title: Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy.
abstract: Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels.
  
  
  CONCLUSIONS
  In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland. Christian.Lange@chuv.ch
authors.forename: Christian M
authors.initials: CM
authors.lastname: Lange
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Kutalik
authors.forename: Kenichi
authors.initials: K
authors.lastname: Morikawa
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bibert
authors.forename: Andreas
authors.initials: A
authors.lastname: Cerny
authors.forename: Günter
authors.initials: G
authors.lastname: Dollenmaier
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Tilman J
authors.initials: TJ
authors.lastname: Gerlach
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Raffaele
authors.initials: R
authors.lastname: Malinverni
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D004359:Drug Therapy, Combination; D005234:Fatty Liver / Q000453:epidemiology; D005260:Female; D005293:Ferritins / Q000097:blood*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D016898:Interferon-alpha / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use*; D012307:Risk Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D005293:Ferritins; C100416:peginterferon alfa-2a