Hepcidin is the master regulator of systemic iron homeostasis. In chronic inflammation (e.g., rheumatoid arthritis), elevated hepcidin causes anemia of chronic disease. The MOLECULAR mechanism of hepcidin action is:
- A Hepcidin inhibits erythropoietin receptor signalling on erythroid progenitors in bone marrow
- B Hepcidin reduces duodenal DMT1 (divalent metal transporter 1) expression, impairing dietary iron absorption
- C Hepcidin binds ferroportin on enterocytes, macrophages, and hepatocytes, causing its internalisation and lysosomal degradation, trapping iron intracellularly ✓
- D Hepcidin activates hephaestin in enterocytes, oxidising Fe2+ to Fe3+ which cannot cross the basolateral membrane
Explanation
Hepcidin (a 25-amino acid peptide secreted by the liver) binds ferroportin (FPN1/SLC40A1), the sole known cellular iron exporter. This binding triggers ferroportin phosphorylation, ubiquitination, internalization, and lysosomal degradation, thereby blocking iron egress from enterocytes (reducing absorption), macrophages (trapping iron recycled from erythrophagocytosis), and hepatocytes. In chronic inflammation, IL-6 induces hepcidin via JAK-STAT3 signalling. Iron is sequestered inside cells, serum iron falls, transferrin saturation drops, and erythropoiesis becomes iron-restricted despite adequate total body iron stores.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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Written and medically reviewed by the StethoPrep medical team.