Measuring the homocysteine level

Homocystinuria, an autosomal recessive disorder, is the second most treatable aminoacidopathy.1 Left untreated, it increases risk for cardiovascular disease (CVD), deep vein thrombosis (DVT), and stroke. Additionally, homocystinuria increases the risk for failure to thrive, mental retardation, seizure disorders, osteoporosis, ectopia lentis, fatty liver disease, and genu valgum.

Hyperhomocysteinemia can occur in the absence of homocystinuria; causes include other genetic mutations, nutritional and vitamin deficiencies, chronic renal insufficiency and failure, advancing age, some medications, and other chronic medical conditions.² There appears to be an association between hyperhomocysteinemia and several vascular conditions, most commonly atherosclerosis, ischemic heart disease (IHD), stroke, transient ischemic attacks, and DVT.³ Additionally, hyperhomocysteinemia appears to be associated with neural tube defects; neuropsychiatric disorders, including depression, decreased cognitive function, and Alzheimer's disease; cancer; and premenstrual syndrome and premenstrual dysphoric disorder.^3,4

Little scientific evidence exists that any of these relationships are causal. A meta-analysis of observational studies suggested that hyperhomocysteinemia is “at most a modest independent predictor of IHD and stroke risk in healthy populations.”⁵

Since vitamin B₉ (folate or folic acid), vitamin B₆ (pyridoxine), and vitamin B₁₂ (cobalamin) are all essential to produce the coenzymes necessary for the metabolic elimination of homocysteine (Hcy), deficiency in any of these B vitamins could result in elevated Hcy levels.³ Some experts also feel that vitamin B₂ (riboflavin) has a role in Hcy homeostasis.³  

Clinical trials

Most trials involving the addition of some or all of these B vitamins in patients with hyperhomocysteinemia have resulted in a reduction of the homocysteine levels.^1,2,5,6 In the studies that compared the effectiveness of the various B vitamins, folate appears to have the most influence.^6,7

Despite the ability of B vitamins to effectively reduce plasma Hcy concentrations, the majority of clinical trials that had cardiovascular risk reduction as an end point failed to show a reduction in cardiovascular morbidity and mortality despite a normalized Hcy level.⁸ Additionally, the reduction does not appear to affect cognition, mood, or dementia.⁹

The preliminary results from the Women's Antioxidant Cardiovascular Study (WACS) evaluating the roles of antioxidants, B vitamins, and antihypertensives for secondary prevention of CVD in women clearly showed that systolic BP control was the most significant intervention.¹⁰  

Bottom line

The majority of the evidence supports an association between elevated plasma Hcy levels and CVD, neuropsychological conditions, and some cancers. However, no evidence suggests that this relationship is causal. The majority of the studies reveal that serum Hcy concentrations can be reduced to normal levels with one or more of the B vitamins. However, there is no proof that vitamin therapy reduces cardiovascular morbidity and mortality or improves neurocognitive dysfunction.

Two very large studies are under way to evaluate further the role of treating elevated Hcy levels with B vitamins in the secondary prevention of CVD.^11,12 Until results are available or other evidence demonstrates that measuring Hcy levels would provide useful clinical information, assessing Hcy levels is not recommended. JAAPA

The author is a physician assistant in family practice in rural West Virginia and a Past President of the AAPA. She has indicated no relationships to disclose relating to the content of this article.

REFERENCES

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