Homocysteine has been the subject of many newspaper and magazine articles recently for its possible effect on cardiovascular disease. Homocysteine is an amino acid produced as a normal byproduct of the breakdown of methionine, which is an essential amino acid acquired mostly from eating meat. High homocysteine levels have been linked to a variety of vascular and heart diseases, including heart attack, stroke, blood clots and other cardiovascular problems. Though homocysteine has been independently associated with an increased risk for cardiovascular disease in some studies, a causal link has not been definitively established.

Because of these findings, there is debate over an appropriate role for the screening and treatment of elevated homocysteine levels. On the one hand, elevated homocysteine levels are clearly associated with adverse cardiovascular effects. On the other hand, few studies have shown that treating elevated homocysteine levels can actually lower the number of people who get heart disease.

Elevated homocysteine levels can be treated with three B-vitamins: vitamin B-6, vitamin B-12 and folic acid (the synthetic and more easily absorbed version of folate). Of these, folate and vitamin B-12 are the most effective in lowering homocysteine levels, and vitamin B-6 has less effect. The decision to treat elevated homocysteine levels usually depends on the patient’s overall risk level for developing heart disease. People who are at higher risk are more likely to be treated, although all individuals should make sure they get enough of the important B vitamins in their diet.

Similarly, the decision to screen for elevated homocysteine levels depends on the presence of other risk factors, such as a family history of heart disease. Currently, the American Heart Association (AHA) does not recommend widespread screening for elevated homocysteine, as is recommended for blood pressure and cholesterol. Instead, the AHA recommends that people who are already at risk may consider having their homocysteine levels checked.

Homocysteine is an amino acid produced as a normal byproduct of the breakdown of methionine, which is an essential amino acid acquired mostly from eating meat. Moderate levels of homocysteine are helpful for the growth and maintenance of healthy tissue. However, excess homocysteine levels are associated with various forms of vascular (blood vessel) damage and heart disease.

With a proper nutritional balance, homocysteine is either converted back into methionine or into simple amino acids (cysteine and cystathionine) that are easily flushed from the body through urine. Homocysteine levels can be raised by genetic influences, problems metabolizing certain vitamins, drugs such as fibrates and nicotinic acid, and possibly also by cigarette smoking.

The conversion of homocysteine cannot occur unless the body has enough of three B-vitamins: vitamin B-6, vitamin B-12 and folic acid (the synthetic and more easily absorbed version of folate). Folic acid is the most effective at lowering homocysteine, followed by vitamin B-12. Vitamin B-6 is the least effective. Without these B-vitamins, homocysteine levels will rise. In fact, about 95 percent of patients with folic acid and vitamin B-12 deficiencies have elevated homocysteine levels.

Homocysteine and heart health

Research on homocysteine and heart disease began in 1968, when Dr. Kilmer McCully of Harvard Medical School investigated the early deaths of children with a rare genetic disorder called homocystinuria, which involved high levels of homocysteine. He was surprised to discover these children had severe “hardening of the arteries” (atherosclerosis) and often died from a heart attack or stroke, which is extremely rare among children. Dr. McCully continued to investigate a potential link between excess homocysteine levels and heart disease, even though his conclusions were not initially well received by the medical community.

Research on a possible connection between high homocysteine levels and atherosclerosis was largely abandoned during the 1970s. In the 1980s, however, interest was rekindled as researchers began looking at a possible link between moderately elevated homocysteine levels and heart disease. In contrast to genetic homocystinuria, which is rare, about 5 to 7 percent of the U.S. population has moderately elevated homocysteine levels.

Since then, many studies have been published, often with contradictory results. For example, one study conducted by researchers at Harvard University followed 15,000 people for five years and found that people with the highest homocysteine levels were more than three times as likely to have a heart attack as people with lower homocysteine. However, another study analyzed 15,000 people and found that a low level of vitamin B-6 was related to heart disease, but homocysteine levels were not.

In 2006, researchers published results of clinical trials that examined the effect of folic acid and B vitamins in lowering homocysteine levels and reducing the risk of cardiovascular events. The results found that folic acid and B vitamins lowered homocysteine levels but the treatment did not significantly decrease the risk of death from coronary disease, heart attack or stroke. In addition, individuals who took all three supplements – folic acid, vitamin B6 and B12 – may have a slight increased risk of cardiovascular problems.

In general, studies indicate that elevated homocysteine is somehow associated with heart disease through its influence on arteries and the blood. Homocysteine has been shown to increase damage to the sensitive interior walls of arteries—the same area that is damaged by atherosclerosis. Also, homocysteine increases the blood's tendency to clot, which may increase the risk for heart attack and stroke. However, even while researchers have shown the mechanism by which homocysteine can damage the heart, studies have not shown that treating homocysteine levels necessarily reduces the incidence of heart disease.

Findings like these, which may directly contradict each other, can be frustrating both for patients who want to lower their risk of developing heart disease and physicians who seek to offer the best treatment possible. However, it is worth noting that medical research is an exacting science in which common, clinically observed facts may require years of intensive study to be confirmed and understood.

At this point, most researchers believe that elevated plasma homocysteine levels may confer an increased risk for developing certain forms of heart disease, blood clots and stroke. This means that homocysteine appears to at least partly cause these conditions, independent of other risk factors such as smoking, a family history of heart disease and elevated cholesterol levels. However, it also appears that homocysteine is a less important causal factor than these other, more traditional measures of risk.

Yet there remains considerable debate over the screening and treatment of elevated homocysteine levels. At this point, the American Heart Association does not recommend widespread screening for elevated homocysteine. Rather, only individuals at elevated risk for heart disease are recommended to have their homocysteine levels screened.

Likewise, although there is a clear connection between elevated homocysteine and heart disease and stoke, studies have failed to establish a link between treating homocysteine and a reduced incidence of heart disease. Homocysteine is treated with B-vitamins, such as folic acid, vitamin B-12 and vitamin B-6. Several large, multi-center trials are under way to help physicians better understand the complex interaction between homocysteine, B vitamins and heart disease. In the meantime, individuals should get adequate vitamin B in their diets, and people at elevated risk for heart disease, including older people, may consider taking vitamin B supplements under the supervision of their physician.

Although the evidence that homocysteine increases risk for heart attacks and stroke is compelling, most medical organizations do not recommend widespread screening for homocysteine, especially among people who are already not at elevated risk for heart disease. The reason for this seeming contradiction is simple: studies have not proven that treating for elevated homocysteine has any effect on overall risk for a heart attack. Moreover, because the treatment for homocysteine consists of B vitamins, a simple multivitamin or a diet rich in fruits and vegetables should bring homocysteine levels to within acceptable ranges.

Some alternative health organizations and vitamin supplement companies promote very high doses of folic acid to lower homocysteine levels to very low levels. This approach, however, is not grounded in rigorous medical science.

Because of the lack of benefit for treating homocysteine levels, the American Heart Association (AHA) does not recommend widespread screening for homocysteine levels. However, the AHA added that people with other coronary risk factors (e.g., a family history of heart disease) might benefit from having their homocysteine levels checked. Testing might also be helpful for people whose other tests (e.g., an ultrafast CT) reveal early signs of atherosclerosis despite healthy lifestyle choices (e.g., not smoking and eating a heart-healthy diet).

Homocysteine is measured based on its molecular weight within the blood. It is measured in micromoles of homocysteine per liter of blood (umol/L), and common levels are classified as follows:

High homocysteine levels may be treated with B-vitamins, including folic acid, vitamin B-12 and, to a lesser extent, vitamin B-6. Since the Food and Drug Administration (FDA) began recommending that cereal and grain products be enriched with folic acid in January 1998, the number of people in the United States with elevated homocysteine levels has been reduced by about 50 percent. In addition, the 2000 Dietary Approaches to Stop Hypertension (DASH) study showed that consuming a diet rich in fruits and vegetables and low-fat dairy foods not only lowered blood pressure but also reduced levels of homocysteine.

There are a wide variety of foods that are rich in B-vitamins. To get as many B-vitamins as possible from these foods, fruits and vegetables are best eaten raw, steamed or only lightly cooked in little or no water. These foods include:

A reduction in homocysteine levels is usually seen in about two weeks, with further reduction in six weeks, after increasing dietary levels of these vitamins. At this point, the American Heart Association (AHA) encourages people to eat a balanced diet with plenty of B-vitamins and avoiding an excessive amount of meat in relation to other foods. In this case, a patient might be advised to take between 1 mg and 5 mg daily of folic acid, 10 mg a day of vitamin B6 and about half a milligram daily of vitamin B12. It is important that the B vitamins are taken as a group to prevent the development of peripheral neuropathy.

The AHA does not recommend widespread use of folic acid and vitamin B supplements to reduce the risk of heart disease and stroke. However, a number of other experts dispute this recommendation and, many physicians recommend higher doses of B-vitamins for patients who have coronary artery disease or who are at risk for it.

In addition to getting more B-vitamins, people are encouraged to use the following strategies to avoid other risk factors for high homocysteine levels:

A few additional useful points of information relative to homocysteine and nutrition:

Preparing questions in advance can help patients have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions about homocysteine:

1. How important is homocysteine in relation to heart disease? 
   
   
2. Am I at risk for elevated homocysteine?
   
   
3. Should I have my homocysteine level chekced?
   
   
4. If so, how and where will I be tested?
   
   
5. What homocysteine level would be considered a problem for me?
   
   
6. Do you recommend that I take folic acid or B vitamin supplements?
   
   
7. What dose should I be taking and for how long?
   
   
8. How quickly can I expect to see a drop in my level?
   
   
9. How often should my homocysteine level be checked?
   
   
10. What lifestyle changes could help reduce my risk for cardiovascular problems?
    
    
11. Am I a candidate for any clinical trials regarding homocysteine?
    
    
12. Can you recommend a dietitian who can help me with nutrition and my diet?