METABOLIC FACTORS IN THE PATHOGENESIS OF CHRONIC HEPATITIS C, WITH PARTICULAR REFERENCE TO HEPCIDIN

Chronic Hepatitis C is a major cause of liver disease worldwide; this condition may progress to severe liver disease with the developement of cirrhosis and eventually of hepatocellular carcinoma. The aim of this thesis was to evaluate some metabolic factors that may influence the progression of disease as well as the responsiveness to treatment: insulin resistance and iron overload. Epidemiological data have documented an increased prevalence of type 2 diabetes in patints with chronic HCV infection, and there are evidences that HCV may promote insulin resistance with a mechanism that is still unclear. Basal IR is also associated with a reduced responsiveness to antiviral treatment. In our study we evaluated a cohort of 412 CHC patients treated with peginterferon and ribavirin; IR was determined by HOMA-IR. The results showed that Insulin resitance is a major independent predictor of rapid virologic response (RVR). RVR is the best predictor of sustained virologic response. Patients with chronic hepatitis C (CHC) often have increased liver iron, condition associated with reduced responsiveness to antiviral therapy and more rapid progression to cirrhosis. The epatic hormone hepcidin is the major regulator of iron metabolism. Decreased levels of this hormone are a possible pathophysiological mechanism of iron overload in CHC but studies in humans have been hampered by the the lack of reliable quantitative assay. We measured with a recently validated immunoassay serum hepcidin levels in a population of 81 CHC patients and 57 controls with rigorous definition of normal iron status. S-hepcidin was significantly lower in CHC patients then in controls (p<0.001); in CHC patients hepcidin correlated with ferritin and hostological total iron score but not with IL-6. After stratification for ferritin quartiles hepcidin increased significantly across quartiles in both patients and controls, however in patients s-hepcidin levels were significantly lower then controls for each corresponding quartile.These results indicate that though hepcidin regulation by iron stores is mantained in CHC patients, the suppression of this hormone by HCV is likely an important factor in liver iron accumilation in this condition.