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The Anemia of Inflammation and Chronic Disease

  • Cindy N. RoyEmail author
Chapter
Part of the Nutrition and Health book series (NH)

Abstract

Anemia associated with inflammation and chronic disease (AICD) is a commonly observed anemia, second only to iron deficiency anemia in its prevalence in developed countries. It is a mild, normocytic, normochromic anemia that is characterized by adequate or increased iron in macrophages and low serum iron, a blunted response of erythroid precursors to erythropoietin (Epo), and decreased erythrocyte survival. Such an anemia is associated with bacterial, viral, or parasitic infections, but as antibiotics have become widely available, the incidence of long-lasting suppurative infections has decreased. AICD is classically associated with chronic disease states that generate systemic inflammatory mediators [1], including autoimmune disorders – like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) [2], or inflammatory bowel disease (IBD) – and cancer. More recently, anemia has been recognized as a significant risk multiplier or comorbid factor in the context of severe trauma [3], heart failure (HF) [4], chronic kidney disease (CKD) [5], aging [6], and frailty [7, 8]. Finally, the anemia associated with inflammation or infection is increasingly recognized as a cause of anemia in the developing world apart from nutritional deficiencies [9]. While the incidence of anemia related to nutritional deficiencies, Epo deficiency, and blood loss overlaps with AICD in many patients, inflammation is clearly involved in the pathogenesis of anemia in these complex disease states.

Keywords

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

Abbreviations

AICD

Anemia associated with inflammation and chronic disease

BFU-E

Erythroid blast forming units

CD71

Transferrin receptor

CD91

Hemopexin receptor

CFU-E

Erythroid colony-forming units

CKD

Chronic kidney disease

Cp

Ceruloplasmin

Epo

Erythropoietin

EpoR

Erythropoietin receptor

FLVCR

Feline leukemia virus subgroup C, receptor

Fpn

Ferroportin

Ft

Ferritin

GATA

Binding protein 2

HF

Heart failure

HNF

Hepatocyte nuclear factor

HO-1

Heme oxygenase 1

IBD

Inflammatory bowel disease

IFN

Interferon

IL

Interleukin

LRP

Low density lipoprotein receptor-related protein

NFkb

Nuclear factor kb

NSAIDS

Nonsteroidal anti-inflammatory drugs

PS

Phosphatidyl serine

RA

Rheumatoid arthritis

SLE

Systemic lupus erythematosus

sTfR

Soluble/serum transferrin receptor

Tf

Transferrin

TfR

Transferrin receptor

TIBC

Total iron binding capacity

TNF

Tumor necrosis factor.

Notes

Acknowledgments

My thanks to my mentor, Dr. Nancy Andrews, for her guidance in the preparation of this chapter and for so much more beyond it.

References

  1. 1.
    Cartwright GE. The anemia of chronic disorders. Semin Hematol. 1966;3:351–75.PubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 3.
    Robinson Y, Hostmann A, Matenov A, Ertel W, Oberholzer A. Erythropoiesis in multiply injured patients. J Trauma. 2006;61:1285–91.PubMedGoogle Scholar
  4. 4.
    Anand I, McMurray JJ, Whitmore J, et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004;110:149–54.PubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 6.
    Ershler WB. Biological interactions of aging and anemia: a focus on cytokines. J Am Geriatr Soc. 2003;51(3 Suppl):S18–21.PubMedGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 9.
    Calis JC, Phiri KS, Faragher EB, et al. Severe anemia in Malawian children. N Engl J Med. 2008;358:888–99.PubMedGoogle Scholar
  10. 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.Google Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.Google Scholar
  13. 13.
    Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21:907–27.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.Google Scholar
  18. 18.
    Bron D, Meuleman N, Mascaux C. Biological basis of anemia. Semin Oncol. 2001;28(2 Suppl. 8):1–6.PubMedGoogle Scholar
  19. 19.
    Birgegard G, Aapro MS, Bokemeyer C, et al. Cancer-related anemia: pathogenesis, prevalence and treatment. Oncology. 2005;68(Suppl. 1):3–11.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.Google Scholar
  22. 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.Google Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 27.
    Chasis JA. Erythroblastic islands: specialized microenvironmental niches for erythropoiesis. Curr Opin Hematol. 2006;13:137–41.PubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 29.
    Graber SE, Krantz SB. Erythropoietin and the control of red cell production. Annu Rev Med. 1978;29:51–66.PubMedGoogle Scholar
  30. 30.
    Koury MJ, Sawyer ST, Brandt SJ. New insights into erythropoiesis. Curr Opin Hematol. 2002;9:93–100.PubMedGoogle Scholar
  31. 31.
    Iacopetta BJ, Morgan EH, Yeoh GC. Transferrin receptors and iron uptake during erythroid cell development. Biochim Biophys Acta. 1982;687:204–10.PubMedGoogle Scholar
  32. 32.
    Horton MA. Expression of transferrin receptors during erythroid maturation. Exp Cell Res. 1983;144:361–6.PubMedGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 34.
    Ponka P, Lok CN. The transferrin receptor: role in health and disease. Int J Biochem Cell Biol. 1999;31:1111–37.PubMedGoogle Scholar
  35. 35.
    Jandl JH. Transfer of iron from serum iron-binding protein to human reticylocytes. J Clin Invest. 1959;38:161–85.PubMedGoogle Scholar
  36. 36.
    Bernstein SE. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med. 1987;110:690–705.PubMedGoogle Scholar
  37. 37.
    Beguin Y. Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta. 2003;329:9–22.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 43.
    Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA. 1997;94:10919–24.PubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.Google Scholar
  50. 50.
    Custer G, Balcerzak S, Rinehart J. Human macrophage hemoglobin–iron metabolism in vitro. Am J Hematol. 1982;13:23–36.PubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. 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.PubMedGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 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.PubMedGoogle Scholar
  56. 56.
    Cartwright GE, Wintrobe MM. The question of copper deficiency in man. Am J Clin Nutr. 1964;15:94–110.PubMedGoogle Scholar
  57. 57.
    Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23.PubMedGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. 59.
    Erslev AJ. Williams hematology. 6th ed. New York: McGraw-Hill; 2001.Google Scholar
  60. 60.
    Kaysen GA. The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol. 2001;12:1549–57.PubMedGoogle Scholar
  61. 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.PubMedGoogle Scholar
  62. 62.
    Brugnara C. Iron deficiency and erythropoiesis: new diagnostic approaches. Clin Chem. 2003;49:1573–8.PubMedGoogle Scholar
  63. 63.
    Raj DS. Role of interleukin-6 in the anemia of chronic disease. Sem Arthrit Rheumat. 2009;38:382–8.Google Scholar
  64. 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.PubMedGoogle Scholar
  65. 65.
    Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008;112:4292–7.PubMedGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.PubMedGoogle Scholar
  69. 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.PubMedGoogle Scholar
  70. 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.PubMedGoogle Scholar
  71. 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.PubMedGoogle Scholar
  72. 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.PubMedGoogle Scholar
  73. 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.PubMedGoogle Scholar
  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.PubMedGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 76.
    Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004;53:1190–7.PubMedGoogle Scholar
  77. 77.
    Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood. 2000;96:823–33.PubMedGoogle Scholar
  78. 78.
    Singh AK, Fishbane S. The optimal hemoglobin in dialysis patients – a critical review. Semin Dial. 2008;21:1–6.PubMedGoogle Scholar
  79. 79.
    Jeffrey MR. Some observations on anemia in rheumatoid arthritis. Blood. 1953;8:502–18.PubMedGoogle Scholar
  80. 80.
    Cartwright GE, Wintrobe MM. The anemia of infection. XVII. A review. Adv Int Med. 1952;5:165–226.Google Scholar
  81. 81.
    Elin RJ, Wolff SM, Finch CA. Effect of induced fever on serum iron and ferritin concentrations in man. Blood. 1977;49:147–53.PubMedGoogle Scholar
  82. 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.PubMedGoogle Scholar
  83. 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.PubMedGoogle Scholar
  84. 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.PubMedGoogle Scholar
  85. 85.
    Cemeroglu AP, Ozsoylu S. Haematologic consequences of viral infections including serum iron status. Eur J Pediatr. 1994;153:171–3.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 87.
    Lalonde RG, Holbein BE. Role of iron in Trypanosoma cruzi infection of mice. J Clin Invest. 1984;73:470–6.PubMedGoogle Scholar
  88. 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.PubMedGoogle Scholar
  89. 89.
    Noyes WD, Bothwell TH, Finch CA. The role of the reticulo-endothelial cell in iron metabolism. Br J Haematol. 1960;6:43–55.PubMedGoogle Scholar
  90. 90.
    Haurani FI, Young K, Tocantins LM. Reutilization of iron in anemia complicating malignant neoplasma. Blood. 1963;22:73–81.PubMedGoogle Scholar
  91. 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.PubMedGoogle Scholar
  92. 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.PubMedGoogle Scholar
  93. 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.PubMedGoogle Scholar
  94. 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.PubMedGoogle Scholar
  95. 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.PubMedGoogle Scholar
  96. 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.PubMedGoogle Scholar
  97. 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.PubMedGoogle Scholar
  98. 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.PubMedGoogle Scholar
  99. 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.PubMedGoogle Scholar
  100. 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.PubMedGoogle Scholar
  101. 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.PubMedGoogle Scholar
  102. 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.PubMedGoogle Scholar
  103. 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.PubMedGoogle Scholar
  104. 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.PubMedGoogle Scholar
  105. 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.PubMedGoogle Scholar
  106. 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.PubMedGoogle Scholar
  107. 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.PubMedGoogle Scholar
  108. 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.PubMedGoogle Scholar
  109. 109.
    Laftah AH, Ramesh B, Simpson RJ, et al. Effect of hepcidin on intestinal iron absorption in mice. Blood. 2004;103:3940–4.PubMedGoogle Scholar
  110. 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.PubMedGoogle Scholar
  111. 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.PubMedGoogle Scholar
  112. 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.PubMedGoogle Scholar
  113. 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.PubMedGoogle Scholar
  114. 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.PubMedGoogle Scholar
  115. 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.PubMedGoogle Scholar
  116. 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.PubMedGoogle Scholar
  117. 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.PubMedGoogle Scholar
  118. 118.
    Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood. 2003;101:4148–54.PubMedGoogle Scholar
  119. 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.PubMedGoogle Scholar
  120. 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.PubMedGoogle Scholar
  121. 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.PubMedGoogle Scholar
  122. 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.PubMedGoogle Scholar
  123. 123.
    Jarnum S, Lassen NA. Albumin and transferrin metabolism in infectious and toxic diseases. Scand J Clin Lab Invest. 1961;13:357–68.PubMedGoogle Scholar
  124. 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.PubMedGoogle Scholar
  125. 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.PubMedGoogle Scholar
  126. 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.PubMedGoogle Scholar
  127. 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.PubMedGoogle Scholar
  128. 128.
    Nangaku M, Eckardt KU. Hypoxia and the HIF system in kidney disease. J Mol Med. 2007;85:1325–30.PubMedGoogle Scholar
  129. 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.PubMedGoogle Scholar
  130. 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.PubMedGoogle Scholar
  131. 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.PubMedGoogle Scholar
  132. 132.
    Baer AN, Dessypris EN, Goldwasser E, Krantz SB. Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol. 1987;66:559–64.PubMedGoogle Scholar
  133. 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.PubMedGoogle Scholar
  134. 134.
    Boyd HK, Lappin TR, Bell AL. Evidence for impaired erythropoietin response to anaemia in rheumatoid disease. Br J Rheumatol. 1991;30:255–9.PubMedGoogle Scholar
  135. 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.PubMedGoogle Scholar
  136. 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.PubMedGoogle Scholar
  137. 137.
    Spivak JL, Barnes DC, Fuchs E, Quinn TC. Serum immunoreactive erythropoietin in HIV-infected patients. J Am Med Assoc. 1989;261:3104–7.Google Scholar
  138. 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.PubMedGoogle Scholar
  139. 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.PubMedGoogle Scholar
  140. 140.
    Ebrahim O, Folb PI, Robson SC, Jacobs P. Blunted erythropoietin response to anaemia in tuberculosis. Eur J Haematol. 1995;55:251–4.PubMedGoogle Scholar
  141. 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.PubMedGoogle Scholar
  142. 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.PubMedGoogle Scholar
  143. 143.
    Ershler WB, Sheng S, McKelvey J, et al. Serum erythropoietin and aging: a longitudinal analysis. J Am Geriatr Soc. 2005;53:1360–5.PubMedGoogle Scholar
  144. 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.PubMedGoogle Scholar
  145. 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.PubMedGoogle Scholar
  146. 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.PubMedGoogle Scholar
  147. 147.
    Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood. 1992;79:1987–94.PubMedGoogle Scholar
  148. 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.PubMedGoogle Scholar
  149. 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.PubMedGoogle Scholar
  150. 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.PubMedGoogle Scholar
  151. 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.PubMedGoogle Scholar
  152. 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.PubMedGoogle Scholar
  153. 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.PubMedGoogle Scholar
  154. 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.PubMedGoogle Scholar
  155. 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.PubMedGoogle Scholar
  156. 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.PubMedGoogle Scholar
  157. 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.PubMedGoogle Scholar
  158. 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.PubMedGoogle Scholar
  159. 159.
    Means Jr RT, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood. 1992;80:1639–47.PubMedGoogle Scholar
  160. 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.PubMedGoogle Scholar
  161. 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.PubMedGoogle Scholar
  162. 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.PubMedGoogle Scholar
  163. 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.PubMedGoogle Scholar
  164. 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.PubMedGoogle Scholar
  165. 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.PubMedGoogle Scholar
  166. 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.PubMedGoogle Scholar
  167. 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.PubMedGoogle Scholar
  168. 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 anti-tumor necrosis factor-alpha antibody therapy. Blood. 2002;100:474–82.PubMedGoogle Scholar
  169. 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.PubMedGoogle Scholar
  170. 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.PubMedGoogle Scholar
  171. 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.PubMedGoogle Scholar
  172. 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.PubMedGoogle Scholar
  173. 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.PubMedGoogle Scholar
  174. 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.PubMedGoogle Scholar
  175. 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.PubMedGoogle Scholar
  176. 176.
    Mullarky IK, Szaba FM, Kummer LW, et al. Gamma interferon suppresses erythropoiesis via interleukin-15. Infect Immun. 2007;75:2630–3.PubMedGoogle Scholar
  177. 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.PubMedGoogle Scholar
  178. 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.PubMedGoogle Scholar
  179. 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.PubMedGoogle Scholar
  180. 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.PubMedGoogle Scholar
  181. 181.
    Dallalio G, Law E, Means Jr RT. Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood. 2006;107:2702–4.PubMedGoogle Scholar
  182. 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.PubMedGoogle Scholar
  183. 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.PubMedGoogle Scholar
  184. 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.PubMedGoogle Scholar
  185. 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.PubMedGoogle Scholar
  186. 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.PubMedGoogle Scholar
  187. 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.PubMedGoogle Scholar
  188. 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.PubMedGoogle Scholar
  189. 189.
    Varma J. Do nonsteroidal anti-inflammatory drugs cause lower gastrointestinal bleeding? A brief review. J Am Board Fam Pract. 1989;2:119–22.PubMedGoogle Scholar
  190. 190.
    Hirschowitz BI. Nonsteroidal antiinflammatory drugs and the gastrointestinal tract. Gastroenterologist. 1994;2:207–23.PubMedGoogle Scholar
  191. 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.PubMedGoogle Scholar
  192. 192.
    Doube A, Collins AJ. Anaemia in patients with arthritis: are simple investigations helpful? Br J Rheumatol. 1988;27:303–5.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Geriatric Medicine and GerontologyJohns Hopkins UniversityBaltimoreUSA

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