What is hepcidin?

Hepcidin: The Master Regulator of Iron Metabolism

Hepcidin is a 25-amino acid peptide hormone produced primarily in the liver that functions as the principal iron-regulatory hormone in the body, controlling iron absorption, recycling, and tissue distribution by binding to ferroportin (the sole cellular iron exporter) on enterocytes and macrophages, causing its internalization and degradation. 1

Structure and Production

• Hepcidin is a cysteine-rich peptide containing 25 amino acids with four disulfide bridges 2, 3
• Synthesized in the liver as a precursor protein (prohepcidin) that is processed to produce the biologically active mature peptide 3
• Secreted into circulation where it acts systemically 1

Physiological Function

Hepcidin regulates iron homeostasis through several key mechanisms:

1. Intestinal iron absorption control: Binds to ferroportin on duodenal enterocytes, causing internalization and degradation of this iron exporter, thereby limiting dietary iron absorption 1, 4

2. Macrophage iron recycling regulation: Controls the release of iron from macrophages that recycle senescent erythrocytes 4, 5

3. Hepatic iron storage management: Regulates iron mobilization from liver stores 5

4. Placental iron transport: Decreases iron transport across the placenta 2

Regulation of Hepcidin Production

Hepcidin synthesis is regulated by multiple factors:

• Iron status:

  • Increased by high plasma iron and iron stores 4, 5
  • Decreased by iron deficiency 4

• Erythropoietic activity:

  • Suppressed during increased erythropoiesis, partly through erythroferrone (a hormone produced by erythropoietin-stimulated erythroblasts) 4
  • This suppression increases iron availability for red blood cell production

• Inflammation and infection:

  • Significantly increased during inflammatory states and infections 4, 5
  • Acts as a defense mechanism by limiting iron availability to pathogens 2

• Hypoxia: Decreased during hypoxic conditions 5

Role in Disease

Hepcidin dysregulation is implicated in various iron disorders:

Hepcidin Deficiency Conditions

• Hereditary hemochromatosis: Most forms result from hepcidin deficiency or resistance to hepcidin action 1, 4, 5
• Iron-loading anemias: Including β-thalassemia, where ineffective erythropoiesis leads to hepcidin suppression and iron overload 4

Hepcidin Excess Conditions

• Iron-refractory iron deficiency anemia (IRIDA): Caused by mutations in matriptase-2/TMPRSS6 (a hepcidin suppressor) 2
• Anemia of inflammation: Elevated hepcidin restricts iron availability for erythropoiesis 4, 6
• Anemia of chronic kidney disease: Increased hepcidin contributes to functional iron deficiency 4

Clinical Significance

• Diagnostic potential: Hepcidin measurement may help diagnose and differentiate various iron disorders 6
• Therapeutic target: Central role in iron disorders makes hepcidin an important target for developing new treatments 4, 6
• Antimicrobial properties: Initially identified as an antimicrobial peptide, hepcidin has defensive roles against infections by limiting iron availability to pathogens 2

Important Considerations

• Hepcidin's biological activity depends on proper folding and disulfide bridge formation 3
• Storage and handling conditions can lead to formation of biologically inactive aggregated forms 3
• The discovery of hepcidin has revolutionized our understanding of systemic iron disorders and provides new opportunities for improved diagnosis and treatment 5