BlueCross BlueShield of Tennessee Medical Policy Manual

Homocysteine Testing in the Screening, Diagnosis, and Management of Dyslipidemia, Cardiovascular Disease and Venous Thromboembolic Disease


Homocysteine is a sulfur-containing amino acid found in the blood; levels are inversely correlated with folate levels. Homocysteine has been evaluated as a potential indicator of cardiovascular disease (CVD) in the general population and as a potential risk factor among people with CVD. The association between homocysteine-lowering interventions and risk of CVD has also been examined. Several homocysteine test systems are currently available.

Homocysteine rapidly oxidized into homocystine and cysteine-homocysteine disulfide within the plasma. It is normally found in the body and the metabolism of homocysteine is linked to that of several vitamins, especially folic acid, B6, and B12. Deficiencies of these vitamins may cause elevated levels of homocysteine.


See also: Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease



Numerous large placebo-controlled RCTs have been published that evaluate the impact of folic acid/ vitamin B supplementation on risk of cardiovascular events, including MI and stroke. With few exceptions, meta-analyses of these RCTs have found that homocysteine-lowering interventions do not have a statistically significant effect on the rate of major cardiovascular events. Two placebo-controlled RCTs have been published that evaluate the impact of folic acid and vitamin B supplementation on the risk of VTE. Homocysteine-lowering interventions do not have a statistically significant effect on the rate of VTE in patients with previous VTE. Based on these trials, there is insufficient evidence to conclude that supplementation to reduce homocysteine will reduce risk of VTE.


American Heart Association. AHA Recommendation. (2014, March). Homocysteine, folic acid and cardiovascular disease. Retrieved September 25, 2014 from

Armitage J., Bowman, L., Clarke, R., Wallendszus, K., Bulbulia, R., Rahimi, K., et al. (2010). Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA, 303 (24), 2486 - 2494. (Level 1 evidence - Industry supported)

BlueCross BlueShield Association. Medical Policy Reference Manual. (12:2016). Homocysteine testing in the screening, diagnosis, and management of cardiovascular disease and venous thromboembolic disorders (2.04.23). Retrieved December 12, 2016 from BlueWeb. (48 articles and/or guidelines reviewed)

Clarke, R., Armitage, J., Lewington, S., Collins, R., & B-Vitamin Treatment Trialists’ Collaboration. (2007). Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Clinical Chemistry and Laboratory Medicine, 45 (12), 1575-1581. Abstract retrieved April 8, 2008 from PubMed database. (Level 1 evidence)

Cotlarciuc, I., Malik, R., Holliday, E., Ahmadi, K., Pare, G., Psaty, B., et al. (2014). Effect of genetic variants associated with plasma homocysteine levels on stroke risk. Stroke, 45 (7), 1920-1924.

den Heijer, M., Willems, H. P., Blom, H. J., Gerrits, W. B., Cattaneo, M., Eichinger, S., et al. (2007). Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood, 109 (1), 139-144. (Level 1 evidence - Independent)

Dent, T. (2010, January). Predicting the risk of coronary heart disease with conventional, genetic and novel molecular biomarkers. Foundation for Genomics and Population Health. Retrieved September 24, 2014 from (Level 1 evidence)

Joachim, E., Goldenberg, N., Bernard, T., Armstrong-Wells, J., Stabler, S., & Manco-Johnson, M. (2013). The methylenetetrahydrofolate reductase polymorphism (MTHFR c.677C>T) and elevated plasma homocysteine levels in a U.S. pediatric population with incident thromboembolism. Thrombosis Research, 132 (2), 170-174. Abstract retrieved January 12, 2016 from PubMed database.

Keijzer, M. B., Borm, G. F., Blom, H. J., Bos, G. M., Rosendaal, F. R., & den Heijer, M. (2007). No interaction between factor V Leiden and hyperhomocysteinemia or MTHFR 677TT genotype in venous thrombosis. Results of a meta-analysis of published studies and a large case-only study. Journal of Thrombosis and Haemostasis, 97 (1), 32-37. Abstract retrieved December 12, 2016 from PubMed database.

National Institute for Health and Care Excellence. (2015, September). Active B12 assay for diagnosing vitamin B12 deficiency.  Retrieved January 12, 2016 from

Park, J. H., Saposnik, G., Ovbiagele, B., Markovic, D., & Towfighi, A. (2016). Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: A meta-analysis. International Journal of Stroke, 11 (2), 206-211. Abstract retrieved December 12, 2016 from PubMed database.

Ray, J. G., Kearon, C., Yi, Q., Sheridan, P., Lonn, E. & Heart Outcomes Prevention Evaluation 2 (HOPE-2) Investigators. (2007). Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Annals of Internal Medicine, 146 (11), 761-767. Abstract retrieved December 12, 2016 from PubMed database.

Royal Australian College of General Practitioners. (2012). Screening tests of unproven benefit. Guidelines for preventive activities in general practice, 8th edition. Retrieved September 24, 2014 from

Shoamanesh, A., Preis, S. R., Beiser, A. S., Kase, C. S., Wolf, P. A., Vasan, R. S., et al. (2016). Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study. Neurology, 87 (12), 1206-1211. Abstract retrieved February 20, 2017 from PubMed database.

Sweetser, D. A., Lin, A. E., Troulis, M. J., Chen, T. C., & Westra, S. J. (2016). Case 34-2016: A 17-year-old boy with myopia and craniofacial and skeletal abnormalities. The New England Journal of Medicine, 375 (19), 1879-1890. (Level 5 evidence - Independent)

U. S. Food and Drug Administration. (2004, February). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K033706. Retrieved April 8, 2008 from

U. S. Food and Drug Administration. (2006, October). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K062808. Retrieved April 8, 2008 from 

Wang, C. Y., Chen, Z. W., Zhang, T., Liu, J., Chen, S. H., Liu, S. Y. (2014). Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients. European Journal of Internal Medicine, 25 (6), 538-544. Abstract retrieved December 12, 2016 from PubMed database.

Zhou, K., Zhao, R., Geng, Z., Jiang, L., Cao, Y., Xu, D., et al. (2012). Association between B-group vitamins and venous thrombosis: systematic review and meta-analysis of epidemiological studies. Journal of Thrombosis and Thrombolysis, 34 (4), 459-467. Abstract retrieved December 12, 2016 from PubMed database.




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