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Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions

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Abstract

Heme oxygenase (HO)-1, a heme-degrading enzyme inducible by various stimuli, plays a key role in the regulation of inflammatory response in monocytes/macrophages. The serum HO-1 level is remarkably increased in patients with secondary hemophagocytic syndrome (HPS) or adult-onset Still’s disease. We measured serum HO-1 levels in patients with a variety of hematological diseases, including secondary HPS, by means of ELISA. Serum HO-1 levels were significantly higher in 22 patients with HPS (134.7 ± 116.2 ng/mL, P < 0.0001) at diagnosis than in 80 patients with other hematological diseases. The most effective cutoff point between HPS and other conditions was 14.5 ng/mL, with 100.0% sensitivity and 96.3% specificity. In HPS patients, the serum HO-1 levels showed the highest correlation with serum ferritin (r = 0.682, P = 0.0005), which reflects the disease activity of HPS. Moreover, both HO-1 and ferritin levels were reduced in parallel after successful treatment in patients with HPS, irrespective of underlying diseases. However, HO-1 levels were not elevated in patients with other causes of hyperferritinemia. These data demonstrate that serum HO-1 can distinguish secondary HPS from other hematological diseases, including those associated with hyperferritinemia.

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References

  1. Otterbein LE, Soares MP, Yamashita K, Bach FH. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 2003;24:449–55.

    Article  CAS  PubMed  Google Scholar 

  2. Morse D, Choi AM. Heme oxygenase-1: the “emerging molecule” has arrived. Am J Respir Cell Mol Biol. 2002;27:8–16.

    CAS  PubMed  Google Scholar 

  3. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest. 1999;103:129–35.

    Article  CAS  PubMed  Google Scholar 

  4. Kawashima A, Oda Y, Yachie A, Koizumi S, Nakanishi I. Heme oxygenase-1 deficiency: the first autopsy case. Hum Pathol. 2002;33:125–30.

    Article  PubMed  Google Scholar 

  5. Poss KD, Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA. 1997;94:10925–30.

    Article  CAS  PubMed  Google Scholar 

  6. Kirino Y, Takeno M, Murakami S, Kobayashi M, Kobayashi H, Miura K, et al. Tumor necrosis factor alpha acceleration of inflammatory responses by down-regulating heme oxygenase 1 in human peripheral monocytes. Arthritis Rheum. 2007;56:464–75.

    Article  CAS  PubMed  Google Scholar 

  7. Yachie A, Toma T, Mizuno K, Okamoto H, Shimura S, Ohta K, et al. Heme oxygenase-1 production by peripheral blood monocytes during acute inflammatory illnesses of children. Exp Biol Med (Maywood). 2003;228:550–6.

    CAS  Google Scholar 

  8. Goda N, Suzuki K, Naito M, Takeoka S, Tsuchida E, Ishimura Y, et al. Distribution of heme oxygenase isoforms in rat liver. Topographic basis for carbon monoxide-mediated microvascular relaxation. J Clin Invest. 1998;101:604–12.

    Article  CAS  PubMed  Google Scholar 

  9. Kirino Y, Takeno M, Iwasaki M, Ueda A, Ohno S, Shirai A, et al. Increased serum HO-1 in hemophagocytic syndrome and adult-onset Still’s disease: use in the differential diagnosis of hyperferritinemia. Arthritis Res Ther. 2005;7:R616–24.

    Article  CAS  PubMed  Google Scholar 

  10. Takahashi A, Mori M, Naruto T, Nakajima S, Miyamae T, Imagawa T, et al. The role of heme oxygenase-1 in systemic-onset juvenile idiopathic arthritis. Mod Rheumatol. 2009;19:302–8.

    Article  CAS  PubMed  Google Scholar 

  11. Kirino M, Kirino Y, Takeno M, Nagashima Y, Takahashi K, Kobayashi M, et al. Heme oxygenase 1 attenuates the development of atopic dermatitis-like lesions in mice: implications for human disease. J Allergy Clin Immunol. 2008;122:290–7. (7 e1–8).

    Article  CAS  PubMed  Google Scholar 

  12. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.

    Article  PubMed  Google Scholar 

  13. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21:245–53.

    Article  CAS  PubMed  Google Scholar 

  14. Esumi N, Ikushima S, Hibi S, Todo S, Imashuku S. High serum ferritin level as a marker of malignant histiocytosis and virus-associated hemophagocytic syndrome. Cancer. 1988;61:2071–6.

    Article  CAS  PubMed  Google Scholar 

  15. Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev. 2009;23:95–104.

    Article  CAS  PubMed  Google Scholar 

  16. Imashuku S. Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol. 1997;66:135–51.

    Article  CAS  PubMed  Google Scholar 

  17. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–8.

    CAS  PubMed  Google Scholar 

  18. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol. 1991;28:250–9.

    CAS  PubMed  Google Scholar 

  19. Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol. 2008;88:24–9.

    Article  PubMed  Google Scholar 

  20. Suzuki T, Tomonaga M, Miyazaki Y, Nakao S, Ohyashiki K, Matsumura I, et al. Japanese epidemiological survey with consensus statement on Japanese guidelines for treatment of iron overload in bone marrow failure syndromes. Int J Hematol. 2008;88:30–5.

    Article  CAS  PubMed  Google Scholar 

  21. Mayerhofer M, Florian S, Krauth MT, Aichberger KJ, Bilban M, Marculescu R, et al. Identification of heme oxygenase-1 as a novel BCR/ABL-dependent survival factor in chronic myeloid leukemia. Cancer Res. 2004;64:3148–54.

    Article  CAS  PubMed  Google Scholar 

  22. Osugi Y, Hara J, Tagawa S, Takai K, Hosoi G, Matsuda Y, et al. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood. 1997;89:4100–3.

    CAS  PubMed  Google Scholar 

  23. Billiau AD, Roskams T, Van Damme-Lombaerts R, Matthys P, Wouters C. Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFN-gamma-producing lymphocytes and IL-6- and TNF-alpha-producing macrophages. Blood. 2005;105:1648–51.

    Article  CAS  PubMed  Google Scholar 

  24. Mazodier K, Marin V, Novick D, Farnarier C, Robitail S, Schleinitz N, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005;106:3483–9.

    Article  CAS  PubMed  Google Scholar 

  25. Schaer DJ, Schaer CA, Schoedon G, Imhof A, Kurrer MO. Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis. Eur J Haematol. 2006;77:432–6.

    Article  CAS  PubMed  Google Scholar 

  26. Kawashima M, Yamamura M, Taniai M, Yamauchi H, Tanimoto T, Kurimoto M, et al. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still’s disease. Arthritis Rheum. 2001;44:550–60.

    Article  CAS  PubMed  Google Scholar 

  27. Kobayashi H, Takeno M, Saito T, Takeda Y, Kirino Y, Noyori K, et al. Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis. Arthritis Rheum. 2006;54:1132–42.

    Article  CAS  PubMed  Google Scholar 

  28. Jozkowicz A, Was H, Dulak J. Heme oxygenase-1 in tumors: is it a false friend? Antioxid Redox Signal. 2007;9:2099–117.

    Article  CAS  PubMed  Google Scholar 

  29. Keller M, Ruegg A, Werner S, Beer HD. Active caspase-1 is a regulator of unconventional protein secretion. Cell. 2008;132:818–31.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by grants from Research on Specific Disease of the Health Science Research Grants from the Ministry of Health, Labor, and Welfare of Japan (Y.I.); a 2008–2010 grant-in-aid for scientific research (project no. 20591174) from the Ministry of Education, Culture, Sports, and Technology of Japan (M. Takeno); and 2007–2009 grants from the Yokohama Foundation for Advancement of Medical Science (M. Takeno). The sources of funding had no role in the writing of the report and did not participate in the decision to publish the results. We thank Dr. Shuji Murakami of the Kanagawa Cancer Center, Yokohama, for statistics advice.

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Correspondence to Yoshiaki Ishigatsubo.

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Miyazaki, T., Kirino, Y., Takeno, M. et al. Serum HO-1 is useful to make differential diagnosis of secondary hemophagocytic syndrome from other similar hematological conditions. Int J Hematol 91, 229–237 (2010). https://doi.org/10.1007/s12185-010-0495-y

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  • DOI: https://doi.org/10.1007/s12185-010-0495-y

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