What is the role of hepcidin in iron metabolism and its implications for managing conditions like hemochromatosis or anemia?

Hepcidin: The Master Regulator of Iron Metabolism

Hepcidin is the principal iron-regulatory hormone that controls systemic iron homeostasis by binding to ferroportin on enterocytes, macrophages, and hepatocytes, causing its internalization and degradation, thereby limiting iron absorption and release into circulation. 1

Structure and Production

• Hepcidin is a 25-amino acid peptide hormone primarily produced by hepatocytes and secreted into circulation 1
• It is encoded by the HAMP gene, 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, with impaired excretion in chronic kidney disease contributing to iron dysregulation 1

Mechanism of Action

• Hepcidin binds to ferroportin (the only known cellular iron exporter) on the cell membrane of enterocytes, macrophages, and hepatocytes 1
• This binding triggers ferroportin internalization and lysosomal degradation, effectively blocking cellular iron export 1, 2
• The result is decreased intestinal iron absorption and reduced iron release from macrophage stores, leading to decreased serum iron levels 1, 3

Regulation of Hepcidin Production

Hepcidin production is regulated by multiple factors:

• Iron status: Iron excess increases hepcidin production, while iron deficiency decreases it 1
• Inflammation: Inflammatory cytokines, particularly IL-6, increase hepcidin production via the JAK/STAT3 pathway 1
• Erythropoiesis: Enhanced erythropoietic activity suppresses hepcidin production through erythroferrone (ERFE) and other mediators 1
• Hypoxia: Low oxygen tension decreases hepcidin production 1, 4

Molecular Signaling Pathways

• The BMP/SMAD pathway is the main regulator of hepcidin transcription 1, 2
• BMP2 maintains basal hepcidin transcription, while BMP6 upregulates hepcidin in response to iron overload 1
• Efficient iron signaling requires co-receptors including hemojuvelin (HJV), hemochromatosis protein (HFE), and transferrin receptor 2 (TfR2) 1
• Inflammation triggers hepcidin production through IL-6 and the JAK/STAT3 pathway 1, 2

Role in Disease States

Hemochromatosis

• Hereditary hemochromatosis is characterized by inappropriately low hepcidin levels relative to body iron stores 1
• Mutations in regulatory genes (HFE, HJV, TfR2, or HAMP) lead to hepcidin deficiency, causing increased intestinal iron absorption and tissue iron overload 1, 5
• Juvenile hemochromatosis, a severe early-onset form, can result from mutations in the hepcidin gene (HAMP) itself 1

Anemias

• Anemia of inflammation/chronic disease: Elevated hepcidin levels trap iron in macrophages and block intestinal iron absorption, leading to functional iron deficiency despite adequate iron stores 3, 6
• Anemia of chronic kidney disease: Decreased hepcidin excretion and increased production contribute to iron dysregulation 1, 7
• Iron-refractory iron deficiency anemia: Mutations in TMPRSS6 (encoding matriptase-2) lead to inappropriately high hepcidin levels and iron-resistant anemia 1, 8
• Iron-loading anemias (e.g., β-thalassemia): Ineffective erythropoiesis suppresses hepcidin despite iron overload, leading to increased iron absorption 8, 5

Hepcidin in Infection and Immunity

• Hepcidin production increases during infection as part of the innate immune response 9, 3
• The resulting hypoferremia restricts iron availability to iron-dependent pathogens, serving as a host defense mechanism 1, 9
• Patients with hemochromatosis (hepcidin deficiency) are particularly susceptible to iron-loving pathogens like Vibrio vulnificus due to higher circulating iron levels 9

Therapeutic Implications

• For iron overload disorders: Hepcidin agonists or mimetics could reduce iron absorption and mobilize iron from stores 8, 5
• For anemia of inflammation: Hepcidin antagonists could increase iron availability for erythropoiesis 6, 8
• For iron-refractory iron deficiency anemia: Approaches to inhibit hepcidin production or activity could improve iron absorption 8, 5
• For β-thalassemia: Increasing hepcidin levels could reduce iron overload and potentially improve ineffective erythropoiesis 5

Clinical Considerations

• Measurement of hepcidin levels may provide diagnostic value in differentiating various iron disorders 2, 4
• Understanding the hepcidin-ferroportin axis helps explain why oral iron supplementation may be ineffective in conditions with elevated hepcidin levels 7, 6
• Novel iron formulations like sucrosomial iron may bypass hepcidin-mediated blockade in inflammatory conditions 7
• Patients with hepcidin deficiency should be cautioned about increased susceptibility to certain infections, particularly from iron-dependent pathogens 9