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Vol. 122, No. 2-3, 2009
Issue release date: November 2009
Acta Haematol 2009;122:103–108

Anemia of Chronic Disease (Anemia of Inflammation)

Agarwal N. · Prchal J.T.
aDivision of Hematology and Oncology, University of Utah School of Medicine and Veterans Affairs Hospital, and bARUP Laboratories, Salt Lake City, Utah, USA

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Mild-to-moderate anemia often develops in the setting of acute or chronic immune activation and is termed anemia of chronic disease (ACD) or anemia of inflammation. Anemia of chronic disease is the second most common type of anemia (after anemia of iron deficiency) and results in increased morbidity and mortality of the underlying disease. Anemia of chronic disease is mediated by inflammatory cytokines and is characterized by low serum iron (hypoferremia) and often increased reticuloendothelial stores of iron. Hepcidin is the master regulator of iron homeostasis and its synthesis is inhibited by iron deficiency and stimulated by inflammation. The serum hepcidin level is useful in identifying iron deficiency in patients with ACD. Successful treatment of the underlying disease improves ACD. If that is not possible and if anemia is symptomatic, treatment with erythropoietic agents, supplemented with iron if necessary, is helpful in many cases.

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  1. Cartwright GE: The anemia of chronic disorders. Semin Hematol 1966;3:351–375.
  2. Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 2005;352:1011–1023.
  3. Ganz T, Nemeth E: Regulation of iron acquisition and iron distribution in mammals. Biochim Biophys Acta 2006;1763:690–699.
  4. Mims MP, Guan Y, Pospisilova D, Priwitzerova M, Indrak K, Ponka P, Divoky V, Prchal JT: Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 2005;105:1337–1342.
  5. Harrison PM, Arosio P: The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1996;1275:161–203.
  6. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090–2093.
  7. De Domenico I, Lo E, Ward DM, Kaplan J: Hepcidin-induced internalization of ferroportin requires binding and cooperative interaction with Jak2. Proc Natl Acad Sci USA 2009;106:3800–3805.
  8. 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;101:2461–2463.
  9. Nemeth E: Iron regulation and erythropoiesis. Curr Opin Hematol 2008;15:169–175.
  10. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ, Andrews NC, Lin HY: Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006;38:531–539.
  11. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, Khovananth K, Mudd S, Mann N, Moresco EM, Beutler E, Beutler B: The serine protease TMPRSS6 is required to sense iron deficiency. Science 2008;320:1088–1092.
  12. Truksa J, Lee P, Beutler E: Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness. Blood 2009;113:688–695.
  13. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL: High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007;13:1096–1101.
  14. Tanno T, Porayette P, Sripichai O, Noh SJ, Byrnes C, Bhupatiraju A, Lee YT, Goodnough JB, Harandi O, Ganz T, Paulson RF, Miller JL: Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 2009;114:181–186.
  15. Jelkmann W: Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998;18:555–559.
  16. Imagawa S, Nakano Y, Obara N, Suzuki N, Doi T, Kodama T, Nagasawa T, Yamamoto M: A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1β, TNF-α, or L-NMMA. FASEB J 2003;17:1742–1744.
  17. Means RT Jr, Krantz SB: Inhibition of human erythroid colony-forming units by gamma interferon can be corrected by recombinant human erythropoietin. Blood 1991;78:2564–2567.
  18. 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;296:175–181.
  19. Means RT Jr: Recent developments in the anemia of chronic disease. Curr Hematol Rep 2003;2:116–121.

    External Resources

  20. Maciejewski JP, Selleri C, Sato T, Cho HJ, Keefer LK, Nathan CF, Young NS: Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest 1995;96:1085–1092.
  21. Lee P, Gelbart T, Waalen J, Beutler E: The anemia of ageing is not associated with increased plasma hepcidin levels. Blood Cells Mol Dis 2008;41:252–254.
  22. Witte DL: Can serum ferritin be effectively interpreted in the presence of the acute-phase response? Clin Chem 1991;37:484–485.
  23. North M, Dallalio G, Donath AS, Melink R, Means RT Jr: Serum transferrin receptor levels in patients undergoing evaluation of iron stores: correlation with other parameters and observed versus predicted results. Clin Lab Haematol 1997;19:93–97.
  24. Lee PL, Beutler E: Regulation of hepcidin and iron-overload disease. Annu Rev Pathol 2009;4:489–515.
  25. Zhang AS, Enns CA: Iron homeostasis: recently identified proteins provide insight into novel control mechanisms. J Biol Chem 2009;284:711–715.
  26. Cook JD, Skikne BS, Baynes RD: Serum transferrin receptor. Annu Rev Med 1993;44:63–74.
  27. Skikne BS, Flowers CH, Cook JD: Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 1990;75:1870–1876.
  28. Punnonen K, Irjala K, Rajamaki A: Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89:1052–1057.
  29. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M: Immunoassay for human serum hepcidin. Blood 2008;112:4292–4297.
  30. Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G: Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009;113:5277–5286.
  31. Egrie JC, Dwyer E, Browne JK, Hitz A, Lykos MA: Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol 2003;31:290–299.
  32. Beutel G, Ganser A: Risks and benefits of erythropoiesis-stimulating agents in cancer management. Semin Hematol 2007;44:157–165.
  33. (FDA) US Food and Drug Administration:
  34. Macdougall IC: CERA (continuous erythropoietin receptor activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 2005;4:436–440.
  35. Sulowicz W, Locatelli F, Ryckelynck JP, Balla J, Csiky B, Harris K, Ehrhard P, Beyer U: Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clin J Am Soc Nephrol 2007;2:637–646.
  36. Levin NW, Fishbane S, Canedo FV, Zeig S, Nassar GM, Moran JE, Villa G, Beyer U, Oguey D: Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007;370:1415–1421.
  37. National Comprehensive Cancer Network®: NCCN Clinical Practice Guidelines in Oncology™: Cancer- and Chemotherapy-Induced Anemia, version 2.2009.
  38. Silverstein SB, Rodgers GM: Parenteral iron therapy options. Am J Hematol 2004;76:74–78.
  39. Chen ZY, Asavaritikrai P, Prchal JT, Noguchi CT: Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 2007;282:25875–25883.
  40. Blau CA: Erythropoietin in cancer: presumption of innocence? Stem Cells 2007;25:2094–2097.
  41. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M: Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008;299:914–924.
  42. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S, Piper M, Rades D, Steensma DP, Djulbegovic B, Fey MF, Ray-Coquard I, Machtay M, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A: Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009;373:1532–1542.
  43. Necas E, Prchal JT: The diverse functions of lipocalin: a recently-recognized mediator of transferrin independent iron transport, innate immunity, and cancer signaling. Hematologist 2006;3:3.
  44. Whitnall M, Howard J, Ponka P, Richardson DR: A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci USA 2006;103:14901–14906.
  45. van der Meer P, Groenveld H, Januzzi JL, van Veldhuisen DJ: Erythropoietin treatment in patients with chronic heart failure: a meta-analysis. Heart 2009;95:1309–1314.

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