Does taking iron increase hepcidin levels?

Iron Supplementation Increases Hepcidin Levels

Yes, taking iron does increase hepcidin levels, which is a key regulatory mechanism to prevent iron overload in the body. 1, 2

Mechanism of Hepcidin Regulation by Iron

Hepcidin is a 25-amino acid peptide hormone primarily synthesized by hepatocytes that serves as the master regulator of systemic iron homeostasis. The relationship between iron intake and hepcidin follows a clear physiological pathway:

1. Iron sensing and hepcidin production:

   • When iron levels increase (such as after iron supplementation), the liver detects this change through multiple pathways 1:
     • Iron induces bone morphogenetic proteins (BMP2/6) production by liver endothelial cells
     • These BMPs bind to hepatocyte BMP receptor complex and hemojuvelin (HJV)
     • The iron-sensing apparatus involving transferrin receptor 2 (TFR2), transferrin receptor 1 (TFR1), and homeostatic iron regulator protein (HFE) also activates hepcidin production

2. Hepcidin's action:

   • Hepcidin binds to ferroportin (the cellular iron exporter) on:
     • Duodenal enterocytes (blocking iron absorption)
     • Macrophages (blocking iron recycling)
     • Hepatocytes (blocking iron mobilization from storage) 1
   • This binding triggers ferroportin degradation, effectively reducing iron entry into plasma

Timing and Magnitude of Hepcidin Response

Research shows that oral iron supplementation has a significant impact on hepcidin levels:

• Within 24 hours after iron doses ≥60 mg, serum hepcidin increases significantly (P < .01) 2
• This increase in hepcidin results in a 35% to 45% decrease in fractional iron absorption from subsequent doses 2
• The duration of the hepcidin response supports alternate day supplementation rather than daily dosing 2

Clinical Implications

The hepcidin response to iron supplementation has important clinical implications:

1. Dosing strategies:

   • Lower iron doses (40-80 mg) maximize fractional absorption 2
   • Avoiding twice-daily dosing is recommended, as total iron absorbed from 3 doses (morning, afternoon, next morning) is not significantly greater than from 2 morning doses on consecutive days 2
   • A sixfold increase in iron dose (40-240 mg) results in only a threefold increase in iron absorbed (6.7-18.1 mg) due to the hepcidin response 2

2. Special populations:

   • In conditions with hepcidin dysregulation:
     • Hemochromatosis: Insufficient hepcidin production leads to iron overload 3, 4
     • Iron-loading anemias (e.g., β-thalassemia): Enhanced erythropoiesis releases erythroferrone, which inhibits hepcidin, worsening iron overload 5, 6
     • Anemia of inflammation: Inflammatory cytokines increase hepcidin, causing iron-restricted erythropoiesis 3, 5

3. Developmental considerations:

   • Young infants (<6 months) may have an impaired ability to downregulate dietary iron absorption despite intact hepcidin upregulation 1
   • This developmental aspect of iron homeostasis may render young infants susceptible to iron excess 1

Practical Recommendations

Based on the hepcidin response to iron supplementation:

• For iron deficiency treatment:

  • Consider alternate-day dosing rather than daily dosing to allow hepcidin levels to return to baseline
  • Use moderate doses (40-80 mg) rather than high doses to maximize fractional absorption
  • Avoid twice-daily dosing as it does not significantly improve total iron absorption

• For monitoring:

  • Be aware that the first dose of iron will affect absorption of subsequent doses through the hepcidin pathway
  • The hepcidin response may explain why some patients have poor response to oral iron despite adherence

The understanding of the hepcidin-ferroportin axis has revolutionized our approach to iron supplementation, suggesting that "more is not always better" when it comes to oral iron dosing.