Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation;Eisenmangel oder Entzündungsanämie?: Differenzialdiagnose und Mechanismen der Entzündungsanämie

Wiener Medizinische Wochenschrift

Volumn 166, Issue 13-14, 2016, Pages 411-423

  Nairz, Manfred ^a   Theurl, Igor ^a   Wolf, Dominik ^b   Weiss, Günter ^a  

^a INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^b UNIVERSITY HOSPITAL BONN   (Germany)

Author keywords

Anemia of chronic disease; Anemia of inflammation; Hepcidin; Iron; Macrophage

Indexed keywords

ANTIANEMIC AGENT; FERRITIN; HEMOGLOBIN; HEPCIDIN; IRON; TRANSFERRIN; TRANSFERRIN RECEPTOR; ZINC; AUTACOID;

ANEMIA OF INFLAMMATION; BLOOD CELL COUNT; DIAGNOSTIC TEST; DIFFERENTIAL DIAGNOSIS; ERYTHROCYTE; ERYTHROID CELL; HUMAN; IMMUNOCOMPETENT CELL; INFLAMMATION; IRON DEFICIENCY ANEMIA; IRON THERAPY; KIDNEY; LIVER; NONHUMAN; PATHOPHYSIOLOGY; RETICULOCYTE; REVIEW; SPLEEN; ANEMIA, IRON-DEFICIENCY; ANIMAL; BLOOD; COMPLICATION; ERYTHROPOIESIS; HEMOGLOBIN DETERMINATION; HOMEOSTASIS; IMMUNOLOGY; MACROPHAGE; PHYSIOLOGY;

ANEMIA, IRON-DEFICIENCY; ANIMALS; DIAGNOSIS, DIFFERENTIAL; ERYTHROPOIESIS; FERRITINS; HEMOGLOBINOMETRY; HEPCIDINS; HOMEOSTASIS; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; IRON; MACROPHAGES;

EID: 84983455413     PISSN: 00435341     EISSN: 1563258X     Source Type: Journal    
DOI: 10.1007/s10354-016-0505-7     Document Type: Review

References (161)

1. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23.
2. Theurl I, Fritsche G, Ludwiczek S, Garimorth K, Bellmann-Weiler R, Weiss G. The macrophage: a cellular factory at the interphase between iron and immunity for the control of infections. Biometals. 2005;18:359–67.
3. Rockey DC. Occult gastrointestinal bleeding. N Engl J Med. 1999;341:38–46.
4. Zoller H, Koch RO, Theurl I, et al. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology. 2001;120:1412–9.
5. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142:24–38.
6. Kloss-Brandstatter A, Erhart G, Lamina C, et al. Candidate gene sequencing of SLC11A2 and TMPRSS6 in a family with severe anaemia: common SNPs, rare haplotypes, no causative mutation. PLoS ONE. 2012;7:e35015.
7. Camaschella C. Iron-Deficiency Anemia. N Engl J Med. 2015;373:485–6.
8. Larrick JW, Hyman ES. Acquired iron-deficiency anemia caused by an antibody against the transferrin receptor. N Engl J Med. 1984;311:214–8.
9. Perlstein TS, Pande R, Berliner N, Vanasse GJ. Prevalence of 25-hydroxyvitamin D deficiency in subgroups of elderly persons with anemia: association with anemia of inflammation. Blood. 2011;117:2800–6.
10. Hershko C, Patz J. Ironing out the mechanism of anemia in celiac disease. Haematologica. 2008;93:1761–5.
11. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123:615–24.
12. Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Semin Hematol. 2015;52:313–20.
13. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010;116:4754–61.
14. Thomas L, Franck S, Messinger M, Linssen J, Thome M, Thomas C. Reticulocyte hemoglobin measurement – comparison of two methods in the diagnosis of iron-restricted erythropoiesis. Clin Chem Lab Med. 2005;43:1193–202.
15. Archer NM, Brugnara C. Diagnosis of iron-deficient states. Crit Rev Clin Lab Sci. 2015;52:256–72.
16. Jankowska EA, Rozentryt P, Witkowska A, et al. Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011;17:899–906.
17. Oexle H, Gnaiger E, Weiss G. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim Biophys Acta. 1999;1413:99–107.
18. Rensvold JW, Ong SE, Jeevananthan A, Carr SA, Mootha VK, Pagliarini DJ. Complementary RNA and protein profiling identifies iron as a key regulator of mitochondrial biogenesis. Cell Rep. 2013;3:237–45.
19. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation. 2003;107:223–5.
20. Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure: the prospective randomized amlodipine survival evaluation (PRAISE). J Am Coll Cardiol. 2003;41:1933–9.
21. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:1780–6.
22. Ebner N, Jankowska EA, Ponikowski P, et al. The impact of iron deficiency and anaemia on exercise capacity and outcomes in patients with chronic heart failure. Results from the Studies Investigating Co-morbidities Aggravating Heart Failure. Int J Cardiol. 2016;205:6–12.
23. Silverberg DS. The role of erythropoiesis stimulating agents and intravenous (IV) iron in the cardio renal anemia syndrome. Heart Fail Rev. 2011;16:609–14.
24. Anker SD, Comin CJ, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436–48.
25. Metzgeroth G, Hastka J. Iron deficiency anemia and anemia of chronic disorders. Internist (Berl). 2015;56:978–88.
26. Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790:682–93.
27. Ferrucci L, Semba RD, Guralnik JM, et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood. 2010;115:3810–6.
28. Boutou AK, Pitsiou GG, Stanopoulos I, Kontakiotis T, Kyriazis G, Argyropoulou P. Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case-control study. QJM. 2012;105:657–63.
29. Maes K, Nemeth E, Roodman GD, et al. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood. 2010;116:3635–44.
30. Bordini J, Bertilaccio MT, Ponzoni M, et al. Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma. Haematologica. 2015;100:834–41.
31. Hohaus S, Massini G, Giachelia M, et al. Anemia in Hodgkin’s lymphoma: the role of interleukin-6 and hepcidin. J Clin Oncol. 2010;28:2538–43.
32. Tisi MC, Bozzoli V, Giachelia M, et al. Anemia in diffuse large B‑cell non-Hodgkin lymphoma: the role of interleukin-6, hepcidin and erythropoietin. Leuk Lymphoma. 2014;55:270–5.
33. Cazzola M, Ponchio L, Benedetti F de, 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.
34. 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.
35. Ludwiczek S, Aigner E, Theurl I, Weiss G. Cytokine-mediated regulation of iron transport in human monocytic cells. Blood. 2003;101:4148–54.
36. Tilg H, Ulmer H, Kaser A, Weiss G. Role of IL-10 for induction of anemia during inflammation. J Immunol. 2002;169:2204–9.
37. Masson C. Rheumatoid anemia. Joint Bone Spine. 2011;78:131–7.
38. Abdel-Khalek MA, El-Barbary AM, Essa SA, Ghobashi AS. Serum hepcidin: a direct link between anemia of inflammation and coronary artery atherosclerosis in patients with rheumatoid arthritis. J Rheumatol. 2011;38:2153–9.
39. Pakoz ZB, Cekic C, Arabul M, et al. An Evaluation of the Correlation between Hepcidin Serum Levels and Disease Activity in Inflammatory Bowel Disease. Gastroenterol Res Pract. 2015; doi:10.1155/2015/810942.
40. Mecklenburg I, Reznik D, Fasler-Kan E, Drewe J, Beglinger C, Hruz P. Serum hepcidin concentrations correlate with ferritin in patients with inflammatory bowel disease. J Crohns Colitis. 2014;8:1392–7.
41. Swellam M, Gabal KM, Youssef SS. Interleukin-1 receptor antagonist gene polymorphism and hepcidin in rheumatoid arthritis: Correlations with clinical and laboratory indices of disease activity. IUBMB Life. 2013;65:883–8.
42. Darton TC, Blohmke CJ, Giannoulatou E, et al. Rapidly Escalating Hepcidin and Associated Serum Iron Starvation Are Features of the Acute Response to Typhoid Infection in Humans. PLoS Negl Trop Dis. 2015;9:e0004029.
43. Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW. Hepcidin in human iron disorders: diagnostic implications. Clin Chem. 2011;57:1650–69.
44. Theurl M, Theurl I, Hochegger K, et al. Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression. J Mol Med. 2008;86:825–35.
45. Montosi G, Corradini E, Garuti C, et al. Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload. Hepatology. 2005;41:545–52.
46. Lou DQ, Lesbordes JC, Nicolas G, et al. Iron- and inflammation-induced hepcidin gene expression in mice is not mediated by Kupffer cells in vivo. Hepatology. 2005;41:1056–64.
47. Song SN, Iwahashi M, Tomosugi N, et al. Comparative evaluation of the effects of treatment with tocilizumab and TNF-alpha inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients. Arthritis Res Ther. 2013;15:R141.
48. Castell JV, Gomez-Lechon MJ, David M, et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett. 1989;242:237–9.
49. Chen G, Fillebeen C, Wang J, Pantopoulos K. Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis. 2007;28:785–91.
50. Smilevska T, Stamatopoulos K, Samara M, et al. Transferrin receptor-1 and 2 expression in chronic lymphocytic leukemia. Leuk Res. 2006;30:183–9.
51. Andrews SC, Robinson AK, Rodriguez-Quinones F. Bacterial iron homeostasis. FEMS Microbiol Rev. 2003;27:215–37.
52. Bachman MA, Lenio S, Schmidt L, Oyler JE, Weiser JN. Interaction of lipocalin 2, transferrin, and siderophores determines the replicative niche of Klebsiella pneumoniae during pneumonia. MBio. 2012;3:00224–00211.
53. Barber MF, Elde NC. Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. Science. 2014;346:1362–6.
54. Soares MP, Weiss G. The Iron age of host-microbe interactions. EMBO Rep. 2015;16:1482–500.
55. Ganz T, Nemeth E. Iron homeostasis in host defence and inflammation. Nat Rev Immunol. 2015;15:500–10.
56. Schaible UE, Kaufmann SH. Iron and microbial infection. Nat Rev Microbiol. 2004;2:946–53.
57. Skaar EP. The battle for iron between bacterial pathogens and their vertebrate hosts. PLoS Pathog. 2010;6:e1000949.
58. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7:205–14.
59. Bartnikas TB, Andrews NC, Fleming MD. Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood. 2011;117:630–7.
60. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096–101.
61. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114:181–6.
62. Frazer DM, Wilkins SJ, Darshan D, Badrick AC, McLaren GD, Anderson GJ. Stimulated erythropoiesis with secondary iron loading leads to a decrease in hepcidin despite an increase in bone morphogenetic protein 6 expression. Br J Haematol. 2012;157:615–26.
63. Kautz L, Jung G, Nemeth E, Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood. 2015;124:2569–74.
64. Theurl I, Finkenstedt A, Schroll A, et al. Growth differentiation factor 15 in anaemia of chronic disease, iron deficiency anaemia and mixed type anaemia. Br J Haematol. 2010;148:449–55.
65. Sonnweber T, Nachbaur D, Schroll A, et al. Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB. Gut. 2014;63:1951–9.
66. Andriopoulos B Jr., Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41:482–7.
67. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–9.
68. Enns CA, Ahmed R, Wang J, et al. Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway. PLoS ONE. 2013;8:e60534.
69. Armitage AE, Eddowes LA, Gileadi U, et al. Hepcidin regulation by innate immune and infectious stimuli. Blood. 2011;118:4129–39.
70. 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.
71. Schaefer B, Haschka D, Finkenstedt A, et al. Impaired hepcidin expression in alpha-1-antitrypsin deficiency associated with iron overload and progressive liver disease. Hum Mol Genet. 2015;24:6254–63.
72. Canali S, Core AB, Zumbrennen-Bullough KB, et al. Activin B induces noncanonical SMAD1/5/8 signaling via BMP type I receptors in hepatocytes: evidence for a role in hepcidin induction by inflammation in male mice. Endocrinology. 2016;: doi:10.1210/en.2015-1747.
73. Yang Q, Jian J, Katz S, Abramson SB, Huang X. 17beta-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinology. 2012;153:3170–8.
74. Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990;97:734–9.
75. Li X, Rhee DK, Malhotra R, et al. Progesterone receptor membrane component-1 regulates hepcidin biosynthesis. J Clin Invest. 2016;126:389–401.
76. Laine F, Angeli A, Ropert M, et al. Variations of hepcidin and iron-status parameters during the menstrual cycle in healthy women. Br J Haematol. 2015; doi:10.1111/bjh.13906.
77. Przybylowski P, Malyszko JS, Macdougall IC, Malyszko J. Iron metabolism, hepcidin, and anemia in orthotopic heart transplantation recipients treated with mammalian target of rapamycin. Transplant Proc. 2013;45:387–90.
78. Kim A, Fung E, Parikh SG, et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood. 2014;123:1129–36.
79. 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;123:1137–45.
80. Lutz HU, Bussolino F, Flepp R, et al. Naturally occurring anti-band-3 antibodies and complement together mediate phagocytosis of oxidatively stressed human erythrocytes. Proc Natl Acad Sci USA. 1987;84:7368–72.
81. Powell RJ, Machiedo GW, Rush BF Jr., Dikdan G. Oxygen free radicals: effect on red cell deformability in sepsis. Crit Care Med. 1991;19:732–5.
82. Jelkmann W. Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res. 1998;18:555–9.
83. Rodriguez RM, Corwin HL, Gettinger A, Corwin MJ, Gubler D, Pearl RG. Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care. 2001;16:36–41.
84. Artunc F, Risler T. Serum erythropoietin concentrations and responses to anaemia in patients with or without chronic kidney disease. Nephrol Dial Transplant. 2007;22:2900–8.
85. Icardi A, Paoletti E, De Nicola L, Mazzaferro S, Russo R, Cozzolino M. Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: the potential role of inflammation. Nephrol Dial Transplant. 2013;28:1672–9.
86. Bacchetta J, Zaritsky JJ, Sea JL, et al. Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol. 2014;25:564–72.
87. Fehr T, Ammann P, Garzoni D, et al. Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia. Kidney Int. 2004;66:1206–11.
88. Forni GL, Girelli D, Lamagna M, et al. Acquired iron overload associated with antitransferrin monoclonal immunoglobulin: a case report. Am J Hematol. 2008;83:932–4.
89. Forni GL, Pinto V, Musso M, et al. Transferrin-immune complex disease: a potentially overlooked gammopathy mediated by IgM and IgG. Am J Hematol. 2013;88:1045–9.
90. 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.
91. 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.
92. 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.
93. Libregts SF, Gutierrez L, Bruin AM de, et al. Chronic IFN-gamma production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis. Blood. 2011;118:2578–88.
94. Lai CM, Swaminathan N, Beilharz MW, Papadimitriou J, Klinken SP. Interferon-alpha inhibits erythropoietin-induced proliferation, but not differentiation, and restricts erythroleukemia development. J Interferon Cytokine Res. 1995;15:669–75.
95. Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 1999;33:63–72.
96. Gilani ST, Khan DA, Khan FA, Ahmed M. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. J Coll Physicians Surg Pak. 2012;22:101–4.
97. Kozak N, Friedman J, Schattner A. Etanercept-associated transient bone marrow aplasia: a review of the literature and pathogenetic mechanisms. Drugs R D. 2014;14:155–8.
98. Skaar EP, Humayun M, Bae T, DeBord KL, Schneewind O. Iron-source preference of Staphylococcus aureus infections. Science. 2004;305:1626–8.
99. Sartorello R, Budu A, Bagnaresi P, et al. In vivo uptake of a haem analogue Zn protoporphyrin IX by the human malaria parasite P. falciparum-infected red blood cells. Cell Biol Int. 2010;34:859–65.
100. Prentice AM, Doherty CP, Abrams SA, et al. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Blood. 2012;119:1922–8.
101. Portugal S, Carret C, Recker M, et al. Host-mediated regulation of superinfection in malaria. Nat Med. 2011;17:732–7.
102. Minchella PA, Armitage AE, Darboe B, et al. Elevated Hepcidin is part of a complex relation that links mortality with iron homeostasis and anemia in men and women with HIV infection. J Nutr. 2015;145:1194–201.
103. Roelcke D. Cold agglutination. Transfus Med Rev. 1989;3:140–66.
104. 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.
105. Ceresa IF, Noris P, Ambaglio C, Pecci A, Balduini CL. Thrombopoietin is not uniquely responsible for thrombocytosis in inflammatory disorders. Platelets. 2007;18:579–82.
106. Kulnigg-Dabsch S, Evstatiev R, Dejaco C, Gasche C. Effect of iron therapy on platelet counts in patients with inflammatory bowel disease-associated anemia. PLoS ONE. 2012; doi:10.1371/journal.pone.0034520.
107. Kaser A, Brandacher G, Steurer W, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001;98:2720–5.
108. Akan H, Guven N, Aydogdu I, Arat M, Beksac M, Dalva K. Thrombopoietic cytokines in patients with iron deficiency anemia with or without thrombocytosis. Acta Haematol. 2000;103:152–6.
109. Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010;116:1574–84.
110. Fautrel B. Ferritin levels in adult Still’s disease: any sugar? Joint Bone Spine. 2002;69:355–7.
111. Coffernils M, Soupart A, Pradier O, Feremans W, Neve P, Decaux G. Hyperferritinemia in adult onset Still’s disease and the hemophagocytic syndrome. J Rheumatol. 1992;19:1425–7.
112. 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;113:5277–86.
113. Zimmermann MB, Hurrell RF. Nutritional iron deficiency. Lancet. 2007;370:511–20.
114. Rimon E, Levy S, Sapir A, et al. Diagnosis of iron deficiency anemia in the elderly by transferrin receptor-ferritin index. Arch Intern Med. 2002;162:445–9.
115. 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.
116. Skikne BS, Punnonen K, Caldron PH, et al. Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. Am J Hematol. 2011;86:923–7.
117. Archer NM, Brugnara C. Diagnosis of iron-deficient states. Crit Rev Clin Lab Sci. 2015;52:256–72.
118. Bergamaschi G, Di Sabatino A, Albertini R, et al. Serum hepcidin in inflammatory bowel diseases: biological and clinical significance. Inflamm Bowel Dis. 2013;19:2166–72.
119. 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;99:1516–24.
120. Bregman DB, Morris D, Koch TA, He A, Goodnough LT. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Am J Hematol. 2013;88:97–101.
121. Tessitore N, Girelli D, Campostrini N, et al. Hepcidin is not useful as a biomarker for iron needs in haemodialysis patients on maintenance erythropoiesis-stimulating agents. Nephrol Dial Transplant. 2010;25:3996–4002.
122. Valenti L, Messa P, Pelusi S, Campostrini N, Girelli D. Hepcidin levels in chronic hemodialysis patients: a critical evaluation. Clin Chem Lab Med. 2014;52:613–9.
123. Kroot JJ, Herwaarden AE van, Tjalsma H, Jansen RT, Hendriks JC, Swinkels DW. Second round robin for plasma hepcidin methods: first steps toward harmonization. Am J Hematol. 2012;87:977–83.
124. Schaible UE, Kaufmann SH. A nutritive view on the host-pathogen interplay. Trends Microbiol. 2005;13:373–80.
125. Nairz M, Haschka D, Demetz E, Weiss G. Iron at the interface of immunity and infection. Front Pharmacol. 2015;5:152.
126. Nairz M, Schroll A, Moschen AR, et al. Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-kappaB-inducible immune pathways. Immunity. 2011;34:61–74.
127. Nairz M, Sonnweber T, Schroll A, Theurl I, Weiss G. The pleiotropic effects of erythropoietin in infection and inflammation. Microbes Infect. 2012;14:238–46.
128. Yasuda Y, Fujita Y, Matsuo T, et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis. 2003;24:1021–9.
129. Vamvakas EC, Blajchman MA. Deleterious clinical effects of transfusion-associated immunomodulation: fact or fiction? Blood. 2001;97:1180–95.
130. Drueke TB, Parfrey PS. Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s). Kidney Int. 2012;82:952–60.
131. Weiss G, Schett G. Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol. 2013;9:205–15.
132. Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005;122:789–801.
133. Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917–28.
134. Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126:1981–9.
135. Nielsen OH, Ainsworth M, Coskun M, Weiss G. Management of iron-deficiency anemia in inflammatory bowel disease: a systematic review. Medicine (Baltimore). 2015;94:e963.
136. Cepeda-Lopez AC, Melse-Boonstra A, Zimmermann MB, Herter-Aeberli I. In overweight and obese women, dietary iron absorption is reduced and the enhancement of iron absorption by ascorbic acid is one-half that in normal-weight women. Am J Clin Nutr. 2015;102:1389–97.
137. Geisser P, Burckhardt S. The pharmacokinetics and pharmacodynamics of iron preparations. Pharmaceutics. 2011;3:12–33.
138. Rampton D, Folkersen J, Fishbane S, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014;99:1671–6.
139. Hardy S, Vandemergel X. Intravenous iron administration and hypophosphatemia in clinical practice. Int J Rheumatol. 2015; doi:10.1155/2015/468675.
140. Chaston T, Chung B, Mascarenhas M, et al. Evidence for differential effects of hepcidin in macrophages and intestinal epithelial cells. Gut. 2008;57:374–82.
141. Kitsati N, Liakos D, Ermeidi E, et al. Rapid elevation of transferrin saturation and serum hepcidin concentration in hemodialysis patients after intravenous iron infusion. Haematologica. 2015;100:e80–e83.
142. Fernandez-Rodriguez AM, Guindeo-Casasus MC, Molero-Labarta T, et al. Diagnosis of iron deficiency in chronic renal failure. Am J Kidney Dis. 1999;34:508–13.
143. Bennett CL, Jacob S, Hymes J, Usvyat LA, Maddux FW. Anaphylaxis and hypotension after administration of peginesatide. N Engl J Med. 2014;370:2055–6.
144. 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.
145. 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;117:739–48.
146. Uhlig K, Berns JS, Kestenbaum B, et al. KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2010;55:773–99.
147. Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Semin Hematol. 2015;52:348–56.
148. Bennett CL, Spiegel DM, Macdougall IC, et al. A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: a report from the Southern Network on Adverse Reactions (SONAR). Semin Thromb Hemost. 2012;38:783–96.
149. Dignass AU, Gasche C, Bettenworth D, et al. European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. J Crohns Colitis. 2015;9:211–22.
150. Poli M, Asperti M, Ruzzenenti P, Regoni M, Arosio P. Hepcidin antagonists for potential treatments of disorders with hepcidin excess. Front Pharmacol. 2014;5:86.
151. Ganz T, Nemeth E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematology Am Soc Hematol Educ Program. 2011;2011(1):538–42.
152. Theurl I, Schroll A, Sonnweber T, et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood. 2011;118:4977–84.
153. 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;122:3054–61.
154. Eijk LT van, John AS, Schwoebel F, et al. Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans. Blood. 2014;124:2643–6.
155. Fung E, Sugianto P, Hsu J, Damoiseaux R, Ganz T, Nemeth E. High-throughput screening of small molecules identifies hepcidin antagonists. Mol Pharmacol. 2013;83:681–90.
156. Skerra A. Alternative binding proteins: anticalins – harnessing the structural plasticity of the lipocalin ligand pocket to engineer novel binding activities. FEBS J. 2008;275:2677–83.
157. Hohlbaum AM, Trentman S, Gille H. et al. Discovery and Preclinical Characterization of a Novel Hepcidin Antagonist with Tunable PK/PD Properties for the Treatment of Anemia in Different Patient Populations. 53rd ASH Annual Meeting and Exposition, 2011.
158. Moebius U, Feurer W, Fenzl E, Swelm R van, Swinkels D, Hohlbaum A. A phase I study investigating the safety, tolerability, pharmakokinetics and pharmacodynamic activty of the hepcidin antagonist PRS-80#022. Results from a randomzed, placebo controlled, double-blind study following single administration to healthy subjects. Blood. 2015;126:536–536.
159. Witcher DR, Leung D, Hill KA, et al. LY2928507, an antibody targeting ferroportin, is a potent inhibitor of hepcidin activity and increases iron mobilization in normal cynomolgus monkeys. Blood. 2013;122. https://ash.confex.com/ash/2013/webprogram/Paper58923.html
160. Soni H. Prolyl hydroxylase domain-2 (PHD2) inhibition may be a better therapeutic strategy in renal anemia. Med Hypotheses. 2014;82:547–50.
161. World Health Organization. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva 2011. http://www.who.int/vmnis/indicators/haemoglobin/en/. WHO reference number: WHO/NMH/NHD/MNM/11.1. Accessed: 01/01/2016