Homocysteine and Cardiovascular Disease
Thirty years ago a MD named Kilmer McCully noticed a relationship between atherosclerosis and homocysteine in children with homocysteinuria. Due to his diligent research, it is now known that elevated homocysteine levels are an independent risk factor for cardiovascular disease and believed to account for at least 10% of the risk of coronary disease in the United States. Many people who have cardiovascular disease do not have elevated cholesterol, triglycerides, blood pressure or any other known risk factor, yet they have heart attacks. Elevated homocysteine explains why many of them have cardiovascular disease. The good news is that elevated homocysteine levels are easily treated with vitamin B12, vitamin B6, folic acid, and betaine. Raising folic acid levels supplementally in foods is expected to prevent up to 50,000 deaths from coronary heart disease annually. This is truly a problem caused by a combination of genetic predisposition and by the milling of grains and processing of foods which depletes essential nutrients. For example, white flour has lost 60-90% of its vitamin B6 after milling. Twenty to seventy-five percent of folic acid is lost from food through processing when compared to fresh food. Vitamin B12 is easily supplied in most diets, but as we age we often become limited in our abilities to absorb vitamin B12.
Homocysteine is a metabolite of methionine, a sulfur containing amino acid. Its only source in the body is from protein foods containing methionine. Our bodies use homocysteine to build and maintain tissues. Methionine is converted to homocysteine and can easily be reconverted to methionine through remethylation. This process happens continually and is dependent on enzymes which require vitamin B12 and folic acid. In normal metabolism, homocysteine is easily disposed by the body through conversion to cystathionine and ultimately to cysteine as a variety of sulfur compounds in urine. This process requires an enzyme which is vitamin B6 dependent.
Some people are genetically susceptible to poor homocysteine metabolism due to lack of one of three enzymes. People who are have homozygous genes and have full blown homocysteinuria are fairly rare - One in 50,000-150,000. The enzyme defect is that of cystathionine synthase which requires vitamin B6. But 1-2% of Americans is heterozygous and have a slight genetic defect. In these people, just doing a homocysteine level may not show any difficulties. In 50% of people with heterozygous homocysteine defects it is necessary to do a methionine load challenge to discover the defect. Homocysteine levels in blood will be more elevated after two to six hours than in normal individuals without this hidden genetic defect.
The second most common cause of elevated homocysteine is a defective enzyme called methylenetetrahydrofolate reductase. In a homozygous state, affected children with homocysteinuria respond to folate supplementation. In a heterozygous state there may be a slight elevation in blood homocysteine and an increased risk of cardiovascular disease. It is estimated that this heterozygous condition is present in up to 38% of all French Canadians.
The third enzyme defect is of methyltransferase and is quite rare. All three types have been estimated to be factors in 1/3 or more of cases of early-onset atherosclerosis in which cholesterol and lipids are normal.
Homocysteine levels rise gradually as we age. This is probably reflective of declining abilities to absorb vitamin B6, folate, and vitamin B12 and nutrient depletion of foods over time. Eventually our body stores of these nutrients become depleted. For example, we have about 3-5 years of vitamin B12 stored in our livers, but over time with poor absorption this can become depleted.
John Ellis has pioneered work with carpel tunnel syndrome and vitamin B6. Many of these people may have a homocysteine defect. He found that the risk of chest pain or heart attack in his patients decreased by 75% compared to patients of other physicians in the country without B6 supplementation. He also noted an increase in longevity of 7-17 years.
Betaine improves homocysteine methylation and lowers homocysteine levels. It has been used supplementally in children with homocysteinuria at doses of 6 grams per day without unwanted side effects. It may take from 1-3 months to see changes in homocysteine levels. Betaine has long been a component of hydrochloric acid supplements. Hydrochloric acid is necessary for production of intrinsic factor which allows for dietary absorption of vitamin B12.
Although research is growing in this area, much more needs to be done. Until then, checking homocysteine levels provides a simple tool for helping our young patients with family histories of early heart disease. It can also be used to screen for vitamin B12 deficiency. Levels of 13-15 are indicative of a deficiency. Although a level of up to 14 is considered normal, increased risk is found above 11.4. In a 1992 study of 14,000 physicians, Harvard researchers found a three-fold risk in men in the upper 95% in comparison to men in the lower 90%.
Homocysteine levels are lower in premenopausal women and rise after menopause. This may in part explain the increase risk to cardiovascular disease in postmenopausal women. Young women with elevated homocysteine levels have double the risk of heart attack.
© Elizabeth Lipski, PhD, CCN
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