The C282Y mutation in HFE disrupts the folding of the protein. The mutant protein does not associate with the transferrin receptor and does not act as a break on iron uptake by cells. These insights do not fully explain the increase in gastrointestinal iron absorption, which is the root of hereditary hemochromatosis. They are, however, the first observations that mechanistically connect HFE and iron metabolism. Improved understanding of the complex process of intestinal iron absorption should surmount this shortcoming.
Hereditary hemochromatosis is remarkably common.
Interestingly, the clinical expression of the disorder is less than predicted by frequency calculations. Variable penetrance, perhaps related to secondary genetic or environmental conditions must influence clinical manifestations. The iron is an integral component of the heme in hemeoglobin and cannot be removed from the blood. Senescent red cells are destroyed by reticuloendothelial cells, primary in the liver and spleen. The iron from the hemeoglobin is not excreted.