Category: endocrine_axis
Hepcidin (HAMP) is the master regulator of systemic iron homeostasis — a 25-aa peptide hormone secreted by hepatocytes that binds ferroportin (SLC40A1, the only known cellular iron exporter) on duodenal enterocytes, macrophages, and hepatocytes → triggers ferroportin internalization + degradation → blocks iron egress → ↓serum iron. Reciprocal regulation: BMP6 (sinusoidal endothelium) + iron-loaded transferrin via TfR2 + HFE → SMAD1/5/8 + BMP-receptor complex on hepatocytes → ↑HAMP transcription (the high-iron limb). IL-6 (inflammation) → STAT3 → ↑HAMP (the inflammation limb; explains anemia of chronic disease + functional iron deficiency). Erythroid demand: erythroferrone (ERFE, secreted by erythroblasts in response to EPO) → suppresses hepcidin → ↑iron availability for erythropoiesis (the bone-marrow demand limb). Tissue effects: ↑hepcidin → enterocyte ferroportin internalized → iron trapped in mucosa, lost in shed enterocyte → ↓absorption; macrophage ferroportin internalized → iron retained in RES (reticuloendothelial sequestration). Disease: hereditary hemochromatosis (HFE, HJV, TfR2, HAMP mutations — failed hepcidin response → unopposed iron absorption → tissue overload + cirrhosis, DM, cardiomyopathy); iron-refractory iron deficiency anemia (TMPRSS6 LOF — constitutively elevated hepcidin); anemia of chronic disease (IL-6 driven hepcidin → functional Fe deficiency); CKD-MBD anemia (multifactorial; hepcidin + EPO). Therapeutics: classical iron supplementation (ferrous sulfate, iron-bisglycinate, heme iron) overcomes mild deficiency; IV iron (sucrose, gluconate, carboxymaltose, derisomaltose) bypasses gut absorption block; iron chelators (deferoxamine SC/IV, deferasirox oral, deferiprone) for overload; hepcidin agonists (PTG-300/rusfertide for polycythemia vera) — clinical pipeline; hepcidin antagonists for hemochromatosis (in development); EPO/darbepoetin → ERFE → ↓hepcidin (functional). Cross-links: [[iron_metabolism]] (transferrin, ferritin, cellular iron), [[heme_biosynthesis]] (iron demand sink), [[ferroptosis_gpx4_lipid_peroxidation]] (Fe²⁺ toxicity downstream).