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Test Summary



Clinical Use

  • Diagnose homocystinuria, vitamin B12 deficiency, and folate deficiency

  • Assess risk of cardiovascular disease (CVD), stroke, and dementia (including Alzheimer disease)

  • Monitor therapy in patients with elevated homocysteine levels

Clinical Background

Severe hyperhomocysteinemia (>100 μmol/L) is generally caused by homocystinuria, an autosomal recessive inborn error of homocysteine metabolism (often involving cystathionine-β-synthase deficiency). While symptoms are often not apparent at birth, affected individuals may develop high myopia, ectopia lentis, marfanoid habitus, intellectual disability, and thromboembolism. Early diagnosis and homocysteine-lowering therapy are important to minimize the effects of this metabolic disorder.

Mild or moderate homocysteine elevation can be caused by deficiencies of cobalamin (vitamin B12), folate, and vitamin B6 (essential cofactors in homocysteine metabolism); variations in the methylenetetrahydrofolate reductase (MTHFR) gene; and certain medications, among other factors. Vitamin B12 deficiency can lead to irreversible neurologic damage, folate deficiency during pregnancy may cause neural tube defects, and either can cause megaloblastic anemia. Although folate and vitamin B12 can be measured directly, homocysteine is a more accurate indicator of deficiency at the tissue level.1 Used in combination with the methylmalonic acid (MMA) assay, homocysteine measurement can differentiate between folate and vitamin B12 deficiency (see below). This can be crucial because folate supplementation can mask signs of vitamin B12 deficiency (such as anemia), allowing neurodegenerative processes to continue. 

Modest elevation in plasma homocysteine has also been reported as a risk factor for atherosclerotic disease in coronary, cerebral, renal, and peripheral vessels,2,3 and for arterial and venous thrombosis.3 The greater the homocysteine level, the greater the risk.2 There appears to be an additive effect with hyperlipidemia4 and a synergistic interaction with hypertension and smoking,4 as well as factor V Leiden.5 In 2 recent meta-analyses, the predictive value of homocysteine level for CVD risk was lower than in earlier, individual reports.6,7 Homocysteine concentrations predict the risk of mortality in patients with known coronary artery disease; mortality ratios across quartiles of homocysteine concentrations are 1.0 (<9.0 µmol/L), 1.9 (9.0-14.9 µmol/L), 2.8 (15.0-19.9 µmol/L), and 4.5 (20 µmol/L).8 Furthermore, homocysteine may be an independent predictor of stroke and dementia, including Alzheimer disease.9 In the Framingham study, involving primarily people of European descent, a 5 µmol/L increase in plasma homocysteine level was associated with a 40% increase in the 8-year risk of Alzheimer disease.9

Supplementation with folate, vitamin B12, and vitamin B6 can lower plasma homocysteine levels in some patients with mild or moderate homocysteinemia, but this has not yet been proven to reduce the risk of a first coronary event. However, B-vitamin supplementation may reduce the risk of restenosis after coronary angioplasty,10 improve endothelial function in patients with coronary heart disease,11 and reduce the rate of subclinical atherosclerosis.12 In individuals with elevated homocysteine levels, adequate folate intake should be ensured once vitamin B12 deficiency is ruled out.13

Individuals Suitable for Testing

  • Individuals with clinical evidence of homocystinuria

  • Elderly individuals with clinical evidence of reduced cobalamin and folate intake

  • Individuals with early (<50 years of age) evidence of CVD

  • Otherwise low-risk individuals with a family history of premature CVD


  • Competitive immunochemiluminometric assay (ICMA)

  • Measures total homocysteine (ie, protein-bound, oxidized, and free, reduced homocysteine)

  • Analytical sensitivity: 2.0 µmol/L

  • Analytical specificity: does not cross-react with carbamazepine, phenytoin, 6-azauridine,
    anthopterin, adenosine, l-cysteine, or gluthathione; cross-reaction is 0.6% with S-adenosyl-l-methionine and 6.1% with cystathionine

Reference Range

Cardiovascular Disease15

Congenital and Nutritional

Men: <11.4 μmol/L

5.4-11.9 μmol/L

Women: <10.4 μmol/L

Interpretive Information

The following are some of the conditions associated with increased homocysteine levels: homocystinuria (cystathionine-β-synthase deficiency); vitamin B12 (MMA increased) and folate deficiency (MMA not increased); CVD; chronic renal disease (typically 9-50 µmol/L); increasing age; male sex; MTHFR mutations; hypothyroidism; selected malignancies (eg, breast, ovarian, and pancreatic cancer); diets rich in methionine (high meat intake); cigarette smoking; and treatment with corticosteroids, methotrexate, nitrous oxide, cyclosporine, vitamin B6 antagonists (isoniazid, azauridine, penicillamine, procarbazine), and anticonvulsants (phenytoin, carbamazepine).

Homocysteine levels are low (typically <9 µmol/L) in individuals who are pregnant (except in cases of fetal neural tube defect), <15 years of age, or taking oral contraceptives or hormone replacement therapy.

Treatment with S-adenosylmethionine may cause falsely elevated homocysteine levels, and human anti-mouse antibodies (HAMA) may also interfere with measurement.


  1. Klee GG. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate. Clin Chem. 2000;46:1277-1283.

  2. Boushey C, Beresford S, Omenn G, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057.

  3. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998;338:1042-1050.

  4. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project. JAMA. 1997;277:1775-1781.

  5. Ridker PM, Hennekens CH, Selhub J, et al. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation. 1997;95:1777-1782.

  6. The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022.

  7. Klerk M, Verhoef P, Clarke R, et al. MTHFR 677CT polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002;288:2023-2031.

  8. Nygard O, Nordrehaug JE, Refsum H, et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230-236.

  9. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer‘s disease. N Engl J Med. 2002;346:476-483.

  10. 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.

  11. Chambers JC, Ueland PM, Obeid OA, et al. Improved vascular endothelial function after oral B vitamins: an effect mediated through reduced concentrations of free plasma homocysteine. Circulation. 2000;102:2479-2483.

  12. Vermeulen E, Stehouwer C, Twisk J, 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.

  13. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Available at http://www.nhlbi.nih.gov/
    guidelines/cholesterol/atp3_rpt.htm. Accessed June 4, 2002.

  14. Selhub J, Jacques PF, Rosenberg IH, et al. Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991-1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med. 1999;131:331-339.

Content reviewed 06/2013
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