Anemia of chronic disease and iron deficiency anemia in inflammatory bowel diseases: Pathophysiology, diagnosis, and treatment

Inflammatory Bowel Diseases

Volumn 22, Issue 5, 2016, Pages 1198-1208

  Murawska, Natalia ^a   Fabisiak, Adam ^a   Fichna, Jakub ^a,b  

^a MEDICAL UNIVERSITY OF LODZ   (Poland)

^b MOSSAKOWSKI MEDICAL RESEARCH CENTRE   (Poland)

Author keywords

anemia; anemia of chronic disease; hepcidin; inflammatory bowel diseases; iron deficiency anemia

Indexed keywords

FERROPORTIN; HEPCIDIN; IRON;

ANEMIA; ANEMIA OF CHRONIC DISEASE; CHRONIC DISEASE; DIAGNOSTIC PROCEDURE; HUMAN; INFLAMMATORY BOWEL DISEASE; IRON DEFICIENCY ANEMIA; IRON THERAPY; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN PROTEIN INTERACTION; REVIEW; STANDARD; ANEMIA, IRON-DEFICIENCY; ANIMAL; COMPLICATION; INFLAMMATORY BOWEL DISEASES;

ANEMIA; ANEMIA, IRON-DEFICIENCY; ANIMALS; CHRONIC DISEASE; HUMANS; INFLAMMATORY BOWEL DISEASES; IRON;

EID: 84964799678     PISSN: 10780998     EISSN: 15364844     Source Type: Journal    
DOI: 10.1097/MIB.0000000000000648     Document Type: Review

References (137)

1. Bernstein CN, Blanchard JF, Rawsthorne P, et al. The prevalence of extraintestinal diseases in inflammatory bowel disease: a populationbased study. Am J Gastroenterol. 2001; 96: 1116-1122
2. Rankin GB, Watts HD, Melnyk CS, et al. National Cooperative Crohn's Disease Study: extraintestinal manifestations and perianal complications. Gastroenterology. 1979; 77: 914-920
3. Su CG, Judge TA, Lichtenstein GR. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Clin North Am. 2002; 31: 307-327
4. Gasche C, Lomer MC, Cavill I, et al. Iron, anaemia, and inflammatory bowel diseases. Gut. 2004; 53: 1190-1197
5. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn's disease. Aliment Pharmacol Ther. 2006; 24: 1507-1523
6. Gerasimidis K, Barclay A, Papangelou A, et al. The epidemiology of anemia in pediatric inflammatory bowel disease: prevalence and associated factors at diagnosis and follow-up and the impact of exclusive enteral nutrition. Inflamm Bowel Dis. 2013; 19: 2411-2422
7. Pizzi LT, Weston CM, Goldfarb NI, et al. Impact of chronic conditions on quality of life in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2006; 12: 47-52
8. Gisbert JP, Bermejo F, Pajares R, et al. Oral and intravenous iron treatment in inflammatory bowel disease: hematological response and quality of life improvement. Inflamm Bowel Dis. 2009; 15: 1485-1491
9. Bager P, Befrits R, Wikman O, et al. The prevalence of anemia and iron deficiency in IBD outpatients in Scandinavia. Scand J Gastroenterol. 2011; 46: 304-309
10. M'Koma AE, Wise PE, Schwartz DA, et al. Prevalence and outcome of anemia after restorative proctocolectomy: a clinical literature review. Dis Colon Rectum. 2009; 52: 726-739
11. Bermejo F, Algaba A, Guerra I, et al. Should we monitor vitamin B12 and folate levels in Crohn's disease patients'. Scand J Gastroenterol. 2013; 48: 1272-1277
12. Dudkowiak R, Neubauer K, Poniewierka E. Hepcidin and its role in inflammatory bowel disease. Adv Clin Exp Med. 2013; 22: 585-591
13. Ruchala P, Nemeth E. The pathophysiology and pharmacology of hepcidin. Trends Pharmacol Sci. 2014; 35: 155-161
14. Stein J, Hartmann F, Dignass AU. Diagnosis and management of iron deficiency anemia in patients with IBD. Nat Rev Gastroenterol Hepatol. 2010; 7: 599-610
15. Vijverman A, Piront P, Belaiche J, et al. Evolution of the prevalence and characteristics of anemia in inflammatory bowel diseases between 1993 and 2003. Acta Gastroenterol Belg. 2006; 69: 1-4
16. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999; 341: 1986-1995
17. Andrews NC. Forging a field: the golden age of iron biology. Blood. 2008; 112: 219-230
18. Monsen ER, Hallberg L, Layrisse M, et al. Estimation of available dietary iron. Am J Clin Nutr. 1978; 31: 134-141
19. Disler PB, Lynch SR, Charlton RW, et al. The effect of tea on iron absorption. Gut. 1975; 16: 193-200
20. Hallberg L, Rossander L, Skanberg AB. Phytates and the inhibitory effect of bran on iron absorption in man. Am J Clin Nutr. 1987; 45: 988-996
21. Hallberg L, Brune M, Erlandsson M, et al. Calcium: effect of different amounts on nonheme- And heme-iron absorption in humans. Am J Clin Nutr. 1991; 53: 112-119
22. Hershko C, Hoffbrand AV, Keret D, et al. Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia. Haematologica. 2005; 90: 585-595
23. Child JA, Brozovic B, Dyer NH, et al. The diagnosis of iron deficiency in patients with Crohn's disease. Gut. 1973; 14: 642-648
24. Bartels U, Pedersen NS, Jarnum S. Iron absorption and serum ferritin in chronic inflammatory bowel disease. Scand J Gastroenterol. 1978; 13: 649-656
25. Loitsch SM, Diehl D, Hartmann F, et al. Impaired intestinal iron absorption in inflammatory bowel disease correlates with disease activity and markers of inflammation but is independent of disease location. Gastroenterology. 2011; 140: S5
26. Lomer MC, Cook WB, Jan-Mohamed HJ, et al. Iron requirements based upon iron absorption tests are poorly predicted by haematological indices in patients with inactive inflammatory bowel disease. Br J Nutr. 2012; 107: 1806-1811
27. Lomer MC, Kodjabashia K, Hutchinson C, et al. Intake of dietary iron is low in patients with Crohn's disease: a case-control study. Br J Nutr. 2004; 91: 141-148
28. Cavill I. Erythropoiesis and iron. Best Pract Res Clin Haematol. 2002; 15: 399-409
29. Recommendations to prevent and control iron deficiency in the United States. Centers for disease control and prevention. MMWR Recomm Rep. 1998; 47: 1-29
30. Umbreit J. Iron deficiency: a concise review. Am J Hematol. 2005; 78: 225-231
31. Clark SF. Iron deficiency anemia. Nutr Clin Pract. 2008; 23: 128-141
32. Goddard AF, James MW, McIntyre AS, et al. Guidelines for the management of iron deficiency anaemia. Gut. 2011; 60: 1309-1316
33. Alleyne M, Horne MK, Miller JL. Individualized treatment for irondeficiency anemia in adults. Am J Med. 2008; 121: 943-948
34. Lugg S, Beal F, Nightingale P, et al. Iron treatment and inflammatory bowel disease: what happens in real practice'. J Crohns Colitis. 2014; 8: 876-880
35. Winterbourn CC. Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicol Lett. 1995; 82-83: 969-974
36. Kaye P, Abdulla K, Wood J, et al. Iron-induced mucosal pathology of the upper gastrointestinal tract: a common finding in patients on oral iron therapy. Histopathology. 2008; 53: 311-317
37. Iqbal T, Stein J, Sharma N, et al. Clinical significance of C-reactive protein levels in predicting responsiveness to iron therapy in patients with inflammatory bowel disease and iron deficiency anemia. Dig Dis Sci. 2015; 60: 1375-1381
38. Gasche C, Ahmad T, Tulassay Z, et al. Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: results from a phase-3 clinical trial program. Inflamm Bowel Dis. 2015; 21: 579-588
39. Stein J, Bager P, Befrits R, et al. Anaemia management in patients with inflammatory bowel disease: routine practice across nine European countries. Eur J Gastroenterol Hepatol. 2013; 25: 1456-1463
40. Danese S, Hoffman C, Vel S, et al. Anaemia from a patient perspective in inflammatory bowel disease: results from the European Federation of Crohn's and Ulcerative Colitis Association's online survey. Eur J Gastroenterol Hepatol. 2014; 26: 1385-1391
41. Ross DN. Oral and intravenous iron therapy in the anaemia of rheumatoid arthritis. Ann Rheum Dis. 1950; 9: 358-362
42. Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol. 2004; 15(suppl 2): S93-S98
43. Gozzard D. When is high-dose intravenous iron repletion needed'. Assessing new treatment options. Drug Des Devel Ther. 2011; 5: 51-60
44. Auerbach M, Coyne D, Ballard H. Intravenous iron: from anathema to standard of care. Am J Hematol. 2008; 83: 580-588
45. Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety. Hematol Am Soc Hematol Educ Program. 2010; 2010: 338-347
46. Chertow GM, Mason PD, Vaage-Nilsen O, et al. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006; 21: 378-382
47. Gasche C, Berstad A, Befrits R, et al. Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis. 2007; 13: 1545-1553
48. Lee TW, Kolber MR, Fedorak RN, et al. Iron replacement therapy in inflammatory bowel disease patients with iron deficiency anemia: a systematic review and meta-Analysis. J Crohns Colitis. 2012; 6: 267-275
49. Mearin F, Balboa A, Castells A, et al. Iron deficiency anemia and use of intravenous iron in digestive disease [in Spanish]. Gastroenterol Hepatol. 2010; 33: 605-613
50. Gomollon F, Gisbert JP. Intravenous iron in inflammatory bowel diseases. Curr Opin Gastroenterol. 2013; 29: 201-207
51. Çekiç C, Ipek S, Aslan F, et al. The effect of intravenous iron treatment on quality of life in inflammatory bowel disease patients with nonanemic iron deficiency. Gastroenterol Res Pract. 2015; 2015: 582163
52. Koutroubakis IE, Oustamanolakis P, Karakoidas C, et al. Safety and efficacy of total-dose infusion of low molecular weight iron dextran for iron deficiency anemia in patients with inflammatory bowel disease. Dig Dis Sci. 2010; 55: 2327-2331
53. Mamula P, Piccoli DA, Peck SN, et al. Total dose intravenous infusion of iron dextran for iron-deficiency anemia in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2002; 34: 286-290
54. Khalil A, Goodhand JR, Wahed M, et al. Efficacy and tolerability of intravenous iron dextran and oral iron in inflammatory bowel disease: a case-matched study in clinical practice. Eur J Gastroenterol Hepatol. 2011; 23: 1029-1035
55. Laman CA, Silverstein SB, Rodgers GM. Parenteral iron therapy: a single institution's experience over a 5-year period. J Natl Compr Canc Netw. 2005; 3: 791795
56. Bodemar G, Kechagias S, Almer S, et al. Treatment of anaemia in inflammatory bowel disease with iron sucrose. Scand J Gastroenterol. 2004; 39: 454-458
57. Gasche C, Dejaco C, Reinisch W, et al. Sequential treatment of anemia in ulcerative colitis with intravenous iron and erythropoietin. Digestion. 1999; 60: 262-267
58. Gasche C, Dejaco C, Waldhoer T, et al. Intravenous iron and erythropoietin for anemia associated with Crohn disease. A randomized, controlled trial. Ann Intern Med. 1997; 126: 782-787
59. Katsanos K, Cavalier E, Ferrante M, et al. Intravenous iron therapy restores functional iron deficiency induced by infliximab. J Crohns Colitis. 2007; 1: 97-105
60. Schroder O, Mickisch O, Seidler U, et al. Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease-A randomized, controlled, open-label, multicenter study. Am J Gastroenterol. 2005; 100: 2503-2509
61. Schroder O, Schrott M, Blumenstein I, et al. A study for the evaluation of safety and tolerability of intravenous high-dose iron sucrose in patients with iron deficiency anemia due to gastrointestinal bleeding. Z Gastroenterol. 2004; 42: 663-667
62. Lindgren S, Wikman O, Befrits R, et al. Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients: a randomized, controlled, evaluator-blind, multicentre study. Scand J Gastroenterol. 2009; 44: 838-845
63. Jahn MR, Andreasen HB, Futterer S, et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm. 2011; 78: 480-491
64. Reinisch W, Staun M, Tandon RK, et al. A randomized, open-label, noninferiority study of intravenous iron isomaltoside 1, 000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED). Am J Gastroenterol. 2013; 108: 1877-1888
65. Evstatiev R, Marteau P, Iqbal T, et al. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology. 2011; 141: 846-853
66. Kulnigg S, Stoinov S, Simanenkov V, et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. Am J Gastroenterol. 2008; 103: 1182-1192
67. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005; 352: 1011-1023
68. Roodman GD, Bird A, Hutzler D, et al. 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: 928-935
69. Blick M, Sherwin SA, Rosenblum M, et al. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res. 1987; 47: 2986-2989
70. Grigorakaki C, Morceau F, Chateauvieux S, et al. Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression. Biochem Pharmacol. 2011; 82: 156-166
71. Ohneda K, Yamamoto M. Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage. Acta Haematol. 2002; 108: 237-245
72. Stopka T, Amanatullah DF, Papetti M, et al. PU.1 inhibits the erythroid program by binding to GATA-1 on DNA and creating a repressive chromatin structure. EMBO J. 2005; 24: 3712-3723
73. Imagawa S, Yamamoto M, Miura Y. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood. 1997; 89: 1430-1439
74. Nakano Y, Imagawa S, Matsumoto K, et al. Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease. Blood. 2004; 104: 4300-4307
75. La FK, Reimann C, Jelkmann W, et al. Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J. 2002; 16: 1811-1813
76. Zhao W, Kitidis C, Fleming MD, et al. Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway. Blood. 2006; 107: 907-915
77. Rusten LS, Jacobsen SE. Tumor necrosis factor (TNF)-Alpha directly inhibits human erythropoiesis in vitro: role of p55 and p75 TNF receptors. Blood. 1995; 85: 989-996
78. Buck I, Morceau F, Cristofanon S, et al. Tumor necrosis factor alpha inhibits erythroid differentiation in human erythropoietin-dependent cells involving p38 MAPK pathway, GATA-1 and FOG-1 downregulation and GATA-2 upregulation. Biochem Pharmacol. 2008; 76: 1229-1239
79. Ikonomi P, Rivera CE, Riordan M, et al. Overexpression of GATA-2 inhibits erythroid and promotes megakaryocyte differentiation. Exp Hematol. 2000; 28: 1423-1431
80. Liu JJ, Hou SC, Shen CK. Erythroid gene suppression by NF-kappa B. J Biol Chem. 2003; 278: 19534-19540
81. Libregts SF, Gutierrez L, De Bruin AM, 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: 2578-2588
82. Felli N, Pedini F, Zeuner A, et al. Multiple members of the TNF superfamily contribute to IFN-gamma-mediated inhibition of erythropoiesis. J Immunol. 2005; 175: 1464-1472
83. Dai CH, Price JO, Brunner T, et al. 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: 1235-1242
84. Atanasiu V, Manolescu B, Stoian I. Hepcidin-central regulator of iron metabolism. Eur J Haematol. 2007; 78: 1-10
85. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306: 2090-2093
86. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfidebonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000; 480: 147-150
87. Rodriguez R, Jung CL, Gabayan V, et al. Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. Infect Immun. 2014; 82: 745-752
88. Besson-Fournier C, Latour C, Kautz L, et al. Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling. Blood. 2012; 120: 431-439
89. 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: 1271-1276
90. Wallace DF, Subramaniam VN. Analysis of IL-22 contribution to hepcidin induction and hypoferremia during the response to LPS in vivo. Int Immunol. 2015; 27: 281-287
91. 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: 2538-2543
92. Tsuchiya K, Nitta K. Hepcidin is a potential regulator of iron status in chronic kidney disease. Ther Apher Dial. 2013; 17: 1-8
93. Demirag MD, Haznedaroglu S, Sancak B, et al. Circulating hepcidin in the crossroads of anemia and inflammation associated with rheumatoid arthritis. Intern Med. 2009; 48: 421-426
94. Basseri RJ, Nemeth E, Vassilaki ME, et al. Hepcidin is a key mediator of anemia of inflammation in Crohn's disease. J Crohns Colitis. 2013; 7: e286-e291
95. Oustamanolakis P, Koutroubakis IE, Messaritakis I, et al. Serum hepcidin and prohepcidin concentrations in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2011; 23: 262-268
96. Nagy J, Lakner L, Poor VS, et al. Serum prohepcidin levels in chronic inflammatory bowel diseases. J Crohns Colitis. 2010; 4: 649-653
97. Mecklenburg I, Reznik D, Fasler-Kan E, et al. Serum hepcidin concentrations correlate with ferritin in patients with inflammatory bowel disease. J Crohns Colitis. 2014; 8: 1392-1397
98. Semrin G, Fishman DS, Bousvaros A, et al. Impaired intestinal iron absorption in Crohn's disease correlates with disease activity and markers of inflammation. Inflamm Bowel Dis. 2006; 12: 1101-1106
99. Shanmugam NK, Trebicka E, Fu LL, et al. Intestinal inflammation modulates expression of the iron-regulating hormone hepcidin depending on erythropoietic activity and the commensal microbiota. J Immunol. 2014; 193: 13981407
100. Evstatiev R, Alexeeva O, Bokemeyer B, et al. Ferric carboxymaltose prevents recurrence of anemia in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013; 11: 269-277
101. Vaughn BP, Shah S, Cheifetz AS. The role of mucosal healing in the treatment of patients with inflammatory bowel disease. Curr Treat Options Gastroenterol. 2014; 12: 103-117
102. Bergamaschi G, Di SA, Albertini R, et al. Prevalence and pathogenesis of anemia in inflammatory bowel disease. Influence of anti-Tumor necrosis factor-Alpha treatment. Haematologica. 2010; 95: 199-205
103. Rubin DT, Mulani P, Chao J, et al. Effect of adalimumab on clinical laboratory parameters in patients with Crohn's disease: results from the CHARM trial. Inflamm Bowel Dis. 2012; 18: 818-825
104. Koutroubakis IE, Karmiris K, Makreas S, et al. Effectiveness of darbepoetin-Alfa in combination with intravenous iron sucrose in patients with inflammatory bowel disease and refractory anaemia: a pilot study. Eur J Gastroenterol Hepatol. 2006; 18: 421-425
105. Kulnigg S, Teischinger L, Dejaco C, et al. Rapid recurrence of IBDassociated anemia and iron deficiency after intravenous iron sucrose and erythropoietin treatment. Am J Gastroenterol. 2009; 104: 1460
106. Katsanos KH, Tatsioni A, Natsi D, et al. Recombinant human erythropoietin in patients with inflammatory bowel disease and refractory anemia: a 15-year single center experience. J Crohns Colitis. 2012; 6: 56-61
107. Liu S, Ren J, Hong Z, et al. Efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease: a prospective cohort study. Nutr Clin Pract. 2013; 28: 120-127
108. Babitt JL, Huang FW, Xia Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007; 117: 1933-1939
109. Theurl I, Schroll A, Sonnweber T, et al. Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. Blood. 2011; 118: 4977-4984
110. Wang L, Trebicka E, Fu Y, et al. The bone morphogenetic proteinhepcidin axis as a therapeutic target in inflammatory bowel disease. Inflamm Bowel Dis. 2012; 18: 112-119
111. Poli M, Girelli D, Campostrini N, et al. Heparin: a potent inhibitor of hepcidin expression in vitro and in vivo. Blood. 2011; 117: 997-1004
112. Chung WS, Lin CL, Hsu WH, et al. Inflammatory bowel disease increases the risks of deep vein thrombosis and pulmonary embolism in the hospitalized patients: a nationwide cohort study. Thromb Res. 2015; 135: 492-496
113. 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: 1564-1573
114. Poli M, Asperti M, Ruzzenenti P, et al. Oversulfated heparins with low anticoagulant activity are strong and fast inhibitors of hepcidin expression in vitro and in vivo. Biochem Pharmacol. 2014; 92: 467-475
115. Hashizume M, Uchiyama Y, Horai N, et al. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production. Rheumatol Int. 2010; 30: 917-923
116. Fatih N, Camberlein E, Island ML, et al. Natural and synthetic STAT3 inhibitors reduce hepcidin expression in differentiated mouse hepatocytes expressing the active phosphorylated STAT3 form. J Mol Med (Berl). 2010; 88: 477-486
117. Zhang SP, Wang Z, Wang LX, et al. AG490: an inhibitor of hepcidin expression in vivo. World J Gastroenterol. 2011; 17: 5032-5034
118. 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: 3616-3624
119. Hohlbaum A, Gille H, Christian J, et al. Iron mobilization and pharmacodynic marker measurements in non-human primates following administration of PRS-080, a novel and highly specific anti-hepcidin therapeutic. Am J Hematol. 2013; 88: E41
120. Leung D, Hill KA, De Rosa DC, et al. LY2928057, an antibody targeting ferroportin, is a potent inhibitor of hepcidin activity and increases iron mobilization in normal cynomolgus monkeys. Blood. 2013; 122: 3433
121. Fung E, Sugianto P, Hsu J, et al. High-Throughput screening of small molecules identifies hepcidin antagonists. Mol Pharmacol. 2013; 83: 681-690
122. Ahn J, Johnstone RM. Origin of a soluble truncated transferrin receptor. Blood. 1993; 81: 2442-2451
123. Kohgo Y, Niitsu Y, Kondo H, et al. Serum transferrin receptor as a new index of erythropoiesis. Blood. 1987; 70: 1955-1958
124. Pettersson T, Kivivuori SM, Siimes M.A. Is serum transferrin receptor useful for detecting iron-deficiency in anaemic patients with chronic inflammatory diseases'. Br J Rheumatol. 1994; 33: 740-744
125. 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
126. Margetic S, Topic E, Ruzic DF, et al. Soluble transferrin receptor and transferrin receptor-ferritin index in iron deficiency anemia and anemia in rheumatoid arthritis. Clin Chem Lab Med. 2005; 43: 326-331
127. Oustamanolakis P, Koutroubakis IE, Messaritakis I, et al. Soluble transferrin receptor-ferritin index in the evaluation of anemia in inflammatory bowel disease: a case-control study. Ann Gastroenterol. 2011; 24: 108-114
128. Brugnara C. Reticulocyte cellular indices: a new approach in the diagnosis of anemias and monitoring of erythropoietic function. Crit Rev Clin Lab Sci. 2000; 37: 93-130
129. Markovi-c M, Majkic-Singh N, Ignjatovic S, et al. Reticulocyte haemoglobin content vs. soluble transferrin receptor and ferritin index in iron deficiency anaemia accompanied with inflammation. Int J Lab Hematol. 2007; 29: 341-346
130. Urrechaga E, Borque L, Escanero JF. Percentage of hypochromic erythrocytes as a potential marker of iron availability. Clin Chem Lab Med. 2012; 50: 685-687
131. Enko D, Wagner H, Kriegshauser G, et al. Hepcidin-25 vs. conventional clinical biomarkers in the diagnosis of functional iron deficiency. Eur J Haematol. 2015. Epub ahead of print
132. Karlsson T. Mass spectrometry evaluation of the hepcidin-25 assay in the differential diagnosis of iron deficiency anaemia with concurrent inflammation and anaemia of inflammation in elderly patients. Eur J Haematol. 2015; 95: 467-471
133. Voudoukis E, Karmiris K, Oustamanolakis P, et al. Association between thrombocytosis and iron deficiency anemia in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2013; 25: 1212-1216
134. Kulnigg-Dabsch S, Evstatiev R, Dejaco C, et al. Effect of iron therapy on platelet counts in patients with inflammatory bowel disease-Associated anemia. PLoS One. 2012; 7: e34520
135. Ganzoni AM. Intravenous iron-dextran: therapeutic and experimental possibilities [in German]. Schweiz Med Wochenschr. 1970; 100: 301-303
136. Walters GO, Miller FM, Worwood M. Serum ferritin concentration and iron stores in normal subjects. J Clin Pathol. 1973; 26: 770-772
137. 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: 211-222