title: HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity.
abstract: There is conflicting evidence regarding inheritance of hemochromatosis gene (HFE) mutations and influence of hepatic iron deposition as cofactors for development of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We studied hepatic iron content (Perls' stain grade), frequency of HFE mutations, and serum iron indices in 93 patients with NASH from a multiethnic background; 59 (63%) were of Anglo-Celtic origin. Data on C282Y mutations were available for all 93 patients and on H63D for 69 patients. Respective controls were 206 (for C282Y, 141 [69%] of whom were Anglo-Celtic) and 180 (for H63D) blood donors. Hyperferritinemia was present in 38 patients (40%) with NASH, but transferrin saturation was increased (>55%) in only 5 (5%). Liver biopsy specimens showed advanced fibrosis in 31 (33%) (cirrhosis in 20%). Altogether, 9 biopsy specimens (10%) showed increased iron: 7 (8%) with grade 2 and 2 (2%) with grade 3 iron staining. Only 1 biopsy specimen with increased iron showed advanced fibrosis. The frequency of C282Y heterozygosity was increased in Anglo-Celtic patients with NASH compared with ethnic blood donor controls (22% vs. 9.2%; P =.035); there were no C282Y homozygotes in the NASH cohort. Although there was a trend toward higher serum ferritin levels among C282Y heterozygotes with NASH, there were no differences in histologic grades of steatosis, inflammation, or fibrosis between individuals with and without C282Y. The frequencies of compound C282Y/H63D heterozygotes (n = 1) or H63D heterozygotes (n = 10) were not increased in NASH. Multivariate analysis identified female sex, diabetes mellitus, and more severe liver inflammation but not HFE mutations, serum ferritin, iron saturation, or hepatic iron staining as independent predictors of hepatic fibrosis. In conclusion, hepatic iron is not a factor linked to hepatic fibrogenesis in patients with NASH. HFE mutations do not confer an additional risk of hepatic fibrosis in this disorder.
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, New South Wales 2145, Australia.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Chitturi
authors.forename: Martin
authors.initials: M
authors.lastname: Weltman
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Farrell
authors.forename: David
authors.initials: D
authors.lastname: McDonald
authors.forename: James
authors.initials: J
authors.lastname: Kench
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Dev
authors.initials: D
authors.lastname: Samarasinghe
authors.forename: Rita
authors.initials: R
authors.lastname: Lin
authors.forename: Shehan
authors.initials: S
authors.lastname: Abeygunasekera
authors.forename: Jacob
authors.initials: J
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D001315:Australia; D001706:Biopsy; D015331:Cohort Studies; D005006:Ethnicity; D005234:Fatty Liver / Q000150:complications / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D005293:Ferritins / Q000097:blood; D006680:HLA Antigens / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D014168:Transferrin / Q000378:metabolism
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D005293:Ferritins; D007501:Iron