Hereditary hemochromatosis is caused by mutations in genes that govern how the body senses iron and how it exports iron from cells. The different forms converge on the same pathway — the hepcidin–ferroportin control of how much iron enters the blood — but they differ in the gene affected, the inheritance pattern, and the age at which iron begins to accumulate.
HFE-related hemochromatosis
By far the most common cause of hereditary hemochromatosis is HFE-related HH. It is a recessive condition, so it develops only when both copies of the HFE gene carry the C282Y mutation, a state called C282Y homozygosity. Carrying a single C282Y mutation, or the milder H63D variant, does not by itself cause progressive iron overload; C282Y and H63D heterozygotes are not at risk of symptomatic disease. A person who inherits C282Y from one parent and H63D from the other is a compound heterozygote and can accumulate a mild excess, and an occasional H63D homozygote does the same.
Other mutations that cause hemochromatosis
Mutations in several other genes produce rarer forms of the disease. Hemojuvelin is a regulatory protein that helps switch on hepcidin production, while hepcidin is the hormone itself; mutations in either cause juvenile hemochromatosis, in which hepcidin production falls sharply, iron accumulates rapidly, and disease appears during childhood or early adult life rather than in middle age. Transferrin receptor 2 (TfR2) is mainly a sensor on hepatocytes that reads the iron concentration of the blood and helps set the liver’s production of hepcidin; its mutations cause an adult form that resembles HFE-related disease. These non-HFE forms are uncommon and together account for a small minority of cases.
Ferroportin
Ferroportin, encoded by the gene SLC40A1, is the protein that exports iron from cells, and its mutations cause an autosomal dominant form of hemochromatosis with two distinct patterns. Loss-of-function mutations reduce the amount of ferroportin that reaches the cell surface, so iron cannot leave macrophages efficiently and instead accumulates inside them — the pattern called ferroportin disease. The second group are gain-of-function mutations that make the protein resistant to the internalisation and degradation that normally follow hepcidin binding; iron export continues despite a normal hepcidin signal, and the iron loads parenchymal cells such as hepatocytes, much as in HFE-related HH. The two patterns differ in where the iron is deposited and in how severe the overload becomes.