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Anemia of chronic disease/inflammation

Stanley L Schrier, MD
Clara Camaschella, MD
Section Editor
William C Mentzer, MD
Deputy Editor
Jennifer S Tirnauer, MD


The anemia of chronic disease (ACD, also called the anemia of inflammation, anemia of chronic inflammation, or hypoferremia of inflammation) was initially thought to be associated primarily with infectious, inflammatory, or neoplastic disease. However, other observations have shown that ACD can be seen in a variety of conditions, including chronic kidney disease, severe trauma, diabetes mellitus, anemia of older adults, and in those with acute or chronic immune activation. The anemia is typically normochromic, normocytic, hypoproliferative, and mild in degree.

The pathogenesis, laboratory findings, and treatment of ACD will be reviewed here. An overview of the approach to the adult patient with anemia is presented separately. (See "Approach to the adult patient with anemia".)


Overview — ACD is thought to primarily reflect a reduction in red blood cell (RBC) production by the bone marrow, with a component due to mild shortening of RBC survival [1,2]. A number of factors are thought to contribute to this hypoproliferative state [3,4]:

Hepcidin-induced alterations in iron metabolism, including reduced absorption of iron from the gastrointestinal tract and trapping of iron in macrophages. This results in reduced plasma iron levels (hypoferremia), making iron unavailable for new hemoglobin synthesis [5-7]. (See 'Hepcidin' below.)

Inability to increase erythropoiesis in response to anemia. Serum erythropoietin (EPO) levels are somewhat elevated in ACD, but there is virtually no increase in erythropoiesis, perhaps due to increased apoptotic death of red cell precursors within the bone marrow [3,8,9].

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Literature review current through: Nov 2017. | This topic last updated: Oct 26, 2017.
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  1. Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol 2011; 154:289.
  2. Gangat N, Wolanskyj AP. Anemia of chronic disease. Semin Hematol 2013; 50:232.
  3. Means RT Jr, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 1992; 80:1639.
  4. Roy CN. Anemia of inflammation. Hematology Am Soc Hematol Educ Program 2010; 2010:276.
  5. Means RT Jr. Advances in the anemia of chronic disease. Int J Hematol 1999; 70:7.
  6. Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 2003; 101:4148.
  7. Theurl I, Mattle V, Seifert M, et al. Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease. Blood 2006; 107:4142.
  8. Papadaki HA, Kritikos HD, Gemetzi C, et al. Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha-mediated effect. Blood 2002; 99:1610.
  9. Papadaki HA, Kritikos HD, Valatas V, et al. 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.
  10. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352:1011.
  11. 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.
  12. Cash JM, Sears DA. The anemia of chronic disease: spectrum of associated diseases in a series of unselected hospitalized patients. Am J Med 1989; 87:638.
  13. Means RT Jr. Recent developments in the anemia of chronic disease. Curr Hematol Rep 2003; 2:116.
  14. Opasich C, Cazzola M, Scelsi L, et al. Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure. Eur Heart J 2005; 26:2232.
  15. Silverberg DS, Wexler D, Palazzuoli A, et al. The anemia of heart failure. Acta Haematol 2009; 122:109.
  16. Price EA, Schrier SL. Unexplained aspects of anemia of inflammation. Adv Hematol 2010; 2010:508739.
  17. Raj DS. Role of interleukin-6 in the anemia of chronic disease. Semin Arthritis Rheum 2009; 38:382.
  18. Boutou AK, Pitsiou GG, Stanopoulos I, et al. Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case-control study. QJM 2012; 105:657.
  19. Means RT Jr, Krantz SB. Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon. J Clin Invest 1993; 91:416.
  20. Means RT Jr, Krantz SB, Luna J, et al. Inhibition of murine erythroid colony formation in vitro by interferon gamma and correction by interferon receptor immunoadhesin. Blood 1994; 83:911.
  21. Voulgari PV, Kolios G, Papadopoulos GK, et al. Role of cytokines in the pathogenesis of anemia of chronic disease in rheumatoid arthritis. Clin Immunol 1999; 92:153.
  22. Libregts SF, Gutiérrez L, de Bruin AM, et al. Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis. Blood 2011; 118:2578.
  23. 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.
  24. 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.
  25. Ganz T. Molecular pathogenesis of anemia of chronic disease. Pediatr Blood Cancer 2006; 46:554.
  26. Davis D, Charles PJ, Potter A, et al. Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade. Br J Rheumatol 1997; 36:950.
  27. Doyle MK, Rahman MU, Han C, et al. Treatment with infliximab plus methotrexate improves anemia in patients with rheumatoid arthritis independent of improvement in other clinical outcome measures-a pooled analysis from three large, multicenter, double-blind, randomized clinical trials. Semin Arthritis Rheum 2009; 39:123.
  28. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367:2385.
  29. Neves PL, Morgado E, Faísca M, et al. Nutritional and inflammatory status influence darbepoetin dose in pre-dialysis elderly patients. Int Urol Nephrol 2006; 38:811.
  30. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003; 101:2461.
  31. Armitage AE, Eddowes LA, Gileadi U, et al. Hepcidin regulation by innate immune and infectious stimuli. Blood 2011; 118:4129.
  32. Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117:4425.
  33. Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012; 338:768.
  34. Michels KR, Zhang Z, Bettina AM, et al. Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia. JCI Insight 2017; 2:e92002.
  35. Stefanova D, Raychev A, Arezes J, et al. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood 2017; 130:245.
  36. Kim A, Fung E, Parikh SG, et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 2014; 123:1129.
  37. Gardenghi S, Renaud TM, Meloni A, et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 2014; 123:1137.
  38. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110:1037.
  39. Roy CN, Custodio AO, de Graaf J, et al. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nat Genet 2004; 36:481.
  40. Sasu BJ, Cooke KS, Arvedson TL, et al. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood 2010; 115:3616.
  41. Cooke KS, Hinkle B, Salimi-Moosavi H, et al. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood 2013; 122:3054.
  42. Kautz L, Jung G, Nemeth E, Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood 2014; 124:2569.
  43. Theurl I, Schroll A, Sonnweber T, et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood 2011; 118:4977.
  44. Steinbicker AU, Sachidanandan C, Vonner AJ, et al. Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. Blood 2011; 117:4915.
  45. Rivera S, Liu L, Nemeth E, et al. Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. Blood 2005; 105:1797.
  46. Schwoebel F, van Eijk LT, Zboralski D, et al. The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys. Blood 2013; 121:2311.
  47. Theurl M, Nairz M, Schroll A, et al. Hepcidin as a predictive factor and therapeutic target in erythropoiesis-stimulating agent treatment for anemia of chronic disease in rats. Haematologica 2014; 99:1516.
  48. Khorramian E, Fung E, Chua K, et al. In a Mouse Model of Sepsis, Hepcidin Ablation Ameliorates Anemia More Effectively than Iron and Erythropoietin Treatment. Shock 2017; 48:490.
  49. 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.
  50. Theurl I, Aigner E, Theurl M, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009; 113:5277.
  51. Hohaus S, Massini G, Giachelia M, et al. Anemia in Hodgkin's lymphoma: the role of interleukin-6 and hepcidin. J Clin Oncol 2010; 28:2538.
  52. de Mast Q, van Dongen-Lases EC, Swinkels DW, et al. Mild increases in serum hepcidin and interleukin-6 concentrations impair iron incorporation in haemoglobin during an experimental human malaria infection. Br J Haematol 2009; 145:657.
  53. Weinstein DA, Roy CN, Fleming MD, et al. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 2002; 100:3776.
  54. Kemna E, Pickkers P, Nemeth E, et al. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005; 106:1864.
  55. Kawabata H, Tomosugi N, Kanda J, et al. Anti-interleukin 6 receptor antibody tocilizumab reduces the level of serum hepcidin in patients with multicentric Castleman's disease. Haematologica 2007; 92:857.
  56. Song SN, Tomosugi N, Kawabata H, et al. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood 2010; 116:3627.
  57. Theurl I, Theurl M, Seifert M, et al. Autocrine formation of hepcidin induces iron retention in human monocytes. Blood 2008; 111:2392.
  58. Maes K, Nemeth E, Roodman GD, et al. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 2010; 116:3635.
  59. Sasu BJ, Li H, Rose MJ, et al. Serum hepcidin but not prohepcidin may be an effective marker for anemia of inflammation (AI). Blood Cells Mol Dis 2010; 45:238.
  60. Arlet JB, Hermine O, Darnige L, et al. Iron-deficiency anemia in Castleman disease: implication of the interleukin 6/hepcidin pathway. Pediatrics 2010; 126:e1608.
  61. Truksa J, Peng H, Lee P, Beutler E. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Br J Haematol 2007; 139:138.
  62. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006; 108:3204.
  63. Verga Falzacappa MV, Vujic Spasic M, Kessler R, et al. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 2007; 109:353.
  64. Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 2007; 132:294.
  65. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010; 116:4754.
  66. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood 2016; 127:2809.
  67. van der Vorm LN, Hendriks JC, Laarakkers CM, et al. Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material. Clin Chem 2016; 62:993.
  68. Thomas C, Kobold U, Thomas L. Serum hepcidin-25 in comparison to biochemical markers and hematological indices for the differentiation of iron-restricted erythropoiesis. Clin Chem Lab Med 2011; 49:207.
  69. Weiss G, Schett G. Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol 2013; 9:205.
  70. Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004; 40:2293.
  71. Macciò A, Madeddu C, Gramignano G, et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica 2015; 100:124.
  72. Birgegård G, Gascón P, Ludwig H. Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European CANCER ANAEMIA SURVEY. Eur J Haematol 2006; 77:378.
  73. Markoulaki D, Kostikas K, Papatheodorou G, et al. Hemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease. Eur J Intern Med 2011; 22:103.
  74. van Iperen CE, van de Wiel A, Marx JJ. Acute event-related anaemia. Br J Haematol 2001; 115:739.
  75. Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998; 18:555.
  76. Rodriguez RM, Corwin HL, Gettinger A, et al. Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care 2001; 16:36.
  77. Corwin HL, Gettinger A, Pearl RG, et al. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA 2002; 288:2827.
  78. Lasocki S, Millot S, Andrieu V, et al. Phlebotomies or erythropoietin injections allow mobilization of iron stores in a mouse model mimicking intensive care anemia. Crit Care Med 2008; 36:2388.
  79. van Eijk LT, Kroot JJ, Tromp M, et al. Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study. Crit Care 2011; 15:R9.
  80. Sihler KC, Raghavendran K, Westerman M, et al. Hepcidin in trauma: linking injury, inflammation, and anemia. J Trauma 2010; 69:831.
  81. Vreugdenhil G, Löwenberg B, van Eijk HG, Swaak AJ. Anaemia of chronic disease in rheumatoid arthritis. Raised serum interleukin-6 (IL-6) levels and effects of IL-6 and anti-IL-6 on in vitro erythropoiesis. Rheumatol Int 1990; 10:127.
  82. Macciò 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.
  83. Suominen P, Möttönen T, Rajamäki A, Irjala K. Single values of serum transferrin receptor and transferrin receptor ferritin index can be used to detect true and functional iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum 2000; 43:1016.
  84. Fitzsimons EJ, Houston T, Munro R, et al. Erythroblast iron metabolism and serum soluble transferrin receptor values in the anemia of rheumatoid arthritis. Arthritis Rheum 2002; 47:166.
  85. Koulaouzidis A, Said E, Cottier R, Saeed AA. Soluble transferrin receptors and iron deficiency, a step beyond ferritin. A systematic review. J Gastrointestin Liver Dis 2009; 18:345.
  86. Infusino I, Braga F, Dolci A, Panteghini M. Soluble transferrin receptor (sTfR) and sTfR/log ferritin index for the diagnosis of iron-deficiency anemia. A meta-analysis. Am J Clin Pathol 2012; 138:642.
  87. Punnonen K, Irjala K, Rajamäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997; 89:1052.
  89. Archer NM, Shmukler BE, Andolfo I, et al. Hereditary xerocytosis revisited. Am J Hematol 2014; 89:1142.
  90. Thomas C, Thomas L. Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem 2002; 48:1066.
  91. Brugnara C. Iron deficiency and erythropoiesis: new diagnostic approaches. Clin Chem 2003; 49:1573.
  92. Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 2013; 161:639.
  93. Chaves PH, Xue QL, Guralnik JM, et al. What constitutes normal hemoglobin concentration in community-dwelling disabled older women? J Am Geriatr Soc 2004; 52:1811.
  94. DeLoughery TG. Microcytic anemia. N Engl J Med 2014; 371:1324.
  95. Zarychanski R, Houston DS. Anemia of chronic disease: a harmful disorder or an adaptive, beneficial response? CMAJ 2008; 179:333.
  96. Lind M, Vernon C, Cruickshank D, et al. The level of haemoglobin in anaemic cancer patients correlates positively with quality of life. Br J Cancer 2002; 86:1243.
  97. Culleton BF, Manns BJ, Zhang J, et al. Impact of anemia on hospitalization and mortality in older adults. Blood 2006; 107:3841.
  98. Denny SD, Kuchibhatla MN, Cohen HJ. Impact of anemia on mortality, cognition, and function in community-dwelling elderly. Am J Med 2006; 119:327.
  99. Spivak JL. Recombinant human erythropoietin and the anemia of cancer. Blood 1994; 84:997.
  100. 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.
  101. Henry DH, Beall GN, Benson CA, et al. Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy. Overview of four clinical trials. Ann Intern Med 1992; 117:739.
  102. Ludwig H, Fritz E, Leitgeb C, et al. Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 1994; 84:1056.
  103. Osterborg A, Brandberg Y, Molostova V, et al. Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 2002; 20:2486.
  104. González-Barón M, Ordóñez A, Franquesa R, et al. Response predicting factors to recombinant human erythropoietin in cancer patients undergoing platinum-based chemotherapy. Cancer 2002; 95:2408.
  105. Cazzola M, Beguin Y, Kloczko J, et al. Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol 2003; 122:386.
  106. Coccia MA, Cooke K, Stoney G, et al. Novel erythropoiesis stimulating protein (darbepoetin alfa) alleviates anemia associated with chronic inflammatory disease in a rodent model. Exp Hematol 2001; 29:1201.
  107. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol 2004; 22:1301.
  108. Fung E, Nemeth E. Manipulation of the hepcidin pathway for therapeutic purposes. Haematologica 2013; 98:1667.
  109. Poli M, Asperti M, Naggi A, et al. Glycol-split nonanticoagulant heparins are inhibitors of hepcidin expression in vitro and in vivo. Blood 2014; 123:1564.
  110. Schmidt PJ, Fleming MD. Modulation of hepcidin as therapy for primary and secondary iron overload disorders: preclinical models and approaches. Hematol Oncol Clin North Am 2014; 28:387.
  111. van Eijk LT, John AS, Schwoebel F, et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood 2014; 124:2643.
  112. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013; 123:2337.
  113. Boyce M, Warrington S, Cortezi B, et al. Safety, pharmacokinetics and pharmacodynamics of the anti-hepcidin Spiegelmer lexaptepid pegol in healthy subjects. Br J Pharmacol 2016; 173:1580.