The anemia of inflammation and chronic disease

Iron Physiology and Pathophysiology in Humans

Volumn , Issue , 2012, Pages 303-320

  Roy, Cindy N ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Anemia; Chronic disease; Erythropoiesis; Erythropoietin; Ferritin; Infection; Inflammation; Macrophage; Reticuloendothelial; Transferrin receptor

Indexed keywords

EID: 84890552617     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-1-60327-485-2_15     Document Type: Chapter

References (192)

1. Cartwright GE. The anemia of chronic disorders. Semin Hematol. 1966;3:351-75.
2. Giannouli S, Voulgarelis M, Ziakas PD, Tzioufas AG. Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment. Ann Rheum Dis. 2006;65:144-8.
3. Robinson Y, Hostmann A, Matenov A, Ertel W, Oberholzer A. Erythropoiesis in multiply injured patients. J Trauma. 2006;61:1285-91.
4. Anand I, McMurray JJ, Whitmore J, et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004;110:149-54.
5. van der Putten K, Braam B, Jie KE, Gaillard CA. Mechanisms of disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Clin Pract Nephrol. 2008;4:47-57.
6. Ershler WB. Biological interactions of aging and anemia: a focus on cytokines. J Am Geriatr Soc. 2003;51(3 Suppl):S18-21.
7. Chaves PH, Xue QL, Guralnik JM, Ferrucci L, Volpato S, Fried LP. What constitutes normal hemoglobin concentration in community-dwelling disabled older women? J Am Geriatr Soc. 2004;52:1811-6.
8. Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002;50:1268-71.
9. Calis JC, Phiri KS, Faragher EB, et al. Severe anemia in Malawian children. N Engl J Med. 2008;358:888-99.
10. Cartwright GE, Lauritsen MA, Jones PJ, Merrill IM, Wintrobe MM. The anemia of infection. I. Hypoferremia, hypercupremia, and alterations in porphyrin metabolism in patients. J Clin Invest. 1946;25:65-80.
11. Sullivan PS, Hanson DL, Chu SY, Jones JL, Ward JW. Epidemiology of anemia in human immunodeficiency virus (HIV)-infected persons: results from the multistate adult and adolescent spectrum of HIV disease surveillance project. Blood. 1998;91:301-8.
12. Muller HM, Horina JH, Kniepeiss D, et al. Characteristics and clinical relevance of chronic anemia in adult heart transplant recipients. Clin Transpl. 2001;15:343-8.
13. Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21:907-27.
14. Burling F, Ng J, Thein H, Ly J, Marshall MR, Gow P. Ethnic, clinical and immunological factors in systemic lupus erythematosus and the development of lupus nephritis: results from a multi-ethnic New Zealand cohort. Lupus. 2007;16:830-7.
15. AlSaleh J, Jassim V, ElSayed M, Saleh N, Harb D. Clinical and immunological manifestations in 151 SLE patients living in Dubai. Lupus. 2008;17:62-6.
16. Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med. 2004;116(Suppl. 7A):44S-9.
17. Revel-Vilk S, Tamary H, Broide E, et al. Serum transferrin receptor in children and adolescents with inflammatory bowel disease. Eur J Pediat. 2000;159:585-9.
18. Bron D, Meuleman N, Mascaux C. Biological basis of anemia. Semin Oncol. 2001;28(2 Suppl. 8):1-6.
19. Birgegard G, Aapro MS, Bokemeyer C, et al. Cancer-related anemia: pathogenesis, prevalence and treatment. Oncology. 2005;68(Suppl. 1):3-11.
20. Harrison L, Shasha D, Shiaova L, White C, Ramdeen B, Portenoy R. Prevalence of anemia in cancer patients undergoing radiation therapy. Semin Oncol. 2001;28(2 Suppl. 8):54-9.
21. Dunn A, Carter J, Carter H. Anemia at the end of life: prevalence, significance, and causes in patients receiving palliative care. J Pain Sympt Manag. 2003;26:1132-9.
22. Agarwal AK. Practical approach to the diagnosis and treatment of anemia associated with CKD in elderly. J Am Med Direct Assoc. 2006;7(9 Suppl):S7-12.
23. de Silva R, Rigby AS, Witte KK, et al. Anemia, renal dysfunction, and their interaction in patients with chronic heart failure. Am J Cardiol. 2006;98:391-8.
24. Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004;104:2263-8.
25. Semba RD, Ricks MO, Ferrucci L, et al. Types of anemia and mortality among older disabled women living in the community: the women's health and aging study I. Aging Clin Exp Res. 2007;19:259-64.
26. Zakai NA, Katz R, Hirsch C, et al. A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the cardiovascular health study. Arch Intern Med. 2005;165:2214-20.
27. Chasis JA. Erythroblastic islands: specialized microenvironmental niches for erythropoiesis. Curr Opin Hematol. 2006;13:137-41.
28. Kawane K, Fukuyama H, Kondoh G, et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science. 2001;292:1546-9.
29. Graber SE, Krantz SB. Erythropoietin and the control of red cell production. Annu Rev Med. 1978;29:51-66.
30. Koury MJ, Sawyer ST, Brandt SJ. New insights into erythropoiesis. Curr Opin Hematol. 2002;9:93-100.
31. Iacopetta BJ, Morgan EH, Yeoh GC. Transferrin receptors and iron uptake during erythroid cell development. Biochim Biophys Acta. 1982;687:204-10.
32. Horton MA. Expression of transferrin receptors during erythroid maturation. Exp Cell Res. 1983;144:361-6.
33. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396-9.
34. Ponka P, Lok CN. The transferrin receptor: role in health and disease. Int J Biochem Cell Biol. 1999;31:1111-37.
35. Jandl JH. Transfer of iron from serum iron-binding protein to human reticylocytes. J Clin Invest. 1959;38:161-85.
36. Bernstein SE. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med. 1987;110:690-705.
37. Beguin Y. Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta. 2003;329:9-22.
38. Bratosin D, Mazurier J, Tissier JP, et al. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. A review. Biochimie. 1998;80:173-95.
39. Schroit AJ, Madsen JW, Tanaka Y. In vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes. J Biol Chem. 1985;260:5131-8.
40. Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annu Rev Immunol. 2005;23:901-44.
41. Keel SB, Doty RT, Yang Z, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science. 2008;319:825-8.
42. Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK. Identification of the receptor scavenging hemopexin-heme complexes. Blood. 2005;106:2572-9.
43. Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA. 1997;94:10919-24.
44. Baranano DE, Wolosker H, Bae BI, Barrow RK, Snyder SH, Ferris CD. A mammalian iron ATPase induced by iron. J Biol Chem. 2000;275:15166-73.
45. Gomes MS, Appelberg R. Evidence for a link between iron metabolism and Nramp1 gene function in innate resistance against Mycobacterium avium . Immunology. 1998;95:165-8.
46. Canonne-Hergaux F, Gruenheid S, Govoni G, Gros P. The Nramp1 protein and its role in resistance to infection and macrophage function. Proc Assoc Am Physicians. 1999;111:283-9.
47. Jabado N, Canonne-Hergaux F, Gruenheid S, Picard V, Gros P. Iron transporter Nramp2/DMT-1 is associated with the membrane of phagosomes in macrophages and Sertoli cells. Blood. 2002;100:2617-22.
48. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191-200.
49. 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 USA. 2005;10:1324-8.
50. Custer G, Balcerzak S, Rinehart J. Human macrophage hemoglobin-iron metabolism in vitro. Am J Hematol. 1982;13:23-36.
51. Galli A, Bergamaschi G, Recalde H, et al. Ferroportin gene silencing induces iron retention and enhances ferritin synthesis in human macrophages. Br J Haematol. 2004;127:598-603.
52. Bornman L, Baladi S, Richard MJ, Tyrrell RM, Polla BS. Differential regulation and expression of stress proteins and ferritin in human monocytes. J Cell Physiol. 1999;178:1-8.
53. Theurl I, Ludwiczek S, Eller P, et al. Pathways for the regulation of body iron homeostasis in response to experimental iron overload. J Hepatol. 2005;43:711-9.
54. Sarkar J, Seshadri V, Tripoulas NA, Ketterer ME, Fox PL. Role of ceruloplasmin in macrophage iron efflux during hypoxia. J Biol Chem. 2003;278:44018-24.
55. Harris ZL, Durley AP, Man TK, Gitlin JD. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA. 1999;96:10812-7.
56. Cartwright GE, Wintrobe MM. The question of copper deficiency in man. Am J Clin Nutr. 1964;15:94-110.
57. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011-23.
58. Song JS, Park W, Bae SK, et al. The usefulness of serum transferrin receptor and ferritin for assessing anemia in rheumatoid arthritis: comparison with bone marrow iron study. Rheumatol Int. 2001;21:24-9.
59. Erslev AJ. Williams hematology. 6th ed. New York: McGraw-Hill; 2001.
60. Kaysen GA. The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol. 2001;12:1549-57.
61. Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997;89:1052-7.
62. Brugnara C. Iron deficiency and erythropoiesis: new diagnostic approaches. Clin Chem. 2003;49:1573-8.
63. Raj DS. Role of interleukin-6 in the anemia of chronic disease. Sem Arthrit Rheumat. 2009;38:382-8.
64. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101:2461-3.
65. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008;112:4292-7.
66. Sibley JT, Blocka KL, Haga M, Martin WA, Murray LM. Clinical course and predictors of length of stay in hospitalized patients with rheumatoid arthritis. J Rheumatol. 1990;17:1623-7.
67. Penninx BW, Guralnik JM, Onder G, Ferrucci L, Wallace RB, Pahor M. Anemia and decline in physical performance among older persons. Am J Med. 2003;115:104-10.
68. Mishra TK, Mishra SK, Mohanty NK, Rath PK. Prevalence, prognostic importance and therapeutic implications of anemia in heart failure. Indian Heart J. 2005;57:670-4.
69. Han C, Rahman MU, Doyle MK, et al. Association of anemia and physical disability among patients with rheumatoid arthritis. J Rheumatol. 2007;34:2177-82.
70. Kaltwasser JP, Kessler U, Gottschalk R, Stucki G, Moller B. Effect of recombinant human erythropoietin and intravenous iron on anemia and disease activity in rheumatoid arthritis. J Rheumatol. 2001;28:2430-6.
71. Silverberg DS, Wexler D, Iaina A, Schwartz D. The interaction between heart failure and other heart diseases, renal failure, and anemia. Semin Nephrol. 2006;26:296-306.
72. Crawford J, Cella D, Cleeland CS, et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer. 2002;95:888-95.
73. Nissenson AR, Wade S, Goodnough T, Knight K, Dubois RW. Economic burden of anemia in an insured population. J Manag Care Pharm. 2005;11:565-74.
74. Ershler WB, Chen K, Reyes EB, Dubois R. Economic burden of patients with anemia in selected diseases. Value Health. 2005;8:629-38.
75. 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.
76. Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004;53:1190-7.
77. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood. 2000;96:823-33.
78. Singh AK, Fishbane S. The optimal hemoglobin in dialysis patients -a critical review. Semin Dial. 2008;21:1-6.
79. Jeffrey MR. Some observations on anemia in rheumatoid arthritis. Blood. 1953;8:502-18.
80. Cartwright GE, Wintrobe MM. The anemia of infection. XVII. A review. Adv Int Med. 1952;5:165-226.
81. Elin RJ, Wolff SM, Finch CA. Effect of induced fever on serum iron and ferritin concentrations in man. Blood. 1977;49:147-53.
82. Letendre ED, Holbein BE. Mechanism of impaired iron release by the reticuloendothelial system during the hypoferremic phase of experimental Neisseria meningitidis infection in mice. Infect Immun. 1984;44:320-5.
83. Olivares M, Walter T, Osorio M, Chadud P, Schlesinger L. Anemia of a mild viral infection: the measles vaccine as a model. Pediatrics. 1989;84:851-5.
84. Fuchs D, Zangerle R, Artner-Dworzak E, et al. Association between immune activation, changes of iron metabolism and anaemia in patients with HIV infection. Eur J Haematol. 1993;50:90-4.
85. Cemeroglu AP, Ozsoylu S. Haematologic consequences of viral infections including serum iron status. Eur J Pediatr. 1994;153:171-3.
86. Spada C, Treitinger A, Hoshikawa-Fujimura AY. HIV influence on hematopoiesis at the initial stage of infection. Eur J Haematol. 1998;61:255-60.
87. Lalonde RG, Holbein BE. Role of iron in Trypanosoma cruzi infection of mice. J Clin Invest. 1984;73:470-6.
88. Freireich EJ, Miller A, Emerson CP, Ross JF. The effect of inflammation on the utilization of erythrocyte and transferrin bound radioiron for red cell production. Blood. 1957;12:972-83.
89. Noyes WD, Bothwell TH, Finch CA. The role of the reticulo-endothelial cell in iron metabolism. Br J Haematol. 1960;6:43-55.
90. Haurani FI, Young K, Tocantins LM. Reutilization of iron in anemia complicating malignant neoplasma. Blood. 1963;22:73-81.
91. Moldawer LL, Marano MA, Wei H, et al. Cachectin/tumor necrosis factor-alpha alters red blood cell kinetics and induces anemia in vivo. FASEB J. 1989;3:1637-43.
92. Alvarez-Hernandez X, Liceaga J, McKay IC, Brock JH. Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab Invest. 1989;61:319-22.
93. Kobune M, Kohgo Y, Kato J, Miyazaki E, Niitsu Y. Interleukin-6 enhances hepatic transferrin uptake and ferritin expression in rats. Hepatology. 1994;19:1468-75.
94. Nieken J, Mulder NH, Buter J, et al. Recombinant human interleukin-6 induces a rapid and reversible anemia in cancer patients. Blood. 1995;86:900-5.
95. Voulgari PV, Kolios G, Papadopoulos GK, Katsaraki A, Seferiadis K, Drosos AA. Role of cytokines in the pathogenesis of anemia of chronic disease in rheumatoid arthritis. Clin Immunol. 1999;92:153-60.
96. Maccio A, Madeddu C, Massa D, et al. Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. Blood. 2005;106:362-7.
97. Ripley BJ, Goncalves B, Isenberg DA, Latchman DS, Rahman A. Raised levels of interleukin 6 in systemic lupus erythematosus correlate with anaemia. Ann Rheum Dis. 2005;64:849-53.
98. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci. 2006;61:575-84.
99. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100:3776-81.
100. Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood. 2005;106:1864-6.
101. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806-10.
102. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480:147-50.
103. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-3.
104. De Domenico I, Ward DM, Langelier C, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18:2569-78.
105. Rivera S, Nemeth E, Gabayan V, Lopez MA, Farshidi D, Ganz T. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood. 2005;106:2196-9.
106. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA. 2002;99:4596-601.
107. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood. 2007;109:4038-44.
108. Theurl I, Mattle V, Seifert M, Mariani M, Marth C, Weiss G. Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Blood. 2006;107:4142-8.
109. Laftah AH, Ramesh B, Simpson RJ, et al. Effect of hepcidin on intestinal iron absorption in mice. Blood. 2004;103:3940-4.
110. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271-6.
111. Feelders RA, Vreugdenhil G, Eggermont AM, Kuiper-Kramer PA, van Eijk HG, Swaak AJ. Regulation of iron metabolism in the acute-phase response: interferon gamma and tumour necrosis factor alpha induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients. Eur J Clin Invest. 1998;28:520-7.
112. Laftah AH, Sharma N, Brookes MJ, et al. Tumour necrosis factor-alpha causes hypoferraemia and reduced intestinal iron absorption in mice. Biochem J. 2006;397:61-7.
113. Johnson RA, Waddelow TA, Caro J, Oliff A, Roodman GD. Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice. Blood. 1989;74:130-8.
114. Capocasale RJ, Makropoulos DA, Achuthanandam R, et al. Myelodysplasia and anemia of chronic disease in human tumor necrosis factor-alpha transgenic mice. Cytometry A. 2008;73:148-59.
115. Fahmy M, Young SP. Modulation of iron metabolism in monocyte cell line U937 by inflammatory cytokines: changes in transferrin uptake, iron handling and ferritin mRNA. Biochem J. 1993;296:175-81.
116. Recalcati S, Taramelli D, Conte D, Cairo G. Nitric oxide-mediated induction of ferritin synthesis in J774 macrophages by inflammatory cytokines: role of selective iron regulatory protein-2 downregulation. Blood. 1998;91:1059-66.
117. Kim S, Ponka P. Effects of interferon gamma and lipopolysaccharide on macrophage iron metabolism are mediated by nitric oxide-induced degradation of iron regulatory protein 2. J Biol Chem. 2000;275:6220-6.
118. Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood. 2003;101:4148-54.
119. Elia G, Polla B, Rossi A, Santoro MG. Induction of ferritin and heat shock proteins by prostaglandin A1 in human monocytes. Evidence for transcriptional and posttranscriptional regulation. Eur J Biochem. 1999;264:736-45.
120. Fedorak RN, Gangl A, Elson CO, et al. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology. 2000;119:1473-82.
121. Tilg H, Ulmer H, Kaser A, Weiss G. Role of IL-10 for induction of anemia during inflammation. J Immunol. 2002;169:2204-9.
122. Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA. 2005;102:1906-10.
123. Jarnum S, Lassen NA. Albumin and transferrin metabolism in infectious and toxic diseases. Scand J Clin Lab Invest. 1961;13:357-68.
124. Markowitz H, Gubler CJ, Mahoney JP, Cartwright GE, Wintrobe MM. Studies on copper metabolism. XIV. Copper, ceruloplasmin and oxidase activity in sera of normal human subjects, pregnant women, and patients with infection, hepatolenticular degeneration and the nephrotic syndrome. J Clin Invest. 1955;34:1498-508.
125. Beaumier DL, Caldwell MA, Holbein BE. Inflammation triggers hypoferremia and de novo synthesis of serum transferrin and ceruloplasmin in mice. Infect Immun. 1984;46:489-94.
126. Graziadei I, Kaserbacher R, Braunsteiner H, Vogel W. The hepatic acute-phase proteins alpha 1-antitrypsin and alpha 2-macroglobulin inhibit binding of transferrin to its receptor. Biochem J. 1993;290:109-13.
127. 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.
128. Nangaku M, Eckardt KU. Hypoxia and the HIF system in kidney disease. J Mol Med. 2007;85:1325-30.
129. Ward HP, Kurnick JE, Pisarczyk MJ. Serum level of erythropoietin in anemias associated with chronic infection, malignancy, and primary hematopoietic disease. J Clin Invest. 1971;50:332-5.
130. Zucker S, Friedman S, Lysik RM. Bone marrow erythropoiesis in the anemia of infection, inflammation, and malignancy. J Clin Invest. 1974;53:1132-8.
131. Pavlovic-Kentera V, Ruvidic R, Milenkovic P, Marinkovic D. Erythropoietin in patients with anaemia in rheumatoid arthritis. Scand J Haematol. 1979;23:141-5.
132. Baer AN, Dessypris EN, Goldwasser E, Krantz SB. Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol. 1987;66:559-64.
133. Hochberg MC, Arnold CM, Hogans BB, Spivak JL. Serum immunoreactive erythropoietin in rheumatoid arthritis: impaired response to anemia. Arthritis Rheum. 1988;31:1318-21.
134. Boyd HK, Lappin TR, Bell AL. Evidence for impaired erythropoietin response to anaemia in rheumatoid disease. Br J Rheumatol. 1991;30:255-9.
135. Remacha AF, la SA Rodriguez-de, Garcia-Die F, Geli C, Diaz C, Gimferrer E. Erythroid abnormalities in rheumatoid arthritis: the role of erythropoietin. J Rheumatol. 1992;19:1687-91.
136. Kendall R, Wasti A, Harvey A, et al. The relationship of haemoglobin to serum erythropoietin concentrations in the anaemia of rheumatoid arthritis: the effect of oral prednisolone. Br J Rheumatol. 1993;32:204-8.
137. Spivak JL, Barnes DC, Fuchs E, Quinn TC. Serum immunoreactive erythropoietin in HIV-infected patients. J Am Med Assoc. 1989;261:3104-7.
138. Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990;322:1689-92.
139. Hobisch-Hagen P, Wiedermann F, Mayr A, et al. Blunted erythropoietic response to anemia in multiply traumatized patients. Crit Care Med. 2001;29:743-7.
140. Ebrahim O, Folb PI, Robson SC, Jacobs P. Blunted erythropoietin response to anaemia in tuberculosis. Eur J Haematol. 1995;55:251-4.
141. el Hassan AM, Saeed AM, Fandrey J, Jelkmann W. Decreased erythropoietin response in Plasmodium falciparum malaria-associated anaemia. Eur J Haematol. 1997;59:299-304.
142. Ferrucci L, Guralnik JM, Bandinelli S, et al. Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of pro-inflammatory markers. Br J Haematol. 2007;136:849-55.
143. Ershler WB, Sheng S, McKelvey J, et al. Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc. 2005;53:1360-5.
144. Carpenter MA, Kendall RG, O'Brien AE, et al. Reduced erythropoietin response to anaemia in elderly patients with normocytic anaemia. Eur J Haematol. 1992;49:119-21.
145. Ferrucci L, Guralnik JM, Woodman RC, et al. Proinflammatory state and circulating erythropoietin in persons with and without anemia. Am J Med. 2005;118:1288.
146. Pincus T, Olsen NJ, Russell IJ, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med. 1990;89:161-8.
147. Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood. 1992;79:1987-94.
148. Krajewski J, Batmunkh C, Jelkmann W, Hellwig-Burgel T. Interleukin-1beta inhibits the hypoxic inducibility of the erythropoietin enhancer by suppressing hepatocyte nuclear factor-4alpha. Cell Mol Life Sci. 2007;64:989-98.
149. La Ferla K, Reimann C, Jelkmann W, Hellwig-Burgel T. Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J. 2002;16:1811-3.
150. Jelkmann W, Pagel H, Wolff M, Fandrey J. Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci. 1992;50:301-8.
151. Frede S, Fandrey J, Pagel H, Hellwig T, Jelkmann W. Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats. Am J Physiol. 1997;273:R1067-71.
152. Cazzola M, Ponchio L, de Benedetti F, et al. Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood. 1996;87:4824-30.
153. Schett G, Firbas U, Fureder W, et al. Decreased serum erythropoietin and its relation to anti-erythropoietin antibodies in anaemia of systemic lupus erythematosus. Rheumatology. 2001;40:424-31.
154. Voulgarelis M, Kokori SI, Ioannidis JP, Tzioufas AG, Kyriaki D, Moutsopoulos HM. Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin. Ann Rheum Dis. 2000;59:217-22.
155. Corazza F, Beguin Y, Bergmann P, et al. Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production. Blood. 1998;92:1793-8.
156. Birgegard G, Hallgren R, Caro J. Serum erythropoietin in rheumatoid arthritis and other inflammatory arthritides: relationship to anaemia and the effect of anti-inflammatory treatment. Br J Haematol. 1987;65:479-83.
157. Nielsen OJ, Andersen LS, Ludwigsen E, et al. Anaemia of rheumatoid arthritis: serum erythropoietin concentrations and red cell distribution width in relation to iron status. Ann Rheum Dis. 1990;49:349-53.
158. Dowlati A, R'Zik S, Fillet G, Beguin Y. Anaemia of lung cancer is due to impaired erythroid marrow response to erythropoietin stimulation as well as relative inadequacy of erythropoietin production. Br J Haematol. 1997;97:297-9.
159. Means Jr RT, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood. 1992;80:1639-47.
160. Smith MA, Knight SM, Maddison PJ, Smith JG. Anaemia of chronic disease in rheumatoid arthritis: effect of the blunted response to erythropoietin and of interleukin 1 production by marrow macrophages. Ann Rheum Dis. 1992;51:753-7.
161. Vreugdenhil G, Lowenberg B, Van Eijk HG, Swaak AJ. Tumor necrosis factor-alpha is associated with disease activity and the degree of anemia in patients with rheumatoid arthritis. Eur J Clin Invest. 1992;22:488-93.
162. Akahane K, Hosoi T, Urabe A, Kawakami M, Takaku F. Effects of recombinant human tumor necrosis factor (rhTNF) on normal human and mouse hemopoietic progenitor cells. Int J Cell Cloning. 1987;5:16-26.
163. Johnson CS, Chang MJ, Furmanski P. In vivo hematopoietic effects of tumor necrosis factor-alpha in normal and erythroleukemic mice: characterization and therapeutic applications. Blood. 1988;72:1875-83.
164. Means Jr RT, Dessypris EN, Krantz SB. Inhibition of human colony-forming-unit erythroid by tumor necrosis factor requires accessory cells. J Clin Invest. 1990;86:538-41.
165. Means Jr RT, Krantz SB. Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon. J Clin Invest. 1993;91:416-9.
166. Roodman GD, Bird A, Hutzler D, Montgomery W. Tumor necrosis factor-alpha and hematopoietic progenitors: effects of tumor necrosis factor on the growth of erythroid progenitors CFU-E and BFU-E and the hematopoietic cell lines K562, HL60, and HEL cells. Exp Hematol. 1987;15:928-35.
167. Davis D, Charles PJ, Potter A, Feldmann M, Maini RN, Elliott MJ. Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade. Br J Rheumatol. 1997;36:950-6.
168. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following antitumor necrosis factor-alpha antibody therapy. Blood. 2002;100:474-82.
169. Schooley JC, Kullgren B, Allison AC. Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias. Br J Haematol. 1987;67:11-7.
170. Means Jr RT, Dessypris EN, Krantz SB. Inhibition of human erythroid colony-forming units by interleukin-1 is mediated by gamma interferon. J Cell Physiol. 1992;150:59-64.
171. Maury CP, Andersson LC, Teppo AM, Partanen S, Juvonen E. Mechanism of anaemia in rheumatoid arthritis: demonstration of raised interleukin 1 beta concentrations in anaemic patients and of interleukin 1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukaemia (HEL) cells in vitro. Ann Rheum Dis. 1988;47:972-8.
172. Raefsky EL, Platanias LC, Zoumbos NC, Young NS. Studies of interferon as a regulator of hematopoietic cell proliferation. J Immunol. 1985;135(4):2507-12.
173. Wang CQ, Udupa KB, Lipschitz DA. Interferon-gamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development. J Cell Physiol. 1995;162:134-8.
174. Mamus SW, Beck-Schroeder S, Zanjani ED. Suppression of normal human erythropoiesis by gamma interferon in vitro. Role of monocytes and T lymphocytes. J Clin Invest. 1985;75:1496-503.
175. Maciejewski JP, Selleri C, Sato T, et al. Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest. 1995;96:1085-92.
176. Mullarky IK, Szaba FM, Kummer LW, et al. Gamma interferon suppresses erythropoiesis via interleukin-15. Infect Immun. 2007;75:2630-3.
177. Taniguchi S, Dai CH, Price JO, Krantz SB. Interferon gamma downregulates stem cell factor and erythropoietin receptors but not insulin-like growth factor-I receptors in human erythroid colony-forming cells. Blood. 1997;90:2244-52.
178. Dai C, Krantz SB. Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Blood. 1999;93:3309-16.
179. Dai CH, Price JO, Brunner T, Krantz SB. Fas ligand is present in human erythroid colony-forming cells and interacts with Fas induced by interferon gamma to produce erythroid cell apoptosis. Blood. 1998;91:1235-42.
180. Yoshida H, Okabe Y, Kawane K, Fukuyama H, Nagata S. Lethal anemia caused by interferon beta produced in mouse embryos carrying undigested DNA. Nat Immunol. 2005;6:49-56.
181. Dallalio G, Law E, Means Jr RT. Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood. 2006;107:2702-4.
182. Hyman GA, Gellhorn A, Harvey JL. Studies on the anemia of disseminated malignant neoplastic disease. II. Study of the life span of the erythrocyte. Blood. 1956;11:618-31.
183. Alexander WR, Richmond J, Roy LM, Duthie JJ. Nature of anaemia in rheumatoid arthritis. II. Survival of transfused erythrocytes in patients with rheumatoid arthritis. Ann Rheum Dis. 1956;15:12-20.
184. Freireich EJ, Ross JF, Bayles TB, Emerson CP, Finch SC. Radioactive iron metabolism and erythrocyte survival studies of the mechanism of the anemia associated with rheumatoid arthritis. J Clin Invest. 1957;36:1043-58.
185. Hollingsworth JW, Hollingsworth DR. Study of total red cell volume and erythrocyte survival using radioactive chromium in patients with advanced pulmonary tuberculosis. Ann Intern Med. 1955;42:810-5.
186. Richmond J, Alexander WR, Potter JL, Duthie JJ. The nature of anaemia in rheumatoid arthritis. V. Red cell survival measured by radioactive chromium. Ann Rheum Dis. 1961;20:133-7.
187. Dinant HJ, de Maat CE. Erythropoiesis and mean red-cell lifespan in normal subjects and in patients with the anaemia of active rheumatoid arthritis. Br J Haematol. 1978;39:437-44.
188. Salvarani C, Casali B, Salvo D, et al. The role of interleukin 1, erythropoietin and red cell-bound immunoglobulins in the anaemia of rheumatoid arthritis. Clin Exp Rheumatol. 1991;9:241-6.
189. Varma J. Do nonsteroidal anti-inflammatory drugs cause lower gastrointestinal bleeding? A brief review. J Am Board Fam Pract. 1989;2:119-22.
190. Hirschowitz BI. Nonsteroidal antiinflammatory drugs and the gastrointestinal tract. Gastroenterologist. 1994;2:207-23.
191. Davies NM, Jamali F, Skeith KJ. Nonsteroidal antiinflammatory drug-induced enteropathy and severe chronic anemia in a patient with rheumatoid arthritis. Arthritis Rheum. 1996;39:321-4.
192. Doube A, Collins AJ. Anaemia in patients with arthritis: are simple investigations helpful? Br J Rheumatol. 1988;27:303-5.