FT. LAUDERDALE, FL—When it comes to homocysteine and stroke risk, the epidemiologic correlation is clear. But the individual clinical course of action is far more cloudy.
Increased homocysteine definitely correlates with increased risk of stroke, according to a recent meta-analysis of 35 published clinical trials. But there is no consensus as to what a “normal” level should be, and no agreement on what constitutes a dangerous elevation. This can make it difficult to determine when a patient needs folic acid to get the homocysteine levels down.
The meta-analysis, presented at the American Stroke Association’s 26th International Stroke Conference, suggests that even mild elevations in homocysteine can increase the risk of stroke by 75%. But experts still disagree about what is “normal,” and what counts as “elevated.”
Data from the Framingham study suggest that about 20% of the population may have elevated homocysteine, said Peter J. Kelly, MD, MRCPI, a research fellow at Massachusetts General Hospital and lead author of the meta-analysis. But he says he cannot give an exact number that defines a normal level. Part of the problem is that serum homocysteine levels change naturally with age. What is high at age 40, is probably not high at age 70.
A number of mechanisms have been proposed to account for the robust relationship between increased homocysteine and stroke risk, but none has been definitively proven.
Souvik Sen, MD, MS, director of stroke service and assistant professor of neurology, NJ Neuroscience Institute, Edison, New Jersey, contends that homocysteine triggers progression of aortic atheroma.
Dr. Sen bases that view on observations of aortic atheromas in 78 stroke or TIA patients who had echocardiograms at one week post-stroke, and again at 9 months. Thirty-seven percent of the patients showed atheroma progression in that 9-month period; progression correlated with increased homocysteine level.
In his clinical practice, Dr. Sen considers a homocysteine measurement above 14 mmol/L to be “elevated,” and treats accordingly.
Ewoud J. van Dijk, MD, of Erasmus Medical Center Rotterdam, posits a different mechanism, one involving cerebral white matter lesions. Data from the Rotterdam Scan Study, a prospective population-based cohort study of 1,077 individuals aged 60 to 90, showed elevated homocysteine was associated with silent infarcts characterized by white matter lesions. He believes homocysteine directly increases the risk of both the infarcts and the white matter lesions.
Regardless of the mechanism, the jackpot clinical question is whether reduction of homocysteine by folic acid supplementation can reduce the risk of stroke on both an individual and a population level.
That probably won’t be answerable any time soon. But fresh insight could emerge from the Vitamin Intervention for Stroke Prevention (VISP) trial, a secondary prevention study of the effect of folic acid, vitamin B6 and vitamin B12 on the incidence of second events in 3,600 stroke survivors.
George Newman, MD, professor of medicine, State University of New York Stony Brook, is one of the VISP investigators. He said that a preliminary step in designing the study was to define “normal” and “elevated” homocysteine levels. Earlier work suggested that women who have levels of 8.5 mmol/L or less, and men with 9.5 mmol/L or less have “virtually no risk for stroke.” Such patients were excluded from the trial.
Above 8.5 mmol/L in women, and 9.5 mmol/L in men, the stroke risk rises incrementally. Dr. Newman says he doesn’t “prescribe” folic acid until the homocysteine level hits 12 mmol/L.
VISP co-investigator, Virginia J. Howard, MSPH, University of Alabama at Birmingham, pointed out that stroke itself first causes a dramatic drop in homocysteine. Later, there is a rebound and the homocysteine level rises.
Part of the difficulty is the fact that in an individual case, the homocysteine level can be bounced around by many different lifestyle factors. “We are dealing with somewhat of a moving target,” said Ralph Sacco, MD, associate chair of neurology, Columbia University. Nutritional deficiencies, some medications, kidney disease, and lack of exercise can all influence homocysteine.
Data from the Framingham Offspring Cohort show that caffeine is positively associated with homocysteine concentrations. There was also a strong association between both cigarette smoking and antihypertensives and homocysteine elevation. Not surprisingly, increased folate and vitamin B12 intake were associated with low homocysteine levels.
In a related study, University of New Mexico researchers looked at the relationship between homocysteine, folate intake, alcohol consumption and other lifestyle factors in 278 volunteers aged 66 to 94. Kathleen M. Koehler, PhD, MPH, found that alcohol has a curious bivalent effect on homocysteine, depending on the level of consumption.
For men and women who drank more than two drinks daily, there was an increase in homocysteine. But those who only had one daily tipple had homocysteine reductions. Moderate alcohol intake appeared to potentiate the beneficial effect of folate supplements. Both the Framingham and the New Mexico studies were published in the March issue of the American Journal of Clinical Nutrition.
Charles Halsted, MD, professor of internal medicine, University of California, Davis, and editor-in-chief of that journal believes the new studies make a strong case that anyone with rising homocysteine should take a multivitamin supplement.
While there are no definitive cut-offs for “normal” and “too high,” there are guideposts. Dr. Halsted cited a metanalysis in the Journal of the American Medical Association back in 1995, showing that any rise of 5 mmol/L is significant.
“My personal opinion is, that on the basis of the epidemiologic data, if a patient with known vascular risk has an elevated homocysteine, you should give them folic acid, B12 and B6 in a multivitamin.” It is a low-risk treatment, and it is far cheaper than tertiary care for stroke or myocardial infarction.
Some stroke experts are skeptical, and caution colleagues against routine homocysteine measurement. Larry B. Goldstein, MD, a member of the AHA’s Stroke Council, said he is not convinced of the validity of the thresholds identified by the VISP researchers as “normal” or “elevated.”
The levels designated in VISP, “are just arbitrarily plucked from prior data,” he said, adding that they need to be validated with further prospective study. Without norms, it is difficult to make solid clinical recommendations. In the midst of all the excitement homocysteine seems to be generating, he said it is important not to lose sight of the well-established stroke risk factors: smoking, hypertension, and diabetes.
THE REDUX: Stroke experts agree that a rising serum homocysteine level over time is a risk factor for stroke, and that this can be reversed with folic acid supplements. But there is no consensus on what constitutes a normal or an “elevated” homocysteine, making it difficult for doctors to know when to hit “go” on the folic acid. Some stroke specialists advocate supplementation whenever homocysteine reaches the 12–14 mmol/L level; but any rise of 5 mmol/L or more from visit to visit may warrant treatment.
