A RISK FACTOR FOR CARDIOVASCULAR DISEASE

Homocysteine (HC) is an amino acid (the building block of protein), which is formed as a by-product of protein metabolism. Recently there is strong evidence suggesting that too much homocysteine (hyperhomocysteinemia [HHC]), is associated with cardiovascular diseases. In healthy individuals, excess homocysteine is excreted. However, high level of homocysteine could result from genetic defects or a deficiency of folic acid (a Vitamin B), vitamin B6 (pyriodoxine) and B12 (cyanocobalamin) which act as cofactors for homocysteine metabolism.

The bulk of homocysteine in blood is attached to proteins and the remainder is present in other forms which collectively contribute to total homocysteine. Blood levels of homocysteine are measured in micromoles per litre (umol/L) and 10 umol/L is considered the normal fasting (abstention from food) plasma (the fluid portion of the blood) concentration. Levels above 12 umol/L are considered high, while levels above 20 umol/L are considered very high. It is estimated that about 20% of the population have elevated homocysteine levels. Currently, measuring homocysteine in blood is not routinely done in Canada, because only a limited number of health facilities are equipped to analyze it, and there is a need to standardize the test. This test currently costs between fifty and one hundred dollars, but this will decline when it is routinely requested in medical practice.

HOMOCYSTEINE AND CARDIOVASCULAR DISEASES

There is strong evidence that elevated homocystein is associated with higher risk of coronary heart disease (CHD). A 5 umol/L homocystein increment elevates CHD risk by as much as cholesterol increases of 0.5 mmol/L (20mg/dl). In addition, hyperhomocysteinemia is associated with significant risk of stroke, narrowing of the carotid (on either side of neck) artery due to atherosclerosis (hardening of blood vessels) and peripheral (outside of central region, e.g. in arms and legs) vascular disease. It is estimated that individuals with hyperhomocysteinemia have twice the risk of the above mentioned diseases when compared to those with normal levels.

HOW DOES DAMAGE OCCUR?

Although the exact mechanism(s) of hyperhomocysteinemia on the risk of cardiovascular disease is not entirely clear, it seems that several mechanisms could explain its detrimental effect. Such factors include damage to the inner lining of blood vessels. This damage is associated with platelet (disk-shaped structure found in the blood, for coagulation) dysfunction, which suggests a coagulation effect of homocysteine . Furthermore, homocysteine can induce smooth muscle (blood vessels are made of smooth muscle) to grow thus is an important process in artherosclerosis. To make matters worse, homocystein interacts with low densisty lipoprotein (LDL, a protein in blood stream carrying cholesterol) and can cause plasma triglycerides (TG, another cholesterol particle in blood) to go up.

FACTORS AFFECTING HOMOCYSTEINE LEVELS

Apart from genetic defects, a number of other factors can influence homocysteine levels. Homocysteine increases with age due to decreases in the production and/or the metabolic activity of the enzymes regulating homocysteine . In addition, the availability of vitamin B6, B12 and folic acid, which function as co-factors, decline with age due to the decrease in absorption from food or other factors.

Gender is another important factor. Hyperhomocysteinemia is more prevalent in men than in pre-menopausal women, and there is an increase in blood homocysteine postmenopausaly. This could be explained by hormonal differences (namely due to female hormone), as well as lower levels of folate (interchange with folic acid), vitamin B6 and B12 in men.
Smoking is associated with hyperhomocysteinemia because smokers have lower blood levels of folate, vitamin B6 and B12.

A number of medications can influence homocysteine levels, and most of this influence is explained by their interactions with folate. Methotrexate, cabamazepine and phenytoin interact with folate. Other drugs that are associated with hyperhomocysteinemia are corticosteroids and cyclosporine.

Several ailments are associated with hyperhomocysteinemia. These are renal failure, kidney and heart transplantation, sever psoriasis, breast cancer, colon cancer and acute leukemia (a progressive, malignant disease of the blood forming organs).

Diet is an essential factor in homocysteine metabolism. Folic acid, vitamin B6 and B12 seem to be most important. Current evidence suggests that high homocysteine levels may be lowered by the intake of folic acid as well as vitamin B6 and B12. Therefore, it is not surprising that higher intake of fruits and vegetables as well as regular use of vitamin supplements is associated with decreased homocysteine levels. Vitamin B12 is of particular importance among elderly men and women, while folate seems to show the strongest correlation with homocysteine among the younger population.

WHAT SHOULD YOU DO?

It seems that increasing the intake, either through food or by vitamin supplementation, of folic acid, vitamin B6 and B12 is prudent in reducing homocysteine levels. So far, the strongest evidence is for folic acid, and there is little doubt that adequate intake of folic acid is associated with lower homocysteine levels. Health Canada recommends at least 0.4mg/day and higher does might be useful therapeutically in higher risk population such as those with a strong family history of cardiovascular diseases or with recurrent stroke. Currently, the average Canadian is consuming approximately 0.2mg/day of folic acid. Finally vitamin B6 and B12 also seem to be beneficial in reducing the elevated homocysteine levels, and the beneficial dose seems to be 10mg and 0.4mg respectively.

CONCLUSIONS

Hyperhomocysteinemia is recognized as a modifiable risk factor for cardiovascular disease and the evidence is strong and consistent. The level of risk is similar to other well established risk factors such as smoking or high cholesterol. Furthermore, hyperhomocysteinemia accentuates the risk of cardiovascular diseases associated with smoking and high blood pressure. One can lower hyperhomocysteinemia most effectively by simply taking adequate folic acid, vitamins B6 and B12 with the strongest evidence to be for folic acid.

Compiled by Gerry Poon
Royal Oak Medicine Centre, Victoria, B.C.