Mechanisms and significance of liver steatosis in hepatitis C virus infection

The pathogenesis of liver damage associated with chronic hepatitis C virus (HCV) infection is thought to be largely immunomediated. However, some frequent histopathological features, such as steatosis, suggest a direct cytopathic effect of HCV. The direct responsibility of HCV in the pathogenesis of steatosis is shown by: (1) the association with HCV genotype 3 infection, suggesting that some viral sequences are involved in the intracellular accumulation of lipids; (2) the correlation between severity of steatosis and HCV replication levels; (3) association between response to treatment and disappearance of steatosis. Experimental studies have shown that the nucleocapsid protein of HCV (core protein) is capable and sufficient to induce lipid accumulation in hepatocytes. Moreover, the observation that chronic hepatitis C patients have reduced serum levels of ApoB suggests an interference with the very-low density lipoprotein (VLDL) assembly, although other mechanisms are possible. In patients with sustained virological response induced by antiviral therapy, such levels are normalized. Other observations suggest that the pathogenesis of steatosis in chronic hepatitis C is not solely due to HCV. The origin of the mild steatosis observed in most patients may be metabolic, since its severity correlates with body mass index and insulin resistance. Most studies have shown a correlation between presence and/or severity of steatosis and fibrosis stage, but it is unclear whether this effect is direct or mediated by the associated insulin resistance, increased susceptibility to apoptosis, or by inflammatory cytokines. Finally, steatosis negatively influences the rate of response to antiviral treatment, as confirmed by large clinical trials. Management of steatosis in chronic hepatitis C requires knowledge of its pathogenesis and may involve both life-style changes and pharmacological interventions, although the latter remain largely experimental. (C) 2006 The WJG Press. All rights reserved.