Homocysteine in Clinical Medicine

Who Should Be Tested?

Elevated Hcy is not only an independent risk factor for cardiovascular disease, but it also interacts synergistically with classical risk factors such as smoking, hypertension, diabetes and hyperlipidemia. Therefore, the identification of hyperhomocysteinemic patients with a high risk of vascular disease is of particular importance.

Patients having the disease indications listed in Table 4 are recommended to have their tHcy levels tested.

How Does Hcy Cause Vascular Disease?

The exact mechanism by which elevated Hcy causes atherosclerosis is still unclear. However, the following hypotheses have been proposed:

  1. Direct toxic effects that damage the cell lining inside arteries.
  2. Promotes vascular inflammation.
  3. Accelerates oxidation of low-density lipoprotein (LDL).
  4. Synergistic effects with other risk factors.


(Figure 4)

Hcy Lowering Therapy

Although there is no conclusive answer on whether lowering plasma tHcy levels reduces the risks in the development of cardiovascular disease, numerous large-scale clinical trials to address the efficacy of using vitamins as a means to lowering Hcy in the treatment of cardiovascular diseases are ongoing in various countries. Hcy Lowering Therapy 28 Figure 22

Raymond Meleady and Ian Graham, two leading scientists in Hcy research, recommend that: "While awaiting the outcome of these trials, there may already be sufficient evidence to prescribe homocysteine- lowering therapy in subjects deemed to be at high risk of cardiovascular disease."

It has been well established that vitamins B12 and folate are effective in lowering plasma levels of tHcy. Ward, M., et al., (QJM, 1997, 90: 519-24) conducted a Hcy lowering study on 30 healthy male volunteers using low doses of folic acid for various periods of time (6-14 weeks) as shown in Figure 23. The tHcy lowering efficacy is dependent on the initial levels of tHcy. People with high levels of initial tHcy will have a higher percentage of tHcy reduction than the reduction of those with lower initial levels of tHcy. The tHcy level will eventually return to the initial level when vitamin treatment is terminated.


(Figure 23)

Similar results have been observed in a study by Ubbink et al. On average, a daily intake of 0.65 mg of folic acid showed similar Hcy lowering effects as compared to a combination of folic acid (0.65 mg), vitamin B6 (10 mg) and vitamin B12 (0.4 mg). Average reductions were 42 and 50%, respectively as shown in Figure 24.

In general, the following regimen of tHcy lowering therapy should be effective to most moderate or mild homocysteinemia patients.

  • Folic acid      400-800 μg/day
  • B12                500 μg/day
  • B6                  25-100 mg/day

It has been estimated that in typical Western populations, supplementation with a combination of 0.5-5 mg folic acid and about 0.5 mg vitamin B12 daily would reduce blood tHcy concentrations by about one-quarter to one-third.

Recently, Ward, et al., conducted a meta-analysis of 72 studies in order to examine whether the association of serum tHcy concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal. The authors found that there were significant associations between tHcy and the three cardiovascular diseases. According to the authors, this meta-analysis provided strong evidence for the hypothesis that the association between tHcy and cardiovascular disease is causal.

The authors estimated that lowering homocysteine concentrations by 3 μmol/L would reduce the risk of ischaemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24% as shown in Figure 25.


(Figure 25)

Another major piece of evidence proving the causal relationship between elevated tHcy and cardiovascular disease and stroke came from a government study conducted by Dr. Quanhe Yang, an epidemiologist at the U.S. Centers for Disease Control and Prevention. The study, published in Circulation (Yang, Q., et al 2006, 1335-1343), compared the mortality rates of stroke and heart attacks before and after folate fortification. The U.S. folate fortification program began in 1996 to prevent birth defects. This government study found that the program also appears to have a striking effect against cardiovascular disease, preventing an estimated 48,000 deaths a year from strokes and heart attacks.

From 1990 to 2001, there were almost 26 million deaths among Americans over age 40, including 8.2 million from heart disease and 3.2 million from stroke.

After commencement of the folate fortification program, stroke mortality declined drastically. Prior to 1997, stroke mortality was declining about 1 percent per year. This decline has accelerated to almost 5 percent annually since. The decline was especially steep among black men, falling 7 percent a year after commencement of the program.

In all, the researchers estimate that folate fortification led to 31,000 fewer deaths from stroke and 17,000 from heart disease each year from 1998 to 2001.

Clinical Action

The proposed clinical action is to check tHcy levels and to adhere to physician's advice for tHcy lowering treatment if the tHcy level is >15 μmol/L. tHcy levels can be lowered by various Hcy-lowering agents including B vitimins, betaine, and N-acetylcysteine. Lifestyle changes can also help to lower levels of tHcy (Danker et al. Aging Clin. Exp. Res. 2004, 16: 437-442). It is recommended that each patient consult with their individual physician for specific tHcy-lowering treatment.