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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

General Review Article

Homocysteine and Hyperhomocysteinaemia

Author(s): Bozidarka L. Zaric*, Milan Obradovic, Vladan Bajic, Mohamed A. Haidara, Milos Jovanovic and Esma R. Isenovic*

Volume 26, Issue 16, 2019

Page: [2948 - 2961] Pages: 14

DOI: 10.2174/0929867325666180313105949

Price: $65


Homocysteine (Hcy) is a thiol group containing the amino acid, which naturally occurs in all humans. Hcy is degraded in the body through two metabolic pathways, while a minor part is excreted through kidneys. The chemical reactions that are necessary for degradation of Hcy require the presence of folic acid, vitamins B6 and B12. Consequently, the level of the total Hcy in the serum is influenced by the presence or absence of these vitamins. An elevated level of the Hcy, hyperhomocysteinemia (HHcy) and homocystinuria is connected with occlusive artery disease, especially in the brain, the heart, and the kidney, in addition to venous thrombosis, chronic renal failure, megaloblastic anemia, osteoporosis, depression, Alzheimer’s disease, pregnancy problems, and others. Elevated Hcy levels are connected with various pathologies both in adult and child population. Causes of HHcy include genetic mutations and enzyme deficiencies in 5, 10-methylenetetrahydrofolate reductase (MTHFR) methionine synthase (MS), and cystathionine β-synthase (CβS). HHcy can be caused by deficiencies in the folate, vitamin B12 and to a lesser extent, deficiency in B6 vitamin what influences methionine metabolism. Additionally, HHcy can be caused by the rich diet and renal impairment. This review presents literature data from recent research related to Hcy metabolism and the etiology of the Hcy blood level disorder. In addition, we also described various pathological mechanisms induced by hereditary disturbances or nutritional influences and their association with HHcy induced pathology in adults and children and treatment of these metabolic disorders.

Keywords: Homocysteine, hyperhomocysteinemia, homocysteine metabolism, disturbance of homocysteine metabolism, nutritional deficiencies, cardiovascular diseases.

McCully, K.S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am. J. Pathol., 1969, 56(1), 111-128. [PMID: 5792556].
McCully, K.S. Homocysteine and the pathogenesis of atherosclerosis. Expert Rev. Clin. Pharmacol., 2015, 8(2), 211-219. []. [PMID: 25653125].
Eikelboom, J.W.; Lonn, E.; Genest, J., Jr; Hankey, G.; Yusuf, S. Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence. Ann. Intern. Med., 1999, 131(5), 363-375. []. [PMID: 10475890].
Brattström, L.; Lindgren, A.; Israelsson, B.; Malinow, M.R.; Norrving, B.; Upson, B.; Hamfelt, A. Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur. J. Clin. Invest., 1992, 22(3), 214-221. []. [PMID: 1582447].
Arnesen, E.; Refsum, H.; Bønaa, K.H.; Ueland, P.M.; Førde, O.H.; Nordrehaug, J.E. Serum total homocysteine and coronary heart disease. Int. J. Epidemiol., 1995, 24(4), 704-709. []. [PMID: 8550266].
Katsiki, N.; Perez-Martinez, P.; Mikhailidis, D.P. Homocysteine and non-cardiac vascular disease. Curr. Pharm. Des., 2017, 23(22), 3224-3232. []. [PMID: 28317478].
Woods, E.; Dawson, C.; Senthil, L.; Geberhiwot, T. Cerebral venous thrombosis as the first presentation of classical homocystinuria in an adult patient. BMJ Case Rep., 2017, 2017(10), 2016-217477. []. [PMID: 28137899].
Boushey, C.J.; Beresford, S.A.; Omenn, G.S.; Motulsky, A.G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA, 1995, 274(13), 1049-1057. []. [PMID: 7563456].
Danesh, J.; Lewington, S. Plasma homocysteine and coronary heart disease: Systematic review of published epidemiological studies. J. Cardiovasc. Risk, 1998, 5(4), 229-232. []. [PMID: 9919470].
Mangoni, A.A.; Jackson, S.H. Homocysteine and cardiovascular disease: Current evidence and future prospects. Am. J. Med., 2002, 112(7), 556-565. []. [PMID: 12015248].
Lai, W.K.; Kan, M.Y. Homocysteine-induced endothelial dysfunction. Ann. Nutr. Metab., 2015, 67(1), 1-12. []. [PMID: 26201664].
Toda, N.; Okamura, T. Hyperhomocysteinemia impairs regional blood flow: Involvements of endothelial and neuronal nitric oxide. Pflugers Arch., 2016, 468(9), 1517-1525. []. [PMID: 27417104].
McCully, K.S. Chemical pathology of homocysteine. IV. Excitotoxicity, oxidative stress, endothelial dysfunction, and inflammation. Ann. Clin. Lab. Sci., 2009, 39(3), 219-232. [PMID: 19667406].
Moustafa, A.A.; Hewedi, D.H.; Eissa, A.M.; Frydecka, D.; Misiak, B. Homocysteine levels in schizophrenia and affective disorders-focus on cognition. Front. Behav. Neurosci., 2014, 8, 343. []. [PMID: 25339876].
Bostom, A.G.; Lathrop, L. Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int., 1997, 52(1), 10-20. []. [PMID: 9211341].
Zhu, Y.; Shen, J.; Cheng, Q.; Fan, Y.; Lin, W. Plasma homocysteine level is a risk factor for osteoporotic fractures in elderly patients. Clin. Interv. Aging, 2016, 11, 1117-1121. []. [PMID: 27574411].
Milovanovic, P.; Hrncic, D.; Radotic, K.; Stankovic, M.; Mutavdzic, D.; Djonic, D.; Rasic-Markovic, A.; Djuric, D.; Stanojlovic, O.; Djuric, M. Moderate hyperhomocysteinemia induced by short-term dietary methionine overload alters bone microarchitecture and collagen features during growth. Life Sci., 2017, 191, 9-16. []. [PMID: 28987632].
Nurk, E.; Refsum, H.; Tell, G.S.; Engedal, K.; Vollset, S.E.; Ueland, P.M.; Nygaard, H.A.; Smith, A.D. Plasma total homocysteine and memory in the elderly: The hordaland homocysteine study. Ann. Neurol., 2005, 58(6), 847-857. []. [PMID: 16254972].
Baines, M.; Kredan, M.B.; Davison, A.; Higgins, G.; West, C.; Fraser, W.D.; Ranganath, L.R. The association between cysteine, bone turnover, and low bone mass. Calcif. Tissue Int., 2007, 81(6), 450-454. []. [PMID: 18058053].
Elshorbagy, A.K.; Gjesdal, C.G.; Nurk, E.; Tell, G.S.; Ueland, P.M.; Nygård, O.; Tverdal, A.; Vollset, S.E.; Smith, A.D.; Refsum, H. Cysteine, homocysteine and bone mineral density: A role for body composition? Bone, 2009, 44(5), 954-958. []. [PMID: 19168166].
Hankey, G.J.; Eikelboom, J.W. Homocysteine and vascular disease. Lancet, 1999, 354(9176), 407-413. []. [PMID: 10437885].
Finkelstein, J.D. Methionine metabolism in mammals. J. Nutr. Biochem., 1990, 1(5), 228-237. []. [PMID: 15539209].
Finkelstein, J.D.; Kyle, W.E.; Harris, B.J. Methionine metabolism in mammals: Regulatory effects of S-adenosylhomocysteine. Arch. Biochem. Biophys., 1974, 165(2), 774-779. []. [PMID: 4441103].
Finkelstein, J.D. The metabolism of homocysteine: Pathways and regulation. Eur. J. Pediatr., 1998, 157(2)(Suppl. 2), S40-S44. []. [PMID: 9587024].
Sørensen, J.T.; Gaustadnes, M.; Stabler, S.P.; Allen, R.H.; Mudd, S.H.; Hvas, A.M. Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. Mol. Genet. Metab., 2016, 117(3), 344-350. []. [PMID: 26750749].
McKeever, M.P.; Weir, D.G.; Molloy, A.; Scott, J.M. Betaine-homocysteine methyltransferase: Organ distribution in man, pig and rat and subcellular distribution in the rat. Clin. Sci. (Lond.), 1991, 81(4), 551-556. []. [PMID: 1657504].
Delgado-Reyes, C.V.; Wallig, M.A.; Garrow, T.A. Immunohistochemical detection of betaine-homocysteine S-methyltransferase in human, pig, and rat liver and kidney. Arch. Biochem. Biophys., 2001, 393(1), 184-186. []. [PMID: 11516176].
Wang, T.J.; Pencina, M.J.; Booth, S.L.; Jacques, P.F.; Ingelsson, E.; Lanier, K.; Benjamin, E.J.; D’Agostino, R.B.; Wolf, M.; Vasan, R.S. Vitamin D deficiency and risk of cardiovascular disease. Circulation, 2008, 117(4), 503-511. []. [PMID: 18180395].
Nakai, K.; Itoh, C.; Nakai, K.; Habano, W.; Gurwitz, D. Correlation between C677T MTHFR gene polymorphism, plasma homocysteine levels and the incidence of CAD. Am. J. Cardiovasc. Drugs, 2001, 1(5), 353-361. []. [PMID: 14728017].
Finkelstein, J.D.; Martin, J.J. Methionine metabolism in mammals. Adaptation to methionine excess. J. Biol. Chem., 1986, 261(4), 1582-1587. [PMID: 3080429].
Jhee, K.H.; Kruger, W.D. The role of cystathionine beta-synthase in homocysteine metabolism. Antioxid. Redox Signal., 2005, 7(5-6), 813-822. []. [PMID: 15890029].
Wiley, V.C.; Dudman, N.P.; Wilcken, D.E. Free and protein-bound homocysteine and cysteine in cystathionine beta-synthase deficiency: Interrelations during short- and long-term changes in plasma concentrations. Metabolism, 1989, 38(8), 734-739. []. [PMID: 2761410].
Wiley, V.C.; Dudman, N.P.; Wilcken, D.E. Free and protein-bound homocysteine and cysteine in cystathionine beta-synthase deficiency: Interrelations during short- and long-term changes in plasma concentrations. Metabolism, 1989, 38(8), 734-739. []. [PMID: 2761410].
Ganguly, P.; Alam, S.F. Role of homocysteine in the development of cardiovascular disease. Nutr. J., 2015, 14(6), 6. []. [PMID: 25577237].
Jiang, Y.; Sun, T.; Xiong, J.; Cao, J.; Li, G.; Wang, S. Hyperhomocysteinemia-mediated DNA hypomethylation and its potential epigenetic role in rats. Acta Biochim. Biophys. Sin. (Shanghai), 2007, 39(9), 657-667. []. [PMID: 17805460].
Libby, P. Inflammation in atherosclerosis. Nature, 2002, 420(6917), 868-874. []. [PMID: 12490960].
Chamberlain, K.L. Homocysteine and cardiovascular disease: a review of current recommendations for screening and treatment. J. Am. Acad. Nurse Pract., 2005, 17(3), 90-95. []. [PMID: 15748221].
Steed, M.M.; Tyagi, S.C. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxid. Redox Signal., 2011, 15(7), 1927-1943. []. [PMID: 21126196].
Jakubowski, H. Homocysteine editing, Thioester chemistry, coenzyme A, and the origin of coded peptide synthesis. Life (Basel), 2017, 7(1)E6 []. [PMID: 28208756].
Soria, C.; Chadefaux, B.; Coudé, M.; Gaillard, O.; Kamoun, P. Concentrations of total homocysteine in plasma in chronic renal failure. Clin. Chem., 1990, 36(12), 2137-2138. [PMID: 2253363].
Obeid, R.; Herrmann, W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett., 2006, 580(13), 2994-3005. []. [PMID: 16697371].
Ramakrishnan, S.; Sulochana, K.N.; Lakshmi, S.; Selvi, R.; Angayarkanni, N. Biochemistry of homocysteine in health and diseases. Indian J. Biochem. Biophys., 2006, 43(5), 275-283. [PMID: 17133733].
Richard, E.; Desviat, L.R.; Ugarte, M.; Pérez, B. Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects. J. Cell. Biochem., 2013, 114(1), 183-191. []. [PMID: 22887477].
Mudd, S.H.; Uhlendorf, B.W.; Freeman, J.M.; Finkelstein, J.D.; Shih, V.E. Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochem. Biophys. Res. Commun., 1972, 46(2), 905-912. []. [PMID: 5057914].
Abhinand, P.A.; Manikandan, M.; Mahalakshmi, R.; Ragunath, P.K. Meta-analysis study to evaluate the association of MTHFR C677T polymorphism with risk of ischemic stroke. Bioinformation, 2017, 13(6), 214-219. []. [PMID: 28729765].
Ogier de Baulny, H.; Gérard, M.; Saudubray, J.M.; Zittoun, J. Remethylation defects: Guidelines for clinical diagnosis and treatment. Eur. J. Pediatr., 1998, 157(2)(Suppl. 2), S77-S83. []. [PMID: 9587031].
Guo, S.J.; Luo, S.C.; Liu, W.Y.; Zuo, Q.N.; Li, X.H. Methionine synthase A2756G polymorphism and lymphoma risk: a meta-analysis. Eur. Rev. Med. Pharmacol. Sci., 2017, 21(13), 3075-3082. [PMID: 28742198].
Welch, G.N.; Upchurch, G.R., Jr; Loscalzo, J. Homocysteine, oxidative stress, and vascular disease. Hosp Pract (1995),, 1997, 32(6)81-82, 85. , 88-92. [] [PMID: 9194803]
Kraus, J.P.; Janosík, M.; Kozich, V.; Mandell, R.; Shih, V.; Sperandeo, M.P.; Sebastio, G.; de Franchis, R.; Andria, G.; Kluijtmans, L.A.; Blom, H.; Boers, G.H.; Gordon, R.B.; Kamoun, P.; Tsai, M.Y.; Kruger, W.D.; Koch, H.G.; Ohura, T.; Gaustadnes, M. Cystathionine beta-synthase mutations in homocystinuria. Hum. Mutat., 1999, 13(5), 362-375. [<362:AID-HUMU4>3.0.CO;2-K]. [PMID: 10338090].
Mudd, S.H.; Skovby, F.; Levy, H.L.; Pettigrew, K.D.; Wilcken, B.; Pyeritz, R.E.; Andria, G.; Boers, G.H.; Bromberg, I.L.; Cerone, R. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am. J. Hum. Genet., 1985, 37(1), 1-31. [PMID: 3872065].
Wang, L.; Manson, J.E.; Song, Y.; Sesso, H.D. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann. Intern. Med., 2010, 152(5), 315-323. []. [PMID: 20194238].
Gupta, S.; Kruger, W.D. Cystathionine beta-synthase deficiency causes fat loss in mice. PLoS One, 2011, 6(11)e27598 []. [PMID: 22096601].
Siva, A.; De Lange, M.; Clayton, D.; Monteith, S.; Spector, T.; Brown, M.J. The heritability of plasma homocysteine, and the influence of genetic variation in the homocysteine methylation pathway. QJM, 2007, 100(8), 495-499. []. [PMID: 17636160].
Barbosa, P.R.; Stabler, S.P.; Machado, A.L.; Braga, R.C.; Hirata, R.D.; Hirata, M.H.; Sampaio-Neto, L.F.; Allen, R.H.; Guerra-Shinohara, E.M. Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women. Eur. J. Clin. Nutr., 2008, 62(8), 1010-1021. []. [PMID: 17522601].
den Heijer, M.; Graafsma, S.; Lee, S.Y.; van Landeghem, B.; Kluijtmans, L.; Verhoef, P.; Beaty, T.H.; Blom, H. Homocysteine levels--before and after methionine loading-in 51 Dutch families. Eur. J. Hum. Genet., 2005, 13(6), 753-762. []. [PMID: 15756298].
Robinson, K.; Mayer, E.L.; Miller, D.P.; Green, R.; van Lente, F.; Gupta, A.; Kottke-Marchant, K.; Savon, S.R.; Selhub, J.; Nissen, S.E. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation, 1995, 92(10), 2825-2830. []. [PMID: 7586248].
Selhub, J.; Jacques, P.F.; Wilson, P.W.; Rush, D.; Rosenberg, I.H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA, 1993, 270(22), 2693-2698. []. [PMID: 8133587].
Ubbink, J.B.; Vermaak, W.J.; Van Der Merwe, A.; Becker, P.J. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am. J. Clin. Nutr., 1993, 57(1), 47-53. []. [PMID: 8416664].
Lee, H.; Kim, H.J.; Kim, J.M.; Chang, N. Effects of dietary folic acid supplementation on cerebrovascular endothelial dysfunction in rats with induced hyperhomocysteinemia. Brain Res., 2004, 996(2), 139-147. []. [PMID: 14697491].
Sunder-Plassmann, G.; Winkelmayer, W.C.; Födinger, M. Therapeutic potential of total homocysteine-lowering drugs on cardiovascular disease. Expert Opin. Investig. Drugs, 2000, 9(11), 2637-2651. []. [PMID: 11060826].
Tyagi, S.C. Homocyst(e)ine and heart disease: pathophysiology of extracellular matrix. Clin. Exp. Hypertens., 1999, 21(3), 181-198. []. [PMID: 10225475].
Jencks, D.A.; Mathews, R.G. Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine. Effects of adenosylmethionine and NADPH on the equilibrium between active and inactive forms of the enzyme and on the kinetics of approach to equilibrium. J. Biol. Chem., 1987, 262(6), 2485-2493. [PMID: 3818603].
Still, R.A.; McDowell, I.F. ACP Broadsheet No 152: March 1998. Clinical implications of plasma homocysteine measurement in cardiovascular disease. J. Clin. Pathol., 1998, 51(3), 183-188. []. [PMID: 9659257].
Rasmussen, K.; Møller, J.; Lyngbak, M.; Pedersen, A.M.; Dybkjaer, L. Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clin. Chem., 1996, 42(4), 630-636. [PMID: 8605683].
Selhub, J.; Troen, A.M. Sulfur amino acids and atherosclerosis: a role for excess dietary methionine. Ann. N. Y. Acad. Sci., 2016, 1363, 18-25. []. [PMID: 26647293].
Ostojic, S.M.; Ostojic, J.; Drid, P.; Vranes, M.; Jovanov, P. Dietary guanidinoacetic acid increases brain creatine levels in healthy men. Nutrition, 2017, 33, 149-156. []. [PMID: 27497517].
Ostojic, S.M.; Stojanovic, M. Guanidinoacetic acid loading affects plasma γ-aminobutyric acid in healthy men. Eur. J. Nutr., 2015, 54(5), 855-858. []. [PMID: 25680689].
Stead, L.M.; Au, K.P.; Jacobs, R.L.; Brosnan, M.E.; Brosnan, J.T. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am. J. Physiol. Endocrinol. Metab., 2001, 281(5), E1095-E1100. []. [PMID: 11595668].
Southern, F.; Eidt, J.; Drouilhet, J.; Mukunyadzi, P.; Williams, D.K.; Cruz, C.; Wang, Y.F.; Poirier, L.A.; Brown, A.T.; Moursi, M.M. Increasing levels of dietary homocystine with carotid endarterectomy produced proportionate increases in plasma homocysteine and intimal hyperplasia. Atherosclerosis, 2001, 158(1), 129-138. []. [PMID: 11500183].
Basu, T.K.; Mann, S. Vitamin B-6 normalizes the altered sulfur amino acid status of rats fed diets containing pharmacological levels of niacin without reducing niacin’s hypolipidemic effects. J. Nutr., 1997, 127(1), 117-121. []. [PMID: 9040554].
Miller, J.W.; Nadeau, M.R.; Smith, J.; Smith, D.; Selhub, J. Folate-deficiency-induced homocysteinaemia in rats: Disruption of S-adenosylmethionine’s co-ordinate regulation of homocysteine metabolism. Biochem. J., 1994, 298(Pt 2), 415-419. []. [PMID: 8135750].
Mudd, S.H.; Ebert, M.H.; Scriver, C.R. Labile methyl group balances in the human: The role of sarcosine. Metabolism, 1980, 29(8), 707-720. []. [PMID: 6157075].
Fukada, S.; Shimada, Y.; Morita, T.; Sugiyama, K. Suppression of methionine-induced hyperhomocysteinemia by glycine and serine in rats. Biosci. Biotechnol. Biochem., 2006, 70(10), 2403-2409. []. [PMID: 17031061].
Setoue, M.; Ohuchi, S.; Morita, T.; Sugiyama, K. Hyperhomocysteinemia induced by guanidinoacetic acid is effectively suppressed by choline and betaine in rats. Biosci. Biotechnol. Biochem., 2008, 72(7), 1696-1703. []. [PMID: 18603787].
Ostojic, S.M. Benefits and drawbacks of guanidinoacetic acid as a possible treatment to replenish cerebral creatine in AGAT deficiency. Nutr. Neurosci., 2017, 3, 1-4. [PMID: 28971744].
Muntjewerff, J.W.; Kahn, R.S.; Blom, H.J.; den Heijer, M. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol. Psychiatry, 2006, 11(2), 143-149. []. [PMID: 16172608].
Applebaum, J.; Shimon, H.; Sela, B.A.; Belmaker, R.H.; Levine, J. Homocysteine levels in newly admitted schizophrenic patients. J. Psychiatr. Res., 2004, 38(4), 413-416. []. [PMID: 15203293].
Levine, J.; Sela, B.A.; Osher, Y.; Belmaker, R.H. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2005, 29(7), 1181-1191. []. [PMID: 16115716].
Adler Nevo, G.; Meged, S.; Sela, B.A.; Hanoch-Levi, A.; Hershko, R.; Weizman, A. Homocysteine levels in adolescent schizophrenia patients. Eur. Neuropsychopharmacol., 2006, 16(8), 588-591. []. [PMID: 16647249].
Lerner, V.; Miodownik, C.; Kaptsan, A.; Vishne, T.; Sela, B.A.; Levine, J. High serum homocysteine levels in young male schizophrenic and schizoaffective patients with tardive parkinsonism and/or tardive dyskinesia. J. Clin. Psychiatry, 2005, 66(12), 1558-1563. []. [PMID: 16401157].
Yıldırım, A.; Keleş, F.; Özdemir, G.; Koşger, P.; Uçar, B.; Alataş, Ö.; Kılıç, Z. Homocysteine levels in normotensive children of hypertensive parents. Anatol. J. Cardiol., 2015, 15(12), 1008-1013. []. [PMID: 25880056].
Chang, J.B.; Chu, N.F.; Shen, M.H.; Wu, D.M.; Liang, Y.H.; Shieh, S.M. Determinants and distributions of plasma total homocysteine concentrations among school children in Taiwan. Eur. J. Epidemiol., 2003, 18(1), 33-38. []. [PMID: 12705621].
Papandreou, D.; Mavromichalis, I.; Makedou, A.; Rousso, I.; Arvanitidou, M. Total serum homocysteine, folate and vitamin B12 in a Greek school age population. Clin. Nutr., 2006, 25(5), 797-802. []. [PMID: 16690175].
Chung, K.H.; Chiou, H.Y.; Chen, Y.H. Associations between serum homocysteine levels and anxiety and depression among children and adolescents in Taiwan. Sci Rep,, 2017, 7(1), 017-08568.
Chen, A.H.; Innis, S.M.; Davidson, A.G.; James, S.J. Phosphatidylcholine and lysophosphatidylcholine excretion is increased in children with cystic fibrosis and is associated with plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine. Am. J. Clin. Nutr., 2005, 81(3), 686-691. []. [PMID: 15755840].
Barić, I.; Staufner, C.; Augoustides-Savvopoulou, P.; Chien, Y.H.; Dobbelaere, D.; Grünert, S.C.; Opladen, T.; Petković Ramadža, D.; Rakić, B.; Wedell, A.; Blom, H.J. Consensus recommendations for the diagnosis, treatment and follow-up of inherited methylation disorders. J. Inherit. Metab. Dis., 2017, 40(1), 5-20. []. [PMID: 27671891].
Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia, 2017, 3(10), 017-4342.
Oakley, G.P., Jr Eat right and take a multivitamin. N. Engl. J. Med., 1998, 338(15), 1060-1061. []. [PMID: 9535672].
Shiran, A.; Remer, E.; Asmer, I.; Karkabi, B.; Zittan, E.; Cassel, A.; Barak, M.; Rozenberg, O.; Karkabi, K.; Flugelman, M.Y. Association of Vitamin B12 Deficiency with Homozygosity of the TT MTHFR C677T Genotype, Hyperhomocysteinemia, and endothelial cell dysfunction. Isr. Med. Assoc. J., 2015, 17(5), 288-292. [PMID: 26137654].
Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. Homocysteine lowering trialists’ collaboration. BMJ, 1998, 316(7135), 894-898. []. [PMID: 9569395].
Malinow, M.R.; Nieto, F.J.; Kruger, W.D.; Duell, P.B.; Hess, D.L.; Gluckman, R.A.; Block, P.C.; Holzgang, C.R.; Anderson, P.H.; Seltzer, D.; Upson, B.; Lin, Q.R. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler. Thromb. Vasc. Biol., 1997, 17(6), 1157-1162. []. [PMID: 9194768].
Malinow, M.R.; Duell, P.B.; Hess, D.L.; Anderson, P.H.; Kruger, W.D.; Phillipson, B.E.; Gluckman, R.A.; Block, P.C.; Upson, B.M. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N. Engl. J. Med., 1998, 338(15), 1009-1015. []. [PMID: 9535664].
Mazza, A.; Cicero, A.F.; Ramazzina, E.; Lenti, S.; Schiavon, L.; Casiglia, E.; Gussoni, G. Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: A multicenter, randomized clinical trial. J. Biol. Regul. Homeost. Agents, 2016, 30(3), 921-927. [PMID: 27655522].
Smith, A.D.; Refsum, H.; Homocysteine, B. Homocysteine, B vitamins, and cognitive impairment. Annu. Rev. Nutr., 2016, 36, 211-239. []. [PMID: 27431367].
Polaski, J.T.; Webster, S.M.; Johnson, J.E., Jr; Batey, R.T. Cobalamin riboswitches exhibit a broad range of ability to discriminate between methylcobalamin and adenosylcobalamin. J. Biol. Chem., 2017, 292(28), 11650-11658. []. [PMID: 28483920].
Gok, U.; Halifeoglu, I.; Canatan, H.; Yildiz, M.; Gursu, M.F.; Gur, B. Comparative analysis of serum homocysteine, folic acid and Vitamin B12 levels in patients with noise-induced hearing loss. Auris Nasus Larynx, 2004, 31(1), 19-22. []. [PMID: 15041049].
Liebson, P.R. Women’s Health Initiative (WHI) Dietary Trial and Norwegian Vitamin Trial (NORVIT). Prev. Cardiol., 2006, 9(3), 178-182. []. [PMID: 16849882].
Saposnik, G.; Ray, J.G.; Sheridan, P.; McQueen, M.; Lonn, E. Homocysteine-lowering therapy and stroke risk, severity, and disability: Additional findings from the HOPE 2 trial. Stroke, 2009, 40(4), 1365-1372. []. [PMID: 19228852].
Toole, J.F.; Malinow, M.R.; Chambless, L.E.; Spence, J.D.; Pettigrew, L.C.; Howard, V.J.; Sides, E.G.; Wang, C.H.; Stampfer, M. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA, 2004, 291(5), 565-575. []. [PMID: 14762035].
Albert, C.M.; Cook, N.R.; Gaziano, J.M.; Zaharris, E.; MacFadyen, J.; Danielson, E.; Buring, J.E.; Manson, J.E. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: A randomized trial. JAMA, 2008, 299(17), 2027-2036. []. [PMID: 18460663].
Clarke, R.; Bennett, D.; Parish, S.; Lewington, S.; Skeaff, M.; Eussen, S.J.; Lewerin, C.; Stott, D.J.; Armitage, J.; Hankey, G.J.; Lonn, E.; Spence, J.D.; Galan, P.; de Groot, L.C.; Halsey, J.; Dangour, A.D.; Collins, R.; Grodstein, F. Effects of homocysteine lowering with B vitamins on cognitive aging: Meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am. J. Clin. Nutr., 2014, 100(2), 657-666. []. [PMID: 24965307].
Grarup, N.; Sulem, P.; Sandholt, C.H.; Thorleifsson, G.; Ahluwalia, T.S.; Steinthorsdottir, V.; Bjarnason, H.; Gudbjartsson, D.F.; Magnusson, O.T.; Sparsø, T.; Albrechtsen, A.; Kong, A.; Masson, G.; Tian, G.; Cao, H.; Nie, C.; Kristiansen, K.; Husemoen, L.L.; Thuesen, B.; Li, Y.; Nielsen, R.; Linneberg, A.; Olafsson, I.; Eyjolfsson, G.I.; Jørgensen, T.; Wang, J.; Hansen, T.; Thorsteinsdottir, U.; Stefánsson, K.; Pedersen, O. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet., 2013, 9(6)e1003530 []. [PMID: 23754956].
Smith, A.D.; Smith, S.M.; de Jager, C.A.; Whitbread, P.; Johnston, C.; Agacinski, G.; Oulhaj, A.; Bradley, K.M.; Jacoby, R.; Refsum, H. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial. PLoS One, 2010, 5(9)e12244 []. [PMID: 20838622].
Fratoni, V.; Brandi, M.L. B vitamins, homocysteine and bone health. Nutrients, 2015, 7(4), 2176-2192. []. [PMID: 25830943].
Stone, K.L.; Lui, L.Y.; Christen, W.G.; Troen, A.M.; Bauer, D.C.; Kado, D.; Schambach, C.; Cummings, S.R.; Manson, J.E. Effect of combination folic acid, vitamin B6, and vitamin B12 supplementation on fracture risk in women: A randomized, controlled trial. J. Bone Miner. Res., 2017, 32(12), 2331-2338. []. [PMID: 29244251].
Ruan, J.; Gong, X.; Kong, J.; Wang, H.; Zheng, X.; Chen, T. Effect of B vitamin (folate, B6, and B12) supplementation on osteoporotic fracture and bone turnover markers: A meta-analysis. Med. Sci. Monit., 2015, 21, 875-881. []. [PMID: 25805360].
Herrmann, M.; Umanskaya, N.; Wildemann, B.; Colaianni, G.; Schmidt, J.; Widmann, T.; Zallone, A.; Herrmann, W. Accumulation of homocysteine by decreasing concentrations of folate, vitamin B12 and B6 does not influence the activity of human osteoblasts in vitro. Clin. Chim. Acta, 2007, 384(1-2), 129-134. []. [PMID: 17673193].
Herrmann, M.; Umanskaya, N.; Wildemann, B.; Colaianni, G.; Widmann, T.; Zallone, A.; Herrmann, W. Stimulation of osteoblast activity by homocysteine. J. Cell. Mol. Med., 2008, 12(4), 1205-1210. []. [PMID: 18782184].

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