Benefits and risks of iron therapy for chronic anaemias

European Journal of Clinical Investigation, Supplement

Volumn 35, Issue 3, 2005, Pages 36-45

  Weiss, Günter ^a,c   Gordeuk, V R ^b,d  

^a INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^b HOWARD UNIVERSITY   (United States)

^c INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^d HOWARD UNIVERSITY   (United States)

Author keywords

Anaemia; Infection; Inflammation; Iron deficiency; Malignancy; Parenteral iron therapy

Indexed keywords

FERRIC GLUCONATE; FERRITIN; FERROUS SULFATE; IRON; IRON DEXTRAN; PROTOPORPHYRIN; TRANSFERRIN;

ABDOMINAL PAIN; ALLERGIC REACTION; ANAPHYLAXIS; BLOOD TRANSFUSION; CELL PROLIFERATION; CELLULAR IMMUNITY; CHRONIC DISEASE; CONSTIPATION; DIARRHEA; EFFECTOR CELL; ERYTHROPOIESIS; HEME SYNTHESIS; HEMODIALYSIS; HOSPITALIZATION; HUMAN; INFLAMMATION; IRON DEFICIENCY ANEMIA; IRON THERAPY; NAUSEA; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; RISK BENEFIT ANALYSIS; SIDE EFFECT; TISSUE INJURY;

EID: 28944446425     PISSN: 0960135X     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1365-2362.2005.01529.x     Document Type: Review

References (117)

1. Ross EM. Evaluation and treatment of iron deficiency in adults. Nutr Clin Care 2002;5:220-4.
2. Leung AK, Chan KW. Iron deficiency anaemia. Adv Pediatr 2001;48:385-8.
3. Roy CN, Weinstein DA, Andrews NC. 2002 E. Mead Johnson Award for Research in Pediatrics Lecture: the molecular biology of the anaemia of chronic disease: a hypothesis. Pediatr Res 2003;53:507-12.
4. Means RT. Recent developments in the anaemia of chronic disease. Curr Hematol Rep 2003;2:116-21.
5. Weiss G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev 2002;16:87-96.
6. Weiss G. Iron and immunity: a double-edged sword. Eur J Clin Invest 2002;32 (Suppl. 1):70-8.
7. Yang F, Liu XB, Quinones M, Melby PC, Ghio A, Haile DJ. Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J Biol Chem 2002;277:39786-91.
8. Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 2003;101:4148-54.
9. Torti SV, Kwak EL, Miller SC, Miller LL, Ringold GM, Myambo KB et al. The molecular cloning and characterization of ferritin heavy chain, a tumour necrosis factor inducible gene. J Biol Chem 1988;263:12638-44.
10. Rogers JT, Bridges KB, Durmowics G, Glass J, Auron PR, Munro HN. Translational control during the acute phase response. Ferritin synthesis in response to interleukin 1. J Biol Chem 1990;265:14572-8.
11. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anaemia of inflammation. Blood 2003;102:783-8.
12. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-3.
13. Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci U S A 2005;102:1324-8.
14. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271-6.
15. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 2002;99:4596-601.
16. Laftah AH, Ramesh B, Simpson RJ, Solanky N, Bahram S, Schumann K et al. Effect of hepcidin on intestinal iron absorption in mice. Blood 2004;103:3940-4.
17. Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest 2004;113:1251-3.
18. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004;36:77-82.
19. Moura E, Verheul AF, Marx JJ. A functional defect in hereditary haemochromatosis monocytes and monocyte-derived macrophages. Eur J Clin Invest 1998;28:164-73.
20. Graziadei I, Gaggl S, Kaserbacher R, Braunsteiner H, Vogel W. The acute-phase protein alpha 1-antitrypsin inhibits growth and proliferation of human early erythroid progenitor cells (burst-forming units-erythroid) and of human erythroleukemic cells (K562) in vitro by interfering with transferrin iron uptake. Blood 1994;83:260-8.
21. Goodnough LT. Red cell growth factors in patients with chronic anemias. Curr Hematol Rep 2002;1:119-23.
22. Spivak LJ. Iron and the anaemia of chronic disease. Oncology (Huntingt) 2002;16 (Suppl. 10):25-33.
23. Eschbach EW. The anaemia of chronic renal failure: pathophysiology and the effects of recombinant erythropoietin. Kidney Int 1989;35:134-48.
24. Lorenz M, Kletzmayr J, Perschl A, Furrer A, Hörl WH, Sunder-Plassmann G. Anemia and iron deficiencies among long-term renal transplant recipients. J Am Soc Nephrol 2002;13:794-7.
25. Santoro A. Anaemia in renal insufficiency. Rev Clin Exp Hematol Supplement 2002;1:12-20.
26. van Riemsdijk IC, Baan CC, Loonen EH, Knoop CJ, Betonico GN, Niesters HGM et al. T cells activate the tumour necrosis factor-alpha system during hemodialysis, resulting in tachyphylaxis. Kidney Int 2001;59:883-92.
27. Stenvinkel P. The role of inflammation in the anaemia of end-stage renal disease. Nephrol Dial Transplant 2001;16:36-40.
28. Drueke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant 2001;16:S25-8.
29. Hastka J, Lasserre JJ, Schwarzbeck A, Strauch M, Hehlmann R. Zinc protoporphyrin in anaemia of chronic disorders. Blood 1993;81:1200-4.
30. Kuiper-Kramer EP, Huisman CM, Van der Molen-Sinke J, Abbes R, vanEijk HG. The expression of transferrin receptors on erythroblasts in anaemia of chronic disease, myelodysplastic syndromes and iron deficiency. Acta Haematol 1997;97:127-31.
31. Weiss G, Bogdan C, Hentze MW. Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13. J Immunol 1997;158:420-5.
32. Mulero V, Brock JH. Regulation of iron metabolism in murine J774 macrophages: role of nitric oxide dependent and independent pathways following activation with gamma interferon and lipopolysaccharide. Blood 1999;94:2383-9.
33. Punnonen K, Irjala K, Rajamäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89:1052-7.
34. DeMaeyer E, Adiels-Teyman M. The prevalence of anemia in the world. World Health Stat Q 1985;38:303-16.
35. Hallberg L. Perspectives on nutritional iron deficiency. Annu Rev Nutr 2001;21:1-21.
36. Bothwell TH, Charlton RW, Cook JD, Finch CA. Iron Metabolism in Man. Oxford: Blackwell Scientific; 1979.
37. Walter T, Olivaries M, Pizarro F, Munoz C. Iron, anemia and infection. Nutr Rev 1997;55:111-24.
38. Sakiewicz E, Paganini P. The use of iron in patients on chronic dialysis: mistakes and misconceptions. J Nephrol 1998;11:5-15.
39. Bonamico M, Vania A, Monti S, Ballati G, Mariani P, Pitzalis G et al. Iron deficiency in children with celiac disease. J Pediatr Gastroenterol Nutr 1987;6:702-6.
40. Bottaro G, Cataldo F, Rotolo N, Spina M, Corazza GR. The clinical pattern of subclinical/silent celiac disease: an analysis of 1026 consecutive cases. Am J Gastroenterol 1999;94:691-6.
41. Gasche C. Anaemia in IBD: the overlooked villain. Inflamm Bowel Dis 2000;6:142-50.
42. Oldenburg B, Koningsberger JC, Berge Henegouwen GP, Van Asbeck BS, Marx JJ. Iron and inflammatory bowel disease. Aliment Pharmacol Ther 2001;15:429-38.
43. Schreiber S, Wedel S. Diagnosis and treatment of anaemia in inflammatory bowel disease. Inflamm Bowel Dis 1997;3:204-16.
44. Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med 1991;325:687-94.
45. Allen LH. Anemia and iron deficiency: effects on pregnancy outcome. Am J Clin Nutr 2000;71 (5 Suppl.):1280-4.
46. Brugnara C. Iron deficiency and erythropoiesis: new diagnostic approaches. Clin Chem 2003;49:1573-8.
47. Bainton DF, Finch CA. The diagnosis of iron deficiency anemia. Am J Med 1964;37:62-70.
48. Bell H, Skinningsrud A, Raknerud N, Try K. Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver diseases. J Intern Med 1994;236:315-22.
49. Gordeuk VR, Brittenham GM, McLaren GD, Spagnuolo PJ. Hyperferremia in immunosuppressed patients with acute non-lymphocytic leukemia and the risk of infection. J Lab Clin Med 1986;108:466-72.
50. Devasthali SD, Gordeuk VR, Brittenham GM, Bravo JR, Hughes MA, Keating LJ. Bioavailability of carbonyl iron: a randomized double-blind study. Eur J Haematol 1991;46:272-8.
51. McCurdy PR. Oral and parenteral iron therapy: a comparison. JAMA 1965;191:859-62.
52. Barton JC, Barton EH, Bertoli LF, Gothard CH, Sherrer JS. Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am J Med 2000;109:27-32.
53. Faich G, Strobos J. Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans. Am J Kidney Dis 1999;33:464-70.
54. McLaren GD, Gordeuk VR. Iron deficiency. In: Rakel RE, Bope ET, editors. Conn's Current Therapy. Philadelphia: WB. Saunders Co;2002. pp. 355-9.
55. Beutler E, Hoffbrand AV, Cook JD. Iron deficiency and overload. Hematology (Am Soc Hematol Educ Program) 2003:40-61.
56. Michael B, Coyne DW, Fishbane S. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int 2002;61:1830-9.
57. Eide DJ. Metal ion transport in eukaryotic microorganisms: insights from Saccharomyces cerevisiae. Adv Microb Physiol 2000;43:1-38.
58. Genco CA, White-Dixon D. Emerging strategies in microbial haem capture. Mol Microbiol 2001;39:1-11.
59. Locatelli F, Pisoni RL, Combe C, Bommer J, Andreucci VE, Piera L et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2004;19:121-32.
60. Erratum in: Nephrol Dial Transplant 2004;19:1666.
61. Rosen GM, Pou S, Ramos CL, Cohen MS, Britigan BE. Free radicals and phagocytic cells. FASEB J 1995;9:200-5.
62. Gaenzer H, Marschang P, Sturm W, Neumayr G, Vogel W, Patsch J et al. Association between increased iron stores and impaired endothelial function in patients with hereditary hemochromatosis. J Am Coll Cardiol 2002;40:2189-94.
63. Sullivan LJ. Iron therapy and cardiovascular disease. Kidney Int Suppl 1999;69:S135-7.
64. Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803-11.
65. Lee NT, Richardson DR. The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta 2002;1603:31-46.
66. Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med 1988;319:1047-52.
67. Weinberg ED. The role of iron in cancer. Eur J Cancer Prev 1996;5:19-36.
68. Weinberg ED. Iron loading and disease surveillance. Emerg Infect Dis 1999;5:346-50.
69. Gordon S. Alternative activation of macrophages. Nat Immunol Rev 2003;3:133-46.
70. Weiss G, Fuchs D, Hausen A, Reibnegger G, Werner ER, Werner-Felmayer G et al. Iron modulates interferon-γ effects in the human myelomonocytic cell line THP-1. Exp Hematol 1992;20:605-10.
71. Recalcati S, Pometta R, Levi S, Conte D, Cairo G. Response of monocyte iron regulatory protein activity to inflammation: abnormal behavior in genetic hemochromatosis. Blood 1998;91:2565-72.
72. Oexle HA, Kaser A, Most J, Bellmann-Weiler R, Werner ER, Werner-Felmayer G et al. Pathways for the regulation of interferon-gamma-inducible genes by iron in human monocytic cells. J Leukoc Biol 2003;74:287-94.
73. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 1991;5:2516-22.
74. Murr C, Wiedner B, Wirleitner B, Fuchs D. Neopterin as a marker for immune system activation. Gurr Drug Metab 2002;3:175-87.
75. Alford CE, King TE, Campell PA. Role of transferrin, transferrin receptors, and iron in listericidal activity. J Exp Med 1991;174:459-66.
76. Barnewell RE, Rikihisa Y. Abrogation of gamma interferon-induced inhibition of Ehrlichia chaffeensis infection in human monocytes with transferrin iron. Infect Immun 1994;62:4804-10.
77. Byrd TF, Horwitz MA. Lactoferrin inhibits or promotes Legionella pneumophila intracellular multiplication in nonactivated and interferon-γ activated human monocytes depending upon its degree of iron saturation: iron-lactoferrin and nonphysiologic iron chelates reverse monocyte action against Legionella pneumophila. J Clin Invest 1991;88:1103-12.
78. Weiss G, Werner-Felmayer G, Werner ER, Grünewald K, Wachter H, Hentze MW. Iron regulates nitric oxide synthase activity by controlling nuclear transcription. J Exp Med 1994;180:969-76.
79. Bogdan C. Nitric oxide and the immune response. Nat Immunol 2001;2:907-16.
80. Blackwell JM, Searle S, Goswami T, Miller EN. Understanding the multiple functions of NRAMP1. Microbes Infect 2000;2:317-21.
81. Forbes JR, Gros P. Divalent metal transport by NRAMP proteins at the interface to host-pathogen interaction. Trends Microbiol 2001;9:397-403.
82. Baker ST, Barton CH, Biggs TE. A negative autoregulatory link between Nramp1 function and expression. J Leukoc Biol 2000;67:501-7.
83. Biggs TE, Baker ST, Bothman MS, Dhital A, Barton CH, Perry HV. Nramp1 modulates iron homeostasis in vivo and in vitro: evidence for a role in cellular iron release involving de-acidification of intracellular vesicles. Eur J Immunol 2001;31:2060-70.
84. Asp169. J Leukoc Biol 1999;66:113-9.
85. Mencacci A, Cenci F, Boelaert JR, Bucci P, Mosci P, Fe d'Ostiani C et al. Iron overload alters innate and T helper cell responses to Candida albicans in mice. J Infect Dis 1997;175:1467-76.
86. Thuma PE, Weiss G, Herold M, Gordeuk VR. Serum neopterin, interleukin-4, and interleukin-6 concentrations in cerebral malaria patients and the effect of iron chelation therapy. Am J Trop Med Hyg 1996;154:164-8.
87. Gordeuk V, Thuma P, Brittenham G, McLaren G, Parry D, Backenstose A et al. Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med 1992;327:1473-7.
88. Hoen B. Iron and infection: clinical experience. Am J Kidney Dis 1999;34:S30-4.
89. De Sousa M, Reimao R, Porto G, Grady RW, Hilgartner MW, Giardina P. Iron and lymphocytes: reciprocal regulatory interactions. Curr Stud Hematol Blood Transfus 1992;58:171-7.
90. Omara FO, Blakley BR. The effects of iron deficiency and iron overload on cell mediated immunity in the mouse. Br J Nutr 1994;72:899-909.
91. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nut 2001;131:S616-33.
92. Sunder-Plassmann G, Patruta SI, Hörl WH. Pathobiology of the role of iron in infection. Am J Kidney Dis 1999;34:25-9.
93. Hoepelman IM, Jaarsma EY, Verhoef J, Marx JJ. Effect of iron on polymorphonuclear granulocyte phagocytic capacity. Role of oxidation state and effect of ascorbic acid. Br J Haematol 1988;70:495-500.
94. Patruta SI, Edlinger R, Sunder-Plassmann G, Hörl WH. Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency. J Am Soc Nephrol 1998;9:655-63.
95. VanAsbeck BS, Marx JJ, Struyvenberg A, vanKats JH, Verhoef J. Deferoxamine enhances phagocytic function of human polymorphonuclear phagocytes. Blood 1984;62:714-20.
96. Gasche C, Dejaco C, Waldhoer T, Tillinger W, Reinisch W, Fueger GF et al. Intravenous iron and erythropoietin for anaemia associated with Crohn disease. A randomized, controlled trial. Ann Intern Med 1997;26:782-7.
97. Kaltwasser JP, Kessler U, Gottschalk R, Stucki G. Effect of recombinant human erythropoietin and intravenous iron on anaemia and disease activity in rheumatoid arthritis. J Rheumatol 2001;28:2430-6.
98. Gasche C, Waldhoer T, Feichtenschlager T, Male C, Mayer A, Mittermaier C et al. Prediction of response to iron sucrose in inflammatory bowel disease-associated anaemia. Am J Gastroenterol 2001;96:2382-7.
99. Gordeuk VR, Delanghe JR, Langlois MR, Boelaert JR. Iron status and the outcome of HIV infection: an overview. J Clin Virol 2001;20:111-5.
100. Kramer A, Biggar RJ, Hampl H, Friedman RM, Fuchs D, Wachter H et al. Immunologic markers of progression to acquired immunodeficiency syndrome are time-dependent and illness-specific. Am J Epidemiol 1992;136:71-80.
101. Sullivan P. Associations of anaemia, treatment for anaemia, and survival in patients with human immunodeficiency virus infection. J Infect Dis 2002;185 (Suppl. 2):S138-42.
102. Hörl WH. Consensus statement. How to diagnose and correct iron deficiency during rhEpo therapy. A consensus report. Nephrol Dial Transplant 1996;11:246-50.
103. Macdougall IC, Cavill I, Hulme B. Detection of functional iron deficiency during erythropoietin treatment. BMJ 1995;304:225-6.
104. Collins AJ, Ma JZ, Ebben J. Impact of hematocrit on morbidity and mortality. Semin Nephrol 2000;20:345-9.
105. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoeitin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995;26:41-6.
106. Kaltwasser JP, Gottschalk R. Erythropoietin and iron. Kidney Int 1999;69:S49-56.
107. Macdougall IC. Strategies for iron supplementation: oral versus intravenous. Kidney Int 1999;55:S61-6.
108. Murphy ST, Parfrey PS. The impact of anaemia correction on cardiovascular disease in end stage renal disease. Semin Nephrol 2000;20:350-5.
109. Sunder-Plassmann G, Hörl WH. Importance of iron supply for erythropoietin therapy. Nephrol Dial Transplant 1995;10:2070-6.
110. Yee L, Besarab A. Iron sucrose: the oldest iron therapy becomes new. Am J Kidney Dis 2002;40:1111-21.
111. Weiss G, Meusburger E, Radacher G, Garimorth K, Neyer U, Mayer G. Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin. Kidney Int 2003;64:572-8.
112. Descamps-Latscha B, Herbelin A, Nguyen AT. Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes. J Immunol 1995;154:882-92.
113. Glaspy J, Cavill I. Role of iron in optimizing responses of cancer patients to erythropoietin. Oncology 1999;13:461-73.
114. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron and erythropoiesis. Blood 2000;96:823-33.
115. Weiss G, Houston T, Kastner S, Grünewald K, Brock J. Regulation of cellular iron metabolism by erythropoietin: activation of iron regulatory protein and up-regulation of transferrin-receptor in erythroid cells. Blood 1997;89:680-7.
116. Busfield SJ, Tilbrook PA, Callus BA, Spandaccini A, Kuhn LC, Klinken PS. Complex regulation of transferrin receptors during erythropoietin-induced differentiation of J2E erythroid cells. Eur J Biochem 1997;249:77-85.
117. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:1011-23.