Russian MedicineRussian Medicine0869-21062412-9100Eco-Vector4413810.18821/0869-2106-2019-25-3-158-165Research ArticleTHE EVALUATION OF FOLATE STATUS USING TOTAL HOMOCYSTEINE IN HYPERTENSIVE PATIENTSZhlobaAleksandr A.doctor of medical sciences, professor, Head of Biochemistry Department of Scientific and Educational Institute of Biomedicine “I.P. Pavlov First Saint Petersburg State Medical University”, 197022, Saint Petersburg, Russian Federationzhlobaaa@1spbgmu.ruSubbotinaT. F-I.P. Pavlov First Saint Petersburg State Medical University1506201925315816514092020Copyright © 2019, Eco-Vector2019A large number of studies have established a link between the progression of arterial hypertension (AH) and folic acid (FA) deficiency. Due to the deficiency of FA, an increase in the level of total homocysteine (tHcy) is observed. The cut-off point for total homocysteine (tHcy), which is not associated with the toxic effect of Hcy itself, indicating the increase in FA deficient state, has not been clearly defined to date. The purpose of this work was to assess the cutoff value of tHcy applied to assesment of functional FA deficiency in hypertensive patients, including group with chronic kidney disease (CKD). Material and methods. The study included blood samples from 60 hypertensive patients aged 61 (45-70) without (N=31) and with (N=29) diagnosed kidney disease and also samples from 30 healthy donors. Clinical and biochemical data, including tHcy, FA and vitamin B12 of blood plasma were assessed. Results and conclusion. Hyperhomocysteinemia in patients with CKD was significantly higher than in patients without CKD. The level of tHcy in all patients was inversely correlated with the level of FA in the blood plasma. Some patients without a deficiency of FA and B12 had an increased level of tHcy, which indicated a functional deficiency of FA. Another situation in few patients without functional deficiency of FA was observed, in which the decreased FA level without increasing level of tHcy established. Frequently used cutoff point for hyperhomocysteinemia above 15 μM indicates the starting point of tHcy concentrations associated with the toxic effects of Hcy by itself. To determine the functional deficiency of FA in the absence of its deficiency in the plasma, the cutoff level of tHcy from 10.9 µM should be used.folic acidhomocysteinevitamin B12arterial hypertensionchronic kidney diseaseфолиевая кислотагомоцистеинвитамин B12артериальная гипертензияхроническая болезнь почек[Полтавцева О.В., Нестеров, Ю.И., Тепляков А.Т. Гомоцистеинемия у пациентов с артериальной гипертензией и цереброваскулярными осложнениями. Сибирский медицинский журнал. 2012; 27(4): 37-41][Baszczuk A., Thielemann A., Musialik K., Kopczynski J., Bielawska L., Dzumak A. et al. The impact of supplementation with folic acid on homocysteine concentration and selected lipoprotein parameters in patients with primary hypertension. J. Nutr. Sci. Vitaminol. (Tokyo). 2017; 63(2): 96-103. doi: 10.3177/jnsv.63.96][Han L., Liu Y., Wang C., Tang L., Feng X., Astell-Burt T. et al. Determinants of hyperhomocysteinemia in healthy and hypertensive subjects: A population-based study and systematic review. Clin. Nutr. 2017; 36(5): 1215-30.][Shen M., Tan H., Zhou S., Retnakaran R., Smith G.N., Davidge S.T. et al. Serum folate shows an inverse association with blood pressure in a cohort of Chinese women of childbearing age: A cross-sectional study. PLoS ONE. 2016; 11(5): e0155801. Doi:10.1371/journal.pone.0155801.][Qin X., Li Y., He M., Tang G., Yin D., Liang M. et al. Folic acid therapy reduces serum uric acid in hypertensive patients: A substudy of the China stroke primary prevention trial (CSPPT) Am. J. Clin. Nutr. 2017; 105(4): 882-9. doi: 10.3945/ajcn.116.143131.][Мухин Н.А., Моисеев С.В., Фомин В.В. Гипергомоцистеинемия - кардиоваскулярные проблемы нефрологических больных. Кардиоваскулярная терапия и профилактика. 2002; 1(3): 85-93.][Мухин Н.А., Моисеев С.В., Фомин В.В. Гипергомоцистеинемия как фактор риска развития заболеваний сердечно-сосудистой системы. Клиническая медицина. 2001; 6: 7-13.][Scazzone C., Bono A., Tornese F., Arsena R., Schillaci R., Butera D., Cottone S. Correlation between low folate levels and hyperhomocysteinemia, but not with vitamin B12 in hypertensive patients. Ann. Clin. Lab. Sci. 2014; 44(3): 286-90.][Sudchada P., Saokaew S., Sridetch S., Incampa S., Jaiyen S., Khaithong W. Effect of folic acid supplementation on plasma total homocysteine levels and glycemic control in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Res. Clin. Pract. 2012; 98(1): 151-8.][Blom H.J., Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J. Inherit. Metab. Dis. 2011; 34(1): 75-81. doi: 10.1007/s10545-010-9177-4.][Bailey S.W., Ayling J.E. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl. Acad. Sci. U S A. 2009; 106(36): 15424-9. doi: 10.1073/pnas.0902072106.][Sobczyńska-Malefora A., Harrington D.J., Voong K., Shearer M.J. Plasma and red cell reference intervals of 5-methyltetrahydrofolate of healthy adults in whom biochemical functional deficiencies of folate and vitamin B 12 had been excluded. Adv. Hematol. 2014; 2014: 465623. doi: 10.1155/2014/465623.][Yang S., Lee J., Park Y., Lee E.K., Hwangbo Y., Ryu J. et al. Interaction between alcohol consumption and methylenetetrahydrofolate reductase polymorphisms in thyroid cancer risk: National Cancer Center cohort in Korea. Sci. Rep. 2018; 8(1): 4077.][Halsted C.H., Villanueva J.A., Devlin A.M., Chandler C.J. Metabolic interactions of alcohol and folate. J. Nutr. 2002; 132(8 Suppl): 2367S-72S. doi: 10.1093/jn/132.8.2367S.][Tao L.X., Yang K., Wu J., Mahara G., Zhang J., Zhang J.B. et al. Association between plasma homocysteine and hypertension: Results from a cross-sectional and longitudinal analysis in Beijing’s adult population from 2012 to 2017. Clin. Hypertens. (Greenwich). 2018; 20(11): 1624-32. doi: 10.1111/jch.13398.][Кулюцина Е.Р., Татарченко И.П., Левашова О.А., Денисова А.Г., Дружинина Т.А. Взаимосвязь показателей гомоцистеина и генетических полиморфизмов, обусловливающих нарушения обмена фолатов у здорового населения. Клиническая лабораторная диагностика. 2017; 62(2): 82-7.][Жлоба А.А. Лабораторная диагностика при гипергомоцистеинемии. Клинико-лабораторный консилиум. 2009; 26(1): 49-60.][Медведев Д.В., Звягина В.И. Молекулярные механизмы токсического действия гомоцистеина. Кардиологический вестник. 2017; 12(1): 52-7.][Андрианова М.Ю., Ройтман Е.В., Исаева А.М., Колесникова И.М., Нуреев М.В. Патогенетическое и клиническое обоснование комплексной профилактики гипергомоцистеинемии. Архивъ внутренней медицины. 2014; 18(4): 32-8.][Мирошниченко И.И., Птицина С.Н., Кузнецова Н.Н., Калмыков Ю.М. Гомоцистеин - предиктор патологических изменений в организме человека. Рус. Мед. Журнал. 2009; 17(4): 224-7.][Nygren-Babol L., Jägerstad M. Folate-binding protein in milk: A review of biochemistry, physiology, and analytical methods. Crit. Rev. Food Sci. Nutr. 2012; 52(5): 410-25. doi: 10.1080/ 10408398.2010.500499.][Kalmbach R.D., Choumenkovitch S.F., Troen A.M., D’Agostino R., Jacques P.F., Selhub J. Circulating folic acid in plasma: Relation to folic acid fortification. Am. J. Clin. Nutr. 2008; 88(3): 763-8.][Servy E., Menezo Y. The methylene tetrahydrofolate reductase (MTHFR) isoform challenge. High doses of folic acid are not a suitable option compared to 5-Methyltetrahydrofolate treatment. Clin. Obstet. Gynecol. Reprod. Med. 2017; 3(6): 1-5. DOI: 10.15761/COGRM.1000204.][Zhloba A.A., Subbotina T.F. Homocysteinylation score of high-molecular weight plasma proteins. Amino Acids. 2014; 46(4): 893-9.][Жлоба А.А., Субботина Т.Ф., Алексеевская Е.С., Моисеева О.М., Гаврилюк Н.Д., Иртюга О.Б. Уровень циркулирующего PGC1a при сердечно-сосудистых заболеваниях. Биомедицинская химия. 2016; 62(2): 198-205][Dankner R., Chetrit A., Lubin F., Sela B.A. Life-style habits and homocysteine levels in an elderly population. Aging Clin. Exp. Res. 2004; 16(6): 437-42.][Venn B.J., Mann J.I., Williams S.M., Riddell L.J., Chisholm A., Harper M.J. et al. Assessment of three levels of folic acid on serum folate and plasma homocysteine: A randomised placebo-controlled double-blind dietary intervention trial. Eur. J. Clin. Nutr. 2002; 56(8): 748-54.][Goyco Ortiz L.E., Servy E.J., Menezo Y.J.R. A successful treatment with 5- methyltetrahydrofolate of a 677 TT MTHFR woman suffering premature ovarian insufficiency post a NHL (non-Hodgkin’s lymphoma) and RPL (repeat pregnancy losses). J. Assist. Reprod. Genet. 2019; 36(1): 65-7. doi: 10.1007/s10815-018-1332-0.][Wald D.S., Bishop L., Wald N.J., Law M., Hennessy E., Weir D. et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch. Intern. Med. 2001; 161(5): 695-700.][Homocysteine Lowering Trialists’ Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: A meta-analysis of the randomized trials. Am. J. Clin. Nutr. 2005; 82(4): 806-12.][Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomized trials. B. M. J. 1998; 316(7135): 894-8.][Zhu H., Blake S., Chan K.T., Pearson R.B., Kang J. Cystathionine β-synthase in physiology and cancer. BioMed. Research International. 2018; 2018: Article ID 3205125, 11 pages. https://doi.org/10.1155/2018/3205125.][van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering?, Nephrol. Dial. Transplant. 2006; 21(5): 1161-6. doi:10.1093/ndt/gfl044.][Cianciolo G., de Pascalis A., di Lullo L., Ronco C., Zannini C., la Manna G. Folic acid and homocysteine in chronic kidney disease and cardiovascular disease progression: Which comes first? Cardiorenal. Med. 2017; 7(4): 255-66. doi: 10.1159/000471813.][Yamada K., Strahler J.R., Andrews P.C. Matthews R.G. Regulation of human methylenetetrahydrofolate reductase by phosphorylation. Proc. Natl. Acad. Sci. U S A. 2005; 102(30): 10454-9.][Смирнов А.В., Добронравов В.А., Жлоба А.А., Голубев Р.В. Новый способ коррекции гипергомоцистеинемии у больных, получающих лечение хроническим гемодиализом. Нефрология. 2006; 10(3): 31-7][Sobczyńska-Malefora A., Harrington D.J. Laboratory assessment of folate (vitamin B9) status. J. Clin. Pathol. 2018; 71(11): 949-56. doi: 10.1136/jclinpath-2018-205048][Жлоба А.А., Маевская Е.Г., Катышева Н.С. Метилмалоновая ацидемия и аминокислоты - источник метилмалоновой кислоты и интермедиатов цикла Кребса у лиц старшего возраста. Клиническая геронтология. 2012; 18(5-6): 35-9]