyde by means of a cytochrome called divided into three categories (French oping hepatitis. Moreover, alcoholic P450 2E1, or CYP2E1, which is found et al. 1993): hepatitis may have a sudden onset and in the endoplasmic reticulum of liver a rapid course, causing death before cells. Normally functioning at a low • Fatty liver. Some degree of fat depo- cirrhosis can develop. level, CYP2E1 is stimulated (i.e., sition in the liver occurs in almost all induced) to a higher level by the pres- heavy drinkers. It also may occur ence of alcohol. Thus, the MEOS transiently in nonalcoholics after a METABOLISM OF ALCOHOL becomes increasingly important as single drinking session. Fatty liver is alcohol consumption becomes heavier An understanding of alcohol metab- reversible and is not believed to lead and more chronic.3 to more serious damage. olism provides the basis for under- standing alcohol-induced liver • Alcoholic hepatitis. This disorder is damage. Most of the alcohol that POSSIBLE MECHANISMS characterized by widespread in- people drink is metabolized in the INFLUENCING ALCOHOL-INDUCED flammation and destruction (i.e., liver. The major pathway for alcohol LIVER DAMAGE necrosis) of liver tissue. Scar tissue metabolism involves the enzyme may begin to replace healthy liver alcohol dehydrogenase (ADH). This The mechanisms that influence liver tissue, a process called fibrosis. enzyme converts alcohol to acetalde- injury are both poorly understood and Symptoms of alcoholic hepatitis hyde through a chemical process controversial. Moreover, they interact in may include fever, jaundice,2 and called oxidation.(For more informa- complex ways. The following sections abdominal pain. The condition can tion on the metabolism of alcohol, see briefly discuss aspects of these mecha- be fatal but may be reversible with the article by Bode, pp. 76–83.) nisms and their interactions. abstinence. Alcoholic hepatitis occurs in up to 50 percent of heavy As alcohol is broken Role of Oxygen drinkers (National Institute on Oxygen-related factors that influence Alcohol Abuse and Alcoholism down in the liver, a alcohol-induced liver damage include [NIAAA] 1993). number of potentially the effects of free radicals, antioxi- • Alcoholic cirrhosis. This most ad- dangerous by-products dants, and hypoxia. vanced form of liver disease is diag- nosed in 15 to 30 percent of heavy are generated. Free Radicals. Much of the direct cell drinkers. Between 40 and 90 percent damage that occurs during alcoholic of the 26,000 annual deaths from liver disease is believed to be caused cirrhosis are alcohol related (Dufour by free radicals. Free radicals are et al. 1993). A cirrhotic liver is char- Acetaldehyde is highly toxic to the highly reactive molecular fragments acterized by extensive fibrosis that body, even in low concentrations. Nor- that frequently contain oxygen. Small quantities of free radicals are pro- stiffens blood vessels and distorts the mally, however, the enzyme aldehyde duced as normal by-products of vari- internal structure of the liver. This dehydrogenase (ALDH) rapidly oxi- ous metabolic processes. These structural damage results in severe dizes acetaldehyde to acetate. Most of fragments are quickly scavenged by functional impairment, which may the acetate travels through the blood- natural protective molecules in the lead secondarily to malfunction of stream to other parts of the body, where cell, called antioxidants (e.g., glu- other organs, such as the brain and it can enter other metabolic cycles tathione and vitamins A and E). How- kidneys. Although alcoholic cirrhosis (Lieber 1994) that produce energy or ever, when free radicals are produced is usually fatal because of complica- useful molecules. The usual biological in excess or when antioxidant defenses tions (e.g., kidney failure and hyper- role of both ADH and ALDH is to metab- are impaired, the free radicals may tension in the vein carrying blood to olize vitamin A (i.e., retinol). interact destructively with vital cell the liver [i.e., the portal vein]), it can The microsomal enzyme oxidizing constituents, potentially causing death stabilize with abstinence. system (MEOS) is an alternate path- way for alcohol metabolism in the of the cell. Traditionally, these three conditions liver. Microsomal enzymes belong to a family of proteins called cytochromes. 3An enzyme called catalase also can convert have been considered sequentially alcohol to acetaldehyde. However, this enzyme Some cytochromes, located in a cellu- rarely plays an important role in humans and 2For definitions of this and other technical lar substructure called the endoplas- will not be discussed further in this article terms, see glossary, pp. 93–96. mic reticulum (see figure in glossary, (Lieber 1994). 6 ALCOHOL HEALTH & RESEARCH WORLD Alcohol’s Effects on Liver Function THE LIVER—STRUCTURE AND FUNCTION The liver is the largest organ of the tine to help digest fats and render blood-clotting mechanisms. The body, weighing 3.3 pounds. It occu- them soluble for absorption. Nutrients liver can mobilize a chemical and pies the upper right—and part of are carried from the small intestine cellular arsenal for self-protec- the left—section of the abdomen. through the portal vein directly to the tion. Fortunately, the liver’s abili- Delicate fibrous tissue divides the liver, which then synthesizes choles- ty to regenerate helps this liver into functional units called terol, metabolizes or stores sugars, important organ survive the wear lobules, cylindrical structures sev- processes fats, stores vitamins, and and tear of a lifetime.