Clinical consequences of iron overload from chronic red blood cell transfusions, its diagnosis, and its management by chelation therapy

Transfusion

Volumn 50, Issue 5, 2010, Pages 1144-1155

  Shander, Aryeh ^a,b   Sazama, Kathleen ^a,b  

^a ENGLEWOOD HOSPITAL AND MEDICAL CENTER   (United States)

^b LifeSouth Community Blood Centers   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DEFERASIROX; DEFERIPRONE; DEFEROXAMINE MESYLATE; FERRIC ION; FERRITIN; IRON;

AGRANULOCYTOSIS; ANEMIA; ARTHRALGIA; BONE DYSPLASIA; CHELATION THERAPY; CLINICAL TRIAL; DRUG COST; DRUG HALF LIFE; ERYTHROCYTE TRANSFUSION; ERYTHROCYTE VOLUME; EYE TOXICITY; FERRITIN BLOOD LEVEL; GASTRIC INTOLERANCE; GASTROINTESTINAL SYMPTOM; GROWTH RETARDATION; HUMAN; HYPERFERRITINEMIA; IRON ABSORPTION; IRON METABOLISM; IRON OVERLOAD; IRON STORAGE; IRON TRANSPORT; LABORATORY TEST; LIVER BIOPSY; LIVER DYSFUNCTION; MUSCULOSKELETAL PAIN; NEPHROTOXICITY; NEUROTOXICITY; NEUTROPENIA; OTOTOXICITY; PATIENT COMPLIANCE; PHLEBOTOMY; QUALITY OF LIFE; RASH; REVIEW; STOMACH DISEASE; THALASSEMIA; ZINC DEFICIENCY;

BIOPSY; ERYTHROCYTE TRANSFUSION; HUMANS; IRON; IRON CHELATING AGENTS; IRON OVERLOAD; LIVER;

EID: 77951677283     PISSN: 00411132     EISSN: 15372995     Source Type: Journal    
DOI: 10.1111/j.1537-2995.2009.02551.x     Document Type: Review

References (96)

1. Bleackley MR, Wong AY, Hudson DM, Wu CH, Macgillivray RT. Blood iron homeostasis: newly discovered proteins and iron imbalance. Transfus Med Rev 2009 23 : 103 23.
2. Zhang AS, Enns CA. Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J Biol Chem 2009 284 : 711 5.
3. Brittenham GM, Badman DG. Noninvasive measurement of iron: report of an NIDDK workshop. Blood 2003 101 : 15 9.
4. Andrews NC. Forging a field: the golden age of iron biology. Blood 2008 112 : 219 2.
5. Nemeth E. Iron regulation and erythropoiesis. Curr Opin Hematol 2008 15 : 169 75. (Pubitemid 351507567)
6. Wrighting DM, Andrews NC. Iron homeostasis and erythropoiesis. Curr Topics Dev Biol 2008 82 : 141 67.
7. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999 341 : 1986 95.
8. Malcovati L. Impact of transfusion dependency and secondary iron overload on the survival of patients with myelodysplastic syndromes. Leuk Res 2007 31 (Suppl 3 S2 6. (Pubitemid 350137500)
9. Porter JB. Practical management of iron overload. Br J Haematol 2001 115 : 239 52.
10. Fleming RE, Bacon BR. Orchestration of iron homeostasis. N Engl J Med 2005 352 : 1741 4.
11. Ganz T. Molecular control of iron transport. J Am Soc Nephrol 2007 18 : 394 400. (Pubitemid 46193304)
12. Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009 113 : 5277 86.
13. Chen J, Enns CA. The cytoplasmic domain of transferrin receptor 2 dictates its stability and response to holo-transferrin in Hep3B cells. J Biol Chem 2007 282 : 6201 9. (Pubitemid 47100900)
14. Fleming MD. The regulation of hepcidin and its effects on systemic and cellular iron metabolism. Hematology Am Soc Hematol Educ Program 2008 2008 : 151 8.
15. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006 38 : 531 9.
16. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997 89 : 739 61.
17. Porter J. Pathophysiology of iron overload. Hematol Oncol Clin 2005 19 (Suppl 1 7 12.
18. Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, Martin M, Koren G, Cohen AR. Survival in medically treated patients with homozygous b-thalassemia. N Engl J Med 1994 331 : 574 8. (Pubitemid 24265699)
19. Darbari DS, Kple-Faget P, Kwagyan J, Rana S, Gordeuk VR, Castro O. Circumstances of death in adult sickle cell disease patients. Am J Hematol 2006 81 : 858 63. (Pubitemid 44682188)
20. Siah CW, Ombiga J, Adams LA, Trinder D, Olynyk JK. Normal iron metabolism and the pathophysiology of overload disorders. Clin Biochem Rev 2006 27 : 5 16.
21. Conte D, Piperno A, Mandelli C, Fargion S, Cesana M, Brunelli L, Ferrario L, Velio P, Zaramella MG, Tiribelli C, Fiorelli G, Bianchi PA. Clinical, biochemical and histological features of primary haemochromatosis: a report of 67 cases. Liver 1986 6 : 310 5.
22. Schwartz KA, Li Z, Schwartz DE, Cooper TG, Braselton WE. Earliest cardiac toxicity induced by iron overload selectively inhibits electrical conduction. J Appl Physiol 2002 93 : 746 51. (Pubitemid 34810241)
23. Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of l-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med 2006 84 : 349 64. (Pubitemid 43673610)
24. Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J. Body iron metabolism and pathophysiology of iron overload. Int J Hematol 2008 88 : 7 15.
25. Crichton RR, Ward RJ. An overview of iron metabolism: molecular and cellular criteria for the selection of iron chelators. Curr Med Chem 2003 10 : 997 1004.
26. Goodnough LT, Bravo J, Hsueh Y, Keating L, Brittenham GM. Red blood cell volume in autologous and homologous blood units: implications for risk/benefit assessment for autologous blood "crossover" and directed blood transfusion. Transfusion 1989 29 : 821 2. (Pubitemid 20008696)
27. National Heart, Lung, and Blood Institute. The management of sickle cell disease. 4th ed.
28. Smiley D, Dagogo-Jack S, Umpierrez G. Therapy insight: metabolic and endocrine disorders in sickle cell disease. Nat Clin Pract Endocrinol Metab 2008 4 : 102 9. (Pubitemid 351156887)
29. Zeller T, Müller JT, Kretschmer V. Flow-cytometric determination of survival time and 24-hour recovery of transfused red blood cells. Transfus Med Hemother 2003 30 : 14 9. (Pubitemid 37499839)
30. Piga A, Longo F, Duca L, Roggero S, Vinciguerra T, Calabrese R, Hershko C, Cappellini MD. High nontransferrin bound iron levels and heart disease in thalassemia major. Am J Hematol 2009 84 : 29 33.
31. Ballas SK. Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease. Semin Hematol 2001 38 (Suppl 1 30 6.
32. Sanz G, Nomdedeu B, Such E, Bernal T, Belkaid M, Ardanaz MT, Marco V, Pedro C, Ramos F, del Cañizo MC, Luño E, Cobo F, Carbonell F, Gomez V, Muñoz JA, Amigo ML, Bailen A, Bonadad S, Tormo M, Andreu R, Arrizabalaga B, Arilla MJ, Bueno J, Requena MJ, Bargay J, Sanchez J, Senent L, Arenillas L, de Paz R, Xicoy B, Duarte R, Cervera J. Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome. Presented at the Annual Meeting of the American Society of Hematology. December 6-9, 2008; San Francisco, California. Abstract 640.
33. Cazzola M, Malcovati L. Myelodysplastic syndromes - coping with ineffective hematopoiesis. N Engl J Med 2005 352 : 536 8. (Pubitemid 40204666)
34. Malcovati L, Della Porta MG, Cazzola M. Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica 2006 91 : 1588 90. (Pubitemid 46032954)
35. Garcia-Manero G, Shan J, Faderl S, Cortes J, Ravandi F, Borthakur G, Wierda WG, Pierce S, Estey E, Liu J, Huang X, Kantarjian H. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia 2008 22 : 538 43. (Pubitemid 351386723)
36. Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP, Soiffer RJ, Antin JH. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007 109 : 4586 8. (Pubitemid 46743431)
37. Isom HC, McDevitt EI, Moon MS. Elevated hepatic iron: a confounding factor in chronic hepatitis C. Biochim Biophys Acta 2009 1790 : 650 62.
38. Jensen PD, Jensen FT, Christensen T, Nielsen JL, Ellegaard J. Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias. Blood 2003 101 : 91 6. (Pubitemid 36025892)
39. Kew MC. Hepatic iron overload and hepatocellular carcinoma. Cancer Lett 2008 Dec 9 [Epub ahead of print GA, Mossanda KS, Kew MC, Paterson AC, Kahler-Venter CP, Siziba K. Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity. Toxicology 2006 219 : 41 52.
40. Leonardi B, Margossian R, Colan SD, Powell AJ. Relationship of magnetic resonance imaging estimation of myocardial iron to left ventricular systolic and diastolic function in thalassemia. JACC Cardiovasc Imaging 2008 1 : 572 8.
41. Wood JC, Enriquez C, Ghugre N, Otto-Duessel M, Aguilar M, Nelson MD, Moats R, Coates TD. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci 2005 1054 : 386 95. (Pubitemid 43031046)
42. Goldberg SL, Mody-Patel N, Chen E. Clinical and economic consequences of myelodysplastic syndromes in the United States: an analysis of the Medicare database. Blood (ASH Annual Meeting Abstracts) 2008 112 : 636.
43. Di Tucci AA, Matta G, Deplano S, Gabbas A, Depau C, Derudas D, Caocci G, Agus A, Angelucci E. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica 2008 93 : 1385 8.
44. Ong CK, Lim SL, Tan WC, Ong EE, Goh AS. Endocrine complications in transfusion dependent thalassaemia in Penang Hospital. Med J Malaysia 2008 63 : 109 12.
45. Toumba M, Serqis A, Kanaris C, Skordis N. Endocrine complications in patients with thalassaemia major. Pediatr Endocrinol Rev 2007 5 : 646 8.
46. Vichinsky E. Consensus document for transfusion-related iron overload. Semin Hematol 2001 38 (Suppl 1 2 4. (Pubitemid 32110266)
47. Morrison ED, Brandhagen DJ, Phatak PD, Barton JC, Krawitt EL, El-Serag HG, Gordon SC, Galan MV, Tung BY, Ioannou GN, Kowdley KV. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 2003 138 : 627 33.
48. Perifanis V, Economou M, Christoforides A, Koussi A, Tsitourides I, Athanassiou-Metaxa M. Evaluation of iron overload in beta-thalassemia patients using magnetic resonance imaging. Hemoglobin 2004 28 : 45 9. (Pubitemid 38263732)
49. Shalitin S, Carmi D, Weintrob N, Phillip M, Miskin H, Kornreich L, Zilber R, Yaniv I, Tamary H. Serum ferritin level as a predictor of impaired growth and puberty in thalassemia major patients. Eur J Hematol 2005 74 : 93 100. (Pubitemid 40175311)
50. Herbert V, Jayatilleke E, Shaw S, Rosman AS, Giardina P, Grady RW, Bowman B, Gunter EW. Serum ferritin iron, a new test, measures human body iron stores unconfounded by inflammation. Stem Cells 1997 15 : 291 6. (Pubitemid 27315333)
51. Khumalo H, Gomo ZA, Moyo VM, Gordeuk VR, Saungweme T, Rouault TA, Gangaidzo IT. Serum transferrin receptors are decreased in the presence of iron overload. Clin Chem 1998 44 : 40 4. (Pubitemid 28042464)
52. Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI - labile plasma iron in iron overload. Best Pract Res Clin Haematol 2005 18 : 277 87. (Pubitemid 40298370)
53. Jacobs EM, Hendriks JC, van Tits BL, Evans PJ, Breuer W, Liu DY, Jansen EH, Jauiainen K, Sturm B, Porter JB, Scheiber-Mojdehkar B, von Bonsdorff L, Cababtchik ZI, Hider RC, Swinkels DW. Results of an international round robin for the quantification of serum non-transferrin-bound iron: need for defining standardization and a clinically relevant isoform. Anal Biochem 2005 341 : 241 50. (Pubitemid 40724808)
54. Vermylen C. What is new in iron overload? Eur J Pediatr 2008 167 : 377 81. (Pubitemid 351322481)
55. Li CK, Chik KW, Lam CW, To KF, Yu SC, Lee V, Shing MM, Cheung AY, Yuen PM. Liver disease in transfusion dependent thalassaemia major. Arch Dis Child 2002 86 : 344 7. (Pubitemid 34478230)
56. Guyader D, Gandon Y. Quantification of iron overload. Bull Acad Natl Med 2000 184 : 337 47. (Pubitemid 29481812)
57. Jensen PD. Evaluation of iron overload. Br J Haematol 2004 124 : 697 711.
58. Mavrogeni SI, Markussis V, Kaklamanis L, Tsiapras D, Paraskevaidis I, Karavolias G, Karagiorga M, Douskou M, Cokkinos DV, Kremastinos DT. A comparison of magnetic resonance imaging and cardiac biopsy in the evaluation of heart iron overload in patients with beta-thalassemia major. Eur J Haematol 2005 75 : 241 7. (Pubitemid 41153105)
59. Park J, Ohyashiki K, Akata S, Takara K, Uno R, Kahizaki D, Miyazawa K, Kimura Y, Tokuuye K. Evaluation of cardiac iron overload in transfusion- dependent adult marrow failure patients by magnetic resonance imaging. Leuk Res 2009 33 : 756 8.
60. Fischer R, Piga A, Harmatz P, Nielsen P. Monitoring long-term efficacy of iron chelation treatment with biomagnetic liver susceptometry. Ann N Y Acad Sci 2005 1054 : 350 7. (Pubitemid 43031042)
61. Avrin WF, Kumar S. Noninvasive liver-iron measurements with a room-temperature susceptometer. Physiol Meas 2007 28 : 349 61. (Pubitemid 46540439)
62. Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE, Allen CJ, Farrell DE, Harris JW. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994 331 : 567 73.
63. Olson LJ, Edwards WD, Mccall JT, Ilstrup DM, Gersh BJ. Cardiac iron deposition in idiopathic hemochromatosis: histologic and analytic assessment of 14 hearts from autopsy. J Am Coll Cardiol 1987 10 : 1239 43.
64. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, Levine GN, Narula J, Starling RC, Towbin J, Virmani R. The role of endomyocardial biopsy in the management of cardiovascular disease. A Scientific Statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Circulation 2009 116 : 2216 33. (Pubitemid 350060359)
65. Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol 2008 88 : 24 9.
66. Araújo A, Drelichman G, Cançado RD, Watman N, Magalhães SM, Duhalde M, Marfil J, Feliú A, Clementina L, Linares Ballesteros A, Di Stefano M, Latin American Experts Panel. Management of transfusional iron overload in Latin America: current outlook and expert panel recommendations. Hematology 2009 14 : 22 32.
67. Tavill AS. Diagnosis and management of hemochromatosis. AASLD Practice Guidelines. Hepatology 2001 33 : 1321 7.
68. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology - v.1.2009: myelodysplastic syndromes.
69. Gattermann N, Porter J, Lopes LF, Seymour J. Consensus statement on iron overload in myelodysplastic syndromes. Hematol Oncol Clin 2005 19 (Suppl 1 18 25.
70. Mittelman M, Lugassy G, Merkel D, Tamary H, Sarid N, Rachmilewitz E, Hershko C. Iron chelation therapy in patients with myelodysplastic syndromes: consensus conference guidelines. Isr Med Assoc J 2008 10 : 374 6. (Pubitemid 351902940)
71. Gattermann N. Guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Leuk Res 2007 31 (Suppl 3 S10 5. (Pubitemid 350137502)
72. McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, Dickson R, Dundar Y, Greenhalgh J, Modell B, Olujohungbe A, Telfer P, Walley T. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anemia: a systematic review and economic evaluation. Health Technol Assess 2009 13 : 1 144.
73. Kalinowsky DS, Richardson DR. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev 2005 57 : 547 83.
74. Hershko C, Link G, Konijn AM, Cabantchik ZI. Objectives and mechanism of iron chelation therapy. Ann N Y Acad Sci 2005 1054 : 124 35. (Pubitemid 43031017)
75. Barton JC. Chelation therapy for iron overload. Curr Gastroenterol Rep 2007 9 : 74 82.
76. Kwiatkowski JL. Oral iron chelators. Pediatr Clin North Am 2008 55 : 461 82.
77. Cappellini MD, Piga A. Current status in iron chelation in hemoglobinopathies. Curr Mol Med 2008 8 : 663 74.
78. Novartis. Desferal (deferoxamine mesylate for injection USP) prescribing information.
79. Cohen AR. New advances in iron chelation therapy. Hematology 2006 1 : 42 7.
80. Porter JB. Concepts and goals in the management of transfusional iron overload. Am J Hematol 2007 82 (Suppl 1136 9.
81. Delea TE, Edelsberg J, Sofrygin O, Thomas SK, Baladi JF, Phatak PD, Coates TD. Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review. Transfusion 2007 47 : 1919 29. (Pubitemid 47438560)
82. Cianciulli P. Treatment of iron overload in thalassemia. Pediatr Endocrinol Rev 2008 6 (Suppl 1 208 13.
83. Cario H, Janka-Schaub G, Janssen G, Jarisch A, Strauss G, Kohne E. Recent developments in iron chelation therapy. Klin Pediatr 2007 219 : 158 65. (Pubitemid 46983779)
84. Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F, Filosa A, Romeo MA, Magnano C, Caruso V, Argento C, Gerardi C, Campisi S, Violi P, Malizia R, Cianciulli P, Rizzo M, D'Ascola DG, Quota A, Prossomariti L, Fidone C, Rigano P, Pepe A, D'Amico G, Morabito A, Gluud C. Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassemia major patients: a randomized clinical trial. Br J Haematol 2009 145 : 245 54.
85. Goldberg SL. Novel treatment options for transfusional iron overload in patients with myelodysplastic syndromes. Leuk Res 2007 31 (Suppl 3 S16 S22.
86. Raphael JL, Bernhardt MB, Mahoney DH, Mueller BU. Oral iron chelation and the treatment of iron overload in a pediatric hematology center. Pediatr Blood Cancer 2009 52 : 616 20.
87. ®) in patients with transfusion-dependent anemias: 1-year results from the large, prospective, multicenter EPIC study. Presented at the Annual Meeting of the American Society of Hematology. December 6-9, 2008; San Francisco, California. Poster III-957.
88. Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev 2008 22 (Suppl 2 S35 S41.
89. ®) in preventing cardiac iron overload in b-thalassemia patients with normal baseline cardiac iron: results from the cardiac substudy of the EPIC trial. Presented at the Annual Meeting of the American Society of Hematology. December 6-9, 2008; San Francisco, California. Poster III-956.
90. Metzgeroth G, Dinter D, Schultheis B, Dorn-Beineke A, Lutz K, Leismann O, Hehlmann R, Hastka J. Deferasirox in MDS patients with transfusion-caused iron overload - a phase-II study. Ann Hematol 2009 88 : 301 10.
91. Wimazal F, Nösslinger T, Baumgartner C, Sperr WR, Pfeilstöcker M, Valent P. Deferasirox induces regression of iron overload in patients with myelodysplastic syndromes. Eur J Clin Invest 2009 39 : 406 11.
92. Taher A, El-Beshlawy A, Elalfy MS, Al Zir K, Daar S, Damanhouri G, Habr D, Kriemler-Krahn U, Hmissi A, Al Jefri A. Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with beta-thalassemia: the ESCALATOR study. Eur J Hematol 2009 82 : 458 65.
93. Vanorden HE, Hagemann TM. Deferasirox - an oral agent for chronic iron overload. Ann Pharmacother 2006 40 : 1110 7. (Pubitemid 43886969)
94. Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, Files B, Hassell K, Kelly P, Wilson F, Bernaudin F, Forni GL, Okpala I, Ressayre-Djaffer C, Alberti D, Holland J, Marks P, Fung E, Fischer R, Mueller BU, Coates T, the Deferasirox in Sickle Cell Investigators. A randomized comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2006 136 : 501 8. (Pubitemid 46046309)
95. Karnon J, Tolley K, Oyee J, Jewitt K, Ossa D, Akehurst R. Cost-utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom. Curr Med Res Opin 2008 24 : 1609 21. (Pubitemid 351929059)
96. Delea TE, Sofrygin O, Thomas SK, Baladi JF, Phatak PD, Coates TD. Cost effectiveness of once-daily oral chelation therapy with deferasirox versus infusional deferoxamine in transfusion-dependent thalassemia patients: US healthcare system perspective. Pharmacoeconomics 2007 25 : 329 42. (Pubitemid 46607383)