Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion

Clinical Chemistry

Volumn 50, Issue 1, 2004, Pages 3-32

  Refsum, Helga ^a,b   Smith, A David ^a   Ueland, Per M ^b   Nexo, Ebba ^c   Clarke, Robert ^a   McPartlin, Joseph ^d   Johnston, Carole ^a   Engbaek, Frode ^c   Schneede, Jørn ^b   McPartlin, Catherine ^d   Scott, John M ^d  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF BERGEN   (Norway)

^c AARHUS UNIVERSITY HOSPITAL   (Denmark)

^d TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

3 DEAZAADENOSINE; ACETYLCYSTEINE; ADENOSINE DERIVATIVE; AMINOGLUTETHIMIDE; ANDROGEN; ANTICOAGULANT AGENT; ANTICONVULSIVE AGENT; AZAURIDINE; COLESTYRAMINE; CREATINE; ESTROGEN DERIVATIVE; FOLIC ACID ANTAGONIST; HISTAMINE H2 RECEPTOR ANTAGONIST; HOMOCYSTEINE; ISONIAZID; LEVODOPA; MESNA; METFORMIN; METHIONINE; METHOTREXATE; NICOTINIC ACID; NITRIC OXIDE; NITROUS OXIDE; OMEPRAZOLE; PENICILLAMINE; STABILIZING AGENT; TAMOXIFEN; THEOPHYLLINE; TRIMETHOPRIM; UNINDEXED DRUG;

ANALYTIC METHOD; BIRTH DEFECT; BLOOD LEVEL; BODY POSITION; CIRCADIAN RHYTHM; CLINICAL PRACTICE; COGNITIVE DEFECT; DIAGNOSTIC TEST; DRUG MECHANISM; ETHNIC DIFFERENCE; FOLIC ACID DEFICIENCY; FOOD INTAKE; HEMOLYSIS; HOMOCYSTINURIA; HUMAN; KIDNEY FUNCTION; LIFESTYLE; LOADING TEST; MEDLINE; MENTAL DISEASE; NUTRITIONAL STATUS; OBSERVER VARIATION; PREGNANCY; PREGNANCY COMPLICATION; REVIEW; RISK ASSESSMENT; SCREENING TEST; SEASONAL VARIATION; SEX DIFFERENCE; TEMPERATURE SENSITIVITY; VENOUS STASIS; VITAMIN DEFICIENCY;

BLOOD SPECIMEN COLLECTION; EVIDENCE-BASED MEDICINE; HOMOCYSTEINE; HUMANS; LABORATORY TECHNIQUES AND PROCEDURES; MASS SCREENING; REFERENCE VALUES; RISK ASSESSMENT;

EID: 9144225352     PISSN: 00099147     EISSN: None     Source Type: Journal    
DOI: 10.1373/clinchem.2003.021634     Document Type: Review

References (288)

1. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96:239-46.
2. 12 and folate. Clin Chem 2000;46:1277-83.
3. Refsum H, Ueland PM, Nygård O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med 1998;49:31-62.
4. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-22.
5. Ray JG, Laskin CA. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. Placenta 1999;20:519-29.
6. Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK, et al. Plasma total homocysteine, pregnancy complications, and adverse outcomes: the Hordaland Homocysteine Study. Am J Clin Nutr 2000;71:962-8.
7. Nilsson K, Gustafson L, Faldt R, Andersson A, Brattstrom L, Lindgren A, et al. Hyperhomocysteinaemia - a common finding in a psychogeriatric population. Eur J Clin Invest 1996;26:853-9.
8. Smith AD. Homocysteine, B vitamins, and cognitive deficit in the elderly [Editorial]. Am J Clin Nutr 2002;75:785-6.
9. Carmel R, Jacobsen DW. Homocysteine in health and disease. Cambridge, UK: Cambridge University Press, 2001:501pp.
10. Refsum H, Helland S, Ueland PM. Radioenzymic determination of homocysteine in plasma and urine. Clin Chem 1985;31:624-8.
11. Stabler SP, Marcell PD, Podell ER, Allen RH. Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-mass spectrometry. Anal Biochem 1987;162:185-96.
12. Shipchandler MT, Moore EG. Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer. Clin Chem 1995;41:991-4.
13. Frantzen F, Faaren AL, Alfheim I, Nordhei AK. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum. Clin Chem 1998;44:311-6.
14. Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total homocysteine in plasma or serum. Methods and clinical applications. Clin Chem 1993;39:1764-79.
15. Rasmussen K, Møller J. Total homocysteine determination in clinical practice. Ann Clin Biochem 2000;37:627-48.
16. Ubbink JB. Assay methods for the measurement of total homocyst(e)ine in plasma. Semin Thromb Hemost 2000;26:233-41.
17. Powers HJ, Moat SJ. Developments in the measurement of plasma total homocysteine. Curr Opin Clin Nutr Metab Care 2000;3:391-7.
18. Ducros V, Demuth K, Sauvant MP, Quillard M, Causse E, Candito M, et al. Methods for homocysteine analysis and biological relevance of the results. J Chromatogr B Anal Technol Biomed Life Sci 2002;781:207-26.
19. Refsum H, Fiskerstrand T, Guttormsen AB, Ueland PM. Assessment of homocysteine status. J Inherit Metab Dis 1997;20:286-94.
20. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178-82.
21. Langman LJ, Cole DE. Homocysteine: cholesterol of the 90s? Clin Chim Acta 1999;286:63-80.
22. Booth GL, Wang EE. Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. Canad Med Assoc J 2000;163:21-9.
23. Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J, et al. D. A. CH.-Liga Homocystein (German, Austrian, and Swiss Homocysteine Society) consensus paper on the rational clinical use of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. J Kardiol 2003;10:190-9.
24. Keffer JH. Guidelines and algorithms: perceptions of why and when they are successful and how to improve them. Clin Chem 2001;47:1563-72.
25. Mudd SH, Finkelstein JD, Refsum H, Ueland PM, Malinow MR, Lentz SR, et al. Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arterioscler Thromb Vasc Biol 2000;20:1704-6.
26. Pernet P, Lasnier E, Vaubourdolle M. Evaluation of the AxSYM homocysteine assay and comparison with the IMx homocysteine assay. Clin Chem 2000;46:1440-1.
27. Nexo E, Engbaek F, Ueland PM, Westby C, O'Gorman P, Johnston C, et al. Evaluation of novel assays in clinical chemistry: quantification of plasma total homocysteine. Clin Chem 2000;46:1150-6.
28. Pfeiffer CM, Huff DL, Smith SJ, Miller DT, Gunter EW. Comparison of plasma total homocysteine measurements in 14 laboratories: an international study. Clin Chem 1999;45:1261-8.
29. Møller J, Rasmussen K, Christensen L. External quality assessment of methylmalonic acid and total homocysteine. Clin Chem 1999;45:1536-42.
30. Tripodi A, Chantarangkul V, Lombardi R, Lecchi A, Mannucci PM, Cattaneo M. Multicenter study of homocysteine measurement-performance characteristics of different methods, influence of standards on interlaboratory agreement results. Thromb Haemost 2001;85:291-5.
31. Hanson NQ, Eckfeldt JH, Schwichtenberg K, Aras O, Tsai MY. Interlaboratory variation of plasma total homocysteine measurements: results of three successive homocysteine proficiency testing surveys. Clin Chem 2002;48:1539-45.
32. Refsum H, Ueland PM, Svardal AM. Fully automated fluorescence assay for determining total homocysteine in plasma. Clin Chem 1989;35:1921-7.
33. Poelepothoff M, van den Berg M, Franken D, Boers G, Jakobs C, Dekroon I, et al. Three different methods for the determination of total homocysteine in plasma. Ann Clin Biochem 1995;32:218-20.
34. Accinni R, Campolo J, Bartesaghi S, De Leo G, Lucarelli C, Cursano CF, et al. High-performance liquid chromatographic determination of total plasma homocysteine with or without internal standards. J Chromatogr A 1998;828:397-400.
35. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. The effect of blood sample aging and food consumption on plasma total homocysteine levels. Clin Chim Acta 1992;207:119-28.
36. Guttormsen AB, Schneede J, Fiskerstrand T, Ueland PM, Refsum H. Plasma concentrations of homocysteine and other aminothiol compounds are related to food intake in healthy subjects. J Nutr 1994;124:1934-41.
37. Nurk E, Tell GS, Nygard O, Refsum H, Ueland PM, Vollset SE. Plasma total homocysteine is influenced by prandial status in humans: the Hordaland Homocysteine Study. J Nutr 2001;131:1214-6.
38. Bremner WF, Holmes EW, Kanabrocki EL, Hermida RC, Ayala D, Garbincius J, et al. Circadian rhythm of serum total homocysteine in men. Am J Cardiol 2000;86:1153-6, A9-10.
39. McKinley MC, Strain JJ, McPartlin J, Scott JM, McNulty H. Plasma homocysteine is not subject to seasonal variation. Clin Chem 2001;47:1430-6.
40. Clarke R, Woodhouse P, Ulvik A, Frost C, Sherliker P, Refsum H, et al. Variability and determinants of total homocysteine concentrations in plasma in an elderly population. Clin Chem 1998;44:102-7.
41. Lindgren A, Brattstrom L, Norrving B, Hultberg B, Andersson A, Johansson BB. Plasma homocysteine in the acute and convalescent phases after stroke. Stroke 1995;26:795-800.
42. Meiklejohn DJ, Vickers MA, Dijkhuisen R, Greaves M. Plasma homocysteine concentrations in the acute and convalescent periods of atherothrombotic stroke. Stroke 2001;32:57-62.
43. Fiskerstrand T, Refsum H, Kvalheim G, Ueland PM. Homocysteine and other thiols in plasma and urine: automated determination and sample stability. Clin Chem 1993;39:263-71.
44. Andersson A, Isaksson A, Hultberg B. Homocysteine export from erythrocytes and its implication for plasma sampling. Clin Chem 1992;38:1311-5.
45. Westby C, Alfheim I, Kvam C, Hveem M, Helgesen ÅL, Clarke R. Blood collection using serum separator tubes for homocysteine determination in clinical practice. Proceedings of the 3rd International Conference on Homocysteine Metabolism, July 1-5, 2001, Sorrento, Italy. Naples, Italy: Edizioni Ziino, 2001:101.
46. Nauck M, Bisse E, Nauck M, Wieland H. Pre-analytical conditions affecting the determination of the plasma homocysteine concentration. Clin Chem Lab Med 2001;39:675-80.
47. Woltersdorf WW, Bowron A, Day AP, Scott J, Stansbie D. Abbott IMx homocysteine assay: significant interference by 3-deazaadenosine [Letter]. Ann Clin Biochem 1999;36:533.
48. Probst R, Brandl R, Blumke M, Neumeier D. Stabilization of homocysteine concentration in whole blood. Clin Chem 1998;44:1567-9.
49. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood 1990;76:871-81.
50. Selhub J, Jacques P, Wilson P, Rush D, Rosenberg I. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693-8.
51. Bates CJ, Mansoor MA, van der Pols J, Prentice A, Cole TJ, Finch S. Plasma total homocysteine in a representative sample of 972 British men and women aged 65 and over. Eur J Clin Nutr 1997;51:691-7.
52. Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 2001;73:613-21.
53. Clarke R, Refsum H, Birks J, Evans JG, Johnston C, Sherliker P, et al. Screening for vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr 2003;77:1241-7.
54. Johnson MA, Hawthorne NA, Brackett WR, Fischer JG, Gunter EW, Allen RH, et al. Hyperhomocysteinemia and vitamin B-12 deficiency in elderly using Title IIIc nutrition services. Am J Clin Nutr 2003;77:211-20.
55. Harmon DL, Woodside JV, Yarnell JW, McMaster D, Young IS, McCrum EE, et al. The common 'thermolabile' variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM 1996;89:571-7.
56. Guttormsen AB, Ueland PM, Nesthus I, Nygård O, Schneede J, Vollset SE, et al. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (≥40 μmol/L). The Hordaland Homocysteine Study. J Clin Invest 1996;98:2174-83.
57. Brattström L, Wilcken DEL, Öhrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 1998;98:2520-6.
58. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 2002;288:2023-31.
59. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996;93:7-9.
60. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 2001;22:195-201.
61. Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J. Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem 2000;46:1065-71.
62. McNulty H, McKinley MC, Wilson B, McPartlin J, Strain JJ, Weir DG, et al. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am J Clin Nutr 2002;76:436-41.
63. Lievers KJ, Kluijtmans LA, Blom HJ. Genetics of hyperhomocysteinaemia in cardiovascular disease. Ann Clin Biochem 2003;40:46-59.
64. Jacques PF, Rosenberg IH, Rogers G, Selhub J, Bowman BA, Gunter EW, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the Third National Health and Nutrition Examination Survey. Am J Clin Nutr 1999;69:482-9.
65. Must A, Jacques PF, Rogers G, Rosenberg IH, Selhub J. Serum Total homocysteine concentrations in children and adolescents: results from the Third National Health and Nutrition Examination Survey (NHANES III). J Nutr 2003;133:2643-9.
66. Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteine levels during normal pregnancy. Am J Obstet Gynecol 1999;180:660-4.
67. Murphy MM, Scott JM, McPartlin JM, Fernandez-Ballart JD. The pregnancy-related decrease in fasting plasma homocysteine is not explained by folic acid supplementation, hemodilution, or a decrease in albumin in a longitudinal study. Am J Clin Nutr 2002;76:614-9.
68. Bostom AG, Culleton BF. Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol 1999;10:891-900.
69. Wollesen F, Brattstrom L, Refsum H, Ueland PM, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999;55:1028-35.
70. Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 1995:1279-327.
71. van Guldener C, Stam F, Stehouwer CD. Homocysteine metabolism in renal failure. Kidney Int Suppl 2001;78:S234-7.
72. Nygård O, Refsum H, Ueland PM, Vollset SE. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr 1998;67:263-70.
73. de Bree A, Verschuren WM, Blom HJ, Kromhout D. Association between B vitamin intake and plasma homocysteine concentration in the general Dutch population aged 20-65 y. Am J Clin Nutr 2001;73:1027-33.
74. Ubbink JB, Becker PJ, Vermaak WJ, Delport R. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem 1995;41:1033-7.
75. Rasmussen K, Möller J, Lyngbak M, Pedersen AM, Dybkjaer L. Age-and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clin Chem 1996;42:630-6.
76. Selhub J, Jacques PF, Bostom AG, Wilson PW, Rosenberg IH. Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. Public Health Rev 2000;28:117-45.
77. Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med 2001;161:695-700.
78. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ 1998;316:894-8.
79. Ubbink JB, Vermaak WJ, Delport R, van der Merwe A, Becker PJ, Potgieter H. Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr 1995;62:802-8.
80. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr 2001;74:233-41.
81. Ubbink JB. What is a desirable homocysteine level? In: Carmel R, Jacobsen DW, eds. Homocysteine in health and disease. Cambridge, UK: Cambridge University Press, 2001:485-90.
82. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990;34:99-107.
83. Fokkema MR, Weijer JM, Dijck-Brouwer DA, van Doormaal JJ, Muskiet FA. Influence of vitamin-optimized plasma homocysteine cutoff values on the prevalence of hyperhomocysteinemia in healthy adults. Clin Chem 2001;47:1001-7.
84. Home MK, McCloskey DJ, Cullinane AM, Merryman PK, Rick ME, Hortin GL, et al. Parameters of coagulant and fibrinolytic capacity and activity in postmenopausal women: within-subject variability. Thromb Res 2002;107:229-33.
85. Clarke R, Lewington S, Donald A, Johnston C, Refsum H, Stratton I, et al. Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies. J Cardiovasc Risk 2001;8:363-9.
86. Brenton DP, Cusworth DC, Gaull GE. Homocystinuria: metabolic studies on 3 patients. J Pediatr 1965;67:58-68.
87. Bostom AG, Jacques PF, Nadeau MR, Williams RR, Ellison RC, Selhub J. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis 1995;116:147-51.
88. Graham IM, Daly LE, Refsum H, Robinson K, Brattström LE, Ueland PM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775-81.
89. Bostom AG, Roubenoff R, Dellaripa P, Nadeau MR, Sutherland P, Wilson PW, et al. Validation of abbreviated oral methionine-loading test [Letter]. Clin Chem 1995;41:948-9.
90. Ubbink JB, Becker PJ, Delport R, Bester M, Riezler R, Vermaak WJ. Variability of post-methionine load plasma homocysteine assays. Clin Chim Acta 2003;330:111-9.
91. Krupkova-Meixnerova L, Vesela K, Vitova A, Janosikova B, Andel M, Kozich V. Methionine-loading test: evaluation of adverse effects and safety in an epidemiological study. Clin Nutr 2002;21:151-6.
92. Cottington EM, LaMantia C, Stabler SP, Allen RH, Tangerman A, Wagner C, et al. Adverse event associated with methionine loading test: a case report. Arterioscler Thromb Vasc Biol 2002;22:1046-50.
93. Hanson NQ, Aras O, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 2001;47:661-6.
94. Andersson A, Brattstrom L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B. Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest 1992;22:79-87.
95. Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, et al. The effect of a subnormal vitamin B6 status on homocysteine metabolism. J Clin Invest 1996;98:177-84.
96. Ventura P, Panini R, Verlato C, Scarpetta G, Salvioli G. Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects. Metabolism 2001;50:1466-71.
97. Guttormsen AB, Ueland PM, Kruger WD, Kim CE, Ose L, Folling I, et al. Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine β-synthase deficiency: relationship between genotype and phenotype. Am J Med Genet 2001;100:204-13.
98. van der Griend R, Biesma DH, Banga JD. Postmethionine-load homocysteine determination for the diagnosis hyperhomocysteinaemia and efficacy of homocysteine lowering treatment regimens. Vasc Med 2002;7:29-33.
99. Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol 1999;36:19-34.
100. Yap S, Boers GH, Wilcken B, Wilcken DE, Brenton DP, Lee PJ, et al. Vascular outcome in patients with homocystinuria due to cystathionine β-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol 2001;21:2080-5.
101. Gaustadnes M, Ingerslev J, Rutiger N. Prevalence of congenital homocystinuria in Denmark [Letter]. N Engl J Med 1999;340:1513.
102. Gaustadnes M, Rudiger N, Rasmussen K, Ingerslev J. Familial thrombophilia associated with homozygosity for the cystathionine β-synthase 833T→C mutation. Arterioscler Thromb Vasc Biol 2000;20:1392-5.
103. Yap S, Naughten E. Homocystinuria due to cystathionine β-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis 1998;21:738-47.
104. Tsai MY, Garg U, Key NS, Hanson NQ, Suh A, Schwichtenberg K. Molecular and biochemical approaches in the identification of heterozygotes for homocystinuria. Atherosclerosis 1996;122:69-77.
105. Steegers-Theunissen RPM, Boers GHJ, Trijbels FJM, Finkelstein JD, Blom HJ, Thomas CMG, et al. Maternal hyperhomocysteinemia: a risk factor for neural-tube defects? Metabolism 1994;43:1475-80.
106. Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, Frosst P, Stevens EMB, van Oost BA, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996;58:35-41.
107. Ramsbottom D, Scott JM, Molloy A, Weir DG, Kirke PN, Mills JL, et al. Are common mutations of cystathionine β-synthase involved in the aetiology of neural tube defects? Clin Genet 1997;51:39-42.
108. Carmel R. Folate deficiency. In: Carmel R, Jacobsen DW, eds. Homocysteine in health and disease. Cambridge, UK: Cambridge University Press, 2001:271-88.
109. Carmel R. Cobalamin deficiency. In: Carmel R, Jacobsen DW, eds. Homocysteine in health and disease. Cambridge, UK: Cambridge University Press, 2001:289-305.
110. Bjorke Monsen AL, Ueland PM. Homocysteine and methylmalonic acid in diagnosis and risk assessment from infancy to adolescence. Am J Clin Nutr 2003;78:7-21.
111. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr 1994;59:1213S-1222S.
112. Lindenbaum J, Healton EB, Savage DG, Brust JCM, Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-8.
113. Frenkel EP, Yardley DA. Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin B12 (cobalamin) in pregnancy and gynecology. Hematol Oncol Clin North Am 2000;14:1079-100.
114. Molloy AM, Scott JM. Folates and prevention of disease. Public Health Nutr 2001;4:601-19.
115. 6 and one carbon metabolism. J Nutr Health Aging 2002;6:39-42.
116. Kang S-S, Wong PWK, Norusis M. Homocysteinemia due to folate deficiency. Metabolism 1987;36:458-62.
117. Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J. Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 1988;81:466-74.
118. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum H, Sandberg S. Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem 1999;45:189-98.
119. Morris MS, Jacques PF, Selhub J, Rosenberg IH. Total homocysteine and estrogen status indicators in the Third National Health and Nutrition Examination Survey. Am J Epidemiol 2000;152:140-8.
120. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990;34:90-8.
121. 12 and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999;159:1289-98.
122. Jaffe JP, Schilling RF. Erythrocyte folate levels: a clinical study. Am J Hematol 1991;36:116-21.
123. Matchar DB, McCrory DC, Millington DS, Feussner JR. Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci 1994;308:276-83.
124. Robinson AR, Mladenovic J. Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia. Am J Med 2001;110:88-90.
125. 12 and folate. Acta Med Austriaca 2002;29:57-60.
126. Pennypacker LC, Allen RH, Kelly JP, Matthews M, Grigsby J, Kaye K, et al. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc 1992;40:1197-204.
127. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92:1191-8.
128. Ulleland M, Eilertsen I, Quadros EV, Rothenberg SP, Fedosov SN, Sundrehagen E, et al. Direct assay for cobalamin bound to transcobalamin (holo-transcobalamin) in serum. Clin Chem 2002;48:526-32.
129. 12 deficiency. Clin Chem 2002;48:561-2.
130. Loikas S, Löppönen M, Suominen P, Møller J, Irjala K, Isoaho R, et al. RIA for serum holo-transcobalamin: method evaluation in the clinical laboratory and reference interval. Clin Chem 2003;49:455-62.
131. Nexo E, Hvas AM, Bleie O, Refsum H, Fedosov SN, Vollset SE, et al. Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clin Chem 2002;48:1768-71.
132. Lindgren A, Kilander A, Bagge E, Nexo E. Holotranscobalamin - a sensitive marker of cobalamin malabsorption. Eur J Clin Invest 1999;29:321-9.
133. Refsum H, Smith AD. Low vitamin B-12 status in confirmed Alzheimer's disease as revealed by serum holotranscobalamin. J Neurol Neurosurg Psychiatry 2003;74:959-61.
134. Nexo E, Hansen M, Rasmussen K, Lindgren A, Grasbeck R. How to diagnose cobalamin deficiency. Scand J Clin Lab Invest Suppl 1994;219:61-76.
135. Bolann BJ, Solli JD, Schneede J, Grottum KA, Loraas A, Stokkeland M, et al. Evaluation of indicators of cobalamin deficiency defined as cobalamin-induced reduction in increased serum methylmalonic acid. Clin Chem 2000;46:1744-50.
136. Hvas AM, Ellegaard J, Nexo E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B-12 deficiency. Arch Intern Med 2001;161:1534-41.
137. Hvas AM, Juul S, Nexo E, Ellegaard J. Vitamin B-12 treatment has limited effect on health-related quality of life among individuals with elevated plasma methylmalonic acid: a randomized placebo-controlled study. J Intern Med 2003;253:146-52.
138. Nilsson K, Gustafson L, Hultberg B. Optimal use of markers for cobalamin and folate status in a psychogeriatric population. Int J Geriatr Psychiatry 2002;17:919-25.
139. van Asselt DZ, Pasman JW, van Lier HJ, Vingerhoets DM, Poels PJ, Kuin Y, et al. Cobalamin supplementation improves cognitive and cerebral function in older, cobalamin-deficient persons. J Gerontol A Biol Sci Med Sci 2001;56:M775-9.
140. Morgan SL, Baggott JE, Refsum H, Ueland PM. Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate. Clin Pharmacol Ther 1991;50:547-56.
141. Niyikiza C, Baker SD, Seitz DE, Walling JM, Nelson K, Rusthoven JJ, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002;1:545-52.
142. Badner NH, Beattie WS, Freeman D, Spence JD. Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy. Anesth Analg 2000;91:1073-9.
143. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969;56:111-28.
144. Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med 2000;160:422-34.
145. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202-8.
146. Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S, et al. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 2001;10:433-43.
147. Dayal S, Bottiglieri T, Arning E, Maeda N, Malinow MR, Sigmund CD, et al. Endothelial dysfunction and elevation of S-adenosyl-homocysteine in cystathionine β-synthase-deficient mice. Circ Res 2001;88:1203-9.
148. Lentz SR. Mechanisms of thrombosis in hyperhomocysteinemia. Curr Opin Hematol 1998;5:343-9.
149. Haynes WG. Hyperhomocysteinemia, vascular function and atherosclerosis: effects of vitamins. Cardiovasc Drugs Ther 2002;16:391-9.
150. Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 2000;72:324-32.
151. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med 1998;158:862-7.
152. Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6.
153. Petri M, Roubenoff R, Dallal GE, Nadeau MR, Selhub J, Rosenberg IH. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 1996;348:1120-4.
154. Stehouwer CD, Gall MA, Hougaard P, Jakobs C, Parving HH. Plasma homocysteine concentration predicts mortality in non-insulin-dependent diabetic patients with and without albuminuria. Kidney Int 1999;55:308-14.
155. Bostom AG, Shemin D, Verhoef P, Nadeau MR, Jacques PF, Selhub J, et al. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study. Arterioscler Thromb Vasc Biol 1997;17:2554-8.
156. Knekt P, Alfthan G, Aromaa A, Heliovaara M, Marniemi J, Rissanen H, et al. Homocysteine and major coronary events: a prospective population study amongst women. J Intern Med 2001;249:461-5.
157. Peterson JC, Spence JD. Vitamins and progression of atherosclerosis in hyper-homocyst(e)inaemia [Letter]. Lancet 1998;351:263.
158. Vermeulen EG, Stehouwer CD, Twisk JW, van den Berg M, de Jong SC, Mackaay AJ, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet 2000;355:517-22.
159. Schnyder G, Rouvinez G. Total plasma homocysteine and restenosis after percutaneous coronary angioplasty: current evidence. Ann Med 2003;35:156-63.
160. Gruberg L. FACIT: results from the folate after coronary intervention trial. 52nd Annual Scientific Session, American College of Cardiology, March 30-April 2, 2003 http://www.medscape. com/viewarticle/452026 (accessed November 12, 2003).
161. Bostom AG, Selhub J, Jacques PF, Rosenberg IH. Power shortage: clinical trials testing the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour. Ann Intern Med 2001;135:133-7.
162. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 2001;285:2481-5.
163. Clarke R, Armitage J. Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin Thromb Hemost 2000;26:341-8.
164. Vollset SE, Refsum H, Nygård O, Tverdal A, Nordrehaug JE, Tell GS, et al. Plasma total homocysteine, cardiovascular and non-cardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr 2001;74:130-6.
165. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395-8.
166. Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, et al. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med 1999;131:321-30.
167. Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, et al. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes:
168. Sunder-Plassmann G, Fodinger M, Buchmayer H, Papagiannopoulos M, Wojcik J, Kletzmayr J, et al. Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study. J Am Soc Nephrol 2000;11:1106-16.
169. Moustapha A, Naso A, Nahlawi M, Gupta A, Arheart KL, Jacobsen DW, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation 1998;97:138-41.
170. Haraki T, Takegoshi T, Kitoh C, Kajinami K, Wakasugi T, Hirai J, et al. Hyperhomocysteinemia, diabetes mellitus, and carotid atherosclerosis independently increase atherosclerotic vascular disease outcome in Japanese patients with end-stage renal disease. Clin Nephrol 2001;56:132-9.
171. Mallamaci F, Zoccali C, Tripepi G, Fermo I, Benedetto FA, Cataliotti A, et al. Hyperhomocysteinemia predicts cardiovascular outcomes in hemodialysis patients. Kidney Int 2002;61:609-14.
172. Shemin D, Lapane KL, Bausserman L, Kanaan E, Kahn S, Dworkin L, et al. Plasma total homocysteine and hemodialysis access thrombosis: a prospective study. J Am Soc Nephrol 1999;10:1095-9.
173. 12 deficiency in the elderly. Annu Rev Nutr 1999;19:357-77.
174. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-32.
175. Alpert JE, Mischoulon D, Nierenberg AA, Fava M. Nutrition and depression: focus on folate. Nutrition 2000;16:544-6.
176. Morris MS, Fava M, Jacques PF, Selhub J, Rosenberg IH. Depression and folate status in the US Population. Psychother Psychosom 2003;72:80-7.
177. 12 deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry 2000;157:715-21.
178. 12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry 2002;159:2099-101.
179. Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T. Folate, vitamin B-12, and homocysteine in major depressive disorder. Am J Psychiatry 1997;154:426-8.
180. Taylor MJ, Carney S, Geddes J, Goodwin G. Folate for depressive disorders. Cochrane Database Syst Rev 2003;2:CD003390.
181. Levine J, Stahl Z, Sela BA, Gavendo S, Ruderman V, Belmaker RH. Elevated homocysteine levels in young male patients with schizophrenia. Am J Psychiatry 2002;159:1790-2.
182. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr 2000;71:614S-20S.
183. Riggs KM, Spiro A, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 1996;63:306-14.
184. Budge M, Johnston C, Hogervorst E, de Jager C, Milwain E, Iversen SD, et al. Plasma total homocysteine and cognitive performance in a volunteer elderly population. Ann N Y Acad Sci 2000;903:407-10.
185. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Hyperhomocysteinemia associated with poor recall in the Third National Health and Nutrition Examination Survey. Am J Clin Nutr 2001;73:927-33.
186. Duthie SJ, Whalley LJ, Collins AR, Leaper S, Berger K, Deary IJ. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 2002;75:908-13.
187. Prins ND, Den Heijer T, Hofman A, Koudstaal PJ, Jolles J, Clarke R, et al. Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study. Neurology 2002;59:1375-80.
188. Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study. Am J Clin Nutr 2000;71:993-8.
189. Vermeer SE, van Dijk EJ, Koudstaal PJ, Oudkerk M, Hofman A, Clarke R, et al. Homocysteine, silent brain infarcts, and white matter lesions: the Rotterdam Scan Study. Ann Neurol 2002;51:285-9.
190. Joosten E, Lesaffre E, Riezler R, Ghekiere V, Dereymaeker L, Pelemans W, et al. Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer's disease? J Gerontol A Biol Sci Med Sci 1997;52:M76-9.
191. McCaddon A, Davies G, Hudson P, Tandy S, Cattell H. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry 1998;13:235-9.
192. 12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 1998;55:1449-55.
193. Hogervorst E, Ribeiro HM, Molyneux A, Budge M, Smith AD. Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol 2002;59:787-93.
194. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 2001;12:309-13.
195. 12 and folate in relation to the development of Alzheimer's disease. Neurology 2001;56:1188-94.
196. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-83.
197. Kang SS, Wong PW, Zhou JM, Cook HY. Total homocyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism 1986;35:889-91.
198. Hogg BB, Tamura T, Johnston KE, Dubard MB, Goldenberg RL. Second-trimester plasma homocysteine levels and pregnancy-induced hypertension, preeclampsia, and intrauterine growth restriction. Am J Obstet Gynecol 2000;183:805-9.
199. McMullin MF, Young PB, Bailie KE, Savage GA, Lappin TR, White R. Homocysteine and methylmalonic acid as indicators of folate and vitamin B12 deficiency in pregnancy. Clin Lab Haematol 2001;23:161-5.
200. Bondevik GT, Schneede J, Refsum H, Lie RT, Ulstein M, Kvåle G. Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalamin supplementation be considered? Eur J Clin Nutr 2001;55:856-64.
201. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 2000;71:1295S-1303S.
202. Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, et al. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 1993;60:820-5.
203. Goddijn-Wessel TA, Wouters MG, van de Molen EF, Spuijbroek MD, Steegers-Theunissen RP, Blom HJ, et al. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996;66:23-9.
204. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000;74:1196-9.
205. Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willett WC, Selhub J, et al. Preconception homocysteine and B vitamin status and birth outcomes in Chinese women. Am J Clin Nutr 2002;76:1385-91.
206. Ronnenberg AG, Goldman MB, Chen D, Aitken IW, Willett WC, Selhub J, et al. Preconception folate and vitamin B(6) status and clinical spontaneous abortion in Chinese women. Obstet Gynecol 2002;100:107-13.
207. Sorensen TK, Malinow MR, Williams MA, King IB, Luthy DA. Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. Gynecol Obstet Invest 1999;48:98-103.
208. Cotter AM, Molloy AM, Scott JM, Daly SF. Elevated plasma homocysteine in early pregnancy: a risk factor for the development of severe preeclampsia. Am J Obstet Gynecol 2001;185:781-5.
209. Gindler J, Li Z, Berry RJ, Zheng J, Correa A, Sun X, et al. Folic acid supplements during pregnancy and risk of miscarriage. Lancet 2001;358:796-800.
210. Wong WY, Eskes TK, Kuijpers-Jagtman AM, Spauwen PH, Steegers EA, Thomas CM, et al. Nonsyndromic orofacial clefts: association with maternal hyperhomocysteinemia. Teratology 1999;60:253-7.
211. van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ. Folate, homocysteine and neural tube defects: an overview. Exp Biol Med 2001;226:243-70.
212. James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr 1999;70:495-501.
213. MRC-Vitamin-Study-Research-Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 1991;338:131-7.
214. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832-5.
215. Kalter H. Folic acid and human malformations: a summary and evaluation. Reprod Toxicol 2000;14:463-76.
216. French MR, Barr SI, Levy-Milne R. Folate intakes and awareness of folate to prevent neural tube defects: a survey of women living in Vancouver, Canada. J Am Diet Assoc 2003;103:181-5.
217. Green NS. Folic acid supplementation and prevention of birth defects. J Nutr 2002;132:2356S-60S.
218. Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 2001;285:2981-6.
219. Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DE. Association of neural tube defects and folic acid food fortification in Canada. Lancet 2002;360:2047-8.
220. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural-tube defects with folic acid in China. China-U. S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med 1999;341:1485-90.
221. van der Molen EF, Arends GE, Nelen WL, van der Put NJ, Heil SG, Eskes TK, et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene as a new risk factor for placental vasculopathy. Am J Obstet Gynecol 2000;182:1258-63.
222. Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 2000;67:623-30.
223. Adams MJ Jr, Khoury MJ, Scanlon KS, Stevenson RE, Knight GJ, Haddow JE, et al. Elevated midtrimester serum methylmalonic acid levels as a risk factor for neural tube defects. Teratology 1995;51:311-7.
224. 12) increases risk for spina bifida. Mol Genet Metab 1999;67:317-23.
225. Allen LH, Rosado JL, Casterline JE, Martinez H, Lopez P, Munoz E, et al. Vitamin B-12 deficiency and malabsorption are highly prevalent in rural Mexican communities. Am J Clin Nutr 1995;62:1013-9.
226. Nielsen C, Lang RS. Principles of screening. Med Clin North Am 1999;83:1323-37.
227. 12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry. Am J Med 1993;94:589-94.
228. 12) deficiency. J Am Geriatr Soc 1995;43:1290-7.
229. Rothenberg SP. Increasing the dietary intake of folate: pros and cons. Semin Hematol 1999;36:65-74.
230. 12 levels in geriatric medical patients. Br J Nutr 1997;78:57-63.
231. van Asselt DZ, Blom HJ, Zuiderent R, Wevers RA, Jakobs C, van den Broek WJ, et al. Clinical significance of low cobalamin levels in older hospital patients. Neth J Med 2000;57:41-9.
232. Jensen E, Dehlin O, Erfurth E-M, Hagberg B, Samuelsson G, Svensson T, et al. Plasma homocysteine in 80-year-olds. Relationships to medical, psychological and social variables. Arch Gerontol Geriatr 1998;26:215-26.
233. Kado DM, Bucur A, Selhub J, Rowe JW, Seeman T. Homocysteine levels and decline in physical function: MacArthur Studies of Successful Aging. Am J Med 2002;113:537-42.
234. Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 1994;60:2-11.
235. Gempel K, Gerbitz K-D, Casetta B, Bauer MF. Rapid determination of total homocysteine in blood sports by liquid chromatography-electrospray-ionization- tandem mass spectrometry. Clin Chem 2000;46:122-3.
236. Minet JC, Bisse E, Aebischer CP, Beil A, Wieland H, Lutschg J. Assessment of vitamin B-12, folate, and vitamin B-6 status and relation to sulfur amino acid metabolism in neonates. Am J Clin Nutr 2000;72:751-7.
237. 12, and the 5,10-methylenetetrahydrofolate reductase 677C→T variant. Am J Obstet Gynecol 2002;186:499-503.
238. Chadefaux B, Ceballos I, Hamet M, Coude M, Poissonnier M, Kamoun P, et al. Is absence of atheroma in Down syndrome due to decreased homocysteine levels? [Letter]. Lancet 1988;2:741.
239. Nygård O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995;274:1526-33.
240. Mijatovic V, van der Mooren MJ. Homocysteine in postmenopausal women and the importance of hormone replacement therapy. Clin Chem Lab Med 2001;39:764-7.
241. Dierkes J, Jeckel A, Ambrosch A, Westphal S, Luley C, Boeing H. Factors explaining the difference of total homocysteine between men and women in the European Investigation Into Cancer and Nutrition Potsdam Study. Metabolism 2001;50:640-5.
242. Nygård O, Refsum H, Nordrehaug J, Kvåle G, Stensvold I, Ueland P, et al. Coffee consumption and plasma total homocysteine: the Hordaland Homocysteine Study. Am J Clin Nutr 1997;65:136-43.
243. Grubben MJ, Boers GH, Blom HJ, Broekhuizen R, de Jong R, van Rijt L, et al. Unfiltered coffee increases plasma homocysteine concentrations in healthy volunteers: a randomized trial. Am J Clin Nutr 2000;71:480-4.
244. Hultberg B, Berglund M, Andersson A, Frank A. Elevated plasma homocysteine in alcoholics. Alcohol Clin Exp Res 1993;17:687-9.
245. Vollset SE, Nygård O, G. K., Ueland PM, Refsum H. The Hordaland homocysteine study: lifestyle and plasma homocysteine in Western Norway. In: Graham I, Refsum H, Rosenberg IH, Ueland PM, eds. Homocysteine metabolism: from basic science to clinical medicine. Norwell, MA: Kluwer Academic Publishers, 1997:177-82.
246. Koehler KM, Baumgartner RN, Garry PJ, Allen RH, Stabler SP, Rimm EB. Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use. Am J Clin Nutr 2001;73:628-37.
247. de Bree A, Verschuren WM, Blom HJ, Kromhout D. Lifestyle factors and plasma homocysteine concentrations in a general population sample. Am J Epidemiol 2001;154:150-4.
248. Wilcken DEL, Gupta VJ. Sulphur containing amino acids in chronic renal failure with particular reference to homocystine and cysteine-homocysteine mixed disulphide. Eur J Clin Invest 1979;9:301-7.
249. Refsum H, Wesenberg F, Ueland PM. Plasma homocysteine in children with acute lymphoblastic leukemia. Changes during a chemotherapeutic regimen including methotrexate. Cancer Res 1991;51:828-35.
250. Refsum H, Helland S, Ueland PM. Fasting plasma homocysteine as a sensitive parameter to antifolate effect. A study on psoriasis patients receiving low-dose methotrexate treatment. Clin Pharmacol Ther 1989;46:510-20.
251. Nedrebø B, Ericsson U-B, Refsum H, Ueland PM, Aakvaag A, Lien EA. Plasma total homocysteine levels in hyperthyroid and hypothyroid patients. Metabolism 1998;47:89-93.
252. Diekman MJ, van der Put NM, Blom HJ, Tijssen JG, Wiersinga WM. Determinants of changes in plasma homocysteine in hyperthyroidism and hypothyroidism. Clin Endocrinol 2001;54:197-204.
253. 12, and transcobalamins in patients undergoing successive hypo-and hyperthyroid states [Letter]. J Clin Endocrinol Metab 2001;86:1845-6.
254. Audelin MC, Genest J Jr. Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis 2001;159:497-511.
255. Hultberg B, Agardh E, Andersson A, Brattström L, Isaksson A, Israelsson B, et al. Increased levels of plasma homocysteine are associated with nephropathy but not severe retinopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest 1991;51:277-82.
256. Smulders YM, de Man AM, Stehouwer CD, Slaats EH. Trimethoprim and fasting plasma homocysteine [Letter]. Lancet 1998;352:1827-8.
257. James GK, Jones MW, Pudek MR. Homocyst(e)ine levels in patients on phenytoin therapy. Clin Biochem 1997;30:647-9.
258. Tonstad S, Refsum H, Ose L, Ueland PM. The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine. J Pediatr 1997;132:365-8.
259. Ermens AAM, Refsum H, Rupreht J, Spijkers LJM, Guttormsen AB, Lindemans J, et al. Monitoring cobalamin inactivation during nitrous oxide anesthesia by determination of homocysteine and folate in plasma and urine. Clin Pharmacol Ther 1991;49:385-93.
260. Danishpajooh IO, Gudi T, Chen Y, Kharitonov VG, Sharma VS, Boss GR. Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway. J Biol Chem 2001;276:27296-303.
261. Carlsen SM, Folling I, Grill V, Bjerve KS, Schneede J, Refsum H. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Lab Invest 1997;57:521-7.
262. Ueland PM, Refsum H, Schneede J. Determinants of plasma homocysteine. In: Robinson K, ed. Homocysteine and vascular disease. Dordrecht: Kluwer Academic Publishers, 2000:59-84.
263. Garg R, Malinow M, Pettinger M, Upson B, Hunninghake D. Niacin treatment increases plasma homocyst(e)ine levels. Am Heart J 1999;138:1082-7.
264. Slavik M, Smith KJ, Blanc O. Decrease of serum pyridoxal phosphate levels and homocystinemia after administration of 6-azauridine triacetate and their prevention by administration of pyridoxine. Biochem Pharmacol 1982;31:4089-92.
265. Kredich NM, Hershfield MS, Falletta JM, Kinney TR, Mitchell B, Koller C. Effects of 2′-deoxycoformycin on homocysteine metabolism in acute lymphoblastic leukemia [Abstract]. Clin Res 1981;29:541A.
266. Stead LM, Au KP, Jacobs RL, Brosnan ME, Brosnan JT. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab 2001;281:E1095-100.
267. Steenge GR, Verhoef P, Greenhaff PL. The effect of creatine and resistance training on plasma homocysteine concentration in healthy volunteers. Arch Intern Med 2001;161:1455-6.
268. Miller JW, Selhub J, Nadeau MR, Thomas CA, Feldman RG, Wolf PA. Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status. Neurology 2003;60:1125-9.
269. Rogers JD, Sanchez-Saffon A, Frol AB, Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease. Arch Neurol 2003;60:59-64.
270. Kang S-S, Wong PWK, Curley K. The effect of D-penicillamine on protein-bound homocyst(e)ine in homocystinurics. Pediatr Res 1982;16:370-2.
271. Ventura P, Panini R, Pasini MC, Scarpetta G, Salvioli G. N-Acetylcysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion. Pharmacol Res 1999;40:345-50.
272. Wiklund O, Fager G, Andersson A, Lundstam U, Masson P, Hultberg B. N-Acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. Atherosclerosis 1996;119:99-106.
273. Lauterburg BH, Nguyen T, Hartmann B, Junker E, Kupfer A, Cerny T. Depletion of total cysteine, glutathione, and homocysteine in plasma by ifosfamide/mesna therapy. Cancer Chemother Pharmacol 1994;35:132-6.
274. Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD. Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. J Clin Endocrinol Metab 1998;83:550-3.
275. Anker G, Lonning PE, Ueland PM, Refsum H, Lien EA. Plasma levels of the atherogenic amino acid homocysteine in postmenopausal women with breast cancer treated with tamoxifen. Int J Cancer 1995;60:365-8.
276. Anker GB, Refsum H, Ueland PM, Johannessen DC, Lien EA, Lonning PE. Influence of aromatase inhibitors on plasma total homocysteine in postmenopausal breast cancer patients. Clin Chem 1999;45:252-6.
277. Brouwer IA, Verhoef P, Urgert R. Betaine supplementation and plasma homocysteine in healthy volunteers [Letter]. Arch Intern Med 2000;160:2546-7.
278. Arnadottir M, Hultberg B, Wahlberg J, Fellstrom B, Dimeny E. Serum total homocysteine concentration before and after renal transplantation. Kidney Int 1998;54:1380-4.
279. Cole DE, Ross HJ, Evrovski J, Langman LJ, Miner SE, Daly PA, et al. Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients. Clin Chem 1998;44:2307-12.
280. Luftjohann D, Sigit JI, Locatelli S, von Bergmann K, Schmidt HH. High-dose simvastin (80 mg/day) decreases plasma concentrations of total homocyst(e)ine in patients with hypercholesteromia [Letter]. Atherosclerosis 2001;155:265-6.
281. de Lorgeril M, Salen P, Paillard F, Lacan P, Richard G. Lipid-lowering drugs and homocysteine [Letter]. Lancet 1999;353:209-10.
282. Dierkes J, Westphal S, Luley C. Fenofibrate-induced hyperhomocysteinaemia: clinical implications and management. Drug Saf 2003;26:81-91.
283. 12, and red blood cell folate concentrations. South Med J 1999;92:866-70.
284. Kark JD, Sinnreich R, Rosenberg IH, Jacques PF, Selhub J. Plasma homocysteine and parental myocardial infarction in young adults in Jerusalem. Circulation 2002;105:2725-9.
285. Bates CJ, Mansoor MA, Gregory J, Pentiev K, Prentice A. Correlates of plasma homocysteine, cysteine and cysteinylglycine in respondents in the British National Diet and Nutrition Survey of young people aged 4-18 years, and a comparison with the survey of people aged 65 years and over. Br J Nutr 2002;87:71-9.
286. Tonstad S, Refsum H, Sivertsen M, Christophersen B, Ose L, Ueland PM. Relation of total homocysteine and lipid levels in children to premature cardiovascular death in male relatives. Pediatr Res 1996;40:47-52.
287. Ueland PM. Homocysteine species as components of plasma redox thiol status. Clin Chem 1995;41:340-2.
288. Nygård O, Vollset SE, Refsum H, Brattström L, Ueland PM. Total homocysteine and cardiovascular disease. J Intern Med 1999;246:425-54.