HFE genotype in patients with hemochromatosis and other liver diseases

Background: Hereditary hemochromatosis is a common inherited disorder of ir on metabolism. The gene HFE, which contains two missense mutations (C282Y a nd H63D), was recently identified. Objective: To determine how HFE genotyping for the C282Y and H63D mutations contributes to the diagnosis of hemochromatosis and to determine the preva lence of HFE mutations in a group of patients with liver disease. Design: Cross-sectional study. Setting: Academic medical center. Patients: 66 patients with hereditary hemochromatosis and 132 referred pati ents with other liver diseases. Measurements: At initial diagnosis, fasting transferrin saturation, ferriti n level, routine chemistry panel, and complete blood count were determined. Percutaneous liver biopsy was done on all patients for histologic analysis and measurement of hepatic iron concentration and hepatic iron index. HFE genotyping for the C282Y and H63D mutations was done on all patients by usi ng genomic DNA samples. Results: Of the 66 patients with hemochromatosis diagnosed on the basis of serum iron studies and liver biopsy findings, 60 (91%) were C282Y homozygot es, 2 (3%) were compound heterozygotes, 1 (1.5%)was a C282Y heterozygote, 2 (3%) were H63D heterozygotes, and 1 (1.5%) was negative for both mutations , Of the 132 patients with liver disease, 6 (5%) were C282Y homozygotes, 8 (6%) were compound heterozygotes, 6 (5%) were C282Y heterozygotes, 5 (4%) w ere H63D homozygotes, 20 (15%) were H63D heterozygotes, and 87 (66%) were n egative for both mutations, All 66 C282Y homozygotes had an elevated hepati c iron concentration, and 65 of the 66 patients (98%) had a transferrin sat uration of at least 45%, Ten of the 66 patients (15% [95% Cl, 7.5% to 26%]) had a hepatic iron index less than 1.9 mmol/kg per year; hemochromatosis w as not suspected in 6 of the 10 patients before genotyping. Cirrhosis or su bstantial hepatic fibrosis was not seen in any (0% [Cl, 0% to 18%]) of the 19 patients younger than 40 years of age who were homozygous for the C282Y mutation. Conclusions: All 66 patients homozygous for the C282Y mutation of HFE had a n elevated hepatic iron concentration, but approximately 15% of these patie nts did not meet a previous diagnostic criterion for hemochromatosis (hepat ic iron index > 1.9 mmol/kg per year). Determination of HFE genotype is cli nically useful in patients with liver disease and suspected iron overload a nd may lead to identification of otherwise unsuspected C282Y homozygotes.