title: Hepatic iron overload: direct HFE (HLA-H) mutation analysis vs quantitative iron assays for the diagnosis of hereditary hemochromatosis.
abstract: Among patients with hepatic iron overload, the distinction between hereditary hemochromatosis (HH), a common yet treatable genetic disease, and other causes of siderosis remains problematic. The recent discovery of a specific homozygous mutation (C282Y) in a novel major histocompatibility complex class I-like gene (named HLA-H or HFE) in 80% to 100% of well-characterized cases of HH suggests that direct DNA-based mutation analysis may help resolve this dilemma. To assess the clinical utility of direct HLA-H mutation analysis in a typical diagnostic setting, we measured genotypic and phenotypic parameters of iron overload in 37 subjects with biopsy-proven hepatic siderosis (2+ or greater) and in 127 healthy control subjects. The prevalence of C282Y homozygotes was significantly greater in the hepatic siderosis group (32%) than in the control group (0%), confirming the association between this homozygous mutation and hepatic iron overload. In the hepatic siderosis group, C282Y homozygotes had significantly higher hepatic iron and ferritin levels, a significantly lower prevalence of hepatitis C virus or alcoholic liver disease, but no significant difference in the saturation of serum transferrin. Of the 20 subjects with a hepatic iron index (HII) in the previously defined "hemochromatosis range" (>1.9), 9 (45%) were C282Y homozygotes. Of the 11 nonhomozygous subjects with an HII greater than 1.9 (presumed false-positive HIIs), 10 (91%) had hepatic cirrhosis compared with 3 of 9 (33%) homozygotes with an HII greater than 1.9 who had cirrhosis (P<.02). The HII thus has poor diagnostic specificity for predicting genotypic HH in patients with cirrhosis. We conclude that direct determination of the HLA-H C282Y genotype may be the single best diagnostic test for HH, particularly in patients with cirrhosis, for whom the HII is quite nonspecific.
authors.affiliation: Department of Pathology, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Press
authors.forename: K
authors.initials: K
authors.lastname: Flora
authors.forename: C
authors.initials: C
authors.lastname: Gross
authors.forename: J M
authors.initials: JM
authors.lastname: Rabkin
authors.forename: C L
authors.initials: CL
authors.lastname: Corless
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006432:Hemochromatosis / Q000175:diagnosis* / Q000235:genetics*; D000071020:Hemochromatosis Protein; D006579:Heterozygote; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000032:analysis*; D019190:Iron Overload / Q000175:diagnosis* / Q000209:etiology; D008103:Liver Cirrhosis / Q000209:etiology; D008104:Liver Cirrhosis, Alcoholic / Q000150:complications; D008107:Liver Diseases / Q000175:diagnosis*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged
chemical_list: C103673:HFE protein, human; D006680:HLA Antigens; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron