Disorders of Iron Metabolism

Summary

Iron (Fe) is an essential element for almost every living organism. In humans and other mammals, iron homeostasis evolved to prevent iron excess, which leads to reactive and toxic oxygen species causing cell damage. This situation is attained by mechanisms for efficient regulation and internal iron recycling; however, this sophisticated control limiting iron absorption may easily promote the development of iron deficiency. Other than secondary iron overload conditions (i.e., transfusional iron overload or iron-loading anemias) and secondary iron deficiency, there are several genetically determined iron disorders. The first type of inherited iron-related disorder is “Hereditary Hemochromatosis (HH),” caused by mutations in genes maintaining Fe homeostasis. Different types of HH have been discovered; however, regardless of the mutated gene, the final outcome is an inappropriate hepcidin expression. The most common type of HH (type I) is caused by a mutation in HFE, with adult onset, and it accounts for >80% of all hemochromatosis patients, mostly Caucasian. The prevalent p.Cys282Tyr substitution leads to the inability of HFE to sense increased levels of Fe and interact with TfR1, which causes decreased hepcidin expression. Type II or juvenile HH, due to hemojuvelin (HJV) or hepcidin mutations, is a more severe disorder that affects younger individuals and causes a fast and heavy Fe overload in the liver and parenchyma. Type III HH is rare; it is similar to type 1, but is caused by mutations in the TFR2 gene. Type IV HH differs from the other ones for having an autosomal dominant transmission and for not directly affecting hepcidin expression. It is caused by mutations in the SLC40A1 gene, which encodes the Fe exporter ferroportin (Fpn), namely the hepcidin target. HH in general is not associated with anemia, whereas the conditions with iron overload associated with anemia suggest congenital atransferrinemia, hereditary aceruloplasminemia, and divalent cation transporter 1 (DMT1)-related iron overload. Finally, there are genetic defects that cause iron deficiency such as mutations occurring in TMPRSS6 (matriptase 2) responsible for an iron-refractory iron deficiency anemia (IRIDA).