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Current concepts in the pathogenesis of alcoholic liver injury

Alcoholic liver disease (ALD) develops as a consequence of priming and sensitizing mecha nisms rendered by cross‐interactions of primary mech anistic factors and secondary risk factors. This concept, albeit not novel, is becoming widely accepted by the field, and more research is directed toward identifying and characterizing the interfaces of the cross‐interactions to help understand individual predisposition to the disease. Another pivotal development is the begin ning of cell type‐specific research to elucidate specific contributions not only of hepatocytes, but also of hepatic macrophages, liver‐associated lymphocytes, si nusoidal endothelial cells, and hepatic stellate cells to sensitizing and priming mechanisms. In particular, the critical role of hepatic macrophages has been high lighted and the priming mechanisms concerning this paracrine effect have been proposed. Glutathione de pletion in hepatocyte mitochondria is considered the most important sensitizing mechanism. One of the contributing factors is decreased methionine metabo lism. Remaining key questions include how altered methionine metabolism contribute to the pathogenesis of ALD; how cross‐talk among nonparenchymal liver cells or between nonparenchymal cells and hepatocytes leads to ALD; how dysfunctional mitochondria deter mine the type of cell death in ALD; and what secondary factors are critical for the development of advanced ALD such as alcoholic hepatitis and cirrhosis.—Tsukamoto, H., Lu, S. C. Current concepts in the pathogenesis of alcoholic liver injury. The FASEB J. 15, 1335–1349 (2001)