The hepatic peptide hormone hepcidin is the principal regulator of iron absorption and tissue iron distribution. Hepcidin circulates in blood plasma and acts at nanomolar concentrations by inducing degradation of its receptor, the cellular iron exporter ferroportin. Ferroportin exports iron into plasma from absorptive enterocytes, from macrophages that recycle the iron of senescent erythrocytes, and from hepatocytes that store iron. Therefore, hepcidin-mediated degradation of ferroportin results in decreased iron absorption in the duodenum, regulating total body iron, as iron losses from the body are normally very small. Hepcidin effect on macrophage ferroportin inhibits the large flux of recycled iron into plasma and decreases plasma iron concentration, as iron is consumed for erythropoiesis and other processes. Hepcidin therefore acts as an endocrine regulator of total body iron stores and plasma iron concentration.
The synthesis of hepcidin is transcriptionally regulated by iron, erythropoiesis and inflammation. Extracellular and intracellular iron concentrations increase hepcidin transcription through a mechanism dependent on the bone morphogenetic protein pathway. Increased iron requirements of erythroid precursors for hemoglobin synthesis cause hepcidin suppression by an unknown pathway. Hepcidin production is also increased by inflammation, primarily through IL6. Dysregulation of these mechanisms leads to aberrant hepcidin production and the development of iron disorders.
Increased hepcidin concentrations in plasma cause or contribute to the pathogenesis of iron-restricted anemias including anemias associated with inflammation (rheumatoid arthritis, inflammatory bowel disease, obesity), chronic kidney disease, some cancers and iron-refractory iron deficiency anemia. Hepcidin deficiency causes iron overload in hereditary hemochromatosis as well as iron-loading anemias such as beta-thalassemia. The hepcidinferroportin axis is the principal regulator of extracellular iron homeostasis in health and disease, and is a promising target for the diagnosis and treatment of iron disorders.
Declaration of interest
I am a co-founder and Chief Scientific Officer of Intrinsic LifeSciences, a biotech company developing hepcidin diagnostics. I am also a co-founder of Merganser Biotech, a biotech company developing hepcidin-targeted therapeutics.
Declaration of funding
This work was supported by grants from the National Institute of Health.