What is the function of hepcidin?

Hepcidin Function

Hepcidin is the principal iron-regulatory hormone that controls systemic iron homeostasis by binding to ferroportin on enterocytes and macrophages, causing ferroportin internalization and degradation, which blocks cellular iron export and thereby decreases intestinal iron absorption and iron release from body stores. 1

Core Mechanism of Action

• Hepcidin is a 25-amino acid peptide hormone produced predominantly by hepatocytes in the liver. 1

• When hepcidin binds to ferroportin (the sole cellular iron exporter), it triggers ferroportin internalization and degradation, effectively blocking iron export from cells into the bloodstream. 2, 3

• This mechanism operates on two critical cell types:

  • Duodenal enterocytes (basolateral surface) - blocking dietary iron absorption 1
  • Macrophages - preventing iron release from recycled senescent erythrocytes 1

Regulation of Hepcidin Expression

Hepcidin production responds dynamically to multiple physiologic signals, creating a sophisticated feedback system for iron homeostasis:

Conditions That Increase Hepcidin:

• Iron excess stimulates hepcidin production, resulting in decreased intestinal iron absorption and diminished iron release from macrophages. 1
• Inflammation increases hepcidin production via the IL-6/JAK2/STAT3 pathway, which sequesters iron intracellularly as a host defense mechanism to deprive microorganisms of iron. 2, 3

Conditions That Decrease Hepcidin:

• Iron deficiency suppresses hepcidin expression, allowing increased iron absorption from the intestine and enhanced iron release from macrophages. 1
• Enhanced erythropoietic activity and hypoxia decrease hepcidin production to match iron supply with increased demand for red blood cell production. 1, 2
• Ineffective erythropoiesis suppresses hepcidin expression. 1

Molecular Signaling Pathways

• The BMP/SMAD pathway serves as the main regulator of hepcidin transcription, with BMP6 upregulating hepcidin in response to iron overload. 2, 3

• The HFE protein, along with transferrin receptor-2 (TfR2) and hemojuvelin (HJV), forms a complex that acts as an iron sensor influencing hepcidin regulation, though the precise mechanisms remain incompletely understood. 1

Clinical Significance in Disease States

Hereditary Hemochromatosis:

• Hepcidin deficiency is the ultimate cause of most forms of hereditary hemochromatosis, whether due to mutations in the hepcidin gene (HAMP) itself or mutations in regulatory genes like HFE, HJV, or TfR2. 1, 3
• This deficiency results in inappropriately low hepcidin relative to body iron stores, causing excessive intestinal iron absorption and progressive tissue iron overload. 3

Anemia of Chronic Disease/Inflammation:

• Pathologically elevated hepcidin concentrations limit iron availability for erythropoiesis, contributing to anemia of inflammation and chronic kidney disease. 4, 5

Infection Defense:

• Hepcidin-mediated iron sequestration serves as a critical innate immune defense mechanism by limiting iron availability to iron-dependent pathogens. 6, 7
• Patients with hepcidin deficiency (such as hemochromatosis) face increased susceptibility to siderophilic infections like Vibrio vulnificus due to elevated circulating iron levels. 6

Important Clinical Caveats

• Hepcidin is excreted by the kidneys; impaired renal excretion in chronic kidney disease contributes to iron dysregulation and anemia. 2

• Measurement of hepcidin levels may provide diagnostic value in screening and monitoring iron disorders, though this remains an evolving area of clinical application. 2, 5

• The discovery of hepcidin's central role has rendered older theories of iron regulation (such as the "crypt cell hypothesis") much less relevant to understanding iron homeostasis. 1