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Review |
1 Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
2 Department of Pharmacology and 3
Locus for Homocysteine and Related Vitamins, University of Bergen, 5021 Bergen, Norway.
4 Department of Clinical Biochemistry AKH, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
5 Clinical Trial Service Unit, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.
6 Departments of Biochemistry and Clinical Medicine, Trinity College, Dublin 2, Ireland
aAddress correspondence to this author at: Department of Pharmacology, University of Oxford, Mansfield Rd., Oxford OX1 3QT, UK. Fax 44-1865-27-1882; e-mail helga.refsum{at}pharmacology.oxford.ac.uk.
Background: Measurement of plasma total homocysteine has become common as new methods have been introduced. A wide range of disorders are associated with increased concentrations of total homocysteine. The purpose of this review is to provide an international expert opinion on the practical aspects of total homocysteine determinations in clinical practice and in the research setting and on the relevance of total homocysteine measurements as diagnostic or screening tests in several target populations.
Methods: Published data available on Medline were used as the basis for the recommendations. Drafts of the recommendations were critically discussed at meetings over a period of 3 years.
Outcome: This review is divided into two sections: (a) determination of homocysteine (methods and their performance, sample collection and handling, biological determinants, reference intervals, within-person variability, and methionine loading test); and (b) risk assessment and disease diagnosis (homocystinuria, folate and cobalamin deficiencies, cardiovascular disease, renal failure, psychiatric disorders and cognitive impairment, pregnancy complications and birth defects, and screening of elderly and newborns). Each of these subsections concludes with a separate series of recommendations to assist the clinician and the research scientist in making informed decisions. The review concludes with a list of unresolved questions.
The following articles in journals at HighWire Press have cited this article:
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  S. J Moat Plasma total homocysteine: instigator or indicator of cardiovascular disease? Ann Clin Biochem, July 1, 2008; 45(4): 345 - 348. [Abstract] [Full Text] [PDF]
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 J. J. Locascio, H. Fukumoto, L. Yap, T. Bottiglieri, J. H. Growdon, B. T. Hyman, and M. C. Irizarry Plasma Amyloid {beta}-Protein and C-reactive Protein in Relation to the Rate of Progression of Alzheimer Disease Arch Neurol, June 1, 2008; 65(6): 776 - 785. [Abstract] [Full Text] [PDF]
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 P. M. Ueland Importance of Chemical Reduction in Plasma and Serum Homocysteine Analysis Clin. Chem., June 1, 2008; 54(6): 1085 - 1086. [Full Text] [PDF]
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 A. D. Dangour, E. Breeze, R. Clarke, P. S. Shetty, R. Uauy, and A. E. Fletcher Plasma Homocysteine, but Not Folate or Vitamin B-12, Predicts Mortality in Older People in the United Kingdom J. Nutr., June 1, 2008; 138(6): 1121 - 1128. [Abstract] [Full Text] [PDF]
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 G. Ravaglia, P. Forti, A. Lucicesare, N. Pisacane, E. Rietti, M. Bianchin, and E. Dalmonte Physical activity and dementia risk in the elderly: Findings from a prospective Italian study Neurology, May 6, 2008; 70(19_Part_2): 1786 - 1794. [Abstract] [Full Text] [PDF]
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 D. Stamopoulos, P. Bouziotis, D. Benaki, C. Kotsovassilis, and P. N. Zirogiannis Utilization of nanobiotechnology in haemodialysis: mock-dialysis experiments on homocysteine Nephrol. Dial. Transplant., April 8, 2008; (2008) gfn189v1. [Abstract] [Full Text] [PDF]
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 S. Cauci, M. Di Santolo, J. F. Culhane, G. Stel, F. Gonano, and S. Guaschino Effects of Third-Generation Oral Contraceptives on High-Sensitivity C-reactive Protein and Homocysteine in Young Women Obstet. Gynecol., April 1, 2008; 111(4): 857 - 864. [Abstract] [Full Text] [PDF]
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 L. Brazionis, K. Rowley Sr., C. Itsiopoulos, C. A. Harper, and K. O'Dea Homocysteine and Diabetic Retinopathy Diabetes Care, January 1, 2008; 31(1): 50 - 56. [Abstract] [Full Text] [PDF]
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 S. Taneja, N. Bhandari, T. A Strand, H. Sommerfelt, H. Refsum, P. M Ueland, J. Schneede, R. Bahl, and M. K. Bhan Cobalamin and folate status in infants and young children in a low-to-middle income community in India Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1302 - 1309. [Abstract] [Full Text] [PDF]
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L. M. de Lau, H. Refsum, A D. Smith, C. Johnston, and M. M. Breteler Plasma folate concentration and cognitive performance: Rotterdam Scan Study Am. J. Clinical Nutrition, September 1, 2007; 86(3): 728 - 734. [Abstract] [Full Text] [PDF]
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 G. Ravaglia, P. Forti, F. Maioli, L. Bastagli, F. Montesi, N. Pisacane, M. Chiappelli, F. Licastro, and C. Patterson Endogenous Sex Hormones as Risk Factors for Dementia in Elderly Men and Women J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2007; 62(9): 1035 - 1041. [Abstract] [Full Text] [PDF]
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M. Herrmann, B. Wildemann, L. Claes, S. Klohs, M. Ohnmacht, O. Taban-Shomal, U. Hubner, A. Pexa, N. Umanskaya, and W. Herrmann Experimental Hyperhomocysteinemia Reduces Bone Quality in Rats Clin. Chem., August 1, 2007; 53(8): 1455 - 1461. [Abstract] [Full Text] [PDF]
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T. A Strand, S. Taneja, N. Bhandari, H. Refsum, P. M Ueland, H. K Gjessing, R. Bahl, J. Schneede, M. K Bhan, and H. Sommerfelt Folate, but not vitamin B-12 status, predicts respiratory morbidity in north Indian children Am. J. Clinical Nutrition, July 1, 2007; 86(1): 139 - 144. [Abstract] [Full Text] [PDF]
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 J. C. Boxmeer, M. Smit, R. F. Weber, J. Lindemans, J. C. Romijn, M. J. Eijkemans, N. S. Macklon, and R. P. Steegers-Theunissen Seminal Plasma Cobalamin Significantly Correlates With Sperm Concentration in Men Undergoing IVF or ICSI Procedures J Androl, July 1, 2007; 28(4): 521 - 527. [Abstract] [Full Text] [PDF]
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 S. Loikas, P. Koskinen, K. Irjala, M. Lopponen, R. Isoaho, S.-L. Kivela, and T.-T. Pelliniemi Vitamin B12 deficiency in the aged: a population-based study Age Ageing, March 1, 2007; 36(2): 177 - 183. [Abstract] [Full Text] [PDF]
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 J. Durga, P. Verhoef, L. J.C. Anteunis, E. Schouten, and F. J. Kok Effects of Folic Acid Supplementation on Hearing in Older Adults: A Randomized, Controlled Trial Ann Intern Med, January 2, 2007; 146(1): 1 - 9. [Abstract] [Full Text] [PDF]
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M. Herrmann, S. Muller, I. Kindermann, L. Gunther, J. Konig, M. Bohm, and W. Herrmann Plasma B vitamins and their relation to the severity of chronic heart failure Am. J. Clinical Nutrition, January 1, 2007; 85(1): 117 - 123. [Abstract] [Full Text] [PDF]
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G. Ravaglia, P. Forti, F. Maioli, M. Chiappelli, F. Montesi, M. Bianchin, F. Licastro, and C. Patterson Apolipoprotein E e4 allele affects risk of hyperhomocysteinemia in the elderly Am. J. Clinical Nutrition, December 1, 2006; 84(6): 1473 - 1480. [Abstract] [Full Text] [PDF]
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L. Feng, T.-P. Ng, L. Chuah, M. Niti, and E.-H. Kua Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study Am. J. Clinical Nutrition, December 1, 2006; 84(6): 1506 - 1512. [Abstract] [Full Text] [PDF]
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G. L. Hortin, N. Seam, and G. T. Hoehn Bound Homocysteine, Cysteine, and Cysteinylglycine Distribution between Albumin and Globulins Clin. Chem., December 1, 2006; 52(12): 2258 - 2264. [Abstract] [Full Text] [PDF]
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 S. Kaul, A. A. Zadeh, and P. K. Shah Homocysteine Hypothesis for Atherothrombotic Cardiovascular Disease: Not Validated J. Am. Coll. Cardiol., September 5, 2006; 48(5): 914 - 923. [Abstract] [Full Text] [PDF]
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L.M.L. de Lau, P. J. Koudstaal, J. C.M. Witteman, A. Hofman, and M. M.B. Breteler Dietary folate, vitamin B12, and vitamin B6 and the risk of Parkinson disease. Neurology, July 25, 2006; 67(2): 315 - 318. [Abstract] [Full Text] [PDF]
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H. Refsum, E. Nurk, A. D. Smith, P. M. Ueland, C. G. Gjesdal, I. Bjelland, A. Tverdal, G. S. Tell, O. Nygard, and S. E. Vollset The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease J. Nutr., June 1, 2006; 136(6): 1731S - 1740S. [Abstract] [Full Text] [PDF]
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H. Refsum, C. Johnston, A. B. Guttormsen, and E. Nexo Holotranscobalamin and Total Transcobalamin in Human Plasma: Determination, Determinants, and Reference Values in Healthy Adults Clin. Chem., January 1, 2006; 52(1): 129 - 137. [Abstract] [Full Text] [PDF]
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M. Herrmann, T. Widmann, G. Colaianni, S. Colucci, A. Zallone, and W. Herrmann Increased Osteoclast Activity in the Presence of Increased Homocysteine Concentrations Clin. Chem., December 1, 2005; 51(12): 2348 - 2353. [Abstract] [Full Text] [PDF]
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 B. M. Gilfix Vitamin B12 and homocysteine Can. Med. Assoc. J., November 22, 2005; 173(11): 1360 - 1360. [Full Text] [PDF]
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G. Ravaglia, P. Forti, F. Maioli, L. Servadei, M. Martelli, N. Brunetti, L. Bastagli, D. Cucinotta, and E. Mariani Folate, But Not Homocysteine, Predicts the Risk of Fracture in Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2005; 60(11): 1458 - 1462. [Abstract] [Full Text] [PDF]
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G. Ravaglia, P. Forti, F. Maioli, M. Martelli, L. Servadei, N. Brunetti, E. Porcellini, and F. Licastro Homocysteine and folate as risk factors for dementia and Alzheimer disease Am. J. Clinical Nutrition, September 1, 2005; 82(3): 636 - 643. [Abstract] [Full Text] [PDF]
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D. R. Warden and H. Refsum Detection of Single-Nucleotide Polymorphisms by PCR with Universal Energy Transfer-Labeled Primers: Application to Folate- and Cobalamin-Related Genes Clin. Chem., September 1, 2005; 51(9): 1713 - 1716. [Full Text] [PDF]
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R. Scheidhauer, B. Guessregen, A. Hohl, and T. Arndt Effects of Prolonged Ambient Storage of Sodium Fluoride/Heparin Specimens on Plasma Homocysteine Clin. Chem., August 1, 2005; 51(8): 1564 - 1565. [Full Text] [PDF]
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 C. O'DONNELL and T. STEPHENS The Significance of Homocysteine Levels in Schizophrenia Am J Psychiatry, July 1, 2005; 162(7): 1387 - 1388. [Full Text] [PDF]
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O. Midttun, S. Hustad, E. Solheim, J. Schneede, and P. M. Ueland Multianalyte Quantification of Vitamin B6 and B2 Species in the Nanomolar Range in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry Clin. Chem., July 1, 2005; 51(7): 1206 - 1216. [Abstract] [Full Text] [PDF]
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 D. E. Handy, Y. Zhang, and J. Loscalzo Homocysteine Down-regulates Cellular Glutathione Peroxidase (GPx1) by Decreasing Translation J. Biol. Chem., April 22, 2005; 280(16): 15518 - 15525. [Abstract] [Full Text] [PDF]
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 R. Marcucci, A. M. Gori, R. Abbate, J. Frederiksen, K. Juul, A. Tybjaerg-Hansen, and B. G. Nordestgaard Hyperhomocysteinemia: cause or effect of disease? Blood, April 15, 2005; 105(8): 3382 - 3384. [Full Text] [PDF]
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 E.-C. Chan, P.-Y. Chang, T.-L. Wu, and J. T. Wu Enzymatic Assay of Homocysteine on Microtiter Plates or a TECAN Analyzer Using Crude Lysate Containing Recombinant Methionine {gamma}-Lyase Ann. Clin. Lab. Sci., April 1, 2005; 35(2): 155 - 160. [Abstract] [Full Text] [PDF]
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 R. G. V. Smolders, K. de Meer, P. Kenemans, C. Jakobs, W. Kulik, and M. J. van der Mooren Oral Estradiol Decreases Plasma Homocysteine, Vitamin B6, and Albumin in Postmenopausal Women But Does Not Change the Whole-Body Homocysteine Remethylation and Transmethylation Flux J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2218 - 2224. [Abstract] [Full Text] [PDF]
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 P. I. Holm, P. M. Ueland, S. E. Vollset, O. Midttun, H. J. Blom, M. B.A.J. Keijzer, and M. den Heijer Betaine and Folate Status as Cooperative Determinants of Plasma Homocysteine in Humans Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 379 - 385. [Abstract] [Full Text] [PDF]
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G. Chwatko and H. Jakubowski Urinary Excretion of Homocysteine-Thiolactone in Humans Clin. Chem., February 1, 2005; 51(2): 408 - 415. [Abstract] [Full Text] [PDF]
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 A. Coppen and C. Bolander-Gouaille Treatment of depression: time to consider folic acid and vitamin B12 J Psychopharmacol, January 1, 2005; 19(1): 59 - 65. [Abstract] [PDF]
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M. E. Suliman, P. Barany, K. Kalantar-Zadeh, B. Lindholm, and P. Stenvinkel Homocysteine in uraemia--a puzzling and conflicting story Nephrol. Dial. Transplant., January 1, 2005; 20(1): 16 - 21. [Full Text] [PDF]
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X. Chen, K.-H. Jhee, and W. D. Kruger Production of the Neuromodulator H2S by Cystathionine {beta}-Synthase via the Condensation of Cysteine and Homocysteine J. Biol. Chem., December 10, 2004; 279(50): 52082 - 52086. [Abstract] [Full Text] [PDF]
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R. Rej Clinical Chemistry through Clinical Chemistry: A Journal Timeline Clin. Chem., December 1, 2004; 50(12): 2415 - 2458. [Abstract] [Full Text] [PDF]
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H. Refsum, A. W. Grindflek, P. M. Ueland, A. Fredriksen, K. Meyer, A. Ulvik, A. B. Guttormsen, O. E. Iversen, J. Schneede, and B. F. Kase Screening for Serum Total Homocysteine in Newborn Children Clin. Chem., October 1, 2004; 50(10): 1769 - 1784. [Abstract] [Full Text] [PDF]
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Q. Han, X. Sun, M. Xu, N. Zhang, L. Tang, Y. Tan, and R. M. Hoffman 3-Deazaadenosine, a Stabilizer of Whole-Blood Homocysteine Content, Does Not Interfere with the Single-Enzyme Homocysteine Assay while Totally Inhibiting the Enzyme Conversion Homocysteine Immunoassay Clin. Chem., September 1, 2004; 50(9): 1703 - 1704. [Full Text] [PDF]
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H. Refsum Is folic acid the answer? Am. J. Clinical Nutrition, August 1, 2004; 80(2): 241 - 242. [Full Text] [PDF]
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E. J. Norman Urinary Methylmalonic Acid Test May Have Greater Value than the Total Homocysteine Assay for Screening Elderly Individuals for Cobalamin Deficiency Clin. Chem., August 1, 2004; 50(8): 1482 - 1483. [Full Text] [PDF]
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Q. Han, M. Xu, L. Tang, X. Sun, N. Zhang, X. Tan, X. Tan, Y. Tan, and R. M. Hoffman Homogeneous Enzymatic Colorimetric Assay for Total Cysteine Clin. Chem., July 1, 2004; 50(7): 1229 - 1231. [Full Text] [PDF]
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T. Arndt, B. Guessregen, A. Hohl, and B. Heicke Total Plasma Homocysteine Measured by Liquid Chromatography-Tandem Mass Spectrometry with Use of 96-Well Plates Clin. Chem., April 1, 2004; 50(4): 755 - 757. [Full Text] [PDF]
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