Iron is essential for various cellular processes, but an excess of
iron may cause organ damage through the production of
reactive oxygen species. Therefore, the amount of
iron in the body must be strictly controlled. The central regulator of systemic
iron homeostasis is
hepcidin, which is primarily produced in the liver. Various molecules, including HFE,
transferrin receptor 2 (TFR2), and hemojuvelin (HJV), are involved in sensing systemic
iron status. Hepatocytes produce
hepcidin in response to excess
iron and inflammatory stimuli (e.g., interleukin-6), whereas
hepcidin expression is downregulated by
hypoxia,
anemia, and erythropoietic activity. In mice, erythroferrone, secreted from erythroblasts, suppresses
hepcidin expression.
Hepcidin downregulates the
protein expression of
ferroportin, the only
iron exporter in mammalian cells, and thereby downregulates
iron absorption from intestine and
iron release from macrophages. Mutations in the genes HFE, TFR2, HJV, HAMP (encoding
hepcidin), and SLC40A1 (encoding
ferroportin) cause hereditary
hemochromatosis, whereas mutations in TMPRSS6 (which encodes
matriptase 2) cause
iron-refractory iron deficiency anemia through the upregulation of
hepcidin expression. In chronic
anemias, such as β-
thalassemia,
myelodysplastic syndromes, and
aplastic anemia, repeated
red blood cell transfusion can cause systemic
iron overload.
Iron chelation therapy improves the prognosis of patients with such conditions.