Hepcidin - ferroportin axis

• in a healthy person, simple indices of iron status such as ferritin (a storage form of iron predominantly found in the liver, which is detectable in serum as it leaks into the circulation) and transferrin saturation (percentage occupation of iron carrier molecules in the circulation) are sufficient to diagnose iron deficiency

• however, in the setting of inflammation
  • ferritin levels are increased - ferritin acts as an acute-phase reactant and serum concentration increases - thus in this setting, interpretation of ferritin alone as a measure of iron deficiency becomes unreliable
    
    
  • also in response to the same inflammatory process that results in a rise in serum ferritin, a 25-amino acid protein is produced, known as hepcidin
    • functions of hepcidin are:
      • prevention of iron overload through limiting excessive iron absorption in the proximal small intestine and regulation of iron release from macrophages participating in recycling
      • prevention of iron acquisition by pathogens as a component of innate immunity e.g. limits supply to bacteria - iron has several roles within a bacterial cell is required to render active many different proteins and enzymes involved in a variety of metabolic processes; also essential for expression of many key virulence determinants
      • hepcidin expression is usually regulated in a negative feedback loop by systemic levels of iron (5)
        • however, under inflammatory conditions, induction of hepcidin expression can occur

Hepcidin impairs the function of the key iron regulatory protein, ferroportin, thereby preventing the transport of iron across basement membranes - this is the hepcidin-ferroportin axis (1,2,3)

• inhibits the uptake of iron from the gastrointestinal tract, the transport of stored iron out of the liver, and the reclamation of iron from circulating macrophages
• ferritin seen in inflammation may be an active player in innate immunity, as opposed to a consequence of cell damage and leakage

Intravenous iron therapy:

• use of intravenous iron replacement therapy bypasses the hepcidin-ferroportin axis, the treatment has an improved clinical effect in the setting of inflammation, and does not have the same gastrointestinal side effects of oral iron
• previously parenteral iron preparations were highly labile and prone to the excessive release of free iron into the circulation, with an associated risk of side effects (4)
  • development of newer, high-molecular-weight and more stable preparations has markedly reduced the incidence of these events
  • therefore, administration of parenteral iron is becoming more widespread

Reference:

• Lim D et al. The hepcidin-ferroportin axis controls the iron content of Salmonella-containing vacuoles in macrophages. Nat Commun. 2018 May 29;9(1):2091
• Nemeth E et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004 Dec 17;306(5704):2090-3
• Drakesmith H et al. Ironing out ferroportin. Cell Metab. 2015 Nov 3; 22(5): 777–787.
• Avni T et al. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clinic Proc. 2015 Jan;90(1):12-23
• Hortova-Kohoutkova M et al.Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation. Front Immunol. 2023 Jan 27;14:1110540. doi: 10.3389/fimmu.2023.1110540. PMID: 36776891; PMCID: PMC9911830.