Homocysteine and carotid intima-media thickness: a critical appraisal of the evidence

This review examines the relationship between hyperhomocysteinemia, a risk factor for vascular disease, and carotid intima-media thickness (CIMT), a valid marker of generalized atherosclerosis and future vascular disease risk. The relationship between two important determinants of hyperhomocysteinemia in the general population—folate status and the 677C→T methylenetetrahydrofolate reductase (MTHFR) polymorphism—and CIMT is also covered. Methods: We searched literature databases for articles examining homocysteine and CIMT published before September 2003. Results: We identified 54 studies. Observational studies generally failed to demonstrate a relationship between homocysteine and CIMT in homocystinuric, uremic, hypercholesterolemic or non-insulin-dependent diabetes mellitus patients or in subjects with insulin insensitivity. Weak associations, but usually only in certain sub-populations were found in vascular disease patients and in population-based studies. B vitamins reduce the progression of CIMT in renal transplant recipients and vascular disease patients as demonstrated by two trials. The majority of studies demonstrated increased CIMT in individuals with the MTHFR 677TT genotype. Folate status showed no relation to CIMT. Discussion: In non-patient populations, hyperhomocysteinemia is weakly associated with CIMT. The association of the 677C→T MTHFR polymorphism with CIMT further supports this finding. Lastly, folate levels may need to reach a critically low status before an association can be found between folate and CIMT. Larger trials in various population types are needed to determine whether folate alone or in combination with Vitamins B6 and B12 will slow down or even reverse atherosclerotic progression.