Iron-Overload–Related Disease in<i>HFE</i>Hereditary Hemochromatosis

TLDR

Homozygous C282Y carriers, the most common HFE mutation linked to hereditary hemochromatosis, typically exhibit elevated serum ferritin and transferrin saturation, yet the magnitude of their risk for iron‑overload‑related disease remains debated. This study aimed to evaluate the long‑term risk of iron‑overload‑related disease among 31,192 northern European adults carrying HFE mutations, followed for an average of 12 years. Researchers sampled 1,438 participants stratified by HFE genotype, including all 203 C282Y homozygotes, and collected clinical and biochemical data, with two iron‑status measurements taken 12 years apart. Among C282Y homozygotes, 28.4 % of men and 1.2 % of women developed documented iron‑overload‑related disease, and men with ferritin ≥1,000 µg/L were more likely to report fatigue, use arthritis medication, and have a history of liver disease.

Abstract

Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial.We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints.The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1000 mug per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene.In persons who are homozygous for the C282Y mutation, iron-overload-related disease developed in a substantial proportion of men but in a small proportion of women.