Homocysteine - Should We Test Everyone?

Our clinical interest in homocysteine began in the 1960's suggesting a link between homocysteine and vascular disease, with elevated homocysteine levels being associated with coronary artery disease and stroke. These associations appeared relevant, as they remained even when controlling for traditional risk factors, such as smoking and cholesterol. Basic science evaluation of homocysteine suggested it worsened the integrity of the lining of blood vessels, supporting its role in vascular disease.

Around the end of the 20th century, extensive work was done to evaluate treatment of elevated homocysteine by supplementing with folic acid and other B vitamins. Three of the larger trials evaluating folate (vitamin B9) and other B vitamins include SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine), HOPE-2 (Heart Outcomes Prevention Evaluation-2), and NORVIT (Norwegian Vitamin Trial), with a total enrolled population of 21,335 individuals. Unfortunately, there was no significant improvement in heart attacks or overall reduction in cardiovascular events from treatment with folic acid and vitamin B12, though there may have been a subtle reduction in stroke risk in some groups.

With little cardiovascular benefit seen with treatment using folic acid and other B vitamins, guidelines argue against routinely testing homocysteine levels in all patients. There may be a modest role of evaluating homocysteine in those with demonstrated vascular disease, though assessing homocysteine in primary prevention is not supported by the American Association of Clinical Endocrinologists and American College of Endocrinology guidelines. Similarly, the American College of Medical Genetics and Genomics guidelines advise against methylenetetrahydrofolate reductase (MTHFR) genetic testing for cardiovascular risk assessment, as the clinical significance is uncertain and treatment does not vary based on polymorphism genotype.

If someone is found with a mildly elevated homocysteine level, the important first steps revolve around managing diet and lifestyle. As with most things in life, the focus should be on a balanced diet, regular physical exercise, and avoidance of tobacco and alcohol. The Mediterranean diet is an evidence-based dietary intervention that is appropriate for helping to treat a mildly elevated homocysteine level, as the Mediterranean diet is rich in folate, vitamin B6, and vitamin B12 from plant-based foods, legumes, and fish. Importantly, the Mediterranean diet is well-known to reduce cardiovascular risk. Dietary choices to consider include intake of folate-rich foods (leafy greens, legumes, citrus fruits), vitamin B6 (poultry, fish, potatoes, bananas), and vitamin B12 (meat, dairy, eggs) when modifying your diet to address a mildly elevated homocysteine level.