To the Editor.
—The meta-analysis by Dr Boushey and colleagues1 provides an excellent overview of the relationship between homocysteine and cardiovascular disease (CVD), but places undue emphasis on the role of folic acid. Despite acknowledging that no appropriate clinical trials have been conducted with folic acid, the authors limited their "quantitative estimates to studies... of folic acid alone that reported fasting tHcy [total homocysteine]." Unfortunately, this homogenization of the literature inadequately addresses both the pathogenesis of hyperhomocysteinemia and appropriate homocysteine-lowering therapy.Experimental2 and clinical3 studies have clearly documented that there are two distinct forms of hyperhomocysteinemia: fasting and postmethionine load (PML). Impaired remethylation of homocysteine to methionine, due to either poor folate/ vitamin B12 status or homozygous severe methylenetetrahydrofolate reductase deficiency, results in fasting hyperhomocysteinemia, but no abnormal increase in fasting homocysteine after a methionine load. Conversely, poor vitamin B6 status or heterozygous cystathionine synthase
Bostom AG. Folic Acid Fortification of Food. JAMA. 1996;275(9):681. doi:10.1001/jama.1996.03530330025012