Maintenance of stable extracellular
iron concentrations requires the coordinate regulation of
iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages and from storage in hepatocytes. Moreover, during fetal development, the
iron requirements of the fetus must be matched by the transport of maternal
iron across the placenta.
Hepcidin is a 25-amino
acid disulfide-rich
peptide synthesized in the liver that acts as a systemic
iron-regulatory
hormone by regulating
iron transport from
iron-exporting tissues into plasma.
Hepcidin inhibits the cellular efflux of
iron by binding to, and inducing the degradation of,
ferroportin, the sole
iron exporter in
iron-transporting cells. In turn,
hepcidin synthesis is increased by
iron loading and decreased by
anemia and
hypoxia. Additionally,
hepcidin synthesis is greatly increased during
inflammation, trapping
iron in macrophages, decreasing plasma
iron concentrations and causing
iron-restricted erythropoiesis characteristic of
anemia of
inflammation (
anemia of
chronic disease). Recent studies indicate that
hepcidin deficiency underlies most known forms of hereditary
hemochromatosis. This implies that, with the exception of very rare mutations that affect the
hepcidin gene itself or modify
ferroportin to make it less responsive to
hepcidin,
hemochromatosis genes encode molecules that regulate
hepcidin synthesis. The central involvement of
hepcidin in
iron regulation and its pathologies should make the eventual
hepcidin assay useful for the diagnosis of
iron disorders and the monitoring of their treatments. The development of
hepcidin agonists and antagonists may provide useful
therapeutics for the treatment of
iron disorders.