Homocysteine is the biggest health breakthrough of the Century

Homocysteine: A Cardiovascular Risk Factor Worth Considering

Stephen Barrett, M.D.

At least nine well-known risk factors can help predict the likelihood of heart attacks and strokes: heredity, being male, advancing age, cigarette smoking, high blood pressure, diabetes, obesity (especially excess abdominal fat), lack of physical activity, and abnormal blood cholesterol levels. The more of these risk factors a person has, the greater the likelihood of becoming ill. Heredity, gender, and age cannot be modified, but the others can be influenced by the individual's behavior. Modifying these factors can lower the risk of having a heart attack.

During the past few years, elevated blood levels of homocysteine (a sulfur-containing amino acid) have been linked to increased risk of premature coronary artery disease, stroke, and thromboembolism (venous blood clots), even among people who have normal cholesterol levels. Abnormal homocysteine levels appear to contribute to atherosclerosis in at least three ways: (1) a direct toxic effect that damages the cells lining the inside of the arteries, (2) interference with clotting factors, and (3) oxidation of low-density lipoproteins (LDL).

A recent study compared 131 patients with severe blockages in two coronary arteries, 88 patients with moderate blockage of one coronary artery, and another group of healthy individuals without heart disease. The researchers found a linear relationship between blood homocysteine levels and severity of the coronary blockages: For every 10% elevation of homocysteine, there was nearly the same rise in the risk of developing severe coronary heart disease [1]. Another study has found that postmenopausal women with elevated homocysteine levels had a higher incidence of coronary heart disease [2]. Another study found that homocysteine levels were much higher in people who developed vein clots than in similar people who did not [3]. Yet another study found that elevated homocysteine levels may be associated with an increased risk of stroke in people who already have coronary heart disease [4]

Blood for measuring serum homocysteine levels is drawn after a 12-hour fast. Levels between 5 and 15 micromoles per liter (µmol/L) are considered normal. Abnormal concentrations are classified as moderate (16-30), intermediate (31-100), and severe (greater than 100 µmol/L). [5]

The connection between homocysteine and cardiovascular disease was suspected about 25 years ago when it was observed that people with a rare condition called homocystinuria are prone to develop severe cardiovascular disease in their teens and twenties. In this condition, an enzyme deficiency causes homocysteine to accumulate in the blood and to be excreted in the urine. Recent studies suggest that elevated blood homocysteine levels are as important as high blood cholesterol levels and can operate independently. Some 10% to 20% of cases of coronary heart disease have been linked to elevated homocysteine levels. Both hereditary and dietary factors may be involved.

Homocystinuria is transmitted by a recessive gene. If both parents transmit the gene, the resultant offspring have very high plasma homocysteine levels. People who receive the defective gene from only one parent do not develop the disease but often have a mildly elevated plasma level of homocysteine. About one person in 100 carries one such gene. Abnormal elevation also occurs among people whose diet contains inadequate amounts of folic acid, vitamin B6, or vitamin B12. Regardless of the cause of the elevation, supplementation with one or more of these vitamins can lower plasma levels of homocysteine.

Dietary supplementation with folic acid can reduce elevated homocysteine levels in most patients. The usual therapeutic dose is 1 mg/day. When this is not effective, vitamins B6 and/or B12 can be added to the regimen, which should be continued permanently. Some doctors routinely recommend that patients known to have atherosclerosis take B-vitamin supplements without being tested to determine whether their homocysteine level is elevated. They reason that since supplementation is harmless and since elevated homocysteine levels might be a factor, testing is not worth bothering with. Even though some patients may be helped with this "shotgun" strategy, I believe it is far better to (a) find out whether a problem exists and (b) to be certain that if homocysteine levels are elevated, the vitamin regimen is adjusted to be sure that lowering is achieved.

A recent study that followed 80,000 women for 14 years found that the incidence of heart attacks was lowest among those who used multivitamins or had the highest intake of folic acid and B6 from dietary sources [6]. This data parallels the finding that elevated homocysteine levels are associated with a higher incidence of heart disease. However, the researchers measured folic acid blood levels but did not measure homocysteine or B12 levels. Rather, they assumed that low folic acid levels were caused by inadequate dietary intake. Victor Herbert, M.D., a leading expert on B12 metabolism, has pointed out that the low folic acid levels among the experimental subjects could have been caused by decreased B12 absorption related to getting older.

Lowering the serum concentration of homocysteine has been proven to reduce the risk of adverse cardiovascular events among people with homocystinuria. Studies have not yet determined whether lowering homocysteine levels reduces the incidence of heart attacks or strokes among people with mildly elevated homocysteine levels [7,8], but many experts believe that scientific studies will prove that it does. This belief has been strongly supported by a four-year study in which 101 men with vascular disease were given supplementary doses of folic acid, B6 , and B12. Ultrasound examinations of their carotid arteries found a decrease in the amount of carortid plaque in their arteries, with the greatest effect in those whose homocyteine levels had been highest before the treatment began [9].

Screening for elevated homocysteine levels is advisable for individuals who manifest coronary artery disease that is out of proportion to their traditional risk factors or who have a family history of premature atherosclerotic disease. Levels above 9 or 10 µmol/l warrant treatment. The effect of supplementation is usually apparent within a month. The laboratory test can be obtained for about $40. Some physicians recommend that all patients with atherosclerotic disease be screened. A recent study of the effect on homocysteine of either folic acid or B12 alone found that the body adjusts its reliance on one or the other and that supplementing with both provides a more certain way to improve homocysteine levels [10].

At least a dozen large-scale studies following a total of more than 60,000 people are underway in the United States, Canada, and Europe to examine the effects of lowering blood homocysteine levels on the incidence of heart attacks and/or strokes [9,11]. The longest one so far involved 553 patients who had had successful angioplasty has found that lowering homocysteine levels significantly decreased the incidence of major cardiac events after angioplasty. The participants were randomly assigned to receive a combination of folic acid, vitamin B12, and vitamin B6 or a placebo for 6 months and were followed for about six more months. The study found that the incidence of heart attacks, death and need for repeat revascularization were about one third less in the vitamin group than in the control group [12].

Since folic acid is nontoxic, it seems prudent to treat elevated homocysteine levels based on current knowledge. The process should be supervised by a well-informed physician.

Caution: Elevated homocysteine levels can be caused by vitamin B12 deficiency due to impaired absorption of B12 caused by gastric atrophy (damage to the lining of the stomach). B12 deficiency leads to anemia and, if not corrected in time, will permanently damage the nervous system. Folic acid supplements will correct the anemia (which can serve as a warning sign before nerve damage develops), but they do not prevent the damage. For this reason, people over 50 who take folic acid supplements should also take at least 25 micrograms of vitamin B12 per day, a dose large enough to enable adequate amounts to be absorbed. Dr. Herbert believes that everyone over age 50 should take B12 supplements anyway, because gastric atrophy is common as people age. Products containing 100 mcg per pill are readily available.