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Methionine Loading, Vitamin B6 Status, and Premature Thromboembolic Disease
- Armando D'Angelo, MD;
- Isabella Fermo, PhD; and
- Silvana Vigano'D'Angelo, MD
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IN RESPONSE:
As suggested by Dr. Bostom, we reevaluated the PML total homocysteine data in our patients as the net increase above fasting levels (change in PML). Determinations of PML total homocysteine levels were available in 19 of the 23 hyperhomocysteinemic patients, 10 with normal and 9 with elevated fasting total homocysteine levels (14.3 ± 3.2 µmol/L compared with 36 ± 25.6 µmol/L; P = 0.001; Mann-Whitney rank test). Change in PML was 40.5 ± 6.8 µmol/L in patients with normal fasting homocysteine levels and 34.1 ± 21.1 µmol/L in those with elevated levels (P = 0.061). Changes in PML exceeding the 95th percentile of the distribution in control men (36.4 µmol/L) and women (30.0 µmol/L) were, by definition, seen in all patients with normal fasting homocysteine levels but in only 3 of the 9 patients with elevated fasting levels (P = 0.0031; Fisher exact test). A family history of hyperhomocysteinemia was investigated in 10 patients (6 with elevated fasting total homocysteine levels) and confirmed in 8 (5 with elevated fasting total homocysteine levels). Because we did not determine pyridoxal 5′-phosphate levels, deficiency of this substance cannot be ruled out as the pathogenic mechanism of methionine intolerance in the four families with potential trans-sulfuration defects.
In our article, we suggested that deficiency of cystathionine β-synthase or of 5,10-methylenetetrahydrofolate reductase (MTHFR) was the main biochemical abnormality responsible for inherited hyperhomocysteinemia. In a study of 64 unrelated patients with early-onset venous or arterial occlusive disease [1] (including 29 patients with elevated fasting total homocysteine levels and 7 patients with isolated methionine intolerance), homozygosity for the 667C→T mutation of the MTHFR gene was detected in 62% of the patients with fasting hyperhomocysteinemia but in no patients with isolated methionine intolerance. These data indicate that thermolabile MTHFR [2] is the main inherited congenital disorder responsible for moderate fasting hyperhomocysteinemia in Italian patients with early-onset vascular occlusive disease and strongly suggest dissociation of this biochemical abnormality from methionine intolerance. Because the lack of evidence of a different thrombotic risk in patients with elevated fasting total homocysteine levels or isolated methionine intolerance, we agree with Dr. Bostom's statement that homocysteine-lowering vascular disease prevention trial should not focus exclusively on determinations of fasting total homocysteine levels and on folic acid monotherapy [3].
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
