Asymmetric Dimethylarginine, Symmetric Dimethyl Arginine, N-Monomethyl-L-Arginine, Arginine and Citrulline as Early Markers of Cardiovascular Disease in Pubertal Girls with Euthyroid Hashimoto Thyroiditis

Year 2023, , 530 - 536, 30.12.2023

Bahri Elmas , Gizem Böke Koçer , Ceylan Bal , Cemil Nural , Gulsen Yilmaz

https://doi.org/10.31832/smj.1386547

Abstract

Objective:
Thyroid dysfunction is known to increase the risk of cardiovascular disease (CVD) in patients with Hashimoto's thyroiditis (HT). However, there is insufficient data regarding CVD risk in euthyroid HT patients who have not yet developed thyroid dysfunction. In our study, we investigated whether Asymmetric Dimethylarginine (ADMA), Symmetric Dimethyl Arginine (SDMA), N-Monomethyl-L-Arginine (L-NMMA), Arginine and Citrulline levels can be used as early indicators of this risk.
Materials and Methods:
63 pubertal female patients without thyroid dysfunction and 68 healthy controls, who were diagnosed with HT based on thyroid antibody positivity and ultrasonographic findings, were included in our study. Blood pressure levels, thyroid function test data, thyroid antibody levels, inflammatory parameters and ADMA, SDMA, L-NMMA, Arginine and Citrulline levels were compared between the groups, and the relationships of ADMA, SDMA, L-NMMA, Arginine and Citrulline levels with other CVD markers were determined.
Results:
While TSH, anti-TPO, anti-Tg and ADMA values were found to be high in the patient group; Citrulline, arginine and arginine/ADMA values were found to be low. While a significant positive correlation was observed between ADMA and SDMA, L-NMMA, fT3, total cholesterol, LDL, triglyceride, waist circumference/hip circumference and BMI SSS values in the patient group, a significant negative correlation was detected with arginine/ADMA values.
Conclusion
In our study, patients with euthyroid Hashimoto's thyroiditis; In the early period, an increase in ADMA levels was detected. ADMA can be used as a CVD risk indicator in patients with euthyroid hypertension due to its relationships with anthropometric measurements, metabolic parameters, SDMA and L-NMMA.

Keywords

ADMA, Arginine, Hashimoto, L-NMMA, SDMA, Citrulline

Ötiroid Hashimoto Tiroiditli Pubertal Kız Hastalarda Kardiyovasküler Risk Belirteçleri Olarak Asimetrik Dimetilarjinin, Simetrik Dimetil Arjinin, N-Monometil-L-Arjinin, Arjinin ve Sitrülin Düzeyleri

Abstract

Giriş ve Amaç:
Tiroid fonksiyon bozukluğu, Hashimoto tiroiditi (HT) hastalarında kardiyovasküler hastalık (KVH) riskini artırdığı bilinmektedir. Ancak henüz tiroid fonksiyon bozukluğu gelişmemiş ötiroid HT hastalarında KVH riski ile ilgili veriler yetersizdir. Biz çalışmamızda asimetrik dimetilarjinin (ADMA), simetrik dimetil arjinin (SDMA), N-monometil-L-arjinin (L-NMMA), Arginine and Citrulline düzeylerinin bu riskin erken belirteçleri olarak kullanılıp kullanılamayacağını araştırmayı amaçladık.
Gereç ve Yöntemler:
Tiroid antikor pozitifliği ve ultrasonografik bulgularla HT tanısı alan, tiroid fonksiyon bozukluğu olmayan 65 pubertal kadın hasta ve 70 sağlıklı kontrol çalışmamıza dahil edildi. Gruplar arasında kan basıncı düzeyleri, tiroid fonksiyon testi verileri, tiroid antikor düzeyleri ve inflamatuar parametreler ile ADMA, SDMA, L-NMMA, Arjinin ve Sitrüllin düzeyleri karşılaştırıldı ve ADMA, SDMA, L-NMMA, Arjinin ve Sitrüllin düzeylerinin diğer KVH belirteçleriyle ilişkileri belirlendi.
Bulgular :
Hasta grubunda TSH, anti-TPO, anti-Tg ve ADMA değerleri yüksek saptanırken; sitrülin, arjinin ve arjinin/ADMA değerleri düşük olarak saptandı. Hasta grubunda ADMA ile SDMA, L-NMMA, sT3, total kolesterol, LDL, trigliserit, bel çevresi/kalça çevresi ve VKİ SSS değerleri arasında anlamlı pozitif korelasyon gözlenirken, arjinin/ADMA değerleri ile anlamlı negatif korelasyon saptandı.
Sonuç:
Çalışmamızda ötiroid Hashimoto tiroiditli hastalarda; erken dönemde, ADMA düzeylerinde artış saptandı. ADMA’nın antropometrik ölçümler, metabolik parametreler, SDMA ve L-NMMA ile olan ilişkileri nedeni ile ötiroid HT’li hastalarda KVH risk belirteci olarak kullanılabilir. Ancak daha büyük örneklem büyüklüğüne sahip ileri çalışmalara ihtiyaç vardır.

Keywords

ADMA, Arjinin, Hashimoto Tiroiditi, L-NMMA, SDMA, Sitrülin

Ethical Statement

Araştırma, Helsinki Bildirgesi ve onun daha sonraki revizyonları veya eşdeğer türdekiler tarafından oluşturulan etik yönergelere uygun olarak yapılmıştır. Çalışmaya T.C. Sakarya Üniversitesi Klinik Araştırmalar Etik Kurulu’ndan onay alınmıştır (Etik kurul tarih:30/07/2018 No: 16214662/050.01.04/62).

Supporting Institution

Yoktur

Thanks

Yoktur

References

• 1. Cappa M, Bizzarri C, Crea F. Autoimmune thyroid diseases in children. J Thyroid Res. 2010;2011:675703. doi: 10.4061/2011/675703.
• 2. Ecemiş GC, Çolak R. Tiroiditler. Deneysel ve Klinik Tıp Dergisi- Journal of Experimental and Clinical Medicine. 2012;29:321-327.
• 3. Binay Ç, Şimşek E. Çocuk ve Adolesanlarda Hashimoto Tiroiditi. Osmangazi Journal of Medicine. 2016;38:1-8.
• 4. Wang X, Shao X, Liu X, Qin Q, Xu J, Zhang JA. Dysregulated Interleukin -33/ST2 Pathway Perpetuates Chronic Inflammation in Hashimoto's Thyroiditis. Endocr Metab Immune Disord Drug Targets. 2019;19:1012-1021.
• 5. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-1143.
• 6. Matsuura E, Atzeni F, Sarzi-Puttini P, Turiel M, Lopez LR, Nurmohamed MT. Is atherosclerosis an autoimmune disease? BMC Med. 2014;12:47.
• 7. Pac-Kożuchowska E, Krawiec P, Mroczkowska-Juchkiewicz A, szka Pawłowska-Kamieniak A, Kominek K. Inflammatory and Lipid-Associated Markers of Cardiovascular Diseases in Children with First Exacerbation of Inflammatory Bowel Disease. Med Sci Monit. 2016;22:1534-1539.
• 8. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, et al. Low-grade systemic inflammation causes endothelial dysfunction in patients with Hashimoto's thyroiditis.J Clin Endocrinol Metab. 2006;91:5076-5082.
• 9. Watanabe T, Sato K, Itoh F, Wakabayashi K, Shichiri M, Hirano T. Endogenous bioactive peptides as potential biomarkers for atherosclerotic coronary heart disease. Sensors (Basel). 2012;12:4974-4985.
• 10. Blinc L, Mlinaric M, Battelino T, Groselj U. High-Sensitivity C-Reactive Protein and Carotid Intima Media Thickness as Markers of Subclinical Inflammation and Atherosclerosis in Pediatric Patients with Hypercholesterolemia. Molecules. 2020;25:5118.
• 11. Burlutskaya AV, Tril VE, Polischuk LV, Pokrovskii VM. Dyslipidemia in pediatrician's practice. Rev Cardiovasc Med. 2021;22:817-834.
• 12. Iritas SB, Dip A, Gunduzoz M, Tutkun L, Turksoy VA, Deniz S, et al. Assessment of potential cardiovascular risk in trichloroethylene exposure by serum methylated arginine levels. Int J Environ Health Res. 2021;31:63-74.
• 13. Bollenbach A, Hanff E, Brunner G, Tsikas D. Asymmetric dimethylation and citrullination of proteinic arginine and homoarginine synthesis in human Helicobacter pylori infection. Amino Acids. 2019;51:961-971.
• 14. Ohike Y, Kozaki K, Iijima K, Eto M, Kojima T, Ohga E, et al. Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure-possible. involvement of nitric oxide and asymmetric NG, NG-dimethylarginine. Circ J. 2005;69:221-226.
• 15. Servillo L, Giovane A, D'Onofrio N, Casale R, Cautela D, Castaldo D, et al. Determination of homoarginine, arginine, NMMA, ADMA, and SDMA in biological samples by HPLC-ESI-mass spectrometry. Int J Mol Sci. 2013;14:20131-20138.
• 16. Matsuoka H, Itoh S, Kimoto M, Kohno K, Tamai O, Wada Y, et al. Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension. 1997;29;242-247.
• 17. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, et al. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999;99:1141-1146.
• 18. Erre GL, Mangoni AA, Castagna F, Paliogiannis P, Carru C, Passiu G, et al. Meta-Analysis of Asymmetric Dimethylarginine Concentrations in Rheumatic Diseases. Sci Rep. 2019;9:5426.
• 19. Brown RS. Autoimmune thyroiditis in childhood. J Clin Res Pediatr Endocrinol. 2013;5:45-49.
• 20. Baş VN, Yılmaz Agladioglu S, Özgür S, Karademir S, Aycan Z. Investigation of autoimmune diseases accompanying Hashimoto's thyroiditis in children and adolescents and evaluation of cardiac signs. J Pediatr Endocrinol Metab. 2015;28:767-771.
• 21. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab. 2003;88:2438-2444.
• 22. Erden S, Buyukozturk S, Vural P, Değirmencioğlu S. Acute-phase reactans in Hashimoto thyroiditis. Int Immunopharmacol. 2008;8:1863-1865.
• 23. Ochs N, Auer R, Bauer DC, Nanchen D, Gussekloo J, Cornuz J, et al. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008;148:832-845.
• 24. Tseng FY, Lin WY, Lin CC, Lee LT, Li TC, Sung PK, et al. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J Am Coll Cardiol. 2012;60:730-737.
• 25. Salerno M, Capalbo D, Cerbone M, De Luca F. Subclinical hypothyroidism in childhood - current knowledge and open issues. Nat Rev Endocrinol. 2016;12:734-746.
• 26. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88:3731-3737.
• 27. İşgüven P, Gündüz Y, Kılıç M. Effects of Thyroid Autoimmunity on Early Atherosclerosis in Euthyroid Girls with Hashimoto's Thyroiditis. J Clin Res Pediatr Endocrinol. 2016;8:150-156.
• 28. Carbotta G, Tartaglia F, Giuliani A, Carbotta S, Tromba L, Jacomelli I, et al. Cardiovascular risk in chronic autoimmune thyroiditis and subclinical hypothyroidism patients. A cluster analysis. Int J Cardiol. 2017;230:115-119.
• 29. Wick G, Knoflach M, Xu Q. Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol. 2004;22:361-403. doi: 10.1146/annurev.immunol.22.012703.104644.
• 30. Grundtman C, Wick G. The autoimmune concept of atherosclerosis. Curr Opin Lipidol. 2011;22:327-334.
• 31. Chirinos JA, David R, Bralley JA, Zea-Díaz H, Muñoz-Atahualpa E, Corrales-Medina F, et al. Endogenous nitric oxide synthase inhibitors, arterial hemodynamics, and subclinical vascular disease: the PREVENCION. Study. Hypertension. 2008;52:1051-1059.
• 32. Caplin B, Leiper J. Endogenous nitric oxide synthase inhibitors in the biology of disease: markers, mediators, and regulators? Arterioscler Thromb Vasc Biol. 2012;32:1343-1353.
• 33. Lorin J, Zeller M, Guilland JC, Cottin Y, Vergely C, Rochette L. Arginine and nitric oxide synthase: regulatory mechanisms and cardiovascular aspects. Mol Nutr Food Res. 2014;58:101-116. 34. Ciccone MM, De Pergola G, Porcelli MT, Scicchitano P, Caldarola P, Iacoviello M, et al. Increased carotid IMT in overweight and obese women affected by Hashimoto's thyroiditis: an adiposity and autoimmune linkage? BMC Cardiovasc Disord. 2010;10:22. doi: 10.1186/1471-2261-10-22.
• 35. Vallance P, Chan N. Endothelial function and nitric oxide: clinical relevance. Heart. 2001;85:342-350.
• 36. Gielis JF, Lin JY, Wingler K, Van Schil PE, Schmidt HH, Moens AL. Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders. Free Radic Biol Med. 2011;50:765-776.
• 37. Aslan E, Sert A, Buyukinan M, Pirgon MO, Kurku H, Yilmaz H, et al. Left and right ventricular function by echocardiography, tissue Doppler imaging, carotid intima-media thickness, and asymmetric dimethyl arginine levels in obese adolescents with metabolic syndrome.Cardiol Young. 2019;29:310-318.
• 38. Engin A. Endothelial Dysfunction in Obesity. Adv Exp Med Biol. 2017;960:345-379.
• 39. Marliss EB, Chevalier S, Gougeon R, Morais JA, Lamarche M, Adegoke OAJ, et al. Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover. Diabetologia. 2006;49:351-359.
• 40. Gu LQ, Zhao L, Zhu W, Li FY, Zhang MJ, Liu Y, et al. Relationships between serum levels of thyroid hormones and serum concentrations of asymmetric dimethylarginine (ADMA) and N-terminal-pro-B type natriuretic peptide (NT-proBNP) in. patients with Graves' disease. Endocrine. 2011;39:266-271.
• 41. Izumi Y, Hidaka Y, Tada H, Takano T, Kashiwai T, Tatsumi KI, et al. Simple and practical parameters for differentiation between destruction-induced thyrotoxicosis and Graves' thyrotoxicosis. Clin Endocrinol (Oxf). 2002;57:51-58.
• 42. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab. 2003;88:2983-2992.