Clinical usefulness of plasma homocysteine in vascular disease

Graeme J Hankey, John W Eikelboom, Wai Khoon Ho and Frank M van Bockxmeer
Med J Aust 2004; 181 (6): 314-318.


  • Raised plasma homocysteine (tHcy) concentrations are caused by genetic mutations, vitamin deficiencies, renal and other diseases, numerous drugs, and increasing age.

  • Raised tHcy concentrations are associated with laboratory evidence of atherogenesis (eg, endothelial dysfunction) and thrombosis, and epidemiological evidence of an increased risk of atherothrombotic vascular disease.

  • An association between raised tHcy concentration and an increased risk of atherothrombosis is independent of other vascular risk factors, strong, dose-related and biologically plausible, but has not been proven to be causal in randomised controlled trials.

  • A recent trial identified no significant benefit from lowering tHcy concentration by folic-acid-based multivitamin therapy among 3680 patients with recent ischaemic stroke, but did not reliably exclude a modest but important reduction in the relative risk of stroke of up to 20%; a difference of only 2 mmol/L in tHcy concentration between the two treatment groups was probably due to widespread vitamin use and fortification of grains and staple foods with folate in North America.

  • There is currently insufficient evidence to recommend routine screening and treatment of high tHcy concentrations with folic acid and other vitamins to prevent atherothrombotic vascular disease.

Please login with your free MJA account to view this article in full

  • Graeme J Hankey1
  • John W Eikelboom2
  • Wai Khoon Ho3
  • Frank M van Bockxmeer4

  • Royal Perth Hospital, Perth, WA.


Competing interests:

None identified.

  • 1. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354: 407-413.
  • 2. D’Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997; 90: 1-11.
  • 3. Moat SJ, Lang D, McDowell IFW, et al. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 2004; 15: 64-79.
  • 4. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004; 50: 3-32.
  • 5. Desouza C, Keebler M, McNamara DB, Fonseca V. Drugs affecting homocysteine metabolism. Impact on cardiovascular risk. Drugs 2002; 62: 605-616.
  • 6. Homocysteine lowering trialist’s collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998; 316: 894-898.
  • 7. Van Guldener C, Janssen MJ, deMeer K, et al. Effect of folic acid and betaine on fasting and methionine-loading plasma homocysteine and methionine concentration in chronic haemodialysis patients. J Intern Med 1999; 245: 175-183.
  • 8. Cottington EM, LaMantia C, Stabler SP, et al. Adverse event associated with methionine loading test. A case report. Arterioscler Thromb Vasc Biol 2002; 22: 1046-1050.
  • 9. Ubbink JB. Assay methods for the measurement of total homocyst(e)ine in plasma. Semin Thromb Hemost 2000; 26: 233-241.
  • 10. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969; 56: 111-128.
  • 11. Symons JD, Mullick AE, Ensunsa JL, et al. Hyperhomocysteinaemia evoked by folate depletion: effects on coronary and carotid arterial function. Arterioscler Thromb Vasc Biol 2002; 22: 772-780.
  • 12. Faraci FM. Hyperhomocysteinaemia: a million ways to lose control. Arterioscler Thromb Vasc Biol 2003; 23: 371-373.
  • 13. Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 2004; 35: 345-347.
  • 14. The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke. A meta-analysis. JAMA 2002; 288: 2015-2022.
  • 15. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325: 1202-1206.
  • 16. Dudman NP: An alternative view of homocysteine. Lancet 1999; 354: 2072-2074.
  • 17. Klerk M, Verhoef P, Clarke R, et al, and the MTHFR Studies Collaboration Group. MTHFR 677CÆT polymorphism and risk of coronary heart disease. A meta-analysis. JAMA 2002; 288: 2023-2031.
  • 18. Bazzano LA, He J, Ogden LG, et al. Dietary intake of folate and risk of stroke in US men and women. NHAMES I Epidemiologic follow-up study. Stroke 2002; 33: 1183-1189.
  • 19. He K, Merchant A, Rimm EB, et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 2004; 35: 169-174.
  • 20. Peterson JC, Spence JD. Vitamins and progression of atherosclerosis in hyper-homocyst(e)inaemia [letter]. Lancet 1998; 351: 263.
  • 21. Hackam DG, Peterson JC, Spence JD. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 μmol/L. Am J Hypertens 2000; 13: 105-110.
  • 22. Marcuci R, Zanazzi M, Bertoni E, et al. Vitamin supplementation reduces the progression of atherosclerosis in hyperhomocysteinaemic renal-transplant recipients. Transplantation 2003; 75: 1551-1555.
  • 23. Vermeulen EGJ, Stehouwer CDA, Twisk JWR, 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: 517-522.
  • 24. Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345: 1593-1600.
  • 25. Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention. JAMA 2002; 288: 973-979.
  • 26. Lange H, Suryapranata H, De luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. New Engl J Med 2004; 350: 2673-2681.
  • 27. Toole JF, Malinow R, Chambless L, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death. The Vitamin Intervention for Stroke Prevention (VISP) randomised controlled trial. JAMA 2004; 291: 565-575.
  • 28. Jacques PF, Selhub J, Bostom AG, Wilson PW, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340: 1449-1454.
  • 29. 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: 133-137.
  • 30. Quinlivan EP, McPartlin J, McNulty H, et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 2002; 359: 227-228.
  • 31. Morris CD, Carson S. Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2003; 139: 56-70.


remove_circle_outline Delete Author
add_circle_outline Add Author

Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Responses are now closed for this article.