Journal of Clinical Immunology

, Volume 32, Issue 4, pp 746–752 | Cite as

Inflammation-Induced Hepcidin is Associated with the Development of Anemia and Coronary Artery Lesions in Kawasaki Disease

  • Ho-Chang Kuo
  • Ya-Ling Yang
  • Jiin-Haur Chuang
  • Mao-Meng Tiao
  • Hong-Ren Yu
  • Li-Tung Huang
  • Kuender D. Yang
  • Wei-Chiao Chang
  • Chiu-Ping Lee
  • Ying-Hsien Huang



Kawasaki disease (KD) is a systemic febrile vasculitis complicated by coronary artery lesions (CAL). Anemia is common in patients with KD and is associated with a prolonged duration of active inflammation. Hepcidin is a central modulator of inflammation-associated anemia, acting via control of iron absorption and a direct inhibitory effect on erythropoiesis. The aims of this study were to investigate the role of inflammation-induced hepcidin in the development of anemia, the occurrence of CAL formation, and IVIG treatment response in patients with KD.


Eighty-six KD patients and 30 febrile controls were enrolled. Levels of interleukin (IL)-6 and serum hepcidin were measured in sera by enzyme-linked immunosorbent assay. Hemoglobin and serum iron levels were also measured.


Hemoglobin and iron levels were lower in KD patients than in controls (p < 0.001 and p = 0.009, respectively). Serum hepcidin and IL-6 levels were higher in KD patients than in controls (both p < 0.001) before intravenous immunoglobulin (IVIG) treatment. After IVIG treatment, serum hepcidin, IL-6, and hemoglobin levels decreased significantly (all p < 0.001). In addition, the serum hepcidin levels before IVIG treatment were negatively correlated with hemoglobin levels after IVIG treatment (R = −0.188, p = 0.046) and positively correlated with the changes of hemoglobin levels after IVIG treatment (R = 0.269, p = 0.015). Furthermore, serum hepcidin levels were negatively correlated with serum iron levels (R = −0.412, p = 0.002), which were positively correlated with hemoglobin levels (R = 0.210, p = 0.045). Additionally, the change of hepcidin levels was associated with IVIG treatment response and the occurrence of CAL formation.


Inappropriately raised hepcidin levels impair iron metabolism and are associated with decreased hemoglobin levels in KD patients. Inflammation-induced hepcidin is associated with the development of anemia and disease outcomes in patients with KD.


Coronary artery lesion hemoglobin hepcidin IL-6 iron Kawasaki disease 



This study was supported by grants from the National Science Council Grant #NSC 99-2314-B-182A-032-MY2, NSC 100-2314-B-182A-048-MY3, and Chang Gung Memorial Hospital CMRPG8A021, Taiwan.

Conflicts of Interest

The authors have indicated that they have no financial relationships relevant to this article to disclose.


  1. 1.
    Wang CL, Wu YT, Liu CA, Kuo HC, Yang KD. Kawasaki disease: infection, immunity and genetics. Pediatr Infect Dis J. 2005;24(11):998–1004.PubMedCrossRefGoogle Scholar
  2. 2.
    Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747–71.PubMedCrossRefGoogle Scholar
  3. 3.
    Alves NR, Magalhaes CM, Almeida Rde F, Santos RC, Gandolfi L, Pratesi R. Prospective study of Kawasaki disease complications: review of 115 cases. Rev Assoc Med Bras. 2011;57(3):295–300.PubMedCrossRefGoogle Scholar
  4. 4.
    Fukushige J, Takahashi N, Ueda Y, Ueda K. Incidence and clinical features of incomplete Kawasaki disease. Acta Paediatr. 1994;83(10):1057–60.PubMedCrossRefGoogle Scholar
  5. 5.
    Kuo HC, Wang CL, Liang CD, Yu HR, Chen HH, Wang L, et al. Persistent monocytosis after intravenous immunoglobulin therapy correlated with the development of coronary artery lesions in patients with Kawasaki disease. J Microbiol Immunol Infect. 2007;40(5):395–400.PubMedGoogle Scholar
  6. 6.
    Kuo HC, Yang KD, Liang CD, Bong CN, Yu HR, Wang L, et al. The relationship of eosinophilia to intravenous immunoglobulin treatment failure in Kawasaki disease. Pediatr Allergy Immunol. 2007;18(4):354–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Nakagawa M, Watanabe N, Okuno M, Kondo M, Okagawa H, Taga T. Severe hemolytic anemia following high-dose intravenous immunoglobulin administration in a patient with Kawasaki disease. Am J Hematol. 2000;63(3):160–1.PubMedCrossRefGoogle Scholar
  8. 8.
    Le NT, Richardson DR. Ferroportin1: a new iron export molecule? Int J Biochem Cell Biol. 2002;34(2):103–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Cherian S, Forbes DA, Cook AG, Sanfilippo FM, Kemna EH, Swinkels DW, et al. An insight into the relationships between hepcidin, anemia, infections and inflammatory cytokines in pediatric refugees: a cross-sectional study. PLoS One. 2008;3(12):e4030.PubMedCrossRefGoogle Scholar
  11. 11.
    Suganami Y, Kawashima H, Hasegawa D, Sato S, Hoshika A. Clinical application of rapid assay of serum interleukin-6 in Kawasaki disease. Pediatr Int. 2008;50(2):264–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Kishimoto S, Suda K, Teramachi Y, Nishino H, Kudo Y, Ishii H, et al. Increased plasma type B natriuretic peptide in the acute phase of Kawasaki disease. Pediatr Int. 2011;53(5):736–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Wu JM, Chiou YY, Hung WP, Chiu NT, Chen MJ, Wang JN. Urinary cytokines and renal Doppler study in Kawasaki disease. J Pediatr. 2010;156(5):792–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Song SN, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki K. 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(18):3627–34.PubMedCrossRefGoogle Scholar
  15. 15.
    Shulman ST, De Inocencio J, Hirsch R. Kawasaki disease. Pediatr Clin North Am. 1995;42(5):1205–22.PubMedGoogle Scholar
  16. 16.
    Kuo HC, Yu HR, Juo SH, Yang KD, Wang YS, Liang CD, et al. CASP3 gene single-nucleotide polymorphism (rs72689236) and Kawasaki disease in Taiwanese children. J Hum Genet. 2011;56(2):161–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Kuo HC, Liang CD, Wang CL, Yu HR, Hwang KP, Yang KD. Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease. Acta Paediatr. 2010;99(10):1578–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Girelli D, Trombini P, Busti F, Campostrini N, Sandri M, Pelucchi S, et al. A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis. Haematologica. 2011;96(4):500–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Armitage AE, Eddowes LA, Gileadi U, Cole S, Spottiswoode N, Selvakumar TA, et al. Hepcidin regulation by innate immune and infectious stimuli. Blood. 2011;118(15):4129–39.PubMedCrossRefGoogle Scholar
  20. 20.
    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(10):2153–9.PubMedCrossRefGoogle Scholar
  21. 21.
    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(5):1864–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Pietrangelo A, Dierssen U, Valli L, Garuti C, Rump A, Corradini E, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007;132(1):294–300.PubMedCrossRefGoogle Scholar
  23. 23.
    Gupta M, Noel GJ, Schaefer M, Friedman D, Bussel J, Johann-Liang R. Cytokine modulation with immune gamma-globulin in peripheral blood of normal children and its implications in Kawasaki disease treatment. J Clin Immunol. 2001;21(3):193–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Taytawat P, Viravud Y, Plakornkul V, Roongruangchai J, Manoonpol C. Identification of the external laryngeal nerve: its anatomical relations to inferior constrictor muscle, superior thyroid artery, and superior pole of the thyroid gland in Thais. J Med Assoc Thai. 2010;93(8):961–8.PubMedGoogle Scholar
  25. 25.
    Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol. 2011;154(3):289–300.PubMedCrossRefGoogle Scholar
  26. 26.
    Sihler KC, Raghavendran K, Westerman M, Ye W, Napolitano LM. Hepcidin in trauma: linking injury, inflammation, and anemia. J Trauma. 2010;69(4):831–7.PubMedCrossRefGoogle Scholar
  27. 27.
    de Mast Q, Nadjm B, Reyburn H, Kemna EH, Amos B, Laarakkers CM, et al. Assessment of urinary concentrations of hepcidin provides novel insight into disturbances in iron homeostasis during malarial infection. J Infect Dis. 2009;199(2):253–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Demirag MD, Haznedaroglu S, Sancak B, Konca C, Gulbahar O, Ozturk MA, et al. Circulating hepcidin in the crossroads of anemia and inflammation associated with rheumatoid arthritis. Intern Med. 2009;48(6):421–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Isoda M, Hanawa H, Watanabe R, Yoshida T, Toba K, Yoshida K, et al. Expression of the peptide hormone hepcidin increases in cardiomyocytes under myocarditis and myocardial infarction. J Nutr Biochem. 2010;21(8):749–56.PubMedCrossRefGoogle Scholar
  30. 30.
    del Giudice EM, Santoro N, Amato A, Brienza C, Calabro P, Wiegerinck ET, et al. Hepcidin in obese children as a potential mediator of the association between obesity and iron deficiency. J Clin Endocrinol Metab. 2009;94(12):5102–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Dallalio G, Law E, Means Jr RT. Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood. 2006;107(7):2702–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Frank GR, Cherrick I, Karayalcin G, Valderrama E, Lanzkowsky P. Transient erythroblastopenia in a child with Kawasaki syndrome: a case report. Am J Pediatr Hematol Oncol. 1994;16(3):271–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Kurtzhals JA, Rodrigues O, Addae M, Commey JO, Nkrumah FK, Hviid L. Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria. Br J Haematol. 1997;97(1):169–74.PubMedCrossRefGoogle Scholar
  34. 34.
    Kim JJ, Hong YM, Yun SW, Han MK, Lee KY, Song MS, et al. Assessment of risk factors for Korean children with Kawasaki disease. Pediatr Cardiol. 2012. doi: 10.1007/s00246-011-0143-1.
  35. 35.
    Saeed O, Otsuka F, Polavarapu R, Karmali V, Weiss D, Davis T, et al. Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(2):299–307.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ho-Chang Kuo
    • 1
  • Ya-Ling Yang
    • 3
  • Jiin-Haur Chuang
    • 4
  • Mao-Meng Tiao
    • 2
  • Hong-Ren Yu
    • 2
  • Li-Tung Huang
    • 2
  • Kuender D. Yang
    • 5
  • Wei-Chiao Chang
    • 6
  • Chiu-Ping Lee
    • 2
  • Ying-Hsien Huang
    • 2
  1. 1.Genomic and Proteomic Core Laboratory, Department of Medical Research and Department of PediatricsKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungRepublic of China
  2. 2.Department of PediatricsKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungRepublic of China
  3. 3.Department of AnesthesiologyKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungRepublic of China
  4. 4.Department of SurgeryKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiungRepublic of China
  5. 5.Department of Medical ResearchShow Chwan Memorial Hospital in Chang BingChanghuaRepublic of China
  6. 6.Department of Medical Genetics, Kaohsiung Medical UniversityCancer Center, Kaohsiung Medical University HospitalKaohsiungRepublic of China

Personalised recommendations