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[Homocysteine General | Homocysteine and Heart Disease ]
[Why Homocysteine?| What Determines Homocysteine levels?]
[Sources of Folic Acid, Vitamin B6 and B12 | Betaine]
[Homocysteine Increases Alzheimer's Risk | References]

Reprinted with permission of the National Heart, Lung, and Blood Institute, National Institutes of Health

Homocysteine General
Homocysteine (pronounced homo-SIS-teen) is an amino acid and is found normally in the body.  Homocysteine’s metabolism is linked to that of several vitamins, especially folic acid, B6, and B12.  Deficiencies of those vitamins may cause elevated levels of homocysteine.

In recent years, studies have accumulated suggesting that a high level of homocysteine increases a person's chance of developing heart disease, stroke, alzheimer’s disease and peripheral vascular disease (a reduced blood flow to the hands and feet).

In September 1995, the National Heart, Lung, and Blood Institute (NHLBI) convened a special panel to review the scientific evidence about homocysteine's possible link to heart disease.  The homocysteine information that follows is based on the panel's conclusions.

Briefly, the panel said that an elevated homocysteine level appears to increase the risk of heart disease, stroke, and peripheral vascular disease.  However, no studies have been done to show that lowering the homocysteine level reduces the risk of heart disease. 

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Homocysteine and Heart Disease
Various studies have found that persons with elevated levels of homocysteine in their blood are at an increased risk of heart and blood vessel disease.  These studies include the Physicians' Health Study, the Tromso Study from Norway, the Framingham Heart Study, and a meta-analysis of nearly 40 studies.

Some studies indicate that persons with elevated homocysteine levels tend to also have other risk factors for heart disease, especially smoking, high blood pressure, and high blood cholesterol.

So far, no clinical trial has been done to show that lowering homocysteine levels alters the progression of heart disease, or prevents heart attacks or strokes.

Why Homocysteine?
Scientists have several theories of how elevated homocysteine affects heart disease:  First, a high level of homocysteine may be involved with the process called atherosclerosis, the gradual buildup of fatty substances in arteries.  Homocysteine also may make blood more likely to clot by increasing the stickiness of blood platelets.  Clots can block blood flow, causing a heart attack or stroke.  Increased homocysteine may affect other substances involved in clotting too.  Finally, higher homocysteine levels may make blood vessels less flexible--and so less able to widen to increase blood flow.  However, none of theories has so far been proven. Much more basic research must be done before scientists understand how an elevated homocysteine level affects the development and progression of heart disease. 

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What Determines Homocysteine Levels?
Individuals differ in their levels of homocysteine.  Two key factors affect a person's homocysteine level--genetics and environment.

Genetic factors help regulate the level of homocysteine in the blood.  For instance, genetic flaws (mutations) can affect homocysteine's metabolism.  The NHLBI Family Heart Study found families with genetic mutations in the enzymes involved in homocysteine metabolism.

The NHLBI Framingham Heart Study and other investigations have found a relationship between elevated homocysteine levels and families with early heart disease.

The level of homocysteine in the blood also is affected by the consumption of vitamins, especially folic acid, B6, and B12.

Data from the Framingham Heart Study show that only 30-40 percent of the population was getting 200 or more micrograms of folic acid in their diet.  The data indicated that for many persons an intake of at least 400 micrograms was needed to keep homocysteine levels from becoming elevated.

Data also indicate that homocysteine levels are higher in older persons than younger ones, and in women after menopause than in those before. But more research is needed to confirm and explain these differences.

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Sources of Folic Acid, Vitamin B6 and B12
Americans who follow a well-balanced diet should get enough vitamins, including folic acid, B6, and B12.  Nutritional supplementation is an option. 

Betaine, also known as trimethylglycine (TMG) has been reported to play a role in reducing blood levels of homocysteine, a toxic breakdown product of amino acid metabolism that is believed to promote atherosclerosis and osteoporosis.  While the main nutrients involved in controlling homocysteine levels are folic acid, vitamin B6, and vitamin B12, betaine or trimethylglycine has been reported to be helpful in some individuals whose elevated homocysteine levels did not improve with these other nutrients.1   

TMG (also known as anhydrous betaine) is a naturally occurring phytonutrient found in a variety of plants and animals, with highest concentrations in beets, leafy green vegetables, and legumes.  Since it can be difficult to eat enough of these foods to provide the body with sufficient amounts of TMG, supplementation may be necessary. 

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Homocysteine Increases Alzheimer's Risk
An article in the February, 2002 issue of the New England Journal of Medicine indicates high levels of the amino acid homocysteine may increase the risk of developing Alzheimer's disease, researchers report.  In a new study, the risk of Alzheimer's was nearly double in people with high levels of homocysteine. 2

Seshadri and colleagues, under the leadership of Dr. Philip A. Wolf at Boston University, report that elderly men and women with high levels of homocysteine seem to have an increased risk of Alzheimer's. The study raises the possibility of staving off dementia by consuming more folic acid, vitamins B6 and B12, and betaine, which can lower homocysteine levels.

The researchers followed 1,092 people who did not have dementia when they enrolled in the study between 1976 and 1978. Participants had their homocysteine levels measured between 1979 and 1982 and again between 1986 and 1990.  After an average of 8 years of follow-up, 111 participants developed dementia. Alzheimer's was thought to be the cause in 83 cases.

People with the highest level of homocysteine were nearly twice as likely to develop dementia or Alzheimer's disease as those with the lowest level, the authors report.  The association between homocysteine levels and dementia was still present even after the researchers accounted for various factors that could have affected the results, including age, sex, blood levels of vitamins and the presence of an Alzheimer's-linked gene type.

The study provides "convincing evidence" that high homocysteine levels put the elderly at risk for Alzheimer's disease or other forms of dementia, according to Dr. Joseph Loscalzo of Boston University Medical Center. Since certain B vitamins and other nutrients can reduce homocysteine levels, Loscalzo notes in an accompanying editorial, "It is intriguing to contemplate the possibility that consumption of these vitamins might prevent the development of Alzheimer's disease and other dementias." This approach must be tested in clinical trials first, however, he notes. 2

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Information from the NATIONAL HEART, LUNG, AND BLOOD INSTITUTE, National Institutes of Health, March 13, 1996, except for footnoted items.

1. Selhub J. Homocysteine Metabolism. Annu Rev Nutr 1999;19:217-46. 
2. The New England Journal of Medicine 2002;346:466-468,476-483.

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