Pathogenesis of Alcoholic Liver Disease

Tsukamoto H, Kaplowitz N.
In: Kaplowitz N, ed. Liver and Biliary Diseases, 2nd Edition, Williams & Wilkins, Baltimore, p121-138, 1996.


Chronic liver disease continues to be one of the leading medical causes of mortality in the United States. Every half hour, one person dies in the this nation from complications associated with irreversible chronic liver disease. Liver cirrhosis and hepatocellular carcinoma are the two most common and devastating sequela responsible for this mortality, and chronic alcohol abuse is the single most important etiologic factor for cirrhosis. This fact is well-illustrated by a historical observation that the number of deaths from cirrhosis decreased by more than 50% during Prohibition, while the mortality from all other causes remained unchanged. Even though a positive correlation exists between per capita consumption of alcohol and the incidence of cirrhosis, only 15-30% of heavy drinkers acquire clinical or histologic signs of alcoholic hepatitis and develop cirrhosis. This trend is confirmed even in animal models of alcoholic liver disease (ALD) which have minimal variability in the contribution of various intrinsic and extrinsic factors to the development of the experimental disease. Why does the liver possess such a heterogeneous response to consumption of alcohol? This question reflects the complexity of the problem, and is in large part due to the fact there are at least seven proposed underlying mechanisms of ALD (Table 1), which can potentially have profound influences over any one of the primary mechanisms. In search of the underlying primary factors and cofactors for ALD, the past 25 years saw the most impressive advances in our knowledge of biochemical, cellular, and molecular basis for the pathogenesis of ALD. Hence, we devote a large portion of this chapter to these areas.

The complexities of the pathogenesis of ALD are underscored by its epidemiology. Although studies have correlated per capita ethanol consumption with the incidence of cirrhosis in comparing different nations or states, and the duration and dose of ethanol with the incidence of cirrhosis in a given population, the relationship remains controversial. Leibach’s studies demonstrating linear relationship between the incidence of cirrhosis and the product of dose and duration of ethanol consumption, have been interpreted to show that the cumulative dose of ethanol determines the development of cirrhosis. However, these data are strongly influenced by the time factor, i.e., duration, suggesting that there may be a constant rate of developing cirrhosis (a linear slope). Such an interpretation would indicate fixed annual rate of developing cirrhosis rather than a cumulative dose-related effect. Indeed, studies of Sorensen and colleagues support the fixed rate interpretation. They prospectively followed a group of chronic alcoholics who initially did not have cirrhosis and found that 2-3% developed cirrhosis per year, regardless of the preceding duration of drinking. Furthermore, although a threshold dose of 80 g/day of ethanol was found, consumption above the threshold to very high doses did not predict who would develop cirrhosis. These data have lead to the view that ethanol “conditions” the liver, i.e., it makes the liver susceptible to injury, but the development of cirrhosis may involve the random interplay of sufficient group of primary and cofactors (Table 1) and/or other unidentified factors. Currently, the issue of epidemiology is unsettled as to whether ethanol simply damages the liver, predisposes the liver to damage caused by other factors, or damages the liver when it is sensitized by cofactors.

In considering the pathogenesis of ALD, it is important to bear in mind that two distinct pathologic processes are seen in the liver: alcoholic hepatitis, characterized by necrosis and inflammation, and liver cirrhosis, which results from progression of liver fibrogenesis from perivenular and perisinusoidal fibrosis to bridging fibrosis. Here again, controversy exists. The bulk of patients with alcoholic hepatitis who continue to ingest alcohol develop cirrhosis. However, the vast majority of patients also develop alcoholic cirrhosis without evidence of preceding alcoholic hepatitis. The question is whether the hepatitis was not clinically apparent and missed, or never existed. Much evidence favors the latter and supports the view that alcohol can promote fibrosis without a necroinflammatory response. The important point for our discussion is to bear in mind, as we consider various pathogenetic mechanisms, that different factors may be responsible for the two pathologic processes, or that the same factor may cause both processes in an independent of interdependent fashion.

Table 1. Primary Factors and Cofactors for the Pathogenesis of Alcoholic Liver Disease

Primary Factors

  1. Acetaldehyde
  2. Reactive oxygen species
  3. Decreased antioxidants
  4. Endotoxin, cytokines, and immune responses
  5. Centrilobular
  6. hypoxia
  7. Membrane alterations
  8. Redox shift


  1. Nutrition
    1. Malnutrition
    2. Dietary Fat
    3. Vitamin A
    4. Iron
  2. Genotypes of alcohol dehydrogenase, aldehyde dehydrogenase and CYP2E1
  3. Viral hepatitis
  4. Gender