HFE Hemochromatosis (C282Y)
The most common inherited iron-overload disorder in people of European descent
Definition
Hereditary hemochromatosis type 1 is an autosomal-recessive genetic disorder caused by mutations in the HFE gene — the most significant being the C282Y variant (p.Cys282Tyr). C282Y homozygotes absorb excess dietary iron over decades, accumulating it in the liver, heart, pancreas and joints. Untreated, it can cause cirrhosis, diabetes, cardiomyopathy and arthropathy. It is the most common monogenic disorder in people of Northern European ancestry (carriers ~1 in 10). Clinical penetrance is incomplete: not every homozygote develops overt disease.
Detailed explanation
The HFE gene was identified by Feder et al. in Nature Genetics (1996) as an MHC class I-like gene. The C282Y mutation prevents the HFE protein from folding and reaching the cell surface correctly, disrupting hepcidin signaling — the master regulator of iron. With low hepcidin, ferroportin stays active and the gut absorbs iron unchecked, driving progressive overload.
Penetrance varies widely. In the UK Biobank, an estimated 56% of C282Y homozygous men and 41% of women are diagnosed with hemochromatosis by age 80; earlier data showed only about 25% (men) and 12.5% (women) by 65. Modifiers such as alcohol, hepatic steatosis, hepatitis C virus and iron polygenic scores raise the risk of fibrosis. C282Y homozygosity is also associated with greater frailty, sarcopenia and chronic pain in older adults.
Diagnosis combines transferrin saturation (TSAT >45%), elevated ferritin and genetic confirmation. First-line treatment is periodic phlebotomy (blood removal) until iron stores normalize; chelation is reserved for those who cannot tolerate phlebotomy. Anyone carrying or homozygous for C282Y who wishes to take iron supplements (e.g. bisglycinate) should first rule out this condition: supplementing iron in an undiagnosed homozygote accelerates organ damage.
Scientific sources
- PubMed — A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis (Feder, Nature Genetics 1996)
- PubMed — HFE genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: UK Biobank prospective cohort
- PubMed — Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain: 200,975 UK Biobank Participants
- PubMed — Diagnosis and Management of Genetic Iron Overload Disorders
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