The epidemiology of alcoholic liver disease.

1One of the most enduring insights into the effects of alcohol has been the assertion that heavy alcohol consumption increases mortality rates, especially those from cirrhosis of the liver and other forms of liver disease (see the sidebar, p. 211). The scientific study of alcohol-related mortality began in the 1920s with of death rates among various types of drinkers. He and others found that heavy drinkers had higher rates of overall mortality and of mortality from cirrhosis than did lighter drinkers or abstainers. Since then, mortality studies have continued to demonstrate that heavy drinkers and alcoholics die from cirrhosis at a much higher rate than the general population. In addition, laboratory studies conducted in the 1930s established that feeding large amounts of alcohol to rats and other animals caused liver disease.

2The most prevalent types of alcoholic liver disease are fatty liver, alcoholic hepatitis, and cirrhosis. Often, as people continue to drink heavily, they progress from fatty liver to hepatitis to cirrhosis. The disorders can also occur together, however, and liver biopsies can show signs of all three in some people.

3Alcoholic Fatty Liver

4About 20 percent of alcoholics and heavy drinkers develop fatty liver, or steatosis. In many cases there are no clinical symptoms except for an enlarged liver (hepatomegaly). Fatty liver can be reversed if alcohol consumption is stopped or significantly reduced, but the condition can lead to death if alcohol consumption is not reduced or stopped. Some biopsies from people with fatty liver show inflammatory changes, an early sign of more serious liver disease.

5Alcoholic Hepatitis

6Alcoholic hepatitis usually is diagnosed when a liver biopsy indicates inflammatory changes, liver degeneration, fibrosis, and other changes to liver cells. Common clinical signs of alcoholic hepatitis include swollen liver, nausea, vomiting, and abdominal pain. Patients also may experience fever, jaundice, liver failure, and bleeding. The rate of mortality in severe cases is about 50 percent. If heavy drinking continues, about 40 percent of cases of alcoholic hepatitis will develop into cirrhosis.

7Alcoholic Cirrhosis

8Cirrhosis of the liver is the most serious form of ALD and a cause of many deaths and serious illnesses. In cirrhosis, scar tissue replaces normal liver tissue, disrupting blood flow through the liver and preventing it from working properly. Clinical signs of cirrhosis include redness of the palms caused by capillary dilation (palmar erythema); shortening of muscles in the fingers (contractures) caused by toxic effects or fibrous changes; white nails; thickening and widening of the fingers and nails (clubbing); liver enlargement or inflammation; and abnormal accumulation of fat in normal liver cells (fatty infiltration). Diagnosis of cirrhosis must be made with biopsies, although laboratory tests can be helpful as well.

9About 10 percent to 15 percent of people with alcoholism develop cirrhosis, but many survive it. Many are unaware that they have it, and about 30 percent to 40 percent of cirrhosis cases are discovered at autopsy. The 5-year survival rate for people with cirrhosis who stop drinking is about 90 percent, compared with 70 percent of those who do not stop drinking. However, for late-stage cirrhosis—that is, when jaundice, accumulation of fluid in the abdomen (ascites), or gastrointestinal bleeding have occurred—the survival rate is only 60 percent for those who stop drinking and 35 percent for those who do not.

10Other Forms of Liver Disease Affected by Alcohol

11Alcohol can be a factor in other forms of liver disease not specifically attributed to it, and alcohol may interact with risk factors for other forms of liver disease. For example, people with alcohol-related cirrhosis are at much higher risk for the development of liver cancer. Likewise, heavy drinking in combination with hepatitis B or C substantially increases the risk of liver cirrhosis, compared with the risk associated with heavy drinking alone.

12— Robert E. Mann, Reginald G. Smart, and Richard Govoni

13Alcohol consumption increased substantially in many countries after World War II, which spurred greater interest in the effects of alcohol consumption on cirrhosis and other forms of alcoholic liver disease (ALD). One of the most influential efforts to summarize research in this area was undertaken in 1975 by an international group of scientists sponsored by the World Health Organization (WHO). The resulting book, Alcohol Control Policies in Public Health Perspective, reviewed studies of clinical and nonclinical populations of heavy drinkers. All studies found that a greater proportion of heavy drinkers died of cirrhosis than would be expected based on rates of cirrhosis deaths in the general population (i.e., liver cirrhosis deaths among heavy drinkers ranged from 2 to 23 times higher than the rate that would be expected in the general population).

14This research established a firm connection between heavy alcohol consumption and liver disease. Investigators also have observed that the price of alcohol is a significant determinant of alcohol consumption and thus of cirrhosis mortality rates. These findings have laid the foundation for an influential public health approach to controlling liver disease and other alcohol problems that emphasizes the control of alcohol’s availability and includes recommendations to control cirrhosis and other alcohol-related problems through taxation. The validity of this availability-control approach has been widely supported (e.g., ), and investigations of the epidemiology of ALD have continued to be central to it (e.g., ).

15Pablo Neruda, 1904–1973

16Nobel Laureate in Literature, 1971

17Translation by Oriana Josseau Kalant

18“Oda al Higado,” by Pablo Neruda, translated by Oriana Josseau Kalant, as published in Alcohol Liver Pathology (J.M. Khana, Y. Israel, and H. Kalant, editors) © 1975. Reprinted with permission of the Centre for Addiction and Mental Health, Toronto.

19Many studies show that the amount of alcohol consumed and the duration of that consumption are closely associated with cirrhosis.1 One of the best demonstrations of this association was presented by, who studied 319 patients in an alcoholism clinic in Germany. He calculated the average amount of alcohol consumed per hour in a 24-hour day. As shown in table 1, patients with normal liver function consumed far less alcohol than did those with cirrhosis. Those who did not have cirrhosis but did have other liver malfunctions had intermediate rates of alcohol intake. In addition, patients with normal liver function had been drinking heavily for only about 8 years on average, whereas those with cirrhosis had been drinking heavily for more than 17 years on average. As this research illustrates, the risk of developing cirrhosis is a function of both quantity and duration of alcohol consumption. recently proposed that cirrhosis does not develop below a lifetime alcohol ingestion of 100 kg of undiluted alcohol. This amount corresponds to an average daily intake of 30 grams of alcohol (between two and three drinks2) for 10 years. These investigators also noted that consuming alcohol with food resulted in somewhat lower levels of risk than consuming alcohol by itself.

20More recent studies confirm the close association between alcohol consumption and cirrhosis risk. examined data from four case control studies in men and women. (Figure 1 shows results from representative studies [, and ].) This investigation showed that the risk of cirrhosis was related to the amount of alcohol consumption in every study. In addition, as alcohol consumption increased, the risk of cirrhosis increased more rapidly for females than it did for males. The link between gender and risk for cirrhosis is addressed in detail in the section on page 215.

21The strong link between heavy or excessive alcohol use and the development of liver disease took on added significance in the middle of the 20th century, when several researchers began exploring cirrhosis as a potential marker for levels of alcohol problems in populations. Of particular importance was the discovery of a relationship between cirrhosis mortality rates and per capita levels of alcohol consumption in the population. This relationship has proved to be remarkably strong and has been consistently observed across time periods and in various regions of the world. European researchers have observed a lagged relationship between cirrhosis mortality and consumption measures, with the rate of cirrhosis mortality in a year being influenced by the alcohol consumption rates of several previous years. To account for this effect, developed a “distributed lag model,” in which the effects of alcohol consumption in a year are distributed over the next several years. Using this model, he was able to explain an apparent inverse relationship between consumption and cirrhosis mortality rates in Great Britain between 1931 and 1958. Incorporating the distributed lag model into the data produced the expected positive relationship between consumption and cirrhosis mortality.

22Liver cirrhosis is a major cause of death in the United States. In 2000, it was the 12th leading cause of death, accounting for 1.1 percent of all deaths, with an age-adjusted death rate3 of 9.6 per 100,000 population. Cirrhosis mortality rates vary substantially among age groups: They are very low among the young but increase considerably in middle age, reaching a peak of 31.1 per 100,000 among people ages 75 to 84. Because of the increase in cirrhosis mortality rates in middle age, the contribution of cirrhosis to total deaths reaches a peak in the 45–54 age group, for which it is the fourth leading cause of death. In relation to the cirrhosis mortality rate in other countries, the United States is in the middle range, as are countries such as Belgium and Canada. Higher rates are seen in countries where people traditionally consume more alcohol than in the United States, such as Spain, France, and Italy. In countries where alcohol consumption is traditionally lower—Iceland, New Zealand, and Norway, for example— cirrhosis death rates are lower.

23Cirrhosis mortality rates in the United States have changed substantially over time. Early in the 20th century, these rates were at their highest point. As shown in figure 2, overall cirrhosis mortality rates declined precipitously with the introduction of Prohibition. When Prohibition ended, alcohol consumption and cirrhosis mortality rates increased until the late 1960s and early 1970s, when these rates began to approach levels seen in the first decade of the century. However, in the mid-1970s cirrhosis mortality rates began to decline as they had with the introduction of Prohibition; cirrhosis was the 8th leading cause of death in 1977 but the 12th leading cause of death by 2000. Similar declines in cirrhosis mortality rates have been observed in many developed countries (including Canada, Sweden, France, and Italy), but in other developed countries (e.g., Great Britain, Finland, Denmark) cirrhosis death rates have increased. The reasons for the dramatic reductions remain a source of considerable interest, as will be discussed below.

24Cirrhosis mortality rates may continue to decline if alcohol consumption rates remain low or fall further. However, the increase in cases of hepatitis C infection in the United States, which are predicted to peak by 2015, may affect the rate of cirrhosis deaths. Because people infected with hepatitis C are more likely to develop cirrhosis when they drink, death rates from cirrhosis may increase in the future, even if drinking levels decline. (For more information on hepatitis C infection and alcohol, see the article by Schiff and Ozden in this issue.)

25Changes in per capita consumption of alcohol must be considered a leading candidate for the cause of recent reductions in cirrhosis mortality rates. Research demonstrates that, over a long period, changes in per capita consumption are broadly consistent with changes in cirrhosis mortality rates (see figure 2). However, cirrhosis mortality in the United States, Canada, and some other regions began to decline in the mid-1970s, before per capita consumption rates began to go down (also see figure 2). This is the opposite of what would be expected based on the hypothesized lagged relationship between per capita consumption and cirrhosis mortality rates. Thus, researchers are considering whether other factors also have influenced cirrhosis mortality rates in recent years.

26The relationship between cirrhosis mortality and alcohol consumption may vary depending on the type of alcoholic beverage—beer, wine, or spirits— consumed. Any such beverage-specific effects could help explain why cirrhosis mortality began to decline in the 1970s despite the continued rise in total alcohol consumption. Researchers over the past four decades have investigated this question (e.g.,;; ).

27Recently, and have proposed that cirrhosis mortality is more strongly associated with consumption of spirits than with other alcoholic beverages, and that this relationship accounts for the apparent discrepancy between per capita alcohol consumption measures and cirrhosis mortality rates. examined U.S. cirrhosis mortality data from 1949 to 1994 and observed that consumption of spirits was more strongly related to cirrhosis mortality than was total alcohol consumption, a finding that is consistent with earlier observations of U.S. data. extended this analysis to several other countries, with similar results. The relationship between spirits consumption and cirrhosis mortality during the 1970s, when cirrhosis mortality rates began to decline in the United States, suggests that the discrepancy between cirrhosis rates and per capita alcohol consumption observed at that time arose because research did not focus on spirits, the beverage most strongly related to cirrhosis mortality.

28The stronger association between cirrhosis mortality and consumption of spirits may be attributable to biological and sociobehavioral mechanisms. Some types of alcoholic beverage may be more toxic to the liver than others. In addition, consumption of certain alcoholic beverages may be associated with different drinking styles—that is, people who tend to drink frequently and heavily, and thus are at greatest risk for developing cirrhosis, also may tend to drink spirits rather than beer or wine. Thus, drinking style may collude with biological mechanisms to significantly raise some drinkers’ risk of liver disease. This interesting and important issue is the subject of ongoing investigation.

29Another possible reason for declines in cirrhosis mortality has been increased participation in treatment for alcohol abuse and in Alcoholics Anonymous meetings. Specifically, cirrhosis morbidity and mortality rates could be influenced if participation in alcoholism treatment and AA are in some degree effective in reducing excessive drinking among heavy or abusive drinkers, if sufficient treatment occurs, and if enough alcoholics become members of AA or receive other treatment services. The 1970s and 1980s saw large increases in AA participation and in the number of people who received alcoholism treatment services. examined whether these increases in treatment and AA participation could affect cirrhosis morbidity and mortality rates. According to estimates derived from the research:

30Alcoholics seeking treatment drink an average of 160 g of undiluted alcohol per day.

31About 14 percent of alcoholics will develop cirrhosis if they drink this quantity for a period of 8 years.

32About 50 percent of alcoholics receiving treatment or attending AA meetings improve sufficiently to postpone the development of cirrhosis or avoid death if they already have cirrhosis.

33The authors applied these figures to the actual number of people who were AA members or were receiving alcohol abuse treatment in 1975 and 1986 in Ontario and the United States. Based on this analysis, between 25 percent and 100 percent of the actual reduction in cirrhosis deaths and hospital discharges during the period could be predicted, depending on the degree of overlap between treatment and AA membership that was assumed.

34Other studies of the relationship between cirrhosis mortality rates and aggregate, or population, levels of treatment and AA membership rates support the hypothesis that increases in treatment and AA membership helped reduce cirrhosis mortality rates, both in the United States and elsewhere. Several studies (for a review, see ) have found an association between reductions in cirrhosis morbidity and mortality and increased levels of treatment and AA membership in Canada, the United States, and Sweden. Examining monthly cirrhosis mortality data from North Carolina, found that alcohol abuse treatment had a significant short-term lagged relationship with cirrhosis mortality, with an increase in treatment being followed 3 months later by a decline in cirrhosis mortality. Finally, found that increased funding for alcoholism treatment was associated with cirrhosis mortality reductions across the United States. Thus, the data so far provide strong support for the proposition that if a large enough portion of the population participates, AA membership and alcohol abuse treatment can influence cirrhosis morbidity and mortality rates at the population level.

35As discussed above, historically the epidemiology of cirrhosis has been linked closely to types and patterns of alcohol consumption. Other factors also may be at work in the development of liver disease. For example, there are important and long-standing gender differences in cirrhosis mortality risk and mortality rates. As shown in figure 2, cirrhosis mortality rates are about two times higher in men than in women. These rates reflect the fact that men typically drink more than women, and that the proportion of heavy drinkers and alcoholics is much higher among men. However, as noted previously, it also appears that at any given level of alcohol consumption, women have a higher likelihood of developing cirrhosis than men (see figure 1). This phenomenon is poorly understood, but several possible explanations have been offered. One is that levels of alcohol dehydrogenase, an enzyme involved in breaking down alcohol, may be lower in the stomachs of females than in males, which would result in a higher blood alcohol content for females than for males who consume equivalent amounts of alcohol. Because damage to the liver is a function of blood alcohol levels and exposure time, factors that lead to higher blood alcohol concentrations could at least partially explain females’ higher risk for alcohol-related cirrhosis. Another possible explanation is that estrogen may increase the susceptibility of the liver to alcohol-related damage. Behavioral factors, including drinking patterns and diet, also may contribute to females’ higher cirrhosis risk.

36Genetic factors, including those that influence alcohol metabolism and risk for alcoholism, also may be involved in the increased risk for cirrhosis seen in women, but there still is considerable debate on this issue, and further research is needed on the nature and the extent of such genetic contributions.

37In a recent study, found that 98.1 percent of cirrhosis cases in men but only 67.0 percent of cases in women could be attributed to alcohol consumption, hepatitis C, and hepatitis B. The risk factors for cirrhosis appear to be more complex for women than they are for men, and more research will be required to identify and understand them.

38Important differences in cirrhosis rates and cirrhosis mortality also exist among ethnic groups. Although ethnic group differences have been declining in recent years, cirrhosis rates remain higher for Blacks than for Whites in the United States (see figure 3), and the highest cirrhosis mortality rates currently are observed among Hispanic groups. Although these differences in cirrhosis rates among Blacks, Whites, and Hispanics seem to suggest higher alcohol consumption levels among Hispanics and Blacks than among Whites, studies of alcohol consumption patterns in these groups tend not to support this interpretation. For example, in recent years, alcohol consumption among Blacks has been less than or comparable with that of Whites (see table 2).

39Several reasons for ethnic group differences in cirrhosis rates have been proposed, including demographic factors related to gender, age, income, education, and employment; biological factors, such as family history of drinking problems; and environmental factors, such as stress (for a review, see ). Other suggested factors are differential access to alcoholism treatment services, although as yet no data are available to support this explanation; and differing rates of hepatitis C infection, which appears to be more prevalent among Hispanics than in Black and White populations. Ethnic group differences in cirrhosis risk and mortality may be linked to the possibility that, over time, general health status has improved more for some ethnic groups than others. However, as summarized in table 3, two general health indicators— age-adjusted death rate and life expectancy at birth—showed comparable gains for Blacks and Whites between 1970 and 2000. Thus, it is not yet possible to attribute changes in cirrhosis rates to changes in general health indicators of various groups.

40As this discussion indicates, cirrhosis rates in subpopulations, such as those based on gender or ethnicity, can show significant deviations from the rates of cirrhosis that would be expected from alcohol consumption levels alone. These differences, which are not yet well understood, have important implications for research and prevention initiatives. From a public health perspective, an understanding of subpopulation dynamics is critical to the development of programs for preventing alcoholic liver disease.

41Alcoholic liver disease is a major source of alcohol-related morbidity and mortality. Heavy drinkers and alcoholics may progress from fatty liver to alcoholic hepatitis to cirrhosis, and it is estimated that 10 percent to 15 percent of alcoholics will develop cirrhosis. The likelihood of developing ALD is, to a large extent, a function of both the duration and amount of heavy drinking, and the per capita consumption of alcohol within populations has been shown to be a strong determinant of cirrhosis mortality rates. Recent studies also suggest that alcohol and hepatitis C may exert a multiplicative effect on risk for cirrhosis and other liver disease.

42Although ALD remains a major cause of death, important declines in ALD death rates have been observed in recent years. Undoubtedly these declines were caused in part by changes in alcohol consumption rates, but because the mortality rate decline began when consumption was still increasing, other factors appear to be involved as well. To date, the evidence indicates that increases in participation in AA and other treatment for alcohol abuse have played an important role in reducing cirrhosis mortality rates. Other research has suggested that cirrhosis mortality rates may be more closely related to consumption of certain alcoholic beverages—specifically spirits—than to total alcohol consumption, and that beverage-specific effects can account for the fact that cirrhosis rates appeared to decrease although consumption rates were increasing in the 1970s. Important differences in ALD rates in men and women and among different ethnic groups have been found as well. Further research into these differences is likely to lead to improved prevention and treatment of alcohol-related liver disease.