The role of iron and ferritin in pathophysiology and as a laboratory marker in COVID-19
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Published:
Aug 29, 2022
Keywords:
Biomarker, COVID-19, Ferritin, Iron, Prognosis, SARS-CoV-2
Main Article Content
Abstract
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) emerged in China exponentially and is recognized as a multisystem disease that gradually elevates markers associated with iron metabolism as the infection becomes more intense, becoming a critical factor in the investigation of prognosis. We review the latest scientific findings on the behavior of iron and ferritin in pathophysiology and as laboratory markers in COVID-19 (Coronavirus Disease 2019).The findings showed that iron and ferritin play a key role in the pathogenesis of COVID-19, contributing to the worsening of the disease. Therefore, iron dysmetabolism, marked by hyperferritinemia, is associated with inflammatory states in SARS-CoV-2 infection, and ferritin measurement has been shown to be a useful laboratory marker with a clinical and discriminatory potential to define the severity and mortality during COVID-19.
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Sampaio SC, Sacramento GS, de Almeida JB. The role of iron and ferritin in pathophysiology and as a laboratory marker in COVID-19. Health Sci J [Internet]. 2022Aug.29 [cited 2024May3];12(3):12-1. Available from: https://portalrcs.hcitajuba.org.br/index.php/rcsfmit_zero/article/view/1275
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NARRATIVE REVIEW
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References
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23. Habib HM, Ibrahim S, Zaim A, Ibrahim WH. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed Pharmacother. 2021;136:111228. https://doi.org/10.1016/j.biopha.2021.111228
24. Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424-32. https://doi.org/10.1002/jmv.25685
25. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infec. 2020;80(6):607-13. https://doi.org/10.1016/j.jinf.2020.03.037
26. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4. https://doi.org/10.1016/S0140-6736(20)30628-0
27. Liu W, Li HJCd. COVID-19: Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv. 2022 (Preprint). https://doi.org/10.26434/chemrxiv-2021-dtpv3-v11
28. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. https://doi.org/10.1039/C3MT00347G
29. Wenzhong L, Hualan L. COVID-19: captures iron and generates reactive oxygen species to damage the human immune system. Autoimmunity. 2021;54(4):213-24. https://doi.org/10.1080/08916934.2021.1913581
30. Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108. https://doi.org/10.1016/j.biopha.2020.110108
31. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and Ageusia: Common Findings in COVID-19 Patients. Laryngoscope. 2020;130(7):1787. https://doi.org/10.1002/lary.28692
32. Temraz S, Santini V, Musallam K, Taher A. Iron overload and chelation therapy in myelodysplastic syndromes. Crit Rev Oncol Hematol. 2014;91(1):64-73. https://doi.org/10.1016/j.critrevonc.2014.01.006
33. Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: Past, present and future. Biochim Biophys Acta. 2010;1800(8):760-9. https://doi.org/10.1016/j.bbagen.2010.03.011
34. Suchdev PS, Williams AM, Mei Z, Flores-Ayala R, Pasricha SR, Rogers LM, et al. Assessment of iron status in settings of inflammation: challenges and potential approaches. Am J Clin Nutr. 2017;106(Suppl 6):1626s-33s. https://doi.org/10.3945/ajcn.117.155937
35. Ruscitti P, Giacomelli R. Ferritin and Severe COVID-19, from clinical observations to pathogenic implications and therapeutic perspectives. Isr Med Assoc J. 2020;22(8):516-8. PMId:33236586
36. Gómez-Pastora J, Weigand M, Kim J, Wu X, Strayer J, Palmer AF, et al. Hyperferritinemia in critically ill COVID-19 patients - Is ferritin the product of inflammation or a pathogenic mediator? Clin Chim Acta. 2020;509:249-51. https://doi.org/10.1016/j.cca.2020.06.033
37. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87. https://doi.org/10.1007/s00134-020-06022-5
38. Banchini F, Cattaneo GM, Capelli P. Serum ferritin levels in inflammation: a retrospective comparative analysis between COVID-19 and emergency surgical non-COVID-19 patients. World J Emerg Surg. 2021;16(1):9. https://doi.org/10.1186/s13017-021-00354-3
39. Bellmann-Weiler R, Lanser L, Barket R, Rangger L, Schapfl A, Schaber M, et al. Prevalence and predictive value of anemia and dysregulated iron homeostasis in patients with COVID-19 infection. J Clin Med. 2020;9(8):2429. https://doi.org/10.3390/jcm9082429
40. Bolondi G, Russo E, Gamberini E, Circelli A, Meca MCC, Brogi E, et al. Iron metabolism and lymphocyte characterisation during Covid-19 infection in ICU patients: an observational cohort study. World J Emerg Surg. 2020;15(1):41. https://doi.org/10.1186/s13017-020-00323-2
41. Dahan S, Segal G, Katz I, Hellou T, Tietel M, Bryk G, et al. Ferritin as a Marker of Severity in COVID-19 Patients: A Fatal Correlation. Isr Med Assoc J. 2020;22(8):494-500. PMId:33236582
42. Hippchen T, Altamura S, Muckenthaler MU, Merle U. Hypoferremia is associated with increased hospitalization and oxygen demand in COVID-19 patients. HemaSphere. 2020;4(6):e492. https://doi.org/10.1097/HS9.0000000000000492
43. Sonnweber T, Boehm A, Sahanic S, Pizzini A, Aichner M, Sonnweber B, et al. Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: a prospective observational cohort study. Respir Res. 2020;21(1):276. https://doi.org/10.1186/s12931-020-01546-2
44. Tojo K, Sugawara Y, Oi Y, Ogawa F, Higurashi T, Yoshimura Y, et al. The U-shaped association of serum iron level with disease severity in adult hospitalized patients with COVID-19. Sci Rep. 2021;11(1):13431. https://doi.org/10.1038/s41598-021-92921-6
45. Zhou C, Chen Y, Ji Y, He X, Xue D. Increased serum levels of hepcidin and ferritin are associated with severity of COVID-19. Med Sci Monit. 2020;26:e926178. https://doi.org/10.12659/MSM.926178
46. Ahmed S, Ansar Ahmed Z, Siddiqui I, Haroon Rashid N, Mansoor M, Jafri L. Evaluation of serum ferritin for prediction of severity and mortality in COVID-19- A cross sectional study. Ann Med Surg. 2021;63:102163. https://doi.org/10.1016/j.amsu.2021.02.009
47. Raman N, Kv P, Ashta KK, Vardhan V, Thareja S, J M, et al. Ferritin and hemoglobin as predictors of fatal outcome in COVID-19: two sides of the same coin. J Assoc Physicians India. 2021;69(8):11-2. PMId:34472812
48. Yağcı S, Serin E, Acicbe Ö, Zeren M, Odabaşı MS. The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID-19. Int J Lab Hematol. 2021;43 Suppl 1(suppl 1):142-51. https://doi.org/10.1111/ijlh.13479
49. Colafrancesco S, Alessandri C, Conti F, Priori R. COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Autoimmun rev. 2020;19(7):102573. https://doi.org/10.1016/j.autrev.2020.102573
50. Rosário C, Shoenfeld Y. The hyperferritinemic syndrome. Isr Med Assoc J. 2014;16(10):664-5. PMId:25438466
2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33. https://doi.org/10.1056/NEJMoa2001017
3. Cavezzi A, Troiani E, Corrao S. COVID-19: hemoglobin, iron, and hypoxia beyond inflammation. A narrative review. Clin Pract. 2020;10(2):1271. https://doi.org/10.4081/cp.2020.1271
4. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13. https://doi.org/10.1016/S0140-6736(20)30211-7
5. Ponti G, Maccaferri M, Ruini C, Tomasi A, Ozben T. Biomarkers associated with COVID-19 disease progression. Crit Rev Clin Lab Sci. 2020;57(6):389-99. https://doi.org/10.1080/10408363.2020.1770685
6. Lv Y, Chen L, Liang X, Liu X, Gao M, Wang Q, et al. Association between iron status and the risk of adverse outcomes in COVID-19. Clin Nutr. 2021;40(5):3462-9. https://doi.org/10.1016/j.clnu.2020.11.033
7. Ganz T, Nemeth E. Iron homeostasis in host defence and inflammation. Nat Rev Immunol. 2015;15(8):500-10. https://doi.org/10.1038/nri3863
8. Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol. 2017;29(9):401-9. https://doi.org/10.1093/intimm/dxx031
9. Coffey R, Ganz T. Iron homeostasis: An anthropocentric perspective. J Biol Chem. 2017;292(31):12727-34. https://doi.org/10.1074/jbc.R117.781823
10. Girelli D, Marchi G, Busti F, Vianello A. Iron metabolism in infections: Focus on COVID-19. Semin Hematol. 2021;58(3):182-7. https://doi.org/10.1053/j.seminhematol.2021.07.001
11. Perricone C, Bartoloni E, Bursi R, Cafaro G, Guidelli GM, Shoenfeld Y, et al. COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol Res. 2020;68(4):213-24. https://doi.org/10.1007/s12026-020-09145-5
12. Ganz T. Iron and infection. Int J Hematol. 2018;107(1):7-15. https://doi.org/10.1007/s12185-017-2366-2
13. Wessling-Resnick M. Iron homeostasis and the inflammatory response. Annu Rev Nutr. 2010;30:105-22. https://doi.org/10.1146/annurev.nutr.012809.104804
14. Camaschella C. Iron deficiency: new insights into diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2015;2015:8-13. https://doi.org/10.1182/asheducation-2015.1.8
15. Wang CY, Babitt JL. Hepcidin regulation in the anemia of inflammation. Curr Opin Hematol. 2016;23(3):189-97. https://doi.org/10.1097/MOH.0000000000000236
16. Daher R, Manceau H, Karim Z. Iron metabolism and the role of the iron-regulating hormone hepcidin in health and disease. Presse Med. 2017;46(12 Pt 2):e272-e8. https://doi.org/10.1016/j.lpm.2017.10.006
17. Polak SB, Van Gool IC, Cohen D, von der Thüsen JH, van Paassen J. A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression. Mod Pathol. 2020;33(11):2128-38. https://doi.org/10.1038/s41379-020-0603-3
18. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. https://doi.org/10.1016/S0140-6736(20)30566-3
19. Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581(7807):221-4. https://doi.org/10.1038/s41586-020-2179-y
20. Cheng H, Wang Y, Wang GQ. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. J Med Virol. 2020;92(7):726-30. https://doi.org/10.1002/jmv.25785
21. Murray E, Tomaszewski M, Guzik TJ. Binding of SARS-CoV-2 and angiotensin-converting enzyme 2: clinical implications. Cardiovasc Res. 2020;116(7):e87-e9. https://doi.org/10.1093/cvr/cvaa096
22. Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008;93(5):543-8. https://doi.org/10.1113/expphysiol.2007.040048
23. Habib HM, Ibrahim S, Zaim A, Ibrahim WH. The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed Pharmacother. 2021;136:111228. https://doi.org/10.1016/j.biopha.2021.111228
24. Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424-32. https://doi.org/10.1002/jmv.25685
25. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infec. 2020;80(6):607-13. https://doi.org/10.1016/j.jinf.2020.03.037
26. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4. https://doi.org/10.1016/S0140-6736(20)30628-0
27. Liu W, Li HJCd. COVID-19: Attacks the 1-beta chain of hemoglobin and captures the porphyrin to inhibit human heme metabolism. ChemRxiv. 2022 (Preprint). https://doi.org/10.26434/chemrxiv-2021-dtpv3-v11
28. Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6(4):748-73. https://doi.org/10.1039/C3MT00347G
29. Wenzhong L, Hualan L. COVID-19: captures iron and generates reactive oxygen species to damage the human immune system. Autoimmunity. 2021;54(4):213-24. https://doi.org/10.1080/08916934.2021.1913581
30. Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, et al. The emerging role of ferroptosis in inflammation. Biomed Pharmacother. 2020;127:110108. https://doi.org/10.1016/j.biopha.2020.110108
31. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and Ageusia: Common Findings in COVID-19 Patients. Laryngoscope. 2020;130(7):1787. https://doi.org/10.1002/lary.28692
32. Temraz S, Santini V, Musallam K, Taher A. Iron overload and chelation therapy in myelodysplastic syndromes. Crit Rev Oncol Hematol. 2014;91(1):64-73. https://doi.org/10.1016/j.critrevonc.2014.01.006
33. Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: Past, present and future. Biochim Biophys Acta. 2010;1800(8):760-9. https://doi.org/10.1016/j.bbagen.2010.03.011
34. Suchdev PS, Williams AM, Mei Z, Flores-Ayala R, Pasricha SR, Rogers LM, et al. Assessment of iron status in settings of inflammation: challenges and potential approaches. Am J Clin Nutr. 2017;106(Suppl 6):1626s-33s. https://doi.org/10.3945/ajcn.117.155937
35. Ruscitti P, Giacomelli R. Ferritin and Severe COVID-19, from clinical observations to pathogenic implications and therapeutic perspectives. Isr Med Assoc J. 2020;22(8):516-8. PMId:33236586
36. Gómez-Pastora J, Weigand M, Kim J, Wu X, Strayer J, Palmer AF, et al. Hyperferritinemia in critically ill COVID-19 patients - Is ferritin the product of inflammation or a pathogenic mediator? Clin Chim Acta. 2020;509:249-51. https://doi.org/10.1016/j.cca.2020.06.033
37. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-87. https://doi.org/10.1007/s00134-020-06022-5
38. Banchini F, Cattaneo GM, Capelli P. Serum ferritin levels in inflammation: a retrospective comparative analysis between COVID-19 and emergency surgical non-COVID-19 patients. World J Emerg Surg. 2021;16(1):9. https://doi.org/10.1186/s13017-021-00354-3
39. Bellmann-Weiler R, Lanser L, Barket R, Rangger L, Schapfl A, Schaber M, et al. Prevalence and predictive value of anemia and dysregulated iron homeostasis in patients with COVID-19 infection. J Clin Med. 2020;9(8):2429. https://doi.org/10.3390/jcm9082429
40. Bolondi G, Russo E, Gamberini E, Circelli A, Meca MCC, Brogi E, et al. Iron metabolism and lymphocyte characterisation during Covid-19 infection in ICU patients: an observational cohort study. World J Emerg Surg. 2020;15(1):41. https://doi.org/10.1186/s13017-020-00323-2
41. Dahan S, Segal G, Katz I, Hellou T, Tietel M, Bryk G, et al. Ferritin as a Marker of Severity in COVID-19 Patients: A Fatal Correlation. Isr Med Assoc J. 2020;22(8):494-500. PMId:33236582
42. Hippchen T, Altamura S, Muckenthaler MU, Merle U. Hypoferremia is associated with increased hospitalization and oxygen demand in COVID-19 patients. HemaSphere. 2020;4(6):e492. https://doi.org/10.1097/HS9.0000000000000492
43. Sonnweber T, Boehm A, Sahanic S, Pizzini A, Aichner M, Sonnweber B, et al. Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: a prospective observational cohort study. Respir Res. 2020;21(1):276. https://doi.org/10.1186/s12931-020-01546-2
44. Tojo K, Sugawara Y, Oi Y, Ogawa F, Higurashi T, Yoshimura Y, et al. The U-shaped association of serum iron level with disease severity in adult hospitalized patients with COVID-19. Sci Rep. 2021;11(1):13431. https://doi.org/10.1038/s41598-021-92921-6
45. Zhou C, Chen Y, Ji Y, He X, Xue D. Increased serum levels of hepcidin and ferritin are associated with severity of COVID-19. Med Sci Monit. 2020;26:e926178. https://doi.org/10.12659/MSM.926178
46. Ahmed S, Ansar Ahmed Z, Siddiqui I, Haroon Rashid N, Mansoor M, Jafri L. Evaluation of serum ferritin for prediction of severity and mortality in COVID-19- A cross sectional study. Ann Med Surg. 2021;63:102163. https://doi.org/10.1016/j.amsu.2021.02.009
47. Raman N, Kv P, Ashta KK, Vardhan V, Thareja S, J M, et al. Ferritin and hemoglobin as predictors of fatal outcome in COVID-19: two sides of the same coin. J Assoc Physicians India. 2021;69(8):11-2. PMId:34472812
48. Yağcı S, Serin E, Acicbe Ö, Zeren M, Odabaşı MS. The relationship between serum erythropoietin, hepcidin, and haptoglobin levels with disease severity and other biochemical values in patients with COVID-19. Int J Lab Hematol. 2021;43 Suppl 1(suppl 1):142-51. https://doi.org/10.1111/ijlh.13479
49. Colafrancesco S, Alessandri C, Conti F, Priori R. COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Autoimmun rev. 2020;19(7):102573. https://doi.org/10.1016/j.autrev.2020.102573
50. Rosário C, Shoenfeld Y. The hyperferritinemic syndrome. Isr Med Assoc J. 2014;16(10):664-5. PMId:25438466