Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin
Open accessAbstract
Expression of hepcidin, the key hormone governing iron transport, is reduced by anemia in a manner which appears dependent on increased bone marrow activity. The temporal associations between plasma hepcidin and other iron parameters were examined in healthy humans after erythropoietin administration and venesection. Profound hepcidin suppression appeared abruptly 24 hours after subcutaneous erythropoietin (P=0.003), and was near maximal at onset, with peak (mid-afternoon) levels reduced by 73.2%, gradually recovering over the following two weeks. Minor changes in circulating iron, soluble transferrin receptor and growth differentiation factor-15 were observed after the reduction in hepcidin. Similar but more gradual changes in these parameters were observed after reducing hematocrit by removal of 250 mL blood. These human studies confirm the importance of a rapidly responsive marrow-hepcidin axis in regulating iron supply in vivo, and suggest that this axis is regulated by factors other than circulating iron, soluble transferrin receptor or growth differentiation factor-15.
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Studies in humans receiving recombinant EPO have not yet shown a significant inverse relationship between serum hepcidin and GDF15 levels.
“studies in humans receiving recombinant EPO have not yet shown a significant inverse relationship between serum hepcidin and GDF15 levels”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [222]
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“Moreover, apart from the direct effect on erythroid precursors, ESAs have been reported to suppress hepcidin production both in animal models and in humans, through a yet unknown mechanism [82, 83].”
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“The mature form of the hormone, Hepcidin-25, is a biomarker for iron dis-metabolisms, inflammations and doping [27, 38]; its determination in serum helps in the clinical assessment of the different iron metabolism disorders, offering indications for the prognosis and therapeutic interventions [39–44].”
BackgroundA dual-monoclonal sandwich ELISA specific for hepcidin-25
Butterfield, A. M., Luan, P., Witcher, D. R., Manetta, J., Murphy, A. T., Wroblewski, V. J., & Konrad, R. J. (2010) · Clinical Chemistry · doi:10.1373/clinchem.2010.151522 · Cited by 59 · see citing works
Modulation of hepcidin to treat iron deregulation: potential clinical applications
Blanchette, N. L., Manz, D. H., Torti, F. M., & Torti, S. V. (2015) · Expert Review of Hematology · doi:10.1586/17474086.2016.1124757 · Cited by 58 · see citing works
“with EPO resulted in a striking reduction of hepcidin transcription and circulating levels, respectively.[61,62] However, additional studies investigating direct regula-”
BackgroundHepcidin: A Critical Regulator of Iron Metabolism during Hypoxia
Hintze, K. J., & McClung, J. P. (2011) · Advances in Hematology · doi:10.1155/2011/510304 · Cited by 58 · see citing works
“Both human and animal studies have demonstrated reductions in serum hepcidin and mRNA levels, respectively, following erythropoietin administration [26, 27].”
BackgroundThe evolving science of detection of ‘blood doping’
Lundby, C., Robach, P., & Saltin, B. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01822.x · Cited by 56 · see citing works
“), it was observed that serum hepcidin levels were profoundly suppressed in six subjects starting 24 h after the injection, and remained suppressed for 2 weeks (Ashby et al., 2010).”
BackgroundBansal, S. S., Abbate, V., Bomford, A. B., Halket, J. M., Macdougall, I. C., Thein, S. L., & Hider, R. C. (2010) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.4512 · Cited by 53 · see citing works
Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression
Gordeuk, V. R., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nouraie, M., Okhotin, D. J., Polyakova, L. A., Ammosova, T., Nekhai, S., Ganz, T., et al. (2011) · Blood · doi:10.1182/blood-2011-03-345512 · Cited by 51 · see citing works
Sasaki, Y., Noguchi‐Sasaki, M., Yasuno, H., Yorozu, K., & Shimonaka, Y. (2012) · International Journal of Hematology · doi:10.1007/s12185-012-1217-4 · Cited by 50 · see citing works
“An injection of rhEPO to healthy volunteers caused a marked reduction of plasma or urinary hepcidin with minor changes in GDF-15, suggesting GDF-15 is unlikely to mediate the hepcidin suppression [16, 17].”
BackgroundHow do we treat life‐threatening anemia in a J ehovah's W itness patient?
Posluszny, J. A., & Napolitano, L. M. (2014) · Transfusion · doi:10.1111/trf.12888 · Cited by 49 · see citing works
“Interestingly, it has been shown that a single dose of ESA can result in rapid suppression of blood hepcidin concentrations.(47) TA B L E 2.”
BackgroundErythropoiesis and Iron Sulfur Cluster Biogenesis
Ye, H., & Rouault, T. A. (2010) · Advances in Hematology · doi:10.1155/2010/329394 · Cited by 44 · see citing works
“However, this potential role of GDF15 remains unproven, as GDF15 has failed to suppress hepcidin expression in cellular models [23, 24].”
BackgroundRobach, P., Gammella, E., Recalcati, S., Girelli, D., Castagna, A., Roustit, M., Lundby, C., Lundby, A., Bouzat, P., Vergès, S., et al. (2020) · Haematologica · doi:10.3324/haematol.2019.233874 · Cited by 46 · see citing works
Treatment of erythropoietin deficiency in mice with systemically administered siRNA
Querbes, W., Bogorad, R. L., Moslehi, J., Wong, J., Chan, A. Y., Bulgakova, E., Kuchimanchi, S., Akinc, A., Fitzgerald, K., Koteliansky, V., et al. (2012) · Blood · doi:10.1182/blood-2012-04-423715 · Cited by 45 · see citing works
TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis
Ganz, T., Nemeth, E., Rivella, S., Goldberg, P., Dibble, A., McCaleb, M. L., Guo, S., Monia, B. P., & Barrett, T. D. (2023) · Advances in Therapy · doi:10.1007/s12325-022-02421-w · Cited by 44 · see citing works
“poietic stimulus results in a sustained decrease of serum hepcidin concentration that begins within hours [30, 31].”
BackgroundPaesano, R., Natalizi, T., Berlutti, F., & Valenti, P. (2012) · Pathogens and Global Health · doi:10.1179/2047773212y.0000000043 · Cited by 42 · see citing works
Anderson, E. R., & Shah, Y. M. (2013) · Comprehensive physiology · doi:10.1002/j.2040-4603.2013.tb00494.x · Cited by 41 · see citing works
“However, their role in hepcidin repression during erythropoiesis is still unclear (9, 82).”
Troutt, J. S., Butterfield, A. M., & Konrad, R. J. (2013) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.21634 · Cited by 41 · see citing works
“Since both ESA usage as well as red cell transfusions would be expected to increase hemoglobin levels while lowering hepcidin-25 concentrations (16,33,34), and thus disrupt any correlation between the two, this may explain why there was no significant correlation between hepcidin-25 and hemoglobin concentrations in th…”
BackgroundEstablished and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases
Petzer, V., Theurl, I., & Weiß, G. (2018) · Pharmaceuticals · doi:10.3390/ph11040135 · Cited by 41 · see citing works
“Notably, EPO at high doses can decrease hepcidin levels [176].”
BackgroundBanfi, G., Lombardi, G., Colombini, A., & Lippi, G. (2010) · Clinica Chimica Acta · doi:10.1016/j.cca.2010.03.039 · Cited by 40 · see citing works
Hepcidin is a Potential Regulator of Iron Status in Chronic Kidney Disease
Tsuchiya, K., & Nitta, K. (2012) · Therapeutic Apheresis and Dialysis · doi:10.1111/1744-9987.12001 · Cited by 41 · see citing works
“Regulation by erythropoietic signals Administration of erythropoiesis-stimulating agents (ESAs) has been found to decrease hepcidin production by hepatocytes (30,40,41).”
BackgroundWagner, M., Ashby, D. R., Kurtz, C. B., Alam, A., Busbridge, M., Raff, U., Zimmermann, J., Heuschmann, P. U., Wanner, C., & Schramm, L. (2015) · PLoS ONE · doi:10.1371/journal.pone.0123072 · Cited by 40 · see citing works
Advancements in anemias related to chronic conditions
Guidi, G. C., & Santonastaso, C. L. (2010) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2010.264 · Cited by 39 · see citing works
Iron: The new advances in therapy
Auerbach, M., Goodnough, L. T., & Shander, A. (2013) · Best practice & research. Clinical anaesthesiology · doi:10.1016/j.bpa.2012.12.001 · Cited by 37 · see citing works
Hennigar, S. R., Berryman, C. E., Harris, M. N., Karl, J. P., Lieberman, H. R., McClung, J. P., Rood, J. C., & Pasiakos, S. M. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz316 · Cited by 36 · see citing works
Erythropoietic drive is the strongest predictor of hepcidin level in adults with sickle cell disease
Karafin, M. S., Koch, K. L., Rankin, A. B., Nischik, D., Rahhal, G., Simpson, P. M., & Field, J. J. (2015) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2015.07.010 · Cited by 35 · see citing works
Investigational therapies for renal disease-induced anemia
Schmid, H., & JELKMANN, W. E. B. (2016) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2016.1182981 · Cited by 33 · see citing works
“Despite beneficial hepcidin-lowering effects in animal models and in humans for, for example, heparin application, alcohol loading[109], ESA treatment, [110] or vitamin D administration [111], none of these options will be able to definitely lower increased hepcidin levels in CKD patients.”
BackgroundLiver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice
Díaz, V., Gammella, E., Recalcati, S., Santambrogio, P., Naldi, A. M., Vogel, J., Gassmann, M., & Cairo, G. (2013) · Hepatology · doi:10.1002/hep.26550 · Cited by 33 · see citing works
Iron and oxygen sensing: a tale of 2 interacting elements?
Simpson, R. J., & McKie, A. T. (2014) · Metallomics · doi:10.1039/c4mt00225c · Cited by 32 · see citing works
Govus, A. D., Abbiss, C. R., Garvican‐Lewis, L. A., Swinkels, D. W., Laarakkers, C. M., Gore, C. J., & Peeling, P. (2014) · European Journal of Applied Physiology · doi:10.1007/s00421-014-2938-2 · Cited by 30 · see citing works
Keel, S., Doty, R. T., Liu, L., Nemeth, E., Cherian, S., Ganz, T., & Abkowitz, J. L. (2015) · Experimental Hematology · doi:10.1016/j.exphem.2015.03.001 · Cited by 29 · see citing works
“We favor the possibility that Tfrc functions as a signaling molecule because the alternative possibility, that soluble Tfrc (released from erythroid cells) directly suppresses liver hepcidin expression, is inconsistent with published work [15,35,36] and our data in Tfrc+/− mice.”
BackgroundResultTreatment of renal anemia: Erythropoiesis stimulating agents and beyond
Biggar, P. H., & Kim, G. (2017) · Kidney Research and Clinical Practice · doi:10.23876/j.krcp.2017.36.3.209 · Cited by 31 · see citing works
“However, conventional ESAs offer a comprehensive safety profile which should be the future comparison standard for the newer substance classes.”
BackgroundInfluentialMechanisms and Regulation of Intestinal Iron Transport
Collins, J. F., Flores, S. R., Wang, X., & Anderson, G. J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809954-4.00060-8 · Cited by 30 · see citing works
Mojzíková, R., Kořalková, P., Holub, D., Zidova, Z., Pospı́šilová, D., Čermák, J., Striezencova, Z. L., Indrák, K., Suková, M., Partschova, M., et al. (2014) · British Journal of Haematology · doi:10.1111/bjh.12779 · Cited by 29 · see citing works
“Candidate erythroid signals regulating hepcidin To clarify the involvement of erythropoiesis in iron metabolism in PK deficiency, serum levels of GDF15 and EPO, two markers of erythropoietic activity known to be associated with hepcidin production, were evaluated.”
BackgroundInfluentialGrowth differentiation factor 15 in erythroid health and disease
Tanno, T., Noel, P., & Miller, J. L. (2010) · Current Opinion in Hematology · doi:10.1097/moh.0b013e328337b52f · Cited by 139 · see citing works
Lainé, F., Laviolle, B., Ropert, M., Bouguen, G., Morçet, J., Hamon, C., Massart, C., Westermann, M., Deugnier, Y., & Loréal, O. (2011) · European Journal of Applied Physiology · doi:10.1007/s00421-011-2097-7 · Cited by 26 · see citing works
Lehmberg, K., Grosse, R., Muckenthaler, M. U., Altamura, S., Nielsen, P., Schmid, H., Graubner, U. B., Oyen, F., Zeller, W., Schneppenheim, R., et al. (2012) · Annals of Hematology · doi:10.1007/s00277-012-1618-8 · Cited by 25 · see citing works
“As erythropoietin (EPO) has been shown to decrease plasma hepcidin in healthy individuals [10], recombinant human EPO may constitute a potential remedy for IRIDA patients.”
BackgroundTarkun, P., Mehtap, Ö., Ateşoğlu, E. B., Gedük, A., Musul, M. M., & Hacıhanefioğlu, A. (2013) · European Journal Of Haematology · doi:10.1111/ejh.12150 · Cited by 25 · see citing works
“On the other hand, studies in patients with effective erythropoiesis after bone marrow transplantation or after injection of erythropoietin failed to demonstrate major increases in serum GDF-15 (18, 19).”
BackgroundRobach, P., Recalcati, S., Girelli, D., Campostrini, N., Kempf, T., Wollert, K. C., Corbella, M., Santambrogio, P., Perbellini, L., Brasse‐Lagnel, C., et al. (2013) · European Journal Of Haematology · doi:10.1111/ejh.12122 · Cited by 25 · see citing works
“However, the fact that 1) GDF-15 levels were still within the normal range and well below the levels necessary to repress hepcidin mRNA expression in human hepatic cells (9), and 2) low-dose Epo blunted hepcidin expression without noticeable GDF-15 changes [(23, 24) and present study] argues against GDF-15 as a putati…”
BackgroundResultInfluentialIron Mining for Erythropoiesis
Correnti, M., Gammella, E., Cairo, G., & Recalcati, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105341 · Cited by 27 · see citing works
“Initial studies showing (1) strong downregulation of hepcidin in mice injected with EPO [18,52,73], (2) inhibition of hepcidin transcription in EPO-treated cell lines [74,75] and (3) a prompt decrease in hepcidin levels [76,77] that preceded any significant change in potential mediators following EPO administration to…”
ResultBone marrow iron distribution, hepcidin, and ferroportin expression in renal anemia
Bârsan, L., Stanciu, A., Stancu, S. H., Căpuşă, C. S., Brătescu, L., Mandache, E., Radu, E., & Mircescu, G. (2015) · Hematology · doi:10.1179/1607845415y.0000000004 · Cited by 24 · see citing works
Hepcidin and Erythropoietin Level in Sickle Cell Disease
Johnkennedy, N., Uche, U. B., Udujih, H. I., Chidozie, N. J., Obeagu, E. I., & Oluchi, A.-A. (2015) · Journal of Advances in Medicine and Medical Research · doi:10.9734/bjmmr/2015/17480 · Cited by 23 · see citing works
“The alteration of hepcidin production affects the erythropoietic activity in humans [7,8].”
BackgroundSong, J. W., Soh, S., Shim, J., Lee, S. H., Lee, S. H., Kim, H.-B., Kim, M.-Y., & Kwak, Y. L. (2021) · Annals of Surgery · doi:10.1097/sla.0000000000005011 · Cited by 23 · see citing works
“Erythropoietin also reduced circulating hepcidin levels 24 hour after subcutaneous administration in healthy humans.(23) In the study of Spahn et al,(24) concomitant erythropoietin treatment with intravenous iron 1 day before surgery resulted in increase of hemoglobin and reticulocyte from the day after surgery, sugge…”
BackgroundOlivera, J. D., Zhang, V., Nemeth, E., & Ganz, T. (2023) · Blood Advances · doi:10.1182/bloodadvances.2022009307 · Cited by 23 · see citing works
Signaling pathways regulating hepcidin
Rishi, G., & Subramaniam, V. N. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.003 · Cited by 23 · see citing works
HDAC1 governs iron homeostasis independent of histone deacetylation in iron-overload murine models
Yin, X., Wu, Q., Monga, J., Xie, E., Wang, H., Wang, S., Zhang, H., Wang, Z.-Y., Zhou, T., Shi, Y., et al. (2018) · Antioxidants & Redox Signaling · doi:10.1089/ars.2017.7161 · Cited by 22 · see citing works
Hepcidin in chronic kidney disease anemia
Santos‐Silva, A., Ribeiro, S., Reis, F., & Belo, L. (2019) · Vitamins and hormones · doi:10.1016/bs.vh.2019.01.012 · Cited by 23 · see citing works
Prolyl hydroxylase inhibitor desidustat improves anemia in erythropoietin hyporesponsive state
Joharapurkar, A. A., Patel, V. J., Kshirsagar, S. G., Patel, M. S., Savsani, H. H., Kajavadara, C. K., Valani, D., & Jain, M. R. (2022) · Current Research in Pharmacology and Drug Discovery · doi:10.1016/j.crphar.2022.100102 · Cited by 21 · see citing works
Elsewefy, D. A., Farweez, B. A. T., Behairy, M., & Yassin, N. R. (2019) · International Urology and Nephrology · doi:10.1007/s11255-018-2062-z · Cited by 22 · see citing works
Hematologic Aspects of Kidney Disease
Brugnara, C., & Eckardt, K. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4160-6193-9.10056-9 · Cited by 21 · see citing works
- Authors
- Ashby, D. R., Gale, D. P., Busbridge, M., Murphy, K. G., Duncan, N. D., Cairns, T. D., Taube, D. H., Bloom, S. R., Tam, F. W. K., Chapman, R., Maxwell, P. H., & Choi, P.
- Affiliations
- Hammersmith Hospital (GB)
- University College London (GB)
- Imperial College London (GB)
- Venue
- Haematologica
- Published
- 2009-10-14
- Volume
- 95
- Issue
- 3
- Pages
- 505-508
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC2833083
- OpenAlex
- W2034565548
- Cited by
- 191
- References
- 26
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 14 · 2016: 11 · 2015: 16 · 2014: 21 · 2013: 21 · 2012: 16
- FWCI
- 10.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0507-10315)
- Medical Research Council
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- erythropoietin, hepcidin, iron metabolism, anemia, bone marrow, phlebotomy, soluble transferrin receptor, growth differentiation factor 15, hematocrit
- MeSH terms
- Adult, Bone Marrow, Erythropoietin, Humans, Injections, Subcutaneous, Iron, Male, Receptors, Transferrin, Transferrin, Antimicrobial Cationic Peptides, Growth Differentiation Factor 15, Hepcidins
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