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Review on Iron, Immunity and Intensive Care

  • Chapter
Annual Update in Intensive Care and Emergency Medicine 2014

Part of the book series: Annual Update in Intensive Care and Emergency Medicine ((AUICEM,volume 2014))

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Abstract

Critically ill patients represent a heterogeneous group of patients with a broad array of (co)morbidities. Although highly diverse, one characteristic that applies to practically all critically ill patients is a greatly disturbed iron homeostasis. Iron redistribution is one of the key factors contributing to the development of anemia, which is common on the intensive care unit (ICU). Nearly all patients develop anemia during their ICU stay [1, 2]. Although blood transfusions are independently associated with worse outcome, 40 to 50 % of patients receive one or more transfusions during their ICU stay [1]. This underscores the need to understand ICU-related anemia and find alternative therapies. The field of iron biology has experienced an enormous surge of interest since the discovery of hepcidin in 2001, the key regulator of iron homeostasis [3]. Since then, many investigations have focused on iron homeostasis and its interactions with inflammation, which are numerous. Although most of the pathophysiological mechanisms have been clarified in animal models and chronically inflamed patients, studies in the critically ill are limited. However, although anemia on the intensive care is frequently encountered, awareness of the changes in iron balance that accompany or underlie this anemia is low. This review provides an overview of iron biology during inflammation, and clarifies its relation with microbial virulence, immunity, and oxidative stress reactions. In addition, consequences for the critically ill patient are discussed.

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References

  1. Corwin HL, Gettinger A, Pearl RG et al (2004) The CRIT Study: Anemia and blood transfusion in the critically ill-current clinical practice in the United States. Crit Care Med 32:39–52

    Article  PubMed  Google Scholar 

  2. Thomas J, Jensen L, Nahirniak S, Gibney RT (2010) Anemia and blood transfusion practices in the critically ill: a prospective cohort review. Heart Lung 39:217–225

    Article  PubMed  Google Scholar 

  3. Ganz T (2003) Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102:783–788

    Article  CAS  PubMed  Google Scholar 

  4. Bullen JJ, Rogers HJ, Griffiths E (1978) Role of iron in bacterial infection. Curr Top Microbiol Immunol 80:1–35

    CAS  PubMed  Google Scholar 

  5. Brissot P, Ropert M, Le Lan C, Loréal O (2012) Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 1820:403–410

    Article  CAS  PubMed  Google Scholar 

  6. Andrews NC, Schmidt PJ (2007) Iron homeostasis. Annu Rev Physiol 69:69–85

    Article  CAS  PubMed  Google Scholar 

  7. Nemeth E, Tuttle MS, Powelson J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093

    Article  CAS  PubMed  Google Scholar 

  8. Fleming RE, Ponka P (2012) Iron overload in human disease. N Engl J Med 366:348–359

    Article  CAS  PubMed  Google Scholar 

  9. Zhao N, Zhang AS, Enns CA (2013) Iron regulation by hepcidin. J Clin Invest 123:2337–2343

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Corwin HL, Krantz SB (2000) Anemia of the critically ill: "acute" anemia of chronic disease. Crit Care Med 28:3098–3099

    Article  CAS  PubMed  Google Scholar 

  11. Kochan I (1973) The role of iron in bacterial infections, with special consideration of host-tubercle bacillus interaction. Curr Top Microbiol Immunol 60:1–30

    CAS  PubMed  Google Scholar 

  12. Bullen JJ, Rogers HJ, Spalding PB, Ward CG (2006) Natural resistance, iron and infection: a challenge for clinical medicine. J Med Microbiol 55:251–258

    Article  CAS  PubMed  Google Scholar 

  13. Sazawal S, Black RE, Ramsan M et al (2006) Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 367:133–143

    Article  CAS  PubMed  Google Scholar 

  14. Zager RA (2005) Parenteral iron treatment induces MCP-1 accumulation in plasma, normal kidneys, and in experimental nephropathy. Kidney Int 68:1533–1542

    Article  CAS  PubMed  Google Scholar 

  15. Messaris E, Antonakis PT, Memos N, Chatzigianni E, Leandros E, Konstadoulakis MM (2004) Deferoxamine administration in septic animals: improved survival and altered apoptotic gene expression. Int Immunopharmacol 4:455–459

    Article  CAS  PubMed  Google Scholar 

  16. Paradkar PN, De Domenico I, Durchfort N, Zohn I, Kaplan J, Ward DM (2008) Iron depletion limits intracellular bacterial growth in macrophages. Blood 112:866–874

    Article  CAS  PubMed  Google Scholar 

  17. Hershko C, Peto TE (1988) Deferoxamine inhibition of malaria is independent of host iron status. J Exp Med 168:375–387

    Article  CAS  PubMed  Google Scholar 

  18. Cherayil BJ (2010) Iron and immunity: immunological consequences of iron deficiency and overload. Arch Immunol Ther Exp (Warsz) 58:407–415

    Article  CAS  Google Scholar 

  19. Bubici C, Papa S, Dean K, Franzoso G (2006) Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance. Oncogene 25:6731–6748

    Article  CAS  PubMed  Google Scholar 

  20. Weiss G, Werner-Felmayer G, Werner ER, Grünewald K, Wachter H, Hentze MW (1994) Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J Exp Med 180:969–976

    Article  CAS  PubMed  Google Scholar 

  21. Kaelin WG, Ratcliffe PJ Jr. (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402

    Article  CAS  PubMed  Google Scholar 

  22. De Domenico I, Koening CL, Zhang TY et al (2010) Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest 120:2395–2405

    Article  PubMed Central  PubMed  Google Scholar 

  23. Pagani A, Nai A, Corna G et al (2011) Low hepcidin accounts for the proinflammatory status associated with iron deficiency. Blood 118:736–746

    Article  CAS  PubMed  Google Scholar 

  24. Wang L, Johnson EE, Shi HN, Walker WA, Wessling-Resnick M, Cherayil BJ (2008) Attenuated inflammatory responses in hemochromatosis reveal a role for iron in the regulation of macrophage cytokine translation. J Immunol 181:2723–2731

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Kemp JD, Thorson JA, Gomez F, Smith KM, Cowdery JS, Ballas ZK (1989) Inhibition of lymphocyte activation with anti-transferrin receptor Mabs: a comparison of three reagents and further studies of their range of effects and mechanism of action. Cell Immunol 122:218–230

    Article  PubMed  Google Scholar 

  26. Ned RM, Swat W, Andrews NC (2003) Transferrin receptor 1 is differentially required in lymphocyte development. Blood 102:3711–3718

    Article  CAS  PubMed  Google Scholar 

  27. Oppenheimer SJ (2001) Iron and its relation to immunity and infectious disease. J Nutr 131:616S–633S

    CAS  PubMed  Google Scholar 

  28. Jason J, Archibald LK, Nwanyanwu OC et al (2001) The effects of iron deficiency on lymphocyte cytokine production and activation: preservation of hepatic iron but not at all cost. Clin Exp Immunol 126:466–473

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Melo RA, Garcia AB, Viana SR, Falcão RP (1997) Lymphocyte subsets in experimental hemochromatosis. Acta Haematol 98:72–75

    Article  CAS  PubMed  Google Scholar 

  30. Gutteridge JM (1986) Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides. FEBS Lett 201:291–295

    Article  CAS  PubMed  Google Scholar 

  31. Hampton MB, Kettle AJ, Winterbourn CC (1998) Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 92:3007–3017

    CAS  PubMed  Google Scholar 

  32. Haase M, Bellomo R, Haase-Fielitz A (2010) Novel biomarkers, oxidative stress, and the role of labile iron toxicity in cardiopulmonary bypass-associated acute kidney injury. J Am Coll Cardiol 55:2024–2033

    Article  CAS  PubMed  Google Scholar 

  33. Khamiees M, Raju P, DeGirolamo A, Amoateng-Adjepong Y, Manthous CA (2001) Predictors of extubation outcome in patients who have successfully completed a spontaneous breathing trial. Chest 120:1262–1270

    Article  CAS  PubMed  Google Scholar 

  34. Thygesen K, Alpert JS, White HD et al (2007) Universal definition of myocardial infarction. Eur Heart J 28:2525–2538

    Article  PubMed  Google Scholar 

  35. Rasmussen L, Christensen S, Lenler-Petersen P, Johnsen SP (2011) Anemia and 90-day mortality in COPD patients requiring invasive mechanical ventilation. Clin Epidemiol 3:1–5

    PubMed Central  Google Scholar 

  36. Bateman AP, McArdle F, Walsh TS (2009) Time course of anemia during six months follow up following intensive care discharge and factors associated with impaired recovery of erythropoiesis. Crit Care Med 37:1906–1912

    Article  PubMed  Google Scholar 

  37. Barie PS (2004) Phlebotomy in the intensive care unit: strategies for blood conservation. Crit Care 8:34–36

    Article  Google Scholar 

  38. von Ahnsen N, Muller C, Serke S, Frei U, Eckardt KU (1999) Important role of nondiagnostic blood loss and blunted erythropoietic response in the anemia of medical intensive care patients. Crit Care Med 27:2630–2639

    Article  Google Scholar 

  39. Reggiori G, Occhipinti G, De Gasperi A, Vincent JL, Piagnerelli M (2009) Early alterations of red blood cell rheology in critically ill patients. Crit Care Med 37:3041–3046

    Article  PubMed  Google Scholar 

  40. Rice L, Alfrey CP (2005) The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations. Cell Physiol Biochem 15:245–250

    Article  CAS  PubMed  Google Scholar 

  41. Weiss G, Goodnough LT (2005) Anemia of chronic disease. N Engl J Med 352:1011–1023

    Article  CAS  PubMed  Google Scholar 

  42. van Eijk LT, Kroot JJ, van der Hoeven JG, Swinkels DW, Pickkers P (2011) Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study. Crit Care 15:R9

    Article  PubMed  Google Scholar 

  43. Zarychanski R, Turgeon AF, McIntyre L, Fergusson DA (2007) Erythropoietin-receptor agonists in critically ill patients: a meta-analysis of randomized controlled trials. CMAJ 177:725–734

    Article  PubMed Central  PubMed  Google Scholar 

  44. Hayat A (2008) Safety issues with intravenous iron products in the management of anemia in chronic kidney disease. Clin Med Res 6:93–102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Hoen B, Paul-Dauphin A, Kessler M (2002) Intravenous iron administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients. Clin Nephrol 57:457–461

    Article  CAS  PubMed  Google Scholar 

  46. Torres S, Kuo YH, Morris K, Neibart R, Holtz JB, Davis JM (2006) Intravenous iron following cardiac surgery does not increase the infection rate. Surg Infect (Larchmt) 7:361–366

    Article  Google Scholar 

  47. Pieracci FM, Henderson P, Rodney JR et al (2009) Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness. Surg Infect (Larchmt) 10:9–19

    Article  Google Scholar 

  48. Shander A, Spence RK, Auerbach M (2010) Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? Transfusion 50:719–732

    Article  CAS  PubMed  Google Scholar 

  49. Bellamy MC, Gedney JA (1998) Unrecognised iron deficiency in critical illness. Lancet 352:1903

    Article  CAS  PubMed  Google Scholar 

  50. Swinkels DW, Janssen MC, Bergmans J, Marx JJ (2006) Hereditary hemochromatosis: genetic complexity and new diagnostic approaches. Clin Chem 52:950–968

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

    L. T. van Eijk & P. Pickkers

  2. Department of Laboratory Medicine, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands

    D. W. Swinkels

Authors
  1. L. T. van Eijk
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  2. D. W. Swinkels
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  3. P. Pickkers
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Correspondence to P. Pickkers .

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Editors and Affiliations

  1. Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium

    Jean-Louis Vincent Prof.

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van Eijk, L.T., Swinkels, D.W., Pickkers, P. (2014). Review on Iron, Immunity and Intensive Care. In: Vincent, JL. (eds) Annual Update in Intensive Care and Emergency Medicine 2014. Annual Update in Intensive Care and Emergency Medicine, vol 2014. Springer, Cham. https://doi.org/10.1007/978-3-319-03746-2_2

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  • DOI: https://doi.org/10.1007/978-3-319-03746-2_2

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-03745-5

  • Online ISBN: 978-3-319-03746-2

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