Alcohol and Alcoholic Liver Disease

The development of alcoholic liver disease (ALD) results from the chronic and excessive consumption of alcoholic beverages. It is estimated that there are more than 30 million alcoholics in the United States, and alcoholism is a major cause of morbidity and mortality as well as a severe economic burden. High per capita alcohol consumption coupled with the lack of predictable, effective therapies explain why ALD is the most prevalent form of chronic liver disease in the western world.

The spectrum of ALD ranges from fatty liver to alcoholic hepatitis and ultimately to fibrosis and cirrhosis. The pathogenic mechanisms underlying alcohol hepatotoxicity are complex and, despite extensive investigative efforts encompassing multiple disciplines, much remains unexplained. The hepatocyte does not exist in splendid isolation, and more recent studies have indicated that the nonparenchymal cells (e.g., endothelial, Kupffer and stellate cells) also actively participate in the pathogenesis of ALD. In this issue of Seminars in Liver Disease, we have attempted to place in perspective the existing concepts encompassing the disparate features of ALD, incorporating both clinical and experimental aspects and, finally, suggest future avenues of research that might lead to clarification of this important pathogenic puzzle.

Three articles in this issue of Seminars focus on information regarding ALD obtained primarily from clinical studies. Epidemiologic data rather than experimental studies on alcohol hepatotoxicity lead to the conclusion that the degree and duration of alcohol ingestion was the important factor in the genesis of fibrosis and cirrhosis. Morgan and co-authors review the epidemiologic evidence surrounding alcoholic liver disease in detail. Levitsky and Mailliard discuss the diagnosis and current standard of treatment of ALD, and at the same time incorporate recent concepts in cellular biology that could lead to more rationale and effective treatment modalities. Finally, Watt and McCashland define the sometimes controversial place of liver transplantation in end-stage ALD.

The development of more effective therapies requires a better understanding of the underlying pathogenic mechanisms. Although vast amounts of experimental data have accumulated, the underlying mechanisms of alcohol-induced hepatotoxicity remain elusive. It has become clear, however, that the fundamental mechanisms of hepatotoxicity of alcohol are complex and multifactorial. The present approach incorporates the concept that several primary and secondary mechanistic factors coexist and interact in such a way as to initiate liver injury and then secondarily perpetuate progression of ALD. Hoek summarizes the multifactorial evidence that leads to alcoholic liver injury. It is now clear that direct hepatotoxicity by itself is not a sufficient explanation encompassing all aspects of alcohol-induced hepatotoxicity. The histopathology of alcoholic hepatitis characterized by the accumulation of inflammatory cells suggests a role for immune-mediated responses in the perpetuation of ALD. The article by Thiele et al describes the clinical and experimental evidence supporting the role of disordered immune mechanisms in ALD. Secondary cofactors also likely play a part in the development of ALD. Two such important cofactors are iron and hepatitis C. Tavill and Quadri discuss the place of iron as a potential cofactor in ALD, while Schiff and colleagues consider the interaction of alcohol and hepatitis C in accelerating the progression of ALD. Finally, no treatment of the ALD would be complete without considering the role of nutrition. Halstead discusses both the role of altered nutrition in the pathogenesis of ALD and considers the role that nutrient supplementation plays in the treatment of ALD.

Anyone interested in the pathogenesis and treatment of ALD realizes that abstinence from drinking is the ultimate answer to this huge problem that includes both societal and health issues. Research devoted to the pathogenesis of hepatotoxicity has shifted from the central role of malnutrition to direct alcohol hepatotoxicity to the final realization that no one central mechanism is operative. The place of other factors as equally important in the pathogenesis of ALD is emphasized by the clinical observation that only 15 to 20% of alcoholics end up with end-stage liver disease. It is our belief that multidisciplinary efforts incorporating cell and molecular biology, immunology, and genetics will ultimately lead to a deeper understanding of the pathogenesis of ALD as well as to improved treatment modalities.