Obesity and alcoholic liver disease.
Obesity potentiates the severity of alcohol-induced liver damage. Ethanol influences adipose tissue production of hormones and cytokines. The mechanisms by which adiposity and ethanol interact to produce hepatic steatosis and steatohepatitis are beginning to be studied. Exacerbation of the proinflammatory state that induces tumor necrosis factor activity and hepatic insulin resistance seems to be involved. However, the precise cellular signals that culminate in hepatocyte dysfunction and death remain controversial. Both hepatocyte apoptosis and necrosis are likely, but further study is needed to develop optimal hepatoprotective strategies. It is currently unclear whether the hepatotoxic consequences of obesity and ethanol ingestion are additive or synergistic. This information has important prognostic implications and might be useful to formulate body mass index-based guidelines for "safe" alcohol consumption. Findings of studies in experimental animals also raise questions about the relation between steatohepatitis and cirrhosis. Despite overwhelming evidence that obesity promotes alcohol-induced steatosis and steatohepatitis, most obese human beings (and mice) who drink alcohol do not become cirrhotic. Moreover, at least in mice, even severe steatohepatitis leads to cirrhosis relatively infrequently. Thus, it is conceivable that, although steatohepatitis is a permissive factor for cirrhosis, it is neither necessary nor sufficient for cirrhosis to occur. The quest to identify the proximal mediators of hepatic fibrosis should probably include an investigation of how various adipokines, neurotransmitters, and cytokines interact to regulate hepatic stellate cells. Armed with such knowledge, further modifying actions of ethanol on these mechanisms can be explored by investigators.
Diehl
Anna Mae
AM
Johns Hopkins University, Baltimore, MD 21205, USA. diehl004@mc.duke.edu
D000818:Animals; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000378:metabolism*