Mechanisms and significance of liver steatosis in hepatitis C virus infection

Abstract

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.

Figure 1

Some of the major mechanisms leading to steatosis in patients with chronic hepatitis C. HCV, especially (but not only) genotype 3a, has been shown to be directly involved in triglyceride accumulation by several mechanisms: activation of fatty acid neosynthesis via SREPBP-1c (2) and RxRα (3), impaired degradation through down-regulation of CPT-1 (4) and PPARα (5), and inhibition and/or down-regulation of MTP (6). Another potential mechanism (not shown) is the cell damage inflicted by reactive oxygen species consequent to localization of the HCV core protein in the mitochondria. This may also trigger lipid peroxidation of microsomal membranes, leading to impaired VLDL secretion. In patients who are insulin resistant, the major mechanism leading to steatosis is the free fatty acid overflow from adipose tissue (1). Hyperglycemic/hyperinsulinemic states are also associated with activation of fatty acid neosynthesis via SREPBP-1c (2) and impaired degradation via down-regulation of CPT-1 (4). It has to be added that HCV may contribute to insulin resistance by impairing the IRS-1 signaling in hepatocytes by multiple mechanisms. Not shown in the figure are also the interference with ApoB synthesis and the activation of MTP reported in insulin resistant states: the latter phenomenon may be partially counterbalanced by the strong inhibition of MTP observed in patients with predominantly viral steatosis .