title: Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C.
abstract: Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important role in innate immunity, we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥ 2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor.
  
  
  CONCLUSIONS
  Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients.
authors.affiliation: Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland. jdpryan@yahoo.co.uk
authors.forename: John D
authors.initials: JD
authors.lastname: Ryan
authors.forename: Sandro
authors.initials: S
authors.lastname: Altamura
authors.forename: Emma
authors.initials: E
authors.lastname: Devitt
authors.forename: Sarah
authors.initials: S
authors.lastname: Mullins
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Lawless
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.forename: John
authors.initials: J
authors.lastname: Crowe
mesh_terms: D000328:Adult; D000368:Aged; D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D000071020:Hemochromatosis Protein; D006526:Hepatitis C / Q000188:drug therapy*; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D007501:Iron / Q000097:blood; D000090463:Iron Deficiencies; D008113:Liver Neoplasms; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D023181:Antimicrobial Cationic Peptides; D000998:Antiviral Agents; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D007501:Iron; D008565:Membrane Proteins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; D050796:STAT3 Transcription Factor; C578702:HAMP protein, human; C103673:HFE protein, human; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494086:STAT3 protein, human; C100416:peginterferon alfa-2a