1932

Abstract

Hepcidin, the iron-regulatory hormone, determines plasma iron concentrations and total body iron content. Hepcidin, secreted by hepatocytes, functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and from iron stores. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Hepcidin excess causes iron-restrictive anemias including anemia of inflammation. The development of hepcidin diagnostics and therapeutic agonists and antagonists should improve the treatment of iron disorders.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-043021-032816
2023-01-27
2024-12-11
Loading full text...

Full text loading...

/deliver/fulltext/med/74/1/annurev-med-043021-032816.html?itemId=/content/journals/10.1146/annurev-med-043021-032816&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Pasricha SR, Tye-Din J, Muckenthaler MU, Swinkels DW. 2021. Iron deficiency. Lancet 397:233–48
    [Google Scholar]
  2. 2.
    Pantopoulos K. 2018. Inherited disorders of iron overload. Front. Nutr. 5:103
    [Google Scholar]
  3. 3.
    Park CH, Valore EV, Waring AJ, Ganz T. 2001. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J. Biol. Chem. 276:7806–10
    [Google Scholar]
  4. 4.
    Sangkhae V, Nemeth E. 2017. Regulation of the iron homeostatic hormone hepcidin. Adv. Nutr. 8:126–36
    [Google Scholar]
  5. 5.
    Ganz T, Nemeth E. 2011. Hepcidin and disorders of iron metabolism. Annu. Rev. Med. 62:347–60
    [Google Scholar]
  6. 6.
    Kautz L, Jung G, Valore EV et al. 2014. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat. Genet. 46:678–84
    [Google Scholar]
  7. 7.
    Sangkhae V, Fisher AL, Chua KJ et al. 2020. Maternal hepcidin determines embryo iron homeostasis in mice. Blood 136:2206–16
    [Google Scholar]
  8. 8.
    Nemeth E, Rivera S, Gabayan V et al. 2004. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Investig. 113:1271–76
    [Google Scholar]
  9. 9.
    Stefanova D, Raychev A, Arezes J et al. 2017. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood 130:245–57
    [Google Scholar]
  10. 10.
    Lakhal-Littleton S, Wolna M, Chung YJ et al. 2016. An essential cell-autonomous role for hepcidin in cardiac iron homeostasis. eLife 5:e19804
    [Google Scholar]
  11. 11.
    Malerba M, Louis S, Cuvellier S et al. 2020. Epidermal hepcidin is required for neutrophil response to bacterial infection. J. Clin. Investig. 130:329–34
    [Google Scholar]
  12. 12.
    Bessman NJ, Mathieu JRR, Renassia C et al. 2020. Dendritic cell-derived hepcidin sequesters iron from the microbiota to promote mucosal healing. Science 368:186–89
    [Google Scholar]
  13. 13.
    Donovan A, Lima CA, Pinkus JL et al. 2005. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200
    [Google Scholar]
  14. 14.
    Taniguchi R, Kato HE, Font J et al. 2015. Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin. Nat. Commun. 6:8545
    [Google Scholar]
  15. 15.
    Zhang DL, Ghosh MC, Ollivierre H et al. 2018. Ferroportin deficiency in erythroid cells causes serum iron deficiency and promotes hemolysis due to oxidative stress. Blood 132:2078–87
    [Google Scholar]
  16. 16.
    Aschemeyer S, Qiao B, Stefanova D et al. 2018. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood 131:899–910
    [Google Scholar]
  17. 17.
    Qiao B, Sugianto P, Fung E et al. 2012. Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab 15:918–24
    [Google Scholar]
  18. 18.
    Nemeth E, Tuttle MS, Powelson J et al. 2004. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–93
    [Google Scholar]
  19. 19.
    Billesbolle CB, Azumaya CM, Kretsch RC et al. 2020. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature 586:807–11
    [Google Scholar]
  20. 20.
    Preza GC, Ruchala P, Pinon R et al. 2011. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J. Clin. Investig. 121:4880–88
    [Google Scholar]
  21. 21.
    Schwartz AJ, Das NK, Ramakrishnan SK et al. 2019. Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload. J. Clin. Investig. 129:336–48
    [Google Scholar]
  22. 22.
    Fisher AL, Babitt JL. 2022. Coordination of iron homeostasis by bone morphogenetic proteins: current understanding and unanswered questions. Dev. Dyn. 251:26–46
    [Google Scholar]
  23. 23.
    Silvestri L, Nai A, Dulja A, Pagani A. 2019. Hepcidin and the BMP-SMAD pathway: an unexpected liaison. Vitam. Horm. 110:71–99
    [Google Scholar]
  24. 24.
    Canali S, Zumbrennen-Bullough KB, Core AB et al. 2017. Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood 129:405–14
    [Google Scholar]
  25. 25.
    Canali S, Wang CY, Zumbrennen-Bullough KB et al. 2017. Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6. Am. J. Hematol. 92:1204–13
    [Google Scholar]
  26. 26.
    Kautz L, Meynard D, Monnier A et al. 2008. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112:1503–9
    [Google Scholar]
  27. 27.
    Kautz L, Jung G, Du X et al. 2015. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of beta-thalassemia. Blood 126:2031–37
    [Google Scholar]
  28. 28.
    Wang CY, Xu Y, Traeger L et al. 2020. Erythroferrone lowers hepcidin by sequestering BMP2/6 heterodimer from binding to the BMP type I receptor ALK3. Blood 135:453–56
    [Google Scholar]
  29. 29.
    Artuso I, Pettinato M, Nai A et al. 2019. Transient decrease of serum iron after acute erythropoietin treatment contributes to hepcidin inhibition by ERFE in mice. Haematologica 104:e87–90
    [Google Scholar]
  30. 30.
    Gonzalez-Fernandez D, Nemeth E, Pons EDC et al. 2021. INTERGROWTH-21 identifies high prevalence of low symphysis-fundal height in indigenous pregnant women experiencing multiple infections, nutrient deficiencies, and inflammation: the Maternal Infections, Nutrient Deficiencies, and Inflammation (MINDI) cohort. Curr. Dev. Nutr. 5:nzab012
    [Google Scholar]
  31. 31.
    Armitage AE, Eddowes LA, Gileadi U et al. 2011. Hepcidin regulation by innate immune and infectious stimuli. Blood 118:4129–39
    [Google Scholar]
  32. 32.
    Kim A, Fung E, Parikh SG et al. 2014. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 123:1129–36
    [Google Scholar]
  33. 33.
    Ganz T. 2019. Anemia of inflammation. N. Engl. J. Med. 381:1148–57
    [Google Scholar]
  34. 34.
    Peters HP, Laarakkers CM, Pickkers P et al. 2013. Tubular reabsorption and local production of urine hepcidin-25. BMC Nephrol 14:70
    [Google Scholar]
  35. 35.
    Zaritsky J, Young B, Gales B et al. 2010. Reduction of serum hepcidin by hemodialysis in pediatric and adult patients. Clin. J. Am. Soc. Nephrol. 5:1010–14
    [Google Scholar]
  36. 36.
    Anderson GJ, Bardou-Jacquet E. 2021. Revisiting hemochromatosis: genetic versus phenotypic manifestations. Ann. Transl. Med. 9:731
    [Google Scholar]
  37. 37.
    Knutson MD. 2019. Non-transferrin-bound iron transporters. Free Radic. Biol. Med. 133:101–11
    [Google Scholar]
  38. 38.
    Cooray SD, Heerasing NM, Selkrig LA et al. 2018. Reversal of end-stage heart failure in juvenile hemochromatosis with iron chelation therapy: a case report. J. Med. Case Rep. 12:18
    [Google Scholar]
  39. 39.
    Girelli D, Trombini P, Busti F et al. 2011. A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis. Haematologica 96:500–6
    [Google Scholar]
  40. 40.
    Girelli D, Busti F, Brissot P et al. 2022. Hemochromatosis classification: update and recommendations by the BIOIRON Society. Blood 139:3018–29
    [Google Scholar]
  41. 41.
    Taher AT, Musallam KM, Cappellini MD. 2021. β-Thalassemias. N. Engl. J. Med. 384:727–43
    [Google Scholar]
  42. 42.
    Ganz T, Jung G, Naeim A et al. 2017. Immunoassay for human serum erythroferrone. Blood 130:1243–46
    [Google Scholar]
  43. 43.
    Pasricha SR, Frazer DM, Bowden DK, Anderson GJ. 2013. Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with β-thalassemia major: a longitudinal study. Blood 122:124–33
    [Google Scholar]
  44. 44.
    Origa R, Galanello R, Ganz T et al. 2007. Liver iron concentrations and urinary hepcidin in β-thalassemia. Haematologica 92:583–88
    [Google Scholar]
  45. 45.
    Finberg KE, Heeney MM, Campagna DR et al. 2008. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat. Genet. 40:569–71
    [Google Scholar]
  46. 46.
    Heeney MM, Guo D, De Falco L et al. 2018. Normalizing hepcidin predicts TMPRSS6 mutation status in patients with chronic iron deficiency. Blood 132:448–52
    [Google Scholar]
  47. 47.
    Silvestri L, Pagani A, Nai A et al. 2008. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 8:502–11
    [Google Scholar]
  48. 48.
    Enns CA, Jue S, Zhang AS. 2020. The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice. Blood 136:989–1001
    [Google Scholar]
  49. 49.
    Weiss G, Ganz T, Goodnough LT. 2019. Anemia of inflammation. Blood 133:40–50
    [Google Scholar]
  50. 50.
    Weir MR. 2021. Managing anemia across the stages of kidney disease in those hyporesponsive to erythropoiesis-stimulating agents. Am. J. Nephrol. 52:450–66
    [Google Scholar]
  51. 51.
    Babitt JL, Eisenga MF, Haase VH et al. 2021. Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) conference. Kidney Int. 99:1280–95
    [Google Scholar]
  52. 52.
    Pergola PE, Devalaraja M, Fishbane S et al. 2021. Ziltivekimab for treatment of anemia of inflammation in patients on hemodialysis: results from a phase 1/2 multicenter, randomized, double-blind, placebo-controlled trial. J. Am. Soc. Nephrol. 32:211–22
    [Google Scholar]
  53. 53.
    Madeddu C, Gramignano G, Astara G et al. 2018. Pathogenesis and treatment options of cancer related anemia: perspective for a targeted mechanism-based approach. Front. Physiol. 9:1294
    [Google Scholar]
  54. 54.
    Maes K, Nemeth E, Roodman GD et al. 2010. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 116:3635–44
    [Google Scholar]
  55. 55.
    Hara M, Ando M, Tsuchiya K, Nitta K. 2015. Serum hepcidin-25 level linked with high mortality in patients with non-Hodgkin lymphoma. Ann. Hematol. 94:603–8
    [Google Scholar]
  56. 56.
    Oh ST, Talpaz M, Gerds AT et al. 2020. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 4:4282–91
    [Google Scholar]
  57. 57.
    Pietrangelo A. 2017. Ferroportin disease: pathogenesis, diagnosis and treatment. Haematologica 102:1972–84
    [Google Scholar]
  58. 58.
    Diepeveen LE, Laarakkers CMM, Martos G et al. 2019. Provisional standardization of hepcidin assays: creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material. Clin. Chem. Lab. Med. 57:864–72
    [Google Scholar]
  59. 59.
    Schaap CC, Hendriks JC, Kortman GA et al. 2013. Diurnal rhythm rather than dietary iron mediates daily hepcidin variations. Clin. Chem. 59:527–35
    [Google Scholar]
  60. 60.
    Ganz T, Olbina G, Girelli D et al. 2008. Immunoassay for human serum hepcidin. Blood 112:4292–97
    [Google Scholar]
  61. 61.
    Beutler B, Jiang Z, Georgel P et al. 2006. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24:353–89
    [Google Scholar]
  62. 62.
    Zaritsky J, Young B, Wang HJ et al. 2009. Hepcidin—a potential novel biomarker for iron status in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 4:1051–56
    [Google Scholar]
  63. 63.
    Theurl I, Aigner E, Theurl M et al. 2009. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 113:5277–86
    [Google Scholar]
  64. 64.
    Bregman DB, Morris D, Koch TA et al. 2013. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Am. J. Hematol. 88:97–101
    [Google Scholar]
  65. 65.
    Martensson J, Glassford NJ, Jones S et al. 2015. Urinary neutrophil gelatinase-associated lipocalin to hepcidin ratio as a biomarker of acute kidney injury in intensive care unit patients. Minerva Anestesiol 81:1192–200
    [Google Scholar]
  66. 66.
    Prowle JR, Calzavacca P, Licari E et al. 2015. Combination of biomarkers for diagnosis of acute kidney injury after cardiopulmonary bypass. Ren. Fail. 37:408–16
    [Google Scholar]
  67. 67.
    Albert C, Haase M, Albert A et al. 2021. Predictive value of plasma NGAL:hepcidin-25 for major adverse kidney events after cardiac surgery with cardiopulmonary bypass: a pilot study. Ann. Lab. Med. 41:357–65
    [Google Scholar]
  68. 68.
    Leaf DE, Rajapurkar M, Lele SS et al. 2019. Iron, hepcidin, and death in human AKI. J. Am. Soc. Nephrol. 30:493–504
    [Google Scholar]
  69. 69.
    Lasocki S, Lefebvre T, Mayeur C et al. 2018. Iron deficiency diagnosed using hepcidin on critical care discharge is an independent risk factor for death and poor quality of life at one year: an observational prospective study on 1161 patients. Crit. Care 22:314
    [Google Scholar]
  70. 70.
    Jiang Y, Jiang FQ, Kong F et al. 2019. Inflammatory anemia-associated parameters are related to 28-day mortality in patients with sepsis admitted to the ICU: a preliminary observational study. Ann. Intensive Care 9:67
    [Google Scholar]
  71. 71.
    Girelli D, Nemeth E, Swinkels DW. 2016. Hepcidin in the diagnosis of iron disorders. Blood 127:2809–13
    [Google Scholar]
  72. 72.
    Casu C, Oikonomidou PR, Chen H et al. 2016. Minihepcidin peptides as disease modifiers in mice affected by beta-thalassemia and polycythemia vera. Blood 128:265–76
    [Google Scholar]
  73. 73.
    Schmidt PJ, Toudjarska I, Sendamarai AK et al. 2013. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe−/− mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. Blood 121:1200–8
    [Google Scholar]
  74. 74.
    Guo S, Casu C, Gardenghi S et al. 2013. Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. J. Clin. Investig. 123:1531–41
    [Google Scholar]
  75. 75.
    Ginzburg Y, Kirubamoorthy K, Salleh S et al. 2021. Rusfertide (PTG-300) induction therapy rapidly achieves hematocrit control in polycythemia vera patients without the need for therapeutic phlebotomy. Blood 138(Suppl. 1):390
    [Google Scholar]
  76. 76.
    Richard F, van Lier JJ, Roubert B et al. 2020. Oral ferroportin inhibitor VIT-2763: first-in-human, phase 1 study in healthy volunteers. Am. J. Hematol. 95:68–77
    [Google Scholar]
  77. 77.
    Altamura S, Schaeper U, Dames S et al. 2019. SLN124, a GalNAc-siRNA conjugate targeting TMPRSS6, efficiently prevents iron overload in hereditary haemochromatosis type 1. Hemasphere 3:e301
    [Google Scholar]
  78. 78.
    Katsarou A, Pantopoulos K 2018. Hepcidin therapeutics. Pharmaceuticals 11:127
    [Google Scholar]
  79. 79.
    Hawula ZJ, Wallace DF, Subramaniam VN, Rishi G. 2019. Therapeutic advances in regulating the hepcidin/ferroportin axis. Pharmaceuticals 12:170
    [Google Scholar]
  80. 80.
    Kurzrock R, Voorhees PM, Casper C et al. 2013. A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. Clin. Cancer Res. 19:3659–70
    [Google Scholar]
  81. 81.
    Kautz L, Jung G, Nemeth E, Ganz T. 2014. Erythroferrone contributes to recovery from anemia of inflammation. Blood 124:2569–74
    [Google Scholar]
  82. 82.
    Theurl I, Schroll A, Sonnweber T et al. 2011. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood 118:4977–84
    [Google Scholar]
  83. 83.
    Kovac S, Boser P, Cui Y et al. 2016. Anti-hemojuvelin antibody corrects anemia caused by inappropriately high hepcidin levels. Haematologica 101:e173–76
    [Google Scholar]
  84. 84.
    Vadhan-Raj S, Abonour R, Goldman JW et al. 2017. A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia. J. Hematol. Oncol. 10:73
    [Google Scholar]
  85. 85.
    Cooke KS, Hinkle B, Salimi-Moosavi H et al. 2013. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood 122:3054–61
    [Google Scholar]
  86. 86.
    Sheetz M, Barrington P, Callies S et al. 2019. Targeting the hepcidin-ferroportin pathway in anaemia of chronic kidney disease. Br. J. Clin. Pharmacol. 85:935–48
    [Google Scholar]
/content/journals/10.1146/annurev-med-043021-032816
Loading
/content/journals/10.1146/annurev-med-043021-032816
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error