Abstract
Background: Behçet's disease is a multysystemic immunoinflammatory disease with a wide variety of clinical manifestations, whereas recurrent aphthous stomatitis is a local oral disease. The aim of this study was to examine the distribution of homocysteine levels in patients with active Behçet's disease, possible association of homocysteine with nitric oxide and neopterin levels, and to characterize the differences between patients with Behçet's disease and those with recurrent aphthous stomatitis in terms of these parameters compared with healthy controls.
Methods: A total of 23 patients with active Behçet's disease, 25 patients with recurrent aphthous stomatitis as positive controls, and 21 healthy subjects were included in this study. Serum homocysteine and neopterin levels were measured flourimetrically by HPLC. Serum nitric oxide production was assayed by measuring total nitrite levels with Griess reagent.
Results: Significantly higher homocysteine (12.9±3.3 μmol/L) and lower nitric oxide (41.5±10.9 μmol/L) and neopterin (6.4±1.0 nmol/L) levels were observed in patients with Behçet's disease compared with healthy controls (10.7±2.0 μmol/L, 49.7±16.2 μmol/L, 8.7±2.2 nmol/L, respectively) (p<0.03 for neopterin, p<0.04 for homocysteine and nitric oxide). However, homocysteine, nitric oxide, biopterin and neopterin levels and the neopterin/biopterin ratio for recurrent aphthous stomatitis patients were not significantly different compared to healthy controls. A significant positive correlation was observed between serum homocysteine and serum neopterin/biopterin ratio in patients with Behçet's disease (r=0.975, p<0.005).
Conclusions: In contrast to recurrent aphthous stomatitis, there is a higher prevalence of hyperhomocysteinemia in Behcet's disease. Homocysteine may have deleterious effects on the pathology of Behcet's disease by decreasing nitric oxide levels and interfering with the immune system.
Clin Chem Lab Med 2007;45:73–7.
References
1. Evereklioglu C. Current concepts in the etiology and treatment of Behçet's Disease. Surv Ophthalmol2005;50:297–350.10.1016/j.survophthal.2005.04.009Search in Google Scholar
2. Jurge S, Kuffer R, Scully C, Porter SR. Recurrent aphthous stomatitis. Oral Dis2006;12:1–21.10.1111/j.1601-0825.2005.01143.xSearch in Google Scholar
3. Finkelstein JD, Martin JJ. Homocysteine. Int J Biochem Cell Biol2000;32:385–89.10.1016/S1357-2725(99)00138-7Search in Google Scholar
4. McCully KS. Hyperhomocysteinemia and arteriosclerosis: historical perspective. Clin Chem Lab Med2005;43:980–6.10.1515/CCLM.2005.172Search in Google Scholar PubMed
5. Green R, Miller JW. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population. Clin Chem Lab Med2005;43:1048–51.10.1515/CCLM.2005.183Search in Google Scholar PubMed
6. Van Guldener C, Stehouwer CD. Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction. Semin Thromb Hemost2000;26:281–9.10.1055/s-2000-8472Search in Google Scholar PubMed
7. Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemostasis2005;94:907–15.10.1160/TH05-05-0313Search in Google Scholar PubMed
8. Weiss N. Mechanisms of increased vascular oxidant stress in hyperhomocysteinemia and its impact on endothelial function. Curr Drug Metab2005;6:27–36.10.2174/1389200052997357Search in Google Scholar PubMed
9. Upchurch GR, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keany JF, et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem1997;272:17012–7.10.1074/jbc.272.27.17012Search in Google Scholar PubMed
10. Dudman NP, Temple SE, Guo XW, Fu W, Perry MA. Homocysteine enhances neutrophil-endothelial interactions in both cultured human cells and rats in vivo. Circ Res1999;84:409–16.10.1161/01.RES.84.4.409Search in Google Scholar
11. Raziuddin S, al-Dalaan A, Bahabri S, Siraj AK, al-Sedairy S. Divergent cytokine production profile in Behcet's disease. Altered Th1/Th2 cell cytokine pattern. J Rheumatol1998;25:329–33.Search in Google Scholar
12. Moutabarrik A, Takahara S, Nakanishi I, Kokado Y, Takano Y, Kameoka H, et al. Interferon-γ stimulates neopterin release from cultured kidney epithelial cells. Scand J Immunol1994;39:27–30.10.1111/j.1365-3083.1994.tb03335.xSearch in Google Scholar
13. Hattori Y, Nakanishi N, Kasai K, Murakami Y, Shimoda S. Tetrahydrobiopterin and GTP cyclohydrolase I in a rat model of endotoxic shock: relation to nitric oxide synthesis. Exp Physiol1996;81:665–71.10.1113/expphysiol.1996.sp003967Search in Google Scholar
14. International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet1990;335:1078–80.Search in Google Scholar
15. Vester B, Rasmussen K. High performance liquid chromatography method for rapid and accurate determination of homocysteine in plasma and serum. Eur J Clin Chem Clin Biochem1991;29:549–54.10.1515/cclm.1991.29.9.549Search in Google Scholar
16. Krijt J, Vackova M, Kozich V. Measurement of homocysteine and other aminothiols in plasma: advantages of using tris(2-carboxyethyl)phosphine as reductant compared with tri-n-butylphosphine. Clin Chem2001;47:1821–8.10.1093/clinchem/47.10.1821Search in Google Scholar
17. Sawabe K, Wakasugi KO, Hasegawa H. Tetrahydrobiopterin uptake in supplemental administration: elevation of tissue tetrahydrobiopterin in mice following uptake of the exogenously oxidized product 7,8-dihydrobiopterin and subsequent reduction by an anti-folate-sensitive process. J Pharmacol Sci2004;96:124–33.10.1254/jphs.FP0040280Search in Google Scholar
18. Hausen A, Fuchs D, Konig K, Wachter H. Determination of neopterin in human urine by reversed-phase high-performance liquid chromatography. J Chromatogr1982;227:61–70.10.1016/S0378-4347(00)80356-4Search in Google Scholar
19. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide2001;5:62–71.10.1006/niox.2000.0319Search in Google Scholar PubMed
20. Koopman WJ. Arthritis and allied conditions. A textbook of rheumatology, 14th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001.Search in Google Scholar
21. Romerio SC, Linder L, Nyfeler J, Wenk M, Litynsky P, Asmis R, et al. Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults. Atherosclerosis2004;176:337–44.10.1016/j.atherosclerosis.2004.05.014Search in Google Scholar PubMed
22. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest2002;109:817–26.10.1172/JCI0214442Search in Google Scholar
23. Weiss N, Zhang Y-Y, Heydrick S, Bierl C, Loscalzo J. Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction. Proc Natl Acad Sci USA2001;98:12503–8.10.1073/pnas.231428998Search in Google Scholar PubMed PubMed Central
24. Orem A, Vanizor B, Cimsit G, Kiran E, Deger O, Malkoc M. Decreased nitric oxide production in patients with Behcet's Disease. Dermatol1999;198:33–6.10.1159/000018061Search in Google Scholar
25. Chambers JC, Haskard DO, Kooner JS. Vascular endothelial function and oxidative stress mechanisms in patients with Behcet's Syndrome. J Am Coll Cardiol2001;37:517–20.10.1016/S0735-1097(00)01137-2Search in Google Scholar
26. Budanlioglu S, Turkmen S, Ayabakan HB, Yenice N, Vardar M, Dogan S, et al. Nitric oxide, lipid peroxidation and antioxidant defence system in patients with active or inactive Behcet's disease. Br J Dermatol2005;153:526–30.10.1111/j.1365-2133.2005.06543.xSearch in Google Scholar
27. Esmat S, El Sherif H, Anwar S, Fahmy I, Elmenyawi M, Shaker O. Lipoprotein (a) and nitrites in Behcet's disease: relationship with disease activity and vascular complications. Eur J Dermatol2006;16:67–71.Search in Google Scholar
28. Aksu K, Turgan N, Oksel F, Keser G, Özmen D, Kitapçıoğlu G, et al. Hyperhomocysteinaemia in Behçet's disease. Rheumatology2001;40:687–90.10.1093/rheumatology/40.6.687Search in Google Scholar
29. Lee YJ, Kang SW, Yang JI, Choi YM, Sheen D, Lee EB, et al. Coagulation parameters and plasma total homocysteine levels in Behçet's disease. Thrombosis Res2002;106:19–24.10.1016/S0049-3848(02)00085-3Search in Google Scholar
30. Canataroglu A, Tanrıverdi K, Inal T, Seydanoglu G, Arslan D, Ozbek S, et al. Methylenetetrahydrofolate reductase gene C677T mutation and plasma homocysteine level in Behcet's disease. Rheumatol Int2003;23:236–40.10.1007/s00296-003-0301-8Search in Google Scholar PubMed
31. Ozdemir R, Barutcu I, Sezgin AT, Acıkgoz N, Ermis N, Esen AM, et al. Vascular endothelial function and plasma homocysteine levels in Behcet's disease. Am J Cardiol2004;94:522–5.10.1016/j.amjcard.2004.04.073Search in Google Scholar PubMed
32. Ateş A, Aydıntuğ O, Ölmez Ü, Düzgün N, Duman M. Serum homocysteine levels is higher in Behçet's disease with vascular involvement. Rheumatol Int2005;25:42–4.10.1007/s00296-003-0398-9Search in Google Scholar PubMed
33. Yesilova Z, Pay S, Oktenli C, Musabak U, Saglam K, Sanisoglu SY, et al. Hyperhomocysteinemia in patients with Behcet's disease: due to inflammation or therapy? Rheumatol Int2005;25:423–8.10.1007/s00296-004-0466-9Search in Google Scholar PubMed
34. Yardım-Akaydın S, Sepici A, Ozkan Y, Şimşek B, Sepici V. Evaluation of allantoin levels as a new marker of oxidative stress in Behçet's Disease. Scand J Rheumatol2005;34:1–4.10.1080/03009740510026878Search in Google Scholar PubMed
35. Hamzaoui K, Hamzaoui A, Guemira F, Bessioud M, Hamza M, Ayek K. Cytokine profile in Behcet's disease patients. Relationship with disease activity. Scand J Rheumatol2002;31:205–10.10.1080/030097402320318387Search in Google Scholar
36. Freysdottir J, Lau SH, Fortune F. γδ T cells in Behçet's disease (BD) and recurrent aphthous stomatitis (RAS). Clin Exp Immunol1999;118:451–7.10.1046/j.1365-2249.1999.01069.xSearch in Google Scholar
37. Koga T, Claycombe K, Meydani H. Homocysteine increases monocyte and T-cell adhesion to human aortic endothelial cells. Atherosclerosis2002;161:365–74.10.1016/S0021-9150(01)00670-0Search in Google Scholar
38. Dawson H, Collins G, Pyle R, Deep-Dixit V, Taub DD. The immunoregulatory effects of homocysteine and its intermediates on T-lymphocyte function. Mech Ageing Dev2004;125:107–10.10.1016/j.mad.2003.11.013Search in Google Scholar
39. Berdowska A, Zwirska-Korczala K. Neopterin measurement in clinical diagnosis. J Clin Pharm Ther2001;26:319–29.10.1046/j.1365-2710.2001.00358.xSearch in Google Scholar
40. Coskun B, Saral Y, Godekmerdan A, Erden I, Coskun N. Activation markers in Behcet's disease. Skin Med2005;4:282–6.Search in Google Scholar
41. Kokcam I, Naziroglu M. Effects of vitamin E supplementation on blood antioxidants levels in patients with Behcet's disease. Clin Biochem2002;35:633–9.10.1016/S0009-9120(02)00400-9Search in Google Scholar
42. Keser G, Oksel F, Aksu K, Kabasakal Y, Gumusdis G, Doganavsargil E, et al. Serum neopterin levels in Behcet's syndrome. Clin Rheumatol2000;19:328–9.Search in Google Scholar
43. al-Dalaan A, al-Sedairy S, al-Balaa S, al-Janadi M, Elramahi K, Bahabri S, et al. Enhanced interleukin 8 secretion in circulation of patients with Behcet's disease. J Rheumatol1995;22:904–7.Search in Google Scholar
44. Altındağ ZZ, Werner-Felmayer G, Sahin G, Wachter H, Fuchs D. Colchicine derivatives inhibit neopterin production in human peripheral blood mononuclear cells (PBMC). Clin Exp Immunol1997;107:574–7.10.1046/j.1365-2249.1997.d01-952.xSearch in Google Scholar PubMed PubMed Central
45. Vasquez-Vivar J, Kalyanaraman B, Martasek P. The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications. Free Radic Res2003;37:121–7.10.1080/1071576021000040655Search in Google Scholar PubMed
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