Hemochromatosis

Hereditary hemochromatosis is usually caused by homozygosity for the HFE C282Y mutation. The mutation disrupts normal hepcidin regulation. Hepcidin ordinarily reduces intestinal iron absorption by causing ferroportin, the iron-export channel on intestinal cells and macrophages, to be removed from the cell surface. With inadequate hepcidin activity, iron continues to enter the circulation even when body stores are already high. The excess iron accumulates gradually in parenchymal cells, especially in the liver, pancreas, heart, skin, pituitary, and joints. Oxidative injury then produces fibrosis and organ dysfunction. This is why a patient may initially report only fatigue or hand arthralgia but later develop cirrhosis, diabetes, bronze or grey skin pigmentation, hypogonadism, dilated cardiomyopathy, or dysrhythmias. The time course helps distinguish hereditary from secondary iron overload. Hereditary disease reflects excessive gastrointestinal absorption over many years. Secondary overload is more likely with repeated transfusions or another acquired disorder affecting the liver or red-cell production. Both can raise ferritin, so the history and the iron-study pattern matter more than ferritin alone.