1162 ASSOCIATION OF SINGLE NUCLEOTIDE POLYMORPHISMS IN INTERFERON STIMULATED GENES WITH CHRONIC HEPATITIS C TREATMENT OUTCOME

Abstract

insulin resistance and hepatic steatosis. Steatosis may increase susceptibility to apoptosis, inflammation and fibrosis by triggering hepatocytes to up-regulate CD95/Fas. We investigated this hypothesis and potential role of adipocytokines in modulating the progression of liver disease in patients with HCV-4. Methods: In 147 HCV patients and 89 controls we measured serum adiponectin, HMW adiponectin, leptin, TNF-a, IL-6 and CK-18. Liver biopsies were evaluated for steatosis/inflammation/ fibrosis, adiponectin mRNA/protein, AdipoR1/-R2 mRNA and phosphoenolpyruvate carboxykinase (PEPCK) gene expression; and adiponectin and CD95 immunoreactivity. The potential associations with hepatic steatosis and fibrosis were analyzed. Results: CD95 immunoreactivity and adiponectin immunoreactivity were readily detected in all biopsies examined and scored as grade 3 in 24 (16.3%) of patients, and as bright in 20 (13.6%) of patients, respectively. Adiponectin immunostaining within the liver correlated positively with the intensity of hepatic CD95/Fas immunostaining within the liver (r = 424; p =0.001). A significant association between high serum adiponectin and HMW adiponectin levels with CD95/Fas immunoreactivity (r = −0.16, p = 0.04, r = 0.21, p = 0.001; respectively), but not with adiponectin immunoreactivity in the liver was also identified. Adiponectin and HMW adiponectin were negatively correlated with the expression of AdipoR1, but positively correlated with the expression of AdipoR2. Hepatocyte CD95/Fas up-regulation correlated with steatosis, inflammation and fibrosis (p = 0.001). Significant correlation of serum adiponectin, HMW adiponectin and AdipoR1 and 2 mRNA expression, as well as liver adiponectin immunostaining within the liver were identified with steatosis. mRNA transcription for PEPCK was also significantly correlated with the amount of steatosis. A positive association between adiponectin and HMW adiponectin and hepatic inflammation was identified. This correlation remained significant even after following adjusting for age, gender and BMI (r = 0.17; p = 0.03; r = 0.45; p = 0.0001) respectively. Factors independently associated with the stage of fibrosis were HOMA-IR, inflammation score and age. Conclusions: Our findings in HCV-4 infection shows that adiponectin correlates with the different stages of liver injury. Steatosis up-regulates hepatocyte CD95/Fas and thus increases apoptosis, which facilitates inflammation and fibrosis. These findings may offer potential clues for future therapeutic intervention.