How Hemochromatosis is Acquired
Hemochromatosis is primarily acquired through autosomal recessive inheritance of mutations in the HFE gene, most commonly homozygosity for the C282Y mutation. 1, 2
Genetic Inheritance Pattern
Hereditary hemochromatosis follows an autosomal recessive transmission, meaning you must inherit one mutated gene copy from each parent to develop the full disease. 3
The C282Y mutation in the HFE gene on chromosome 6p accounts for more than 90% of hereditary hemochromatosis cases. 1, 3
Most affected patients are C282Y homozygotes (C282Y/C282Y), carrying the mutation on both chromosome 6 copies. 2, 3
Compound heterozygosity (C282Y/H63D) accounts for only 3–5% of hemochromatosis cases and typically requires additional environmental or genetic factors to cause clinically significant iron overload. 2, 3
Population Prevalence and Risk
Approximately 0.44–0.5% of individuals of northern European descent are homozygous for C282Y, making this one of the most common genetic disorders in Caucasian populations. 3
The C282Y mutation shows geographic variation across Europe, with highest frequencies in Ireland (12.5%) and lowest in Southern Europe (approaching 0%). 3
Simple heterozygotes (carriers) do not develop hemochromatosis—approximately 1 in 10 individuals carry one C282Y mutation but remain clinically unaffected. 2, 3
Mechanism of Disease
The C282Y mutation causes the HFE protein to lose its ability to bind the transferrin receptor on intestinal cells, preventing normal iron-sensing mechanisms. 4, 5
Without functional HFE protein, enterocytes are "programmed" to absorb slightly more dietary iron than the body requires, leading to gradual accumulation over decades. 4, 5
This results in inappropriately low hepcidin levels, the master negative regulator of iron absorption, allowing excessive dietary iron uptake. 2, 6
Incomplete Penetrance: A Critical Caveat
Not all individuals with the C282Y/C282Y genotype develop clinical disease—only 58–70% of homozygotes develop progressive tissue iron overload, and fewer than 10% progress to end-organ damage such as cirrhosis, diabetes, or cardiomyopathy. 2, 5
Environmental and genetic modifiers influence disease expression, including alcohol consumption, dietary iron intake, blood loss (menstruation in women), viral hepatitis, and fatty liver disease. 2, 4
Women develop symptoms later than men because monthly menstrual blood loss slows iron accumulation; symptoms typically appear after menopause. 6
Non-HFE Hemochromatosis
Rare forms of hereditary hemochromatosis occur without HFE mutations, involving other genes in iron metabolism such as transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin. 1, 7, 8
These non-HFE forms account for cases where patients have classic iron overload but test negative for C282Y and H63D mutations. 8
Secondary (Acquired) Iron Overload
While the question asks about hemochromatosis specifically, it is important to distinguish hereditary hemochromatosis from secondary iron overload, which is not acquired through the same mechanism:
Iron-loading anemias (thalassemia major, sideroblastic anemia, chronic hemolytic anemia) cause iron overload through both increased intestinal absorption and chronic transfusions. 2
Parenteral iron overload from repeated blood transfusions, iron-dextran injections, or long-term hemodialysis. 2
Chronic liver diseases (alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis) can cause elevated iron markers without true hereditary hemochromatosis. 2
Key Clinical Pitfall
Do not confuse genetic susceptibility with clinical disease—having the C282Y/C282Y genotype means you can develop iron overload, but most homozygotes remain asymptomatic or develop only mild biochemical abnormalities without organ damage. 2, 5 Early detection through transferrin saturation ≥45% and elevated ferritin, followed by genetic confirmation, allows therapeutic phlebotomy before irreversible complications develop. 1, 6