Regulation of systemic iron homeostasis. Increased diferric transferrin, Fe₂-Tf, is detected by the liver via an as-yet unknown complex regulatory pathway involving HFE, TFR2, and HJV. Hepatocytes respond to this signal by inducing HAMP expression and hepcidin secretion. Circulating hepcidin acts in turn to diminish dietary iron absorption by the enterocytes and iron recycling by the macrophages through the internalization of ferroportin, which blocks iron export. As a consequence, serum iron decreases. As a feedback response, hepcidin synthesis is downregulated, which allows ferroportin molecules to be displayed on the surface of the target cells. In classical and juvenile hemochromatosis the mutations in HFE, TFR2, and HJV lead to abnormal hepcidin regulation, hypohepcidinemia, and ferroportin hyperactivity. The latter results in increased iron absorption and uncontrolled iron release from macrophages, 2 defects characteristic of hereditary hemochromatosis. DMT1, divalent metal transporter 1.