Alcoholic liver disease (ALD) is responsible for approximately 15,000 to 20,000 deaths per year in this nation, and its medical and social costs are estimated to exceed $2.5 billion annually. It is a difficult disease to prevent or treat since alcohol remains a socially acceptable drug that is consumed by 50% of the adult population. Even though advanced ALD was previously considered to develop only in individuals who consume excessive amounts of alcohol (>120 g of daily intake) during 15-20 years, it is now known that much smaller quantities of alcohol can induce the disease. The minimum daily alcohol intake during 15-20 years to induce cirrhosis is estimated to be 40 g (3-4 drinks) for men and 20 g (2-3 drinks) for women. Only 15-30 percent of heavy drinkers develop advanced ALD such as alcoholic hepatitis and liver cirrhosis. Why are the responses and sensitivity to alcohol consumption so heterogeneous? Epidemiological and experimental studies suggest the importance of secondary risk factors that have profound effects on primary factors/mechanisms of alcoholic liver injury to precipitate disease processes. In fact, it appears that the interactions among and between primary and secondary factors determine the predisposition of individuals toward development of ALD. Thus, elucidation of how the interactions take place in high-risk populations appears a critical prerequisite for better understanding and management of ALD.

One important class of the risk factors is nutrition. It is well recognized that protein-calorie deficiency commonly accompanies ALD and a nutritional support to alleviate this condition has shown some beneficial effects on patients with ALD. Polyunsaturated fat (vegetable or fish oil) is known as a critical nutritional factor for induction of experimental ALD and feeding saturated fat (beef fat) results in remarkable prevention of or accelerated recovery from experimental ALD. Indeed, epidemiological studies support these observations by revealing a positive correlation of the incidence of cirrhosis in various countries with consumption per capita of polyunsaturated fatty acids, particularly linoleic acid and an inverse correlation with saturated fat. It is postulated that polyunsaturated fat accentuates alcohol-induced oxidative injury via its synergistic effect on induction of microsomal ethanol-oxidizing enzymes (e.g., cytochrome P4502E1, CYP2E1). Iron is another pro-oxidant nutrient. Iron catalyzes generation of hydroxyl radical, a most potent radical responsible for oxidative damage to lipids, protein, and DNA. Even a moderate dietary iron supplementation, which raises the hepatic iron concentration only to a higher portion of a normal range in humans (400-600 micrograms/g), causes remarkable promotion and acceleration of experimental ALD, resulting in induction of micronodular cirrhosis in some animals. This potentiating effect on ALD is accompanied by accentuated lipid peroxidation and a close association of immunohistochemical staining for adduct epitopes generated by lipid peroxidation aldehydic products and liver fibrogenesis. These results support a critical role of hepatic iron and iron-catalyzed oxidative stress in promoting the severity and progression of ALD. In fact, mild to moderate hepatic iron accumulation is found in 50-60% of alcoholic patients, and consumption of wine, which contains high levels of iron, is associated with a higher risk of developing ALD. Alcohol consumption itself enhances the gastrointestinal absorption of iron which will be accumulated in both hepatocytes and Kupffer cells. In Kupffer cells, the increased iron pool has recently been shown to facilitate enhanced iron-mediated intracellular signaling leading to increased expression of proinflammatory cytokines such as TNFa. Thus, in this scenario, iron as a secondary risk factor, effectively interacts with the two primary factors of ALD, oxidative stress and immune response, for promotion of the disease process. To this end, patients with the hereditary form of hepatic iron load (hemochromatosis) should be considered in a high-risk group. Similarly, copper accumulation as seen in Wilson disease will also be a risk factor for ALD since copper likewise catalyzes generation of hydroxyl radicals.

Another important risk factor, which contributes to the susceptibility to progression of ALD, is concomitant infection with hepatitis B (HBV) and hepatitis C (HCV) viruses. Patients with advanced ALD have a high prevalence of seropositivity for HBV or HCV. In particular, the prevalence of infection with these hepatotropic viruses in alcoholic patients with liver cirrhosis or hepatocellular carcinoma is often higher than that in patients with early ALD, indicating the increased risk of developing these two devastating sequella of ALD by the viral infection.

Alcoholic hepatitis and cirrhosis develop at a younger age and after less alcohol intake in women than men. The increased susceptibility of women to alcoholic pancreatitis is also reported. Thus, this gender issue may not be organ-specific. Two hypothetical mechanisms are proposed for this gender effect. One is related to the differences in the pharmacokinetics of ethanol. Women appear to have higher peak blood alcohol levels than men after an equal dose of alcohol due possibly to lower gastric content of alcohol dehydrogenase (ADH) in women, allowing more ethanol to escape the gastric elimination and to reach the liver. Another possibility is the sensitizing effect of estrogen on endotoxin-mediated signaling in Kupffer cells. Animals treated with estrogen are more sensitive to endotoxin (lipopolysaccharide, LPS) in terms of their plasma TNFa levels and mortality, and these effects are completely eliminated with gadolinium chloride, a Kupffer cell toxin. Further, Kupffer cells from estrogen-treated animals express more CD14, the receptor for LPS/LPS binding protein, and estrogen treatment causes drastic induction of LPS binding protein in the liver.

The genetic predisposition for the development of ALD has long been suspected. Molecular biologic techniques have enabled identification of genetic polymorphisms for ADH, aldehyde dehydrogenase (ALDH), and CYP2E1. These genetic variants of the enzymes are associated with different expression or activities of the enzymes, as well as different risks for alcoholism and possibly for ALD. However, further studies with larger numbers of subjects and additional candidate genes are needed to confirm the associations or establish the genetic basis for the predisposition.

In summary, the pathogenesis of ALD is multifactorial. We now know that the predisposition to severe ALD is predicated by the contribution of the secondary risk factors. We have just begun to identify these factors and mechanisms by which they interact with primary pathogenetic factors to precipitate the disease processes. An understanding of these interactive effects helps us devise better preventive and therapeutic interventions. The newly established USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases supports integrated basic research endeavors directed to molecular elucidation of the interface between the primary and secondary factors in the pathogenesis of ALD.