What is homocysteine?

Homocysteine is an amino acid that is produced by the body, usually as a byproduct of consuming meat. Amino acids are naturally made products, which are the building blocks of all the proteins in the body.

Why is it important to monitor homocysteine levels?

Elevated levels of homocysteine (>10 micromoles/liter) in the blood may be associated with atherosclerosis (hardening and narrowing of the arteries) as well as an increased risk of heart attacks, strokes, blood clot formation, and possibly Alzheimer's disease.

In 1969, Dr. Kilmer S. McCully reported that children born with a genetic disorder called homocystinuria, which causes the homocysteine levels to be very high, sometimes died at a very young age with advanced atherosclerosis in their arteries. However, it was not until the 1990's that the importance of homocysteine in heart disease and stroke was appreciated.

What are the possible symptoms or features of elevated homocysteine levels?

Theoretically, an elevated level of homocysteine in the blood (hyperhomocysteinemia) is believed to cause narrowing and hardening of the arteries (atherosclerosis). This narrowing and hardening of the vessels is thought to occur through a variety of ways involving elevated homocysteine. The blood vessel narrowing in turn leads to diminished blood flow through the affected arteries.

Elevated levels of homocysteine in the blood may also increase the tendency to excessive blood clotting. Blood clots inside the arteries can further diminish the flow of blood. The resultant lack of blood supply to the heart muscles may cause heart attacks, and the lack of blood supply to the brain causes strokes.

Elevated homocysteine levels also have been shown to be associated with formation of blood clots in veins (deep vein thrombosis and pulmonary embolism). The mechanism is complex, but it is similar to the way that they contribute to atherosclerosis. In some studies, even moderate levels of homocysteine level showed higher rates of repeated incidence of blood clot formation. ^(1,2)

What is considered a high level for homocysteine?

Homocysteine levels are measured in the blood by taking a blood sample. Normal levels are in the range between 5 to 15 micromoles (measurement unit of small amount of a molecule) per liter. Elevated levels are classified as follows:

• 15-30 micromoles per liter as moderate
  
  
• 30-100 micromoles per liter as intermediate
  
  
• Greater than 100 micromoles per liter as severe

What causes elevated homocysteine levels?

Homocysteine is chemically transformed into methionine and cysteine (similar amino acids) with the help of folic acid, vitamin B12, and vitamin B6. This transformation utilizes a set of mediator molecules (called enzymes) and happens via a delicate sequence of specific steps.

Therefore, insufficient amounts of these vitamins in the body can hamper the natural breakdown of homocysteine. In addition, if there are any deficiencies in the mediator molecules, the breakdown is also hampered. This can cause homocysteine to accumulate in the blood because its breakdown is slow and inadequate.

Can elevated homocysteine levels be genetic?

Homocysteine levels in the blood may be elevated for many reasons as briefly described in the above section. More specifically, these can be divided into severe genetic causes and other milder causes.

In the genetic condition called homocystinuria, there is a deficiency or lack of an important mediator molecule (enzymes) in the complicated homocysteine breakdown pathway. This leads to severely elevated levels of homocysteine. In this rare and serious condition, there is a constellation of symptoms that include developmental delay, osteoporosis (thin bones), visual abnormalities, formation of blood clots, and advanced atherosclerosis (narrowing and hardening of blood vessels). This condition is mainly recognized in childhood.

Milder genetic variations are more common causes of elevated homocysteine levels (hyperhomocysteinemia). In these conditions, the mediator molecules malfunction and are less efficient because of minor abnormality in their structure. They also lead to elevation of homocysteine levels, although much milder than in homocystinuria, by slowing down the breakdown of homocysteine.

Can nutritional problems cause elevated homocysteine levels?

The other more common (5%-7% of the population) and less severe type of elevated homocysteine level may be caused by nutritional deficiencies in folate, vitamin B6 and vitamin B12, chronic (long-term) kidney disease, and cigarette smoking.

As mentioned above, these vitamins are essential in the breakdown of homocysteine. In some studies, lower levels of these vitamins, especially folate, have been demonstrated in people with elevated homocysteine levels. On the other hand, other studies have suggested that adequate intake of folate, Vitamin B6, and Vitamin B12 have resulted in lowering of the homocysteine level. ⁽³⁾

How common is hyperhomocysteinemia?

Mild hyperhomocysteinemia levels are seen in about 5%-12% of the general population. In specific populations such as, alcoholics (due to poor vitamin intake) or patients with chronic kidney disease, this may be more common. The severe genetic form, homocystinuria, is rare.

How can homocysteine levels be lowered?

The consumption of folic acid supplements or cereals that are fortified with folic acid, and to a lesser extent vitamins B6 and B12, can lower blood homocysteine levels. These supplements may even be beneficial in people with mild genetic hyperhomocysteinemia to lower their homocysteine levels. However, it is noteworthy that so far there is no compelling data to support the treatment of hyperhomocysteinemia for prevention of heart disease or treatment of known heart disease or blood clots. There are many studies underway to determine whether there may be any benefit to treat high levels of homocysteine in patients with known heart disease or blood clots. Further recommendations may be available when these studies are completed. ⁽⁴⁾

How many vitamins should I take to lower my homocysteine level?

Daily recommended doses of folate, B vitamins, and multivitamins are generally sufficient in regard to lowering homocysteine levels. These daily doses are recommended by the Food and Drug Administration (FDA) and the doses in a specific product are printed on the label of the vitamin bottle by the manufacturer. Usually, folate supplementation is recommended at 1 milligram daily; vitamin B6 is recommended at 10 milligram per day; and vitamin B12 at one-half milligram per day.

Does lowering homocysteine levels prevent heart attacks and strokes?

Currently, there is no direct proof that taking folic acid and B vitamins to lower homocysteine levels prevents heart attacks and strokes. However, in a large population study involving women, those who had the highest consumption of folic acid (usually in the form of multivitamins) had fewer heart attacks than those who consumed the least amount of folic acid. In this study, the association between dietary intake of folate and vitamin B6 and risk of heart disease was more noticeable than between dietary intake of vitamin B12 and heart disease, which was minimal.

Many other observational studies have been performed to assess the effect of folate and the other B vitamins on heart disease. Most of these studies have concluded that oral intake of folate has been associated to lower risk of heart disease, possibly because due to lowering of homocysteine levels. The relation between oral intake of vitamin B12 and B6 and heart disease was not as obvious in many of these studies. ^(5,6,7)

In one study, it was concluded that even in people with elevated homocysteine levels due to genetic reasons, oral intake of folate and possibly the other B vitamins was related to lower incidence of heart disease. ^(5,6,7)

Most of these data, however, are obtained from observational studies rather than purely controlled scientific data. Therefore, it is important to mention that despite these studies suggesting an association between the intake of these vitamins and the lower incidence of heart disease, in general, there is no compelling clinical evidence to treat hyperhomocysteinemia other than homocystinuria (the severe genetic form) in regards to heart disease, stroke, or blood clots.

What should I do to prevent heart attacks and strokes?

Losing excess weight, exercising regularly, controlling diabetes and high blood pressure, lowering the bad LDL cholesterol, and stopping cigarette smoking are crucial steps in preventing heart attacks and strokes. The association between homocysteine levels and atherosclerosis is generally weaker compared to the known risk factors of diabetes, high blood pressure (hypertension), high cholesterol level, and cigarette smoking.

It is recommended that healthy adults eat more fresh fruits and vegetable, eat less saturated fat and cholesterol, and take one multivitamin daily. One multivitamin will supply 400 mcg (microgram or one-one thousandth of a gram)/day of folic acid in addition to vitamins B6, B12, and other important vitamins.

Who should undergo testing for homocysteine blood levels?

Some doctors screen for elevated homocysteine levels in patients with early onset of blood clot formation, heart attacks, strokes, or other symptoms related to atherosclerosis, especially if these patients do not have typical risk factors, such as smoking cigarettes, diabetes, high blood pressure, or high LDL cholesterol levels.

Currently, there are no official recommendations as to who should undergo testing for homocysteine blood levels. Before more scientific data become available from the currently ongoing studies, many experts do not recommend a screening test for blood homocysteine levels, even in patients with unexplained blood clot formation. In addition, the consensus recommendation is against treating elevated homocysteine levels with vitamins to prevent heart disease.

There is also no consensus as to the optimal dose of folic acid and other B vitamins for the treatment of elevated blood homocysteine levels. (For example, treatment of patients with high homocysteine levels may require higher doses of folic acid and other B vitamins than the amounts contained in a multivitamin.) Therefore, a decision regarding testing should be individualized after consulting with your doctor.

References:

1. Ray, JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998; 158:2101.

2. den Heijer, M, Rosendaal, FR, Blom, HJ, et al. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998; 80:874.

3. Vermeulen, EG, Stehouwer, CD, Twisk, JW, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo- controlled trial. Lancet 2000; 355:517.

4. Eikelboom, JW, Lonn, E, Genest, J Jr, et al. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 1999; 131:363

5. Robinson, K, Arheart, K, Refsum, H, et al. for the European COMCAC Group. Low circulating folate and vitamin B6 concentrations. Risk factors for stroke, peripheral vascular disease, and coronary artery disease. Circulation 1998; 97:437.

6. He, K, Merchant, A, Rimm, EB, et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke 2004; 35:169.

7. McNulty, H, Dowey le, RC, Strain, JJ, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C->T polymorphism. Circulation 2006; 113:74.

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