title: HFE mutations in alpha-1-antitrypsin deficiency: an examination of cirrhotic explants.
abstract: Increased iron deposition is often seen in liver explants with alpha-1-antitrypsin deficiency, but it remains unclear if this is a nonspecific effect of end-stage liver disease or if individuals with alpha-1-antitrypsin deficiency and excess iron are at increased risk for HFE mutations. To further examine this question, 45 liver explants with alpha-1-antitrypsin deficiency and 33 control livers with chronic hepatitis C were examined for histological iron accumulation, graded on a scale of 0 to 4+, and HFE mutations. Interestingly, the alpha-1-antitrypsin cirrhotic livers showed a bimodal distribution of iron accumulation, with peaks at grades 1 and 3. In contrast, hepatitis C cirrhotic livers showed a unimodal distribution with a peak at grade 2. HFE mutations in livers with alpha-1-antitrypsin deficiency were as follows: C282Y=2%, H63D=42%. H63D mutations were more frequent in alpha-1-antitrypsin deficiency cases than in controls (42 vs 27%), but was not statistically significant, P=0.17. However, there was a significant association with HFE mutations in alpha-1-antitrypsin deficiency livers with grade 3+ or 4+ iron, P=0.02. In contrast, livers with hepatitis C showed a similar frequency of HFE mutations as the general population: C282Y=15%, H63D=27%. A rare S65C mutation and a novel A271S mutation were also found in this study; the latter patient had 4+ iron in the liver and later developed heart failure with cardiac iron. In conclusion, total H63D mutations were high (42%) in cirrhotics with alpha-1-antitrypsin deficiency and there was a significant association between HFE mutations and high levels of iron accumulation.
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Maggie
authors.initials: M
authors.lastname: Lam
authors.forename: Michael
authors.initials: M
authors.lastname: Torbenson
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Perumal
authors.initials: P
authors.lastname: Vivekanandan
authors.forename: Linda
authors.initials: L
authors.lastname: Ferrell
mesh_terms: D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D005787:Gene Frequency; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D019190:Iron Overload / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000473:pathology*; D016031:Liver Transplantation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000473:pathology
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins