Session II

The striking histological similarity between ASH and NASH strongly suggests that they are due to similar pathogenic mechanisms. We have proposed the hypothesis that both are diseases of “two hits”. In this model the first hit is the development of steatosis and the second a trigger of necroinflammation, with the role of steatosis being to increase the liver’s sensitivity to the second hit. Candidates for the necroinflammatory trigger are: endotoxin-induced cytokine release, oxidative stress and an increased supply of potentially toxic free fatty acids. Candidate genes with a potential role in genetic susceptibility to ASH and NASH are therefore those whose products are involved in: (i) hepatic fat accumulation; (ii) oxidative stress; (iii) fatty acid metabolism as well as cytokine genes. Evidence supporting a role for immunological mechanisms in the pathogenesis of ASH implicates immunoregulatory genes as further potential candidates.