What is the role of hepcidin in iron metabolism?

Hepcidin: The Master Regulator of Iron Metabolism

Hepcidin is a 25-amino acid peptide hormone produced primarily by hepatocytes that functions as the principal regulator of systemic iron homeostasis by binding to and degrading ferroportin, the sole cellular iron exporter, thereby controlling iron absorption, recycling, and distribution throughout the body. 1

Structure and Production

• Hepcidin is encoded by the HAMP gene on chromosome 19, which produces an 84-amino acid precursor that undergoes post-translational processing to form the mature 25-amino acid active peptide 2
• The hormone is predominantly synthesized by hepatocytes in the liver and secreted into circulation 1
• Hepcidin is excreted by the kidneys; impaired renal excretion in chronic kidney disease leads to hepcidin accumulation and iron dysregulation 1, 2

Mechanism of Action: The Hepcidin-Ferroportin Axis

Hepcidin exerts its iron-regulatory effects by binding to ferroportin, the transmembrane iron export channel located on the basolateral surface of enterocytes, macrophages, and hepatocytes. 1

Cellular Level Effects

• When hepcidin binds ferroportin, it causes the ferroportin protein to be internalized into the cell and degraded in lysosomes 1, 3, 4
• This degradation blocks iron export from these critical cell types, effectively trapping iron inside cells 1, 3
• The net result is decreased intestinal iron absorption (from enterocytes) and diminished iron release from macrophages and hepatic stores 1

Regulation of Hepcidin Production

Hepcidin synthesis responds to multiple physiologic and pathologic signals that reflect the body's iron needs and inflammatory state 1, 2:

Conditions That Increase Hepcidin

• Iron overload: Excess body iron stimulates hepcidin production to prevent further iron absorption 1, 2
• Inflammation and infection: Inflammatory cytokines (particularly IL-6) increase hepcidin via the JAK/STAT3 pathway, restricting iron availability to pathogens as a host defense mechanism 1, 5, 2, 3
• Chronic kidney disease: Both increased production and decreased excretion elevate hepcidin levels 1, 2

Conditions That Decrease Hepcidin

• Iron deficiency: Low iron stores suppress hepcidin to maximize iron absorption 1, 2
• Enhanced erythropoiesis: Increased red blood cell production signals for more iron availability by suppressing hepcidin 1, 2
• Anemia-induced tissue hypoxia: Hypoxia decreases hepcidin to ensure adequate iron supply for hemoglobin synthesis 1
• Erythropoiesis-stimulating agents: EPO treatment suppresses hepcidin 1
• Chronic liver disease with impaired hepatic function: Reduced hepatocyte function decreases hepcidin synthesis 1
• Sex hormones: Testosterone and estrogen supplementation decrease hepcidin production 1

Molecular Signaling Pathways

BMP/SMAD Pathway (Primary Regulator)

• The BMP/SMAD pathway is the main mechanism controlling hepcidin transcription in hepatocytes 1, 2
• BMP2 maintains basal hepcidin transcription under normal conditions 1, 2
• BMP6 upregulates hepcidin in response to iron overload 1, 2
• Both BMP2 and BMP6 are produced by liver sinusoidal endothelial cells 1
• The pathway requires co-receptors including hemojuvelin (HJV), HFE protein, and transferrin receptor 2 (TfR2) for efficient iron signaling 1

Integration with Other Regulatory Systems

• The HFE protein and TfR2 form complexes that may interact with HJV, suggesting they function as iron sensors at the hepatocyte membrane to influence hepcidin production 1
• High transferrin-bound iron levels positively regulate hepcidin synthesis to prevent iron overload 1

Clinical Significance in Disease States

Hereditary Hemochromatosis

• Hepcidin deficiency is the ultimate cause of most forms of hereditary hemochromatosis, resulting from mutations in the hepcidin gene (HAMP) itself or in its regulatory genes (HFE, HJV, TfR2) 1, 2, 6
• Low hepcidin levels lead to excessive iron absorption and progressive iron overload in tissues 1, 7
• Juvenile hemochromatosis results from mutations in either the hemojuvelin (HJV) gene or the hepcidin (HAMP) gene, with HJV mutations being more common 1

Anemia of Chronic Disease/Inflammation

• Inflammation-induced hepcidin elevation causes iron sequestration in macrophages and decreased intestinal absorption, contributing to anemia despite adequate iron stores 1, 3, 6
• This represents a host defense mechanism to limit iron availability to pathogens 1, 5, 3

Infection Defense

• Hepcidin-mediated iron restriction is a crucial innate immune defense mechanism that limits iron supply to iron-dependent pathogens 5, 3
• Patients with hepcidin deficiency (such as those with hemochromatosis) face increased susceptibility to siderophilic organisms like Vibrio vulnificus, which can cause fulminant sepsis with >50% mortality 5
• These patients should avoid raw or undercooked seafood that may harbor Vibrio species 5

Chronic Kidney Disease

• Decreased hepcidin excretion combined with increased production leads to functional iron deficiency and contributes to anemia 1, 2

Diagnostic and Therapeutic Implications

• Hepcidin measurement may provide diagnostic value in screening and monitoring iron disorders, though assay standardization and clinical decision limits require further development 2, 8
• Hepcidin agonists and antagonists are being developed as therapeutic targets for various iron disorders, with some agents already in clinical trials 4, 6
• Understanding hepcidin regulation has revealed it as the pathogenic factor in most systemic iron disorders, providing opportunities for improved diagnosis and treatment 6

Key Clinical Pitfalls

• The human body cannot actively excrete excess iron in a regulated manner, making hepcidin-mediated control of iron absorption the only mechanism to prevent iron overload 1, 9
• Distinguishing between hereditary hemochromatosis (hepcidin deficiency) and secondary iron overload from chronic liver disease requires evaluation of hepatic iron content and distribution patterns 7
• In chronic liver disease, iron deposits occur in both Kupffer cells and hepatocytes in a panlobular pattern, contrasting with the periportal hepatocyte-predominant pattern in hereditary hemochromatosis 7