Nutritional aspects and possible pathological mechanisms of hyperhomocysteinaemia: an independent risk factor for vascular disease

Numerous case-control and prospective studies have identified elevated plasma homocysteine as a strong independent risk factor for cerebovascular, cardiovascular and peripheral vascular disease. Homocysteine is formed as a result of the breakdown of the dietary amino acid methionine. Once formed, homocysteine is either remethylated to methionine, or undergoes a trans-sulfuration reaction to form cysteine. The re-methylation of homocysteine to methionine is dependent on three B-vitamins, i.e. riboflavin, vitamin B-12 and folate. The second pathway of homocysteine metabolism is the trans-sulfuration pathway which requires both vitamin B-6 and riboflavin for its activity. Thus, up to four B-vitamins are required for intracellular homocysteine metabolism. Many studies have noted strong inverse relationships between homocysteine levels and the status of both vitamin B-12 and folate. However, the relationship between vitamin Bg status and homocysteine is still uncertain. Similarly, numerous intervention studies have demonstrated effective lowering of homocysteine levels as a result of folate and vitamin B-12 supplementation, while the homocysteine-lowering ability of vitamin B-6 is unclear. Even though riboflavin plays a crucial role in both the trans-sulfuration and remethylation pathways of homocysteine metabolism, the relationship between riboflavin status and homocysteine levels has not been investigated. The exact mechanism that explains the vascular toxicity of elevated homocysteine levels is unknown at present, studies indicate that it is both atherogenic and thrombogenic. To date, no randomized clinical trial has demonstrated that lowering of homocysteine levels is beneficial in terms of reducing the prevalence of vascular disease. It is probable, however, that optimal B-vitamin status is important in the prevention of vascular disease.