TNFalpha genotype affects TNFalpha release, insulin sensitivity and the severity of liver disease in HCV chronic hepatitis

Background/Aims: TNFα induces insulin resistance and promoter polymorphisms of TNFα gene affect the release of this cytokine, implicated in the pathogenesis of HCV-related diabetes and fatty liver. The aim was to define whether in patients with HCV chronic hepatitis TNFα genotype influences TNFα activity, insulin resistance, and the severity of the disease. Methods: 186 patients, 65% with steatosis, 17% with diabetes. TNFα and sTNFR2 were determined by ELISA, insulin resistance by HOMA-R index and TNFα -238, -308, and -863 polymorphisms by restriction analysis. Results: TNFα, sTNFR2, and insulin resistance were higher in patients than in 89 controls. TNFα pathway activity was correlated with LDL cholesterol, steatosis, and insulin resistance, which, in turn, was correlated with the severity of liver damage. Patients subdivided according to TNFα genotype significantly differed for TNFα release, insulin sensitivity and the prevalence of cirrhosis. The -308 and -238 TNFα polymorphisms, characterized by increased promoter activity, were associated with higher TNFα activity, insulin resistance and severity of the disease, whereas the -863 polymorphism, characterized by reduced promoter activity, with lower TNFα activity, and higher insulin sensitivity. Conclusions: TNFα genotype modulates the activity of the TNFα pathway, influences insulin sensitivity and the severity of HCV chronic hepatitis.