Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
권호 표지

Serum homocysteine and tumor necrosis factor-alpha levels after intravenous gammaglobulin treatment in patients with Kawasaki disease

가와사키병 환자에서 면역글로불린 투여 전 후 호모시스테인, tumor necrosis factor-alpha 혈중 농도에 대한 연구 - 가와사키병 환아에서 호모시스테인, TNF-α 혈중 농도 비교 분석 -

  • Cha, Jung Hwa (Department of Pediatrics, College of Medicine, Ewha Womans University) ;
  • Hong, Young Mi (Department of Pediatrics, College of Medicine, Ewha Womans University)
  • 차정화 (이화대학교 의과대학 소아과학교실) ;
  • 홍영미 (이화대학교 의과대학 소아과학교실)
  • Received : 2006.06.13
  • Accepted : 2006.07.10
  • Published : 2006.10.15
Download PDF
⟨ Previous Next ⟩

Abstract

Purpose : Homocysteine is a strong and independent risk factor for cardiovascular disease. The deleterious effects of homocysteine included endothelial dysfunction, arterial intimal-medial thickening, wall stiffness and procoagulant activity. However, the precise mechanism responsible for homocysteine release in children with coronary artery disease is still unknown. The purpose of this study was to investigate serum homocysteine and tumor necrosis $factor(TNF)-{\alpha}$ levels and identify whether these levels had any association with the development of coronary artery lesions in Kawasaki disease(KD). Methods : Serum homocysteine and $TNF-{\alpha}$ levels were measured in 24 KD patients(group 1, eight patients with normal coronary artery; group 2, 16 patients with coronary artery lesions) and 21 controls(group 3, 10 afebrile controls; group 4, 11 febrile controls). Blood samples were drawn from each study group before and after intravenous immunoglobulin(IVIG) therapy and in the convalescent stage. Results : The homocysteine levels before IVIG therapy were significantly higher in group 1 than in group 3, and in group 2 than in group 3 and 4. The $TNF-{\alpha}$ levels before IVIG therapy were significantly higher in group 2 than group 3 and 4. Serum homocysteine and $TNF-{\alpha}$ levels were highest in group 2 before IVIG therapy. In the acute KD patients, serum homocysteine levels correlated significantly with $TNF-{\alpha}$ levels. Conclusion : The increased serum homocysteine levels in the acute stage increase the susceptibility to coronary arterial lesions in KD. $TNF-{\alpha}$ may also play an important role in the formation of coronary arterial lesions in KD.

목 적 : 호모시스테인은 성인에서 관상동맥 질환을 포함한 심혈관 질환의 독립적인 위험 인자로서, 혈관 내피세포 손상과 혈액 응고 촉진, 혈전 형성 등의 기전으로 동맥경화증의 위험을 증가시킨다고 알려져 있으나 이러한 호모시스테인이 소아에 미치는 영향은 아직까지 연구된 바가 없다. $TNF-{\alpha}$는 전염증성 사이토카인으로서 혈관 내피세포 손상과 관상동맥의 염증 반응을 초래한다. 본 연구에서는 호모시스테인이 가와사키병의 관상동맥 합병증에 미치는 영향과 $TNF-{\alpha}$의 연관성에 대해 알아보고자 하였다. 방 법 : 가와사키병 환아 24명(관상동맥 확장이 없는 군(1군) : 8명, 관상동맥 확장이 있는 군(2군) : 16명)에 대한 임상 양상과 면역글로불린 투여 전과 후, 회복기에서의 호모시스테인과 $TNF-{\alpha}$ 혈중 농도를 비교하였다. 대조군은 같은 시기에 내원한 열이 없는 정상 소아(3군 : 10명)와 열성 질환 소아(4군 : 11명)로 정하였다. 결 과 : 면역글로불린 투여 전의 호모시스테인은 1군($14.0{\pm}7.0{\mu}mol/L$)에서 3군($5.9{\pm}1.1{\mu}mol/L$)에 비해 유의하게 높았으며(P<0.05), 2군($17.4{\pm}8.0{\mu}mol/L$)에서는 3군($5.9{\pm}1.1{\mu}mol/L$)과 4군($9.2{\pm}2.0{\mu}mol/L$) 각각에 비해 유의하게 높았다(P<0.05). $TNF-{\alpha}$에서도 면역글로불린 투여 전 2군($858.4{\pm}934.0pg/mL$)이 3군($8.0{\pm}1.1pg/mL$)과 4군($54.1{\pm}146.3pg/mL$)에 비해 유의하게 높았다(P<0.05). 2군에서 시간 경과에 따른 호모시스테인과 $TNF-{\alpha}$를 비교해 보면 면역글로불린 투여 전에 각각 $17.4{\pm}8.0{\mu}mol/L$, $858.4{\pm}934.0pg/mL$로 가장 높았고, 면역글로불린 투여 후와 회복기로 갈수록 감소하였다. 또한 가와사키병 급성기에서 호모시스테인과 $TNF-{\alpha}$는 양의 상관관계를 가진다(r=0.488, P<0.05). 결 론 : 호모시스테인의 혈중 농도가 높을수록 가와사키병에서 관상동맥 병변이 발생할 가능성이 더 높았으며 $TNF-{\alpha}$와 같은 사이토카인도 관상동맥 병변의 형성에 중요한 역할을 할 것으로 생각된다.

Keywords

References

  1. Furusho K, Kamiya T, Nakano H, Kivosawa N, Shinomiya K, Havashidera T, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984;2:1055-8
  2. Newburger JW, Takahashi M, Burns JC, Beiser AC, Chung KJ, Duffy CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315:341-7 https://doi.org/10.1056/NEJM198608073150601
  3. Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr 1997; 131:888-93 https://doi.org/10.1016/S0022-3476(97)70038-6
  4. Suzuki H, Uemura S, Tone S, Iizuka T, Kolike M, Hirayama K, et al. Effects of immunoglobulin and gammainterferon on the production of tumour necrosis factor-$\alpha$ and interleukin-1$\beta$ by peripheral blood monocytes in the acute phase of Kawasaki disease. Eur J Pediatr 1996;155: 291-6 https://doi.org/10.1007/BF02002715
  5. Freeman AF, Shulman ST. Recent developments in Kawasaki disease. Curr Opin Infect Dis 2001;14:357-61 https://doi.org/10.1097/00001432-200106000-00017
  6. Kim DS. Serum interleukin-6 in Kawasaki disease. Yonsei Med J 1992;33:183-8 https://doi.org/10.3349/ymj.1992.33.2.183
  7. Suzuki H, Noda E, Miyawaki M, Takeuchi T, Uemura S, Koike M. Serum levels of neutrophil activation cytokines in Kawasaki disease. Pediatr Int 2001;43:115-9 https://doi.org/10.1046/j.1442-200x.2001.01362.x
  8. Gupta M, Noel GJ, Schaefer M, Friedman D, Bussel J, Johann-Liang R. Cytokine modulation with immune γ- globulin in peripheral blood of normal children and its implications in Kawasaki disease treatment. J Clin Immunol 2001;21:193-9 https://doi.org/10.1023/A:1011039216251
  9. Eberhard BA, Andersson U, Laxer RM, Rose V, Silverman ED. Evaluation of the cytokine response in Kawasaki disease. Pediatr Infect Dis J 1995;14:199-203
  10. Takeshita S, Nakatani K, Kawase H, Seki S, Yammamoto M, Sekine I, et al. The role of bacterial lipopolysaccharide- bound neutrophils in the pathogenesis of Kawasaki disease. J Infect Dis 1999;179:508-12 https://doi.org/10.1086/314600
  11. Mangoni AA, Jackson SM. Homocysteine and cardiovascular disease : Current evidence and future prospects. Am J Med 2002:112:556-65 https://doi.org/10.1016/S0002-9343(02)01021-5
  12. Scott CH, Sutton MS. Homocysteine : evidence for a causal relationship with cardiovascular disease. Cardiol Rev 1999;7: 101-7 https://doi.org/10.1097/00045415-199903000-00013
  13. van Guldener C, Stehouwer CD. Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction. Semin Thromb Hemost 2000;26:281-9 https://doi.org/10.1055/s-2000-8472
  14. Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casua? Arch Intern Med 2000; 160:422-34 https://doi.org/10.1001/archinte.160.4.422
  15. Lin CY, Lin CC, Hwang B, Chiang B. Serial changes of serum interleukin-6, interleukin-8, and tumor necrosis factor alpha among patients with Kawasaki disease. J Pediatr 1992;121:924-6 https://doi.org/10.1016/S0022-3476(05)80343-9
  16. Furukawa S, Matsubara T, Yone K, Hirano Y, Okumura K, Yabuta K. Kawasaki disease differs from anaphylactoid purpura and measles with regard to tumor necrosis factor- alpha and interleukin 6 in serum. Eur J Pediatr 1992; 151:44-7 https://doi.org/10.1007/BF02073890
  17. Japan Kawasaki disease Research Committe. Diagnostic guidline of Kawasaki disease, Japan Kawasaki disease Research Committe, Tokyo, 1984
  18. Research Committe on Kawasaki disease. Report of subcommitte on standardization of diagnostic criteria and reporting of coronary artery lesions in Kawasaki disease. Ministry of Health and Welfare, Tokyo, 1984
  19. Rowley AH, Shulman ST. Kawasaki syndrome. Pediatr Clin North Am 1999;46:313-29 https://doi.org/10.1016/S0031-3955(05)70120-6
  20. Mason WH, Burns JC. Clinical presentation of Kawasaki disease. Prog Pediatr Cardiol 1997;6:193-201 https://doi.org/10.1016/S1058-9813(97)00190-2
  21. Suzuki A, Miyagawa-Tomita S, Komatsu K, Nishikawa T, Sakomura Y, Horie T, et al. Active remodeling of the coronary arterial lesions in the late phase of Kawasaki disease : immunohistochemical study. Circulation 2000;101: 2935-41 https://doi.org/10.1161/01.CIR.101.25.2935
  22. Hui-Yuen JS, Duong TT, Yeung RS. TNF-$\alpha$ is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease. J Immunol 2006;176:6294 -301 https://doi.org/10.4049/jimmunol.176.10.6294
  23. Takahashi H, Nakanishi T, Nishimura M, Tanaka H, Yoshimura M. Measurements of serum levels of nitrate ions in men and women : implications of endothelium-derived relaxing factor in blood pressure regulation and atherosclerosis. J Cardiovasc Pharmacol 1992;20 Suppl 12:214-6 https://doi.org/10.1097/00005344-199204002-00061
  24. Matsubara T, Furukawa S, Yabuta K. Serum levels of tumor necrosis factor, interleukin 2 receptor and interferon- gamma in Kawasaki disease involved coronary artery lesions. Clin Immunol Immunopathol 1990;56:29-36 https://doi.org/10.1016/0090-1229(90)90166-N
  25. Lee R, Park S, Kim Y, Kim S, Kim HH, Lee WB. Comparison of cytokine expressions among Kawasaki disease and its symptom-related disease. Korean J Pediatr 2004;27: 567-73
  26. Samuels N. Screening for homocysteine levels in Israel in primary care clinics : a need for guidelines. Prev Med 2003; 37:668-71 https://doi.org/10.1016/j.ypmed.2003.09.001
  27. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intake. JAMA 1995;274:1049-57 https://doi.org/10.1001/jama.274.13.1049
  28. Mayer EL, Jacobsen DW, Robinson K. Homocysteine and coronary atherosclerosis. J Am Coll Cardiol 1996;27:517-27 https://doi.org/10.1016/0735-1097(95)00508-0
  29. Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Clinical evidence and genetic and metabolic background. Arch Intern Med 1997;157:2299-308 https://doi.org/10.1001/archinte.157.20.2299
  30. Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocysteine and cardiovascular disease : a critical review of the epidermiologic evidence. Ann Intern Med 1999;131: 363-75 https://doi.org/10.7326/0003-4819-131-5-199909070-00008
  31. Poddar R, Sivasubramanian N, DiBello PM, Ribunson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin- 8 in human aortic endothelial cells : implications of vascular disease. Circulation 2001;103:2717-23 https://doi.org/10.1161/01.CIR.103.22.2717
  32. Laet CD, Wautrecht JC, Brasseur D, Dramaix M, Boeynaems JM, Decuyper J, et al. Plasma homocysteine concentrations in a Belgian school-age population. Am J Clin Nutr 1999;69:968-72 https://doi.org/10.1093/ajcn/69.5.968
  33. Cheung YF, Yung TC, Tam SC, Ho MH, Chau AK. Novel and traditional cardiovascular risk factors in children after Kawasaki disease implications for premature atherosclerosis. J Am Coll Cardiol 2004;43:120-4 https://doi.org/10.1016/j.jacc.2003.08.030
  34. Miner SE, Evrovski J, Cole DE. Clinical chemistry and molecular biology of homocysteine metabolisms : an update. Clin Biochem 1997;30:189-201 https://doi.org/10.1016/S0009-9120(96)00172-5
  35. Tsukahara H, Hiraoka M, Saito M, Nishida K, Kobata R, Tsuchida S, et al. Methylenetetrahydrofolate reductase polymorphism in Kawasaki disease. Pediatr Int 2000;42:236- 40 https://doi.org/10.1046/j.1442-200x.2000.01229.x
  36. Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, et al. Long-term consequences of Kawasaki disease : a 10- to 21-year follow-up study of 594 patients. Circulation 1996;94:1379-85 https://doi.org/10.1161/01.CIR.94.6.1379
  37. Burns JC, Shike H, Gordon JB, Malhotra A, Schoenwetter M, Kawasaki T. Sequelae of Kawasaki disease in adolescents and young adults. J Am Coll Cardiol 1996;28:253-7 https://doi.org/10.1016/0735-1097(96)00099-X
  38. Kato H, Inoue O, Kawasaki T, Fujiwara H, Watanabe T, Toshima H. Adult coronary artery disease probably due to childhood Kawasaki disease. Lancet 1992;340:1127-9 https://doi.org/10.1016/0140-6736(92)93152-D
  39. Ishiwata S, Fuse K, Nishiyama S, Nakanishi S, Watanabe Y, Seki A. Adult coronary artery disease secondary to Kawasaki disease in childhood. Am J Cardiol 1992;69:692-4 https://doi.org/10.1016/0002-9149(92)90168-X
  40. Silva AA, Maeno Y, Hashmi A, Smallborn JF, Silverman ED, McCrindle BW. Cardiovascular risk factors after Kawasaki disease : a case-control study. J Pediatr 2001;138: 400-5 https://doi.org/10.1067/mpd.2001.111430