Hepcidin: The Master Regulator of Iron Homeostasis
Hepcidin is a 25-amino acid peptide hormone produced primarily by hepatocytes that functions as the principal regulator of systemic iron metabolism by binding to ferroportin and causing its internalization and degradation, thereby blocking iron export from cells. 1
Structure and Production
Hepcidin is encoded by the HAMP gene on chromosome 19, which initially produces an 84-amino acid pre-prohepcidin that undergoes post-translational processing to form the mature 25-amino acid active peptide. 1, 2
The hormone is synthesized predominantly in hepatocytes and secreted into circulation, though it can also be produced by macrophages, adipocytes, and cardiac tissue. 1
Hepcidin is excreted by the kidneys, making chronic kidney disease a significant factor in iron dysregulation due to impaired excretion. 2
Mechanism of Action: The Hepcidin-Ferroportin Axis
Hepcidin binds to ferroportin, the only known cellular iron export protein located on the basolateral surface of enterocytes and on macrophages. 1, 3
When hepcidin binds ferroportin, the complex is internalized and degraded, effectively blocking iron export from these two critical cell types (enterocytes and macrophages). 1, 2
This mechanism simultaneously decreases intestinal iron absorption AND diminishes iron release from macrophages, providing dual control over iron entry into circulation. 1
Regulation of Hepcidin Expression
Factors That Increase Hepcidin
Iron excess stimulates hepcidin production, creating a negative feedback loop that prevents further iron absorption when body stores are adequate. 1, 2
Inflammation increases hepcidin expression via interleukin-6 (IL-6) and the JAK/STAT3 pathway, which explains the anemia of chronic disease where iron becomes sequestered despite adequate stores. 1, 2
Factors That Decrease Hepcidin
Iron deficiency suppresses hepcidin production, allowing increased ferroportin expression and enhanced iron absorption from the intestine and release from macrophages. 1, 2
Hypoxia, anemia, and enhanced erythropoiesis all down-regulate hepcidin synthesis, ensuring adequate iron availability for red blood cell production. 1, 2
Erythropoietin and the newly discovered hormone erythroferrone (secreted by erythroblasts) directly suppress hepatic hepcidin synthesis after blood loss or during increased erythropoietic demand. 1
Molecular Signaling Pathways
The BMP6/SMAD pathway is the primary regulator of hepcidin transcription, with BMP6 upregulating hepcidin in response to iron overload. 1, 2
HFE protein, transferrin receptor 2 (TfR2), and hemojuvelin (HJV) form a complex that acts as an iron sensor at the hepatocyte membrane, modulating hepcidin expression based on systemic iron status. 1
This complex may play a regulatory role in BMP6 signaling, though the precise mechanisms by which HFE influences iron-dependent regulation of hepcidin remain incompletely understood. 1
Clinical Implications in Disease States
Iron Overload Disorders (Hepcidin Deficiency)
Hereditary hemochromatosis results from hepcidin deficiency due to mutations in HFE (most common), HJV, HAMP (hepcidin gene itself), or TfR2. 1, 2
Juvenile hemochromatosis is caused by mutations in the hemojuvelin (HJV) gene on chromosome 1q or less commonly in the HAMP gene, leading to rapid iron accumulation. 1
In all forms of hereditary hemochromatosis, inadequate hepcidin production fails to suppress ferroportin, resulting in excessive intestinal iron absorption and progressive tissue iron deposition. 1, 4
Iron-loading anemias (such as β-thalassemia) also feature hepcidin deficiency, contributing to iron overload even beyond transfusional iron. 4, 5, 6
Hepcidin knockout mice develop massive iron overload, confirming its essential role in preventing pathologic iron accumulation. 1
Iron-Restrictive Anemias (Hepcidin Excess)
Anemia of chronic disease/inflammation results from pathologically elevated hepcidin, which sequesters iron in macrophages and hepatocytes despite adequate total body stores. 7, 5, 6
Chronic kidney disease causes decreased hepcidin excretion and paradoxically increased production, contributing to functional iron deficiency and resistance to erythropoiesis-stimulating agents. 2, 8, 6
Iron-refractory iron deficiency anemia (IRIDA) is caused by mutations in the TMPRSS6 gene encoding matriptase-2, resulting in unregulated hepcidin synthesis that is refractory to oral iron but responds partially to intravenous iron. 1
Mice engineered to overproduce hepcidin develop severe anemia, demonstrating the critical balance required for normal erythropoiesis. 1
Infection and Host Defense
Hepcidin-mediated hypoferremia is a crucial host defense mechanism that limits iron availability to iron-dependent pathogens during infection. 3, 9
Patients with hemochromatosis and hepcidin deficiency have markedly increased susceptibility to Vibrio vulnificus infections (>50% mortality in fulminant sepsis), as high circulating iron levels trigger rapid bacterial growth. 3
These patients should be specifically counseled to avoid raw or undercooked seafood that may harbor Vibrio vulnificus, particularly those from coastal waters. 3
During inflammation and infection, increased hepcidin shifts iron from circulation into cellular stores, making it less available for invading microorganisms and potentially tumor cells. 9
Chronic Liver Disease
In chronic liver disease, iron deposition is typically mild (1+ to 2+) with a panlobular distribution in both Kupffer cells and hepatocytes, contrasting with the periportal hepatocyte-predominant pattern of hereditary hemochromatosis. 8
Low hepcidin levels in liver disease result in secondary iron overload through failure to negatively regulate intestinal iron absorption. 8
Diagnostic and Therapeutic Implications
Diagnostic Utility
Hepcidin measurement may provide diagnostic value in screening and monitoring iron disorders, helping distinguish between iron deficiency, anemia of inflammation, and iron overload conditions. 1, 2, 5
Mass spectrometry techniques can identify various hepcidin isoforms in urine and serum, potentially enabling more precise diagnosis and monitoring. 1
Lower hepcidin levels are observed in hereditary hemochromatosis and non-hemochromatosis iron overload diseases, supporting its use in differential diagnosis. 1
Therapeutic Targeting
Elevating hepcidin concentration is an optimal strategy for iron overload diseases, offering an alternative to conventional phlebotomy and chelation therapy. 4, 5
Hepcidin agonists are under development for treating iron overload in hemochromatosis and β-thalassemia, with the potential to improve ineffective erythropoiesis. 4, 5
Hepcidin antagonists are being investigated for iron-restrictive anemias, including anemia of chronic disease, chronic kidney disease, and cancer-associated anemia. 5, 6
Strategies targeting hepcidin, ferroportin, and hepcidin regulators represent novel therapeutic approaches for diseases associated with iron dysregulation. 5, 6
Common Pitfalls and Clinical Caveats
Do not assume all iron overload is due to hereditary hemochromatosis—secondary causes including chronic liver disease (hepatitis C, alcoholic liver disease, NAFLD) must be distinguished, as they have different patterns of iron deposition and hepcidin dysregulation. 8
In dialysis patients, avoid "blind" intravenous iron administration without assessing true iron deficiency (ferritin <100 µg/L), as excessive iron can cause iatrogenic overload despite altered hepcidin regulation in chronic kidney disease. 1
Recognize that inflammation can mask iron deficiency—elevated hepcidin from inflammation may prevent adequate iron mobilization even when stores are depleted, creating a functional iron deficiency. 7, 6
Understand that hepcidin deficiency in hemochromatosis creates vulnerability to specific infections—counsel these patients about their increased risk and provide specific avoidance strategies for high-risk exposures like raw seafood. 3