Current concepts in the pathogenesis of alcoholic liver injury

Alcoholic liver disease (ALD) develops as a consequence of priming and sens itizing mechanisms rendered by cross-interactions of primary mechanistic fa ctors and secondary risk factors. This concept, albeit not novel, is becomi ng widely accepted by the field, and more research is directed toward ident ifying and characterizing the interfaces of the cross-interactions to help understand individual predisposition to the disease. Another pivotal develo pment is the beginning of cell type-specific research to elucidate specific contributions not only of hepatocytes, but also of hepatic macrophages, li ver-associated lymphocytes, sinusoidal endothelial cells, and hepatic stell ate cells to sensitizing and priming mechanisms. In particular, the critica l role of hepatic macrophages has been highlighted and the priming mechanis ms concerning this paracrine effect have been proposed. Glutathione depleti on in hepatocyte mitochondria is considered the most important sensitizing mechanism. One of the contributing factors is decreased methionine metaboli sm. Remaining key questions include how altered methionine metabolism contr ibute to the pathogenesis of ALD; how cross-talk among nonparenchymal liver cells or between nonparenchymal cells and hepatocytes leads to ALD; how dy sfunctional mitochondria determine 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.