ALCOHOL AND LIVER REGENERATION

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The liver is a major target tissue for alcohol-induced damage. Given the prevalent use of alcohol, it is not surprising that alcohol abuse is the most common cause of clinically significant liver disease in the United States. Deaths from cirrhosis (the eventual consequence of chronic liver injury) correlate with per capita consumption of alcohol. Alcoholic cirrhosis , the end-stage of alcohol-induced liver injury, currently is the fourth leading cause of death in middle-aged men and is likely to remain a major cause of morbidity and mortality due to recent increases in alcohol consumption among women and young teenagers. 36 Unfortunately, there is no effective medical therapy for most patients with alcoholic liver disease . Orthotopic liver transplantation improves the survival of patients with terminal alcoholic cirrhosis; however, transplantation carries a risk of perioperative mortality and necessitates lifelong immunosuppressive therapy with attendant risks of serious infection and malignancy. Furthermore, if all patients with advanced alcoholic liver disease received liver transplants, there would be no donor organs available for patients with other forms of cirrhosis. 84 Therefore, there still is a desperate need to develop effective medical therapy for alcoholic liver disease. Over the past 3 decades, considerable progress has been made towards understanding the mechanisms by which alcohol produces liver injury. 82 It now is clear that liver injury is the end result of multiple events that are triggered by the oxidation of ethanol to acetaldehyde , a highly reactive metabolite. One important intermediary event in this pathogenic process appears to be the release of pro-inflammatory cytokines, including tumor necrosis factor–α (TNF). Plasma concentrations of TNF and TNF-inducible cytokines, including interleukins 6 (IL-6) and 8 (IL-8), correlate with mortality in patients hospitalized with alcoholic hepatitis. 10 , 41 , 49 , 62 , 63 , 64 This suggests that anticytokine agents may be useful for interrupting the pathogenesis of alcohol-induced liver injury. Indeed, treatments that decrease endotoxemia (a potent stimulus for TNF production) inhibit the evolution of hepatitis in rats that are being fed alcohol. 1 , 70 Unfortunately, unlike experimental animals that receive the antidote and the toxin concomitantly, most alcoholic patients already have sustained significant liver damage before they seek medical attention. Therefore, in clinical practice another major goal of treatment is to facilitate liver repair. Data from a number of groups, 37 , 38 , 43 , 59 , 77 , 92 including the author's, 28 , 29 , 30 , 35 indicate that ethanol inhibits the normally immense regenerative capacity of the liver. Thus, alcohol consumption may produce liver disease both by injuring the liver and by impairing the regenerative response to that injury. Relatively little is known about the mechanisms underlying ethanol's antiregenerative actions; however, these must be defined and reversed to optimize speedy and complete recovery from alcohol-induced liver injury.