What is the principal regulatory hormone for iron?

Principal Regulatory Hormone for Iron

Hepcidin is the principal regulatory hormone for iron homeostasis. 1, 2

Structure and Production

• Hepcidin is a 25-amino acid peptide hormone produced predominantly in hepatocytes and secreted into the circulation 1, 2
• The hormone is encoded by the HAMP gene on chromosome 19, initially producing an 84-amino acid pre-prohepcidin that undergoes post-translational processing to form the mature peptide 2
• Hepcidin is excreted by the kidneys, and impaired renal excretion in chronic kidney disease contributes to iron dysregulation 2

Mechanism of Action

Hepcidin controls systemic iron homeostasis by binding to ferroportin, the sole cellular iron exporter, causing its internalization and degradation. 1, 2

• When hepcidin binds to ferroportin (found on macrophages and the basolateral surface of enterocytes), ferroportin is internalized and degraded, thereby inhibiting iron export from these cells 1
• This mechanism effectively blocks iron release into circulation from three critical sources: intestinal absorption, macrophage iron recycling, and hepatic iron stores 2, 3

Physiologic Regulation

Hepcidin production responds to multiple physiologic signals to maintain iron balance:

Iron-responsive regulation:

• Iron excess increases hepcidin production, resulting in decreased intestinal iron absorption and diminished iron release from macrophages 1, 2
• Iron deficiency decreases hepcidin expression, allowing increased iron absorption from the intestine and release of iron from macrophages 1, 2

Erythropoietic and hypoxic regulation:

• Enhanced erythropoiesis and hypoxia suppress hepcidin production to ensure sufficient iron supply to the bone marrow for red blood cell production 1, 2

Inflammatory regulation:

• Inflammation increases hepcidin production via IL-6 and the JAK/STAT3 pathway, leading to hypoferremia as a host defense mechanism to limit iron availability to pathogens 1, 4, 2

Molecular Signaling

• The BMP/SMAD pathway is the main regulator of hepcidin transcription, with BMP2 maintaining basal transcription and BMP6 upregulating hepcidin in response to iron overload 2
• The HFE protein, transferrin receptor 2 (TfR2), and hemojuvelin (HJV) interact to influence hepcidin regulation, though the exact mechanisms remain incompletely understood 1

Clinical Significance

Hepcidin deficiency is the ultimate cause of most forms of hereditary hemochromatosis, either due to mutations in the hepcidin gene itself or mutations in regulators of hepcidin synthesis 1, 2

• Patients with hemochromatosis have inappropriately low hepcidin levels relative to their iron stores, leading to excessive iron absorption and tissue iron overload 1
• Conversely, hepcidin excess contributes to anemia of chronic disease by restricting iron availability for erythropoiesis despite adequate iron stores 1, 2
• Patients with hepcidin deficiency face increased susceptibility to siderophilic pathogens like Vibrio vulnificus due to elevated circulating iron levels 4