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Methionine Loading, Vitamin B6 Status, and Premature Thromboembolic Disease
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TO THE EDITOR:
Fermo and colleagues [1] clearly showed the importance of determining postmethionine loading (PML) levels of total homocysteine as a way to assess the risk for premature thromboembolic disease attributable to moderate hyperhomocysteinemia. Unfortunately, they did not measure plasma levels of pyridoxal 5′-phosphate (the active metabolic form of vitamin B6). Pyridoxal 5′-phosphate is the co-factor for cystathionine synthase, the key enzyme responsible for the irreversible trans-sulfuration of homocysteine. Furthermore, the presentation of the PML total homocysteine levels as absolute values (rather than as the net increase above fasting levels [2]) blurs the distinction between isolated re-methylation defects (inadequate folate or B12 status or inborn errors of folate or B12 metabolism), which result in fasting hyperhomocysteinemia with a normal increase in total homocysteine levels and isolated trans-sulfuration defects (inadequate B6 status or heterozygous cystathionine synthase deficiency), which result in essentially normal fasting total homocysteine levels with an abnormally large PML increase in total homocysteine levels [3, 4].
Without determining PLP levels, the authors cannot infer that inherited cystathionine synthase deficiency was one of the main biochemical abnormalities associated with hyperhomocysteinemia when plasma folate or B12 levels were normal. Even the control frequency of PML hyperhomocysteinemia (5%) greatly exceeds the maximum population frequency for heterozygous cystathionine synthase deficiency. A much more likely explanation for the high prevalence (approximate 22%) of PML hyperhomocysteinemia in the patients with thromboembolic disease is inadequate B6 (in the form of pyridoxal 5′-phosphate) status [2-4].
The authors should consider determining fasting PLP levels in cryopreserved aliquots and reevaluating the PML findings using the net increase above fasting total homocysteine levels. These data are crucial in light of the growing momentum for homocysteine-lowering, vascular disease prevention trials that focus exclusively and inappropriately on determining fasting total homocysteine levels and folic acid monotherapy [5].
Andrew G. Bostom, MD, MS
The Editors welcome submissions for possible publication in the Letters section. Authors of letters should:
•Include no more than 300 words of text, three authors, and five references
•Type with double-spacing
•Send three copies of the letter, an authors' form signed by all authors, and a cover letter describing any conflicts of interest related to the contents of the letter.
Letters commenting on an Annals article will be considered if they are received within 6 weeks of the time the article was published. Only some of the letters received can be published. Published letters are edited and may be shortened; tables and figures are included only selectively. Authors will be notified that the letter has been received. If the letter is selected for publication, the author will be notified about 3 weeks before the publication date. Unpublished letters cannot be returned.
Annals welcomes electronically submitted letters.
- Copyright ©2004 by the American College of Physicians
