Iron overload and Hepcidin overexpression could play a key role in COVID infection, and may explain vulnerability in elderly, diabetics, and obese patients

Iron overload and Hepcidin overexpression could play a key role in COVID infection, and may explain vulnerability in elderly, diabetics, and obese patients


  • Filippo Banchini Department of General Surgery, Guglielmo da Saliceto Hospital, Piacenza, Italy
  • Daniele Vallisa Department of Hematology , Guglielmo da Saliceto Hospital, Piacenza, Italy
  • Pietro Maniscalco Orthopedics and Traumatology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy
  • Patrizio Capelli Department of General Surgery, Guglielmo da Saliceto Hospital, Piacenza, Italy


COVID, sars-cov, diabetes, elderly, iron, hepcidin, ferritin, heparin, erythropoietin, chloroquine


Background: The COVID epidemic hit like a tsunami worldwide. At the time of its arrival in Italy, available literary data were meager, and most of them concerned its epidemiology. World Health Organization proposed guidelines in march 2020, a strategy of treatment has been developed, and a significant number of subsequent articles have been published to understand, prevent, and cure COVID patients. Methods: From the observation of two patients, we performed a careful analysis of scientific literature to unearth the relation between COVID infection, clinical manifestations as pneumonia and thrombosis, and to find out why it frequently affects obese, diabetics, and elderly patients. Results: The analysis shows that hepcidin could represent one of such correlating factors. Hepcidin is most elevated in older age, in non-insulin diabetics patients and in obese people. It is the final target therapy of many medicaments frequently used. Viral disease, and in particular SARS-CoV19, could induce activation of the hepcidin pathway, which in turn is responsible for an increase in the iron load. Excess of iron can lead to cell death by ferroptosis and release into the bloodstream, such as free iron, which in turn has toxic and pro-coagulative effects. Conclusions: Overexpression of hepcidin and iron overload might play a crucial role in COVID infection, becoming potential targets for treatment. Hepcidin could also be considered as a biomarker to measure the effectiveness of our treatments and the restoration of iron homeostasis the final intent. (


S Garg MMWR / April 17, 2020 / Vol. 69 / No. 15 US Department of Health and Human Services/Centers for Disease Control and Prevention (

B Lipinski, E Pretorius Novel pathway of iron‑induced blood coagulation: implications for diabetes mellitus and its complications Polskie archiwum medycyny wewnȩtrznej • March 2012; 122 (3):115-121 DOI: 10.20452/pamw.1201

J C. Ciciliano, Y Sakurai, D R. Myers, M E. Fay, B Hechler, S Meeks, R Li, J. B Dixon, L. A Lyon, C Gachet, WA. Lam Resolving the multifaceted mechanisms of the ferric chloride thrombosis model using an interdisciplinary microfluidic approach BLOOD, 6 AUGUST 2015;126 (6):817-824 DOI 10.1182/blood-2015-02-628594

M E. Stegenga, S N. van der Crabben, M Levi, A F. de Vos, MW. Tanck, H P. Sauerwein, T van der Poll Hyperglycemia Stimulates Coagulation, Whereas Hyperinsulinemia Impairs Fibrinolysis in Healthy Humans DIABETES, UNE 2006; 55: 1807-1812 DOI: 10.2337/db05-1543

H Wang, H Li, X Jiang, W Shi, Z Shen, M Li Hepcidin Is Directly Regulated by Insulin and Plays an Important Role in Iron Overload in Streptozotocin-Induced Diabetic Rats Diabetes 2014;63:1506–1518 | DOI: 10.2337/db13-1195

Hadadi A, Mortezazadeh M , Kolahdouzan K, Alavian G Does recombinant human Erythropoietin administration in critically ill COVID-19 patients have miraculous therapeutic effects? J Med Virol. 2020 Apr 8. doi: 10.1002/jmv.25839. [Epub ahead of print]

Asperti M, Denardo A, Gryzik M, Arosio P, Poli M Chapter Eight - The role of heparin, heparanase and heparin sulfates in hepcidin regulation Vitamins and Hormones Volume 110, 2019, Pages 157-188 Https://

A E. Armitagea,1, A R. Stacey, Ei Giannoulatou, E Marshall, P Sturges, K Chatha, N M. G. Smith, XJ Huang, X Ning Xu, SR Pasricha, N Li, H Wu, C Webster, AM. Prentice, P Pellegrino, I Williams, PJ. Norris, H Drakesmith, P Borrow Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections PNAS 2014 19 (111)33:12187–12192

C Cagnoni , F Corsini, D Pancotti, G Carrara Effect of iron depletion on long-term response to interferon in patients with chronic hepatitis C with increased plasma iron without accumulation of liver iron Ann Ital Med Int. 2000 Apr-Jun;15(2):132-8.

SM Schmidt. The role of iron in viral infections. Front Biosci (Landmark Ed). 2020 Jan 1;25:893-911.

F Greco, a Piperno, S Pelucci VARIABILITA’ FENOTIPICA NELL’EMOCROMATOSI: STUDIO DI DUE POTENZIALI MODIFICATORI GENETICI IN PCSK7 E GNPAT Dipartimento di Medicina e Chirurgia Dottorato di Ricerca in EMATOLOGIA SPERIMENTALE XXVIII Ciclo Università degli studi Milano Bicocca

M Wessling-Resnick Iron Homeostasis and the Inflammatory Response Annu Rev Nutr. 2010 August 21; 30: 105–122. doi:10.1146/annurev.nutr.012809.104804

HAMP hepcidin antimicrobial peptide[Homo sapiens] Gene ID: 57817, updated on 29-Mar-2020

D.P. Clark, N.J. Pazdernik Molecular Biology 2nd Edition 2012 Chapter 18; p:557-558 Elsevier Publication ISBN: 9780123785954

Bataille S, Pedinielli N, Bergougnioux JP, Could ferritin help the screening for COVID-19 in hemodialysis patients?, Kidney International (2020), doi:

KG Connelly, M Moss, PE Parsons, EE Moore, FA Moore, PC Giclas, PA Seligman, JE Repine. Serum ferritin as a predictor of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997 Jan;155(1):21-5. DOI: 10.1164/ajrccm.155.1.9001283

S J. Dixon, K M. Lemberg, M R. Lamprecht, R Skouta, E M. Zaitsev, C E. Gleason1, D N. Patel, A J. Bauer, A M. Cantley, W S Yang, B Morrison III, and B R. Stockwell Ferroptosis: An Iron-Dependent Form of Non-Apoptotic Cell Death Cell. 2012 May 25; 149(5): 1060–1072. doi:10.1016/j.cell.2012.03.042

W Liu, S Zhang,S Nekha,S Liu Depriving Iron Supply to the Virus Represents a Promising Adjuvant

Therapeutic Against Viral Survival Curr Clin Microbiol Rep. 2020 Apr 20:1-7. doi: 10.1007/s40588-020-00140-w. [Epub ahead of print]

Gutteridge JM , Mumby S, Quinlan GJ, Chung KF, Evans TW. Pro-oxidant iron is present in human pulmonary epithelial lining fluid: implications for oxidative stress in the lung. Biochem Biophys Res Commun. 1996 Mar 27;220(3):1024-7. DOI: 10.1006/bbrc.1996.0518

YT Huang , AJ Ghio , E Nozik-Grayck , CA Piantadosi Vascular release of nonheme iron in perfused rabbit lungs Am J Physiol Lung Cell Mol Physiol. 2001 Mar;280(3):L474-81. DOI: 10.1152/ajplung.2001.280.3.L474


P Liu, Y Feng, H Li, X Chen, G Wang, S Xu, Y Li, Zhao Ferrostatin-1 alleviates lipopolysaccharideinduced acute lung injury via inhibiting ferroptosis Cellular & Molecular Biology Letters (2020) 25:10: 2-14

M Sauler, I S. Bazan, P J. Lee Cell Death in the Lung: The Apoptosis–Necroptosis Axis Annu Rev Physiol. 2019 February 10; 81: 375–402. doi:10.1146/annurev-physiol-020518-114320.

C Pugh, V Hathwar, JH Richards, J Stonehuerner, AJ Ghio. Disruption of iron homeostasis in the lungs of transplant patients. J Heart Lung Transplant. 2005 Nov;24(11):1821-7. Epub 2005 Jul 27. DOI: 10.1016/j.healun.2005.03.016

Halon-Golabek M, Borkowska A, Herman-Antosiewicz A and Antosiewicz J (2019) Iron Metabolism of the Skeletal Muscle and Neurodegeneration. Front. Neurosci. 13:165. doi: 10.3389/fnins.2019.00165

M Bayeva, M Gheorghiade, H Ardehali Mitochondria as a Therapeutic Target in Heart Failure Journal of the American College of Cardiology Vol. 61, No. 6, 2013

T I. Martinson, P.D. Falsely elevated D-dimer level after iron sucrose infusion American Journal of Health-System Pharmacy, Volume 74, Issue 23, 1 December 2017, Pages 1942–1944,

R Vuppalanchi, J S Troutt, R J. Konrad, M Ghabril, R Saxena, L N Bell, K V. Kowdley, N Chalasani. Serum Hepcidin Levels Are Associated With Obesity but Not Liver Disease Obesity (Silver Spring). 2014 March ; 22(3): 836–841. doi:10.1002/oby.20403

T E. Galesloot, S H. Vermeulen, A J. Geurts-Moespot, S M. Klaver, J J. Kroot, D van Tienoven, K F. M. Wetzels, L A. L. M. Kiemeney, F C. Sweep, M den Heijer, D W. Swinkels Serum hepcidin: reference ranges and biochemical correlates in the general population BLOOD, JUNE 2011 23 ; 117, 25 :e218-225 DOI 10.1182/blood-2011-02-337907

N Ishizaka, K Saito , K Furuta , G Matsuzaki , K Koike , E Noiri ,R Nagai . Angiotensin II-induced regulation of the expression and localization of iron metabolism-related genes in the rat kidney. Hypertens Res. 2007 Feb;30(2):195-202. DOI: 10.1291/hypres.30.195

H.H Ahmed, N.N Fadl, S.E.Kotob Impact of Long Term Metformin Therapy on Hepcidin and Iron Status in Type II Diabetic Patients International Journal of Pharmaceutical and Clinical Research 2015; 7(3): 185-193 Available online at

J Olejnik, A J. Hume, E Mu¨ hlberger Toll-like receptor 4 in acute viral Infection: Too much of a good thing PLoS Pathog. 2018 Dec 20;14(12):e1007390. doi: 10.1371/journal.ppat.1007390. eCollection 2018 Dec

J P. Pinto,S Ribeiro, H Pontes, S Thowfeequ, D Tosh, F Carvalho, G Porto Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBP BLOOD , 15 (111)12;5727-5733 DOI 10.1182/blood-2007- 08-106195.

F Azizi‑Soleiman, M Vafa, B Abiri, M Safavi Effects of Iron on Vitamin D Metabolism: A Systematic Review International Journal of Preventive Medicine 2016, 7:126 DOI: 10.4103/2008-7802.195212

Lane DJ, Richardson DR The active role of vitamin C in mammalian iron metabolism: much more than just enhanced iron absorption Free Radic Biol Med. 2014 Oct;75:69-83. doi: 10.1016/j.freeradbiomed.2014.07.007. Epub 2014 Jul 15 DOI: 10.1016/j.freeradbiomed.2014.07.007

Muñoz-Castañeda JR, Túnez I, Herencia C, Ranchal I, González R, Ramírez LM, Arjona A, Barcos M, Espejo I, Cruz A, Montilla P, Padillo FJ, Muntané J Melatonin exerts a more potent effect than S-adenosyl-l-methionine against iron metabolism disturbances, oxidative stress and tissue injury induced by obstructive jaundice in rats Chem Biol Interact. 2008 Jul 30;174(2):79-87. doi: 10.1016/j.cbi.2008.05.016. Epub 2008 May 18. DOI: 10.1016/j.cbi.2008.05.016

C A. Devaux, J-M Rolain, P Colson, D Raoult New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 Mar 12:105938. doi: 10.1016/j.ijantimicag.2020.105938.

Kazuyuki Yoshizaki , Soken-Nakazawa J Song , Hiroshi Kawabata Suppressing Hepcidin By Tocilizumab Effectively Improve Anemia in Inflammatory Diseases: Clinical Evidence and Basic Mechanisms Blood (2014) 124 (21): 4006.

N Squillace , D Trabattoni , A Muscatello , F Sabbatini , A Maloberti , C Giannattasio, M Masetti , C Fenizia , A Soria , M Clerici , A Gori , A Bandera Evaluation of adhesion molecules and immune parameters in HIV-infected patients treated with an atazanavir/ritonavir- compared with a lopinavir/ritonavir-based regimen J Antimicrob Chemother. 2018 Aug 1;73(8):2162-2170. doi: 10.1093/jac/dky178.

Y Xu, S Chen , Y Cao , P Zhou, Z Chen , K Cheng Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents. ur J Med Chem. 2018 Jun 25;154:253-266. doi: 10.1016/j.ejmech.2018.05.033. Epub 2018 May 22.

M Molteni, A Bosi, C Rossetti Natural Products with Toll-Like Receptor 4 Antagonist Activity. Int J Inflam. 2018 Mar 1;2018:2859135. doi: 10.1155/2018/2859135. eCollection 2018.

S Colucci, A Pagani, M Pettinato, I Artuso, A Nai, C Camaschella, L Silvestri The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes Blood. 2017 Nov 9;130(19):2111-2120. doi: 10.1182/blood-2017-04-780692. Epub 2017 Sep 1.

G Sebastiani, N Wilkinson , K Pantopoul Pharmacological Targeting of the Hepcidin/Ferroportin Axis Front Pharmacol. 2016 Jun 21;7:160. doi: 10.3389/fphar.2016.00160. eCollection 2016.

A Katsarou , K Pantopoulos Hepcidin Therapeutics Pharmaceuticals (Basel). 2018 Nov 21;11(4). pii: E127. doi: 10.3390/ph11040127.

SK Das , W Wang , P Zhabyeyev , R Basu , B McLean , D Fan , N Parajuli , J DesAulniers , VB Patel , RJ Hajjar , JR Dyck , Z Kassiri , GY Oudit Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy. Sci Rep. 2015 Dec 7;5:18132. doi: 10.1038/srep18132.

ZJ Hawula, DF Wallace , VN Subramaniam , G Rishi Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis.Pharmaceuticals (Basel). 2019 Nov 25;12(4). pii: E170. doi: 10.3390/ph12040170.







How to Cite

Iron overload and Hepcidin overexpression could play a key role in COVID infection, and may explain vulnerability in elderly, diabetics, and obese patients. Acta Biomed [Internet]. 2020 Sep. 7 [cited 2024 Jun. 21];91(3):e2020013. Available from:

Most read articles by the same author(s)

1 2 3 > >>