This study analyzed the relaptionship between liver fat, insulin resistance and fibrosis in two large cohorts of subjects with a similar degree of steatosis, in whom steatosis was principally of viral (genotype 3 Chronic Hepatitis C [CHC-3]) or of metabolic (NAFLD) origin. Patients (n= 132 in each group) were matched by age, BMI, and degree of fat accumulation. Tests of liver function were comparable in the two groups.
At liver biopsy, steatosis was grade 1 in 56%, 2 in 32.5% and 3 in 11.5% of both groups. Despite similar degree of steatosis, fibrosis was significantly more severe in CHC-3 than in NAFLD. A similar trend was observed for necroinflammation.
The authors note that in individual patients, host factors, particularly abdominal obesity and type 2 diabetes may contribute to the development of steatosis and liver fibrosis through a mechanism mediated by insulin resistance. The coexistence of host and viral factors contributing to steatosis in the same individual has long blurred the analysis of their independent contributions to liver fibrosis in persons infected with HCV. To minimize this possible source of bias, this study examined non-obese, non-diabetic subjects infected with genotype 3. In this subset of HCV patients, the viral core protein is ?3-fold more efficient than the corresponding protein from genotype 1 in inducing lipid accumulation in the liver. In the CHC-3 cohort, low total plasma cholesterol and high viral load were the sole determinants of steatosis, while metabolic, host-related factors were ruled out. The association of steatosis with metabolic abnormalities was confirmed in the NAFLD group.
The different etiological factors for steatosis in the two patient cohorts verified the relative impact of liver fat of different etiology on hepatic inflammation and fibrosis. Steatosis had no association with fibrosis in CHC-3, while it was a major determinant of liver damage in NAFLD, where fibrosis paralleled the severity of fat infiltration. In both groups insulin resistance was an independent predictor of severe fibrosis, despite the fact that steatosis correlated with fibrosis severity only in persons with NAFLD.
In CHC-3, insulin resistance and virus-induced liver inflammation appear to the likely determinants of fibrosis progression. By contrast, in NAFLD, these data suggest that hepatic fibrosis might stem from a complex triad of independent risk factors: steatosis, insulin resistance and systemic inflammation, the latter indicated by elevated ferritin levels.
In conclusion, insulin resistance is associated with advanced hepatic fibrosis in metabolic as well as in viral liver disease. In contrast, only "metabolic" steatosis contributes to liver fibrosis. Virus-induced steatosis as seen in CHC-3 does not appear to directly promote necroinflammation and hepatic fibrogenesis.