Fibrogenesis in alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. In developed countries, ALD is a major cause of end-stage liver disease that requires transplantation. The spectrum of ALD includes simple steatosis, alcoholic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Alcohol abstinence is the most effective therapy for ALD. However, targeted therapies are urgently needed for patients with severe ALD (i.e., alcoholic hepatitis) or those who do not abstain from alcohol. The lack of studies and the availability of animal models that do not reflect all the features of this disease in humans inhibit the development of new drugs for ALD. In ALD-associated fibrosis, hepatic stellate cells are the principal cell type responsible for extracellular matrix production. Although the mechanisms underlying fibrosis in ALD are largely similar to those observed in other chronic liver diseases, oxidative stress, methionine metabolism abnormalities, hepatocyte apoptosis, and endotoxin lipopolysaccharides that activate Kupffer cells may play unique roles in disease-related fibrogenesis. Lipogenesis during the early stages of ALD has recently been implicated as a risk factor for the progression of cirrhosis. Other topics include osteopontin, interleukin-1 signaling, and genetic polymorphism. In this review, we discuss the basic pathogenesis of ALD and focus on liver fibrogenesis.

Keywords: Stellate cell, Kupffer cell, Steatohepatitis, Fibrosis, Cytokine, Oxidative stress

Core tip: Alcoholic liver disease (ALD) is a major cause of preventable morbidity and mortality worldwide. In ALD-associated fibrosis, hepatic stellate cells are the principal cell type responsible for extracellular matrix production. Although the mechanisms underlying ALD-associated fibrosis are largely similar to those observed in other chronic liver diseases, oxidative stress, abnormal methionine metabolism, hepatocyte apoptosis, and endotoxin lipopolysaccharides that activate Kupffer cells play unique roles in fibrogenesis in ALD. Recently, lipogenesis during the early stages of ALD has been implicated as a risk factor for progression of cirrhosis. Other critical factors include osteopontin, interleukin-1 signaling, and genetic polymorphisms.