Normal iron homeostasis in humans and how this is altered in hereditary hemochromatosis
The human body normally contains 3 to 4 g of iron, two-thirds of which is contained in hemoglobin, myoglobin, and a variety of enzymes, and one-third as storage iron in ferritin and hemosiderin within hepatocytes and macrophages of the liver, bone marrow, spleen, and muscle. Although the typical Western diet contains 10 to 20 mg of iron a day, only 1 to 2 mg is absorbed daily by the duodenal mucosa, which balances the iron loss from exfoliated gastrointestinal epithelial cells and desquamation of the skin. Hepcidin is normally synthesized by the liver under the control of a variety of proteins and cytokines. When plasma iron is low, hepcidin is also low, allowing efflux of iron into serum through the iron exporter ferroportin (FPN) on duodenal enterocytes and macrophages. When plasma iron is elevated, hepcidin is increased and binds to FPN, causing internalization and degradation and resulting in less iron release into serum ( Fig. 57.1 ). In HHC, there is an abnormality of one of the iron regulatory proteins, which leads to excess gastrointestinal iron absorption that ranges from 3 to 4 mg/day; this results in accumulation of 15 to 35 g of iron in tissues over a period of 35 to 60 years. Iron exerts its adverse effects when deposited in tissues through the generation of reactive oxygen species (Haber–Weiss reaction). The reactive oxygen species increase lipid peroxidation resulting in damage to cell organelles and DNA.
