Skip to main content
SpringerLink
Log in

Assessment of homocysteine status

  • Published:
Journal of Inherited Metabolic Disease

Abstract

Plasma total homocysteine (tHcy) determination is used in the diagnosis of homocystinuria, in cobalamin and folate deficiency and in cardiovascular risk assessment. However, determination of tHcy includes many pitfalls which complicate the assessment of homocysteine status. In the present article, we review basic knowledge for a rational use of plasma tHcy in diagnostic as well as scientific work. The subjects dealt with are procedures for sample handling and processing, the principles of tHcy analyses, and genetic and acquired determinants of the plasma tHcy concentration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Allen RH, Stabler SP, Savage DG, Lindenbaum J (1994) Metabolic abnormalities in cobalamin (vitamin-B12) and folate deficiency. FASEB J 7: 1344–1353.

    Google Scholar 

  • Arnesen E, Refsum H, Bønaa KH, Ueland PM, Førde OH, Nordrehaug JE (1995) Serum total homocysteine and coronary heart disease. Int J Epidemiol 24: 704–709.

    Google Scholar 

  • Blankenhorn DH, Malinow MR, Mack WJ (1991) Colestipol plus niacin therapy elevates plasma homocyst(e)ine levels. Coron Arter Dis 2; 357–360.

    Google Scholar 

  • Bostom A, Brosnan JT, Hall B, Nadeau MR, Selhub J (1995a) Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis 116: 59–62.

    Google Scholar 

  • Bostom AG, Jacques PF, Nadeau MR, Williams RR, Ellison RC, Selhub J (1995b) Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis 116: 147–151.

    Google Scholar 

  • Bostom AG, Roubenoff R, Dellaripa P, et al (1995c) Validation of abbreviated oral methionine-loading test [letter]. Clin Chem 41: 948–949.

    Google Scholar 

  • Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. J Am Med Assoc 274: 1049–1057.

    Google Scholar 

  • Brattström L, Israelsson B, Norrving B, et al (1990) Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease — effects of pyridoxine and folic acid treatment. Atherosclerosis 81: 51–60.

    Google Scholar 

  • Brattström L, Lindgren A, Israelsson B, Andersson A, Hultberg B (1994) Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects. J Intern Med 236: 633–641.

    Google Scholar 

  • Brenton DP, Cusworth DC, Dent CE, Jones EE (1966) Homocystinuria: clinical and dietary studies. Q J Med 35: 325–346.

    Google Scholar 

  • Chauveau P, Chadefaux B, Coudé M, et al (1993) Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int 43(supplement 41): S72–S77.

    Google Scholar 

  • Dennis VW, Robinson K (1996) Homocysteinemia and vascular disease in end-stage renal disease. Kidney Int 50(supplement 57): 51–57.

    Google Scholar 

  • Dudman NP, Wilcken DE, Wang J, Lynch JF, Macey D, Lundberg P (1993) Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology. Arterioscler Thromb 13: 1253–1260.

    Google Scholar 

  • Engbersen AMT, Franken DG, Boers GHJ, Stevens EMB, Trijbels FJM, Blom HJ (1995) Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 56: 142–150.

    Google Scholar 

  • Fiskerstrand T, Refsum H, Kvalheim G, Ueland PM (1993) Homocysteine and other thiols in plasma and urine: automated determination and sample stability. Clin Chem 39: 263–271.

    Google Scholar 

  • Fowler B, Sardharwalla IB, Robins AJ (1971) The detection of heterozygotes for homocystinuria by oral loading with L-methionine. Biochem J 122: 23p–24p.

    Google Scholar 

  • Franken DG, Boers GH, Blom HJ, Trijbels FJ, Kloppenborg PW (1994) Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb 14: 465–470.

    Google Scholar 

  • Frosst P, Blom HJ, Milos R, et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 10: 111–113.

    Google Scholar 

  • Guttormsen AB, Mansoor MA, Fiskerstrand T, Ueland PM, Refsum H (1993) Kinetics of plasma homocysteine in healthy subjects after peroral homocysteine loading. Clin Chem 39: 1390–1397.

    Google Scholar 

  • Guttormsen AB, Schneede J, Fiskerstrand T, Ueland PM, Refsum H (1994) Plasma concentrations of homocysteine and other aminothiol compounds are related to food intake in healthy subjects. J Nutr 124: 1934–1941.

    Google Scholar 

  • Guttormsen AB, Svarstad E, Ueland PM, Refsum H (1995) Elimination of homocysteine from plasma in subjects with endstage renal failure. Irish J Med Sci 164(Suppl. 15): 8.

    Google Scholar 

  • Guttormsen AB, Ueland PM, Nesthus I, et al (1996a) Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (≥40 μmol/L): The Hordaland Homocysteine Study. J Clin Invest, 98: 2174–2183.

    Google Scholar 

  • Guttormsen AB, Schneede J, Ueland PM, Refsum H (1996b) Kinetics of total plasma homocysteine in subjects with hyperhomocysteinemia due to folate and cobalamin deficiency. Am J Clin Nutr, 63: 194–202.

    Google Scholar 

  • Kang S-S, Wong PWK, Norusis M (1987) Homocysteinemia due to folate deficiency. Metabolism 36: 458–462.

    Google Scholar 

  • Kang S-S, Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N (1991) Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 48: 536–545.

    Google Scholar 

  • Kang S-S, Wong PWK, Malinow MR (1992) Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12: 279–298.

    Google Scholar 

  • Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al (1996) 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 58: 35–41.

    Google Scholar 

  • Kozich V, Kraus E, DeFranchis R, et al (1995) Hyperhomocysteinemia in premature arterial disease: examination of cystathionine beta-synthase alleles at the molecular level. Hum Mol Genet 4: 623–629.

    Google Scholar 

  • Leppanen EA, Grasbeck R (1988) Experimental basis of standardized specimen collection: effect of posture on blood picture. Eur J Haematol 40: 222–226.

    Google Scholar 

  • Mansoor MA, Svardal AM, Schneede J, Ueland PM (1992) Dynamic relation between reduced, oxidized and protein-bound homocysteine and other thiol components in plasma during methionine loading in healthy men. Clin Chem 38: 1316–1321.

    Google Scholar 

  • Mansoor MA, Guttormsen AB, Fiskerstrand T, Refsum H, Ueland PM, Svardal AM (1993) Redox status and protein-binding of plasma aminothiols during the transient hyperhomocysteinemia that follows homocysteine administration. Clin Chem 39: 980–985.

    Google Scholar 

  • Mansoor MA, Ueland PM, Svardal AM (1994) Redox status and protein binding of plasma homocysteine and other aminothiols in patients with hyperhomocysteinemia due to cobalamin deficiency. Am J Clin Nutr 59: 631–635.

    Google Scholar 

  • Mansoor MA, Bergmark C, Svardal AM, Lønning PE, Ueland PM (1995) Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Arterioscler Thromb Vasc Biol 15: 232–240.

    Google Scholar 

  • Möller J, Rasmussen K (1995) Homocysteine in plasma: stabilization of blood samples with fluoride. Clin Chem 41: 758–759.

    Google Scholar 

  • Motulsky AG (1996) Nutritional ecogenetics: homocysteine-related arteriosclerotic vascular disease, neural tube defects, and folic acid [editorial comment]. Am J Hum Genet 58: 17–20.

    Google Scholar 

  • Mudd SH, Levy HL, Skovby F (1995) Disorders of transsulfuration. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th edn. New York: McGraw-Hill, 1279–1327.

    Google Scholar 

  • Nygård O, Vollset SE, Refsum H, et al (1995) Total plasma homocysteine and cardiovascular risk profile: The Hordaland Homocysteine Study. J Am Med Assoc 274: 1526–1533.

    Google Scholar 

  • Nygård O, Refsum H, Nordrehaug J, et al (1997) Coffee consumption and plasma total homocysteine: The Hordaland Homocysteine Study. Am J Clin Nutr, 65: 136–143.

    Google Scholar 

  • Rasmussen K, Möller J, Lyngbak M, Pedersen AM, Dybkjaer L (1996) Age-and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clin Chem 42: 630–636.

    Google Scholar 

  • Refsum H, Ueland PM (1990) Clinical significance of pharmacological modulation of homocysteine metabolism. Trends Pharmacol Sci 11: 411–416.

    Google Scholar 

  • Refsum H, Helland S, Ueland PM (1985) Radioenzymic determination of homocysteine in plasma and urine. Clin Chem 31: 624–628.

    Google Scholar 

  • Refsum H, Helland S, Ueland PM (1989) Fasting plasma homocysteine as a sensitive parameter to antifolate effect. A study on psoriasis patients receiving low-dose methotrexate treatment. Clin Pharmacol Ther 46: 510–520.

    Google Scholar 

  • Rosenblatt DS, Cooper BA (1990) Inherited disorders of vitamin B-12 utilization. BioEssays 12: 331–334.

    Google Scholar 

  • Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assoc 270: 2693–2698.

    Google Scholar 

  • Shipchandler MT, Moore EG (1995) Rapid, fully automated measurement of plasma homocyst(e)ine with the Abbott IMx analyzer. Clin Chem 41: 991–994.

    Google Scholar 

  • Ubbink JB, Vermaak WJH, Vandermerwe A, Becker PJ (1992) The effect of blood sample aging and food consumption on plasma total homocysteine levels. Clin Chim Acta 207: 119–128.

    Google Scholar 

  • Ubbink JB, Becker PJ, Vermaak WJ, Delport R (1995a) Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem 41: 1033–1037.

    Google Scholar 

  • Ubbink JB, Vermaak WJ, Delport R, van der Merwe A, Becker PJ, Potgieter H (1995b) Effective homocysteine metabolism may protect South African blacks against coronary heart disease. Am J Clin Nutr 62: 802–808.

    Google Scholar 

  • Ubbink JB, Delport R, Vermaak WJ (1996a) Plasma homocysteine concentrations in a population with a low coronary heart disease prevalence. J Nutr 126(4 supplement): 1254S–1257S.

    Google Scholar 

  • Ubbink JB, van der Merwe A, Delport R, et al (1996b) The effect of a subnormal vitamin B6 status on homocysteine metabolism. J Clin Invest 98: 177–184.

    Google Scholar 

  • Ueland PM (1995) Homocysteine species as components of plasma redox thiol status. Clin Chem 41: 340–342.

    Google Scholar 

  • Ueland PM, Refsum H, Brattström L (1992) Plasma homocysteine and cardiovascular disease. In Francis RB Jr, ed. Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function. New York: Marcel Dekker, 183–236.

    Google Scholar 

  • Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH (1993) Total homocysteine in plasma or serum. Methods and clinical applications. Clin Chem 39: 1764–1779.

    Google Scholar 

  • van der Put NMJ, Steegers-Theunissen RPM, Frosst P, et al (1995) Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 346: 1070–1071.

    Google Scholar 

  • Verhoef P, Kok FJ, Kruyssen DACM, et al (1997) Plasma total homocysteine, B-vitamins and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol, in press.

  • Vermaak WJ, Ubbink JB, Delport R, Becker PJ, Bissbort SH, Ungerer JP (1991) Ethnic immunity to coronary heart disease? Atherosclerosis 89: 155–162.

    Google Scholar 

  • Wilcken DEL, Gupta VJ, Betts AK (1981) Homocysteine in the plasma of renal transplant recipients: effects of cofactors for methionine metabolism. Clin Sci 61: 743–749.

    Google Scholar 

  • Wu LL, Wu J, Hunt SC, et al (1994) Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem 40: 552–561.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Bergen, Armauer Hansens hus, 5021, Bergen, Norway

    H. Refsum, T. Fiskerstrand, A. B. Guttormsen & P. M. Ueland

Authors
  1. H. Refsum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Fiskerstrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. B. Guttormsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. M. Ueland
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Refsum, H., Fiskerstrand, T., Guttormsen, A.B. et al. Assessment of homocysteine status. J Inherit Metab Dis 20, 286–294 (1997). https://doi.org/10.1023/A:1005321225893

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005321225893

Keywords

Search

Navigation