Hepcidin Suppression Relative to Iron Status in Patients with Chronic Hepatitis C.

Patients with chronic hepatitis C (CHC) often have increased liver iron deposits, a condition associated with reduced sustained response to antiviral therapy, more rapid progression to cirrhosis, and development of hepatocellular carcinoma. The hepatic hormone hepcidin is a major regulator of iron metabolism that inhibits iron absorption and recycling from erythrophagocytosis. Hepcidin decrease is a possible pathophysiological mechanism of iron overload in CHC, but studies in humans have been hampered so far by the lack of reliable quantitative assays for the 25-amino acid bioactive peptide in serum (s-hepcidin). Using a recently validated immunoassay (Ganz T, Blood 2008, epub Aug 8), we measured s-hepcidin levels in 82 CHC naïve patients and 57 sex-matched healthy controls with rigorous definition of normal iron status. All CHC patients underwent liver biopsy with histological iron score (according to Deugnier YM, Gastroenterology 1992). S-hepcidin was much lower in CHC than in controls (geometric means with 95% CIs: 33.7, 21.5–52.9 versus 90.9, 76.1–108.4 ng/ml, respectively; P<0.001), while both serum ferritin and transferrin saturation were significantly higher in CHC than in controls, as expected. S-hepcidin strongly correlated with serum ferritin in both controls (r=0.741; P<0.001) and CHC patients (r = 0.718; P<0.001). In CHC patients, s-hepcidin also correlated with histological total iron score (r = 0.46; P<0.001), but not with serum interleukin-6 (r = −0.042; P = n.s.). After stratification for serum ferritin quartiles, s-hepcidin levels increased significantly across quartiles in both controls and CHC patients (chi for trend, P<0.001). However, in the latter group s-hepcidin levels were significantly lower than in controls for each corresponding quartile (ANOVA, P<0.001). In the lowest ferritin quartile, s-hepcidin was significantly inversely correlated with viral loading (e.g. serum HCV-RNA IU/ml; r = −0.526; P=0.036), while this association gradually disappeared with increasing ferritin quartiles. These results, together with very recent studies in animal and cellular models (Nishina S, Gastroenterology 2008; Miura K, Hepatology 2008), indicate that though hepcidin regulation by iron stores is maintained in CHC, the suppression of this hormone by HCV is likely an important factor in liver iron accumulation in this condition.