Correspondence
Plasma Homocyst(e)ine Levels and Folic Acid Supplementation
N Engl J Med 1998; 339:475-477August 13, 1998
- Article
To the Editor:
In Table 2 of the article by Malinow et al. (April 9 issue),1 the group that received the lowest level of folate supplementation (group A) appeared to have lower homocyst(e)ine values than group B or C. Although the authors state that there was no difference in basal homocysteine levels in the three groups, the basal level in group A (9.9±3.7 and 10.0±3.0 μmol per liter in the placebo and experimental phases, respectively) appears to be much closer to the significant postsupplementation value in group B (9.7±2.3 μmol per liter) than it does to the basal levels in group B (10.7±3.3 and 11.4±3.4 μmol per liter, respectively). The difference or lack of difference seems to be related more to a narrowing of the standard deviation than to a decrease in homocyst(e)ine values with folate supplementation. Furthermore, the values and standard deviations in group C suggest that this group may have included subjects with true folate deficiency,2 whereas group A did not. Is the basal homocyst(e)ine level in group A (before folate supplementation) significantly lower than that in group C after folate supplementation?
Plasma folate values reflect folate flux,3 whereas red-cell values better reflect folate stores. Do the authors have red-cell folate values for their subjects, particularly so that a comparison of group A with group C can be made? Reports have shown that there is a variable response in homocyst(e)ine values to folate supplementation, with up to 15 percent of subjects having a significant increase in homocyst(e)ine during folate supplementation,4,5 probably as a result of other dietary variables. What percentage of subjects in group A had an increase in homocyst(e)ine values during supplementation, and how does this proportion compare with that in group C during supplementation?
Finally, a small point: Table 3 of the article refers to “plasma folic acid level,” as does the footnote on the factor to use to convert values for folic acid to nanomoles per liter. Plasma does not contain folic acid. The authors were careful with their homocyst(e)ine terminology but inaccurate with their folate terminology.
5 ReferencesJohn C. Deutsch, M.D.
James S. Bisping
J. Fred Kolhouse, M.D.
University of Colorado Health Sciences Center, Denver, CO 802621
Malinow MR ,Duell PB ,Hess DL , et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998;338:1009-1015
Full Text | Web of Science | Medline2
Savage DG ,Lindenbaum J ,Stabler SP ,Allen RH . Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96:239-246
CrossRef | Web of Science | Medline3
Herbert V . Making sense of laboratory tests of folate status: folate requirements to sustain normality. Am J Hematol 1987;26:199-207[Erratum, J Hematol 1988;28:134.]
CrossRef | Web of Science | Medline4
Brattstrom LE ,Israelsson B ,Jeppsson JO ,Hultberg BL . Folic acid -- an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest 1988;48:215-221
CrossRef | Web of Science | Medline5
Santhosh-Kumar CR ,Deutsch JC ,Ryder JW ,Kolhouse JF . Unpredictable intra-individual variations in serum homocysteine levels on folic acid supplementation. Eur J Nutr 1997;51:188-192
CrossRef | Web of Science
To the Editor:
The editorial by Oakley (April 9 issue)1 downplaying the role of dietary modification and advocating routine multivitamin supplementation for the U.S. population illustrates the confusion that exists with respect to the use of nutrient pills as research tools as opposed to an effective public nutrition measure. Furthermore, it contributes to the worrisome U.S. trend toward the medicalization of public nutrition. Nutrient-containing capsules are ideal vehicles for testing diet–health hypotheses, following double-blind, randomized clinical-trial designs. Public nutrition measures in response to these trials should be based first and foremost on dietary recommendations. When diet alone may be insufficient, as for example, in cases of iron deficiency during pregnancy, then carefully targeted supplementation becomes a reasonable option.
Folic acid supplementation as a public nutrition measure for the prevention of neural-tube defects2 or heart disease is unwarranted. Contrary to what is implied in the editorial, it is quite possible to obtain recommended intakes of folate or folic acid daily through dietary means, particularly now that flour-based products are fortified with folic acid. Oakley indicates that we have no conclusive evidence on which to base food-based recommendations because studies have used folic acid capsules. The plausibility of this is low, since dietary folate is likely to offer the same benefits as those derived from synthetic folic acid.
Oakley's position has major flaws. First, he bases recommendations for the whole United States on studies conducted in samples with unique biomedical, demographic, socioeconomic, and cultural characteristics. Second, there is not a single published randomized trial to support the folic acid–heart disease argument being made. Third, he advocates the use of higher doses for fortification when there are potential adverse effects associated with this recommendation.2 Fourth, he advocates multivitamin supplementation when his rationale is based on folic acid findings.
Magic-bullet approaches have not worked before, either because the delivery of the bullet at a public level is difficult or because the bullet turned out not to be magic. Recently, many of us were surprised to learn that a higher consumption of beta carotene supplements increased the incidence of lung cancer among smokers.3 A policy of promoting greater consumption of fruits, vegetables, and cereal-based fiber to increase folate and folic acid intake would be consistent with national health objectives concerned with the prevention of chronic diseases through dietary means.4
4 ReferencesRafael Pérez-Escamilla, Ph.D.
University of Connecticut, Storrs, CT 06269-40171
Oakley GP Jr . Eat right and take a multivitamin. N Engl J Med 1998;338:1060-1061
Full Text | Web of Science | Medline2
Perez-Escamilla R . Periconceptional folic acid and neural tube defects: public health issues. Bull Pan Am Health Organ 1995;29:250-263
Medline3
World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition and the prevention of cancer: a global perspective. Washington, D.C.: American Institute for Cancer Research, 1997:138-41.
4
Department of Health and Human Services. Healthy People 2000: midcourse review and 1995 revisions. Sudbury, Mass.: Jones and Bartlett, 1996.
To the Editor:
In his editorial, Dr. Oakley suggests the use of higher concentrations of folic acid in fortified cereal without mentioning the concomitant risks involved. Carmel1 has elegantly demonstrated the high frequency of undiagnosed cobalamin deficiency in the elderly. This large segment of the population (about 800,000 people) would be at increasing risk for neurologic and psychiatric damage, the greater the amount of folic acid they consumed.2
We thus reiterate our previous concern3 regarding food fortification with excessive amounts of folic acid, in spite of the potential benefit in terms of preventing neural-tube defects and possibly even arterial occlusive diseases.
3 ReferencesHans W. Grünwald, M.D.
Fred Rosner, M.D.
Mount Sinai Services at Queens Hospital Center, Jamaica, NY 114321
Carmel R . Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996;156:1097-1100
CrossRef | Web of Science | Medline2
Lindenbaum J ,Healton EB ,Savage DG , et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-1728
Full Text | Web of Science | Medline3
Rosner F ,Grunwald HW . Folic acid food supplementation: an idea whose time has not come. J Womens Health 1996;5:427-428
CrossRef
Author/Editor Response
The authors reply:
To the Editor: Dr. Deutsch and colleagues have raised several issues concerning our study. Some appear to be related to confusion regarding the independent information provided by the standard deviation, which reflects heterogeneity among subjects in the study population, and treatment-induced changes in study variables, which reflect responses within subjects to intervention. No subjects in the trial had folate deficiency. Red-cell folate concentrations were not determined. As we explained in our article, the slightly (nonsignificantly) higher mean basal plasma homocyst(e)ine concentrations in group C were largely attributable to the inclusion of one subject with an initial level of 66.8 μmol per liter. To help clarify these issues, we have presented individual changes in plasma homocyst(e)ine concentrations in the three groups in Figure 1Figure 1
Individual Plasma Homocyst(e)ine Concentrations Measured after Five Weeks of Placebo Cereal and Five Weeks of Fortified Cereal..Paradoxical increases in plasma homocyst(e)ine concentrations after treatment with folic acid have been reported previously,1,2 and may have resulted from regression to the mean or variability in the folate and B vitamin content of other foods in the diet. In our study, the frequencies of higher plasma homocyst(e)ine concentrations after the consumption of fortified cereal as compared with the consumption of placebo cereal were 29 percent, 8 percent, and 15 percent, respectively, in groups A, B, and C (no significant difference between groups by chi-square analysis). The clinical significance and reproducibility of increased plasma homocyst(e)ine concentrations after folic acid supplementation are unclear.
It is true that plasma folate was incorrectly referred to as folic acid. Although unprocessed foods may contain a variety of folate compounds whose bioavailability varies, the cereals used in this study were fortified with folic acid, which is efficiently absorbed. The assertion that plasma does not contain folic acid is untenable.3,4
4 ReferencesP. Barton Duell, M.D.
M. René Malinow, M.D.
Oregon Health Sciences University, Portland, OR 97201-30981
Brattstrom LE ,Israelsson B ,Jeppsson JO ,Hultberg BL . Folic acid -- an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest 1988;48:215-221
CrossRef | Web of Science | Medline2
Santhosh-Kumar CR ,Deutsch JC ,Ryder JW ,Kolhouse JF . Unpredictable intra-individual variations in serum homocysteine levels on folic acid supplementation. Eur J Clin Nutr 1997;51:188-192
CrossRef | Web of Science | Medline3
Kelly P ,McPartlin J ,Goggins M ,Weir DG ,Scott JM . Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997;65:1790-1795
Web of Science | Medline4
Perry J ,Chanarin I . Intestinal absorption of reduced folate compounds in man. Br J Haematol 1970;18:329-339
CrossRef | Web of Science | Medline
Author/Editor Response
In response to Drs. Grünwald and Rosner: I did not mention the possible risk associated with increasing folic acid fortification because there is little evidence (and no controlled studies) to suggest that folic acid, rather than the absence of adequate vitamin B12 therapy, affects the neurologic or psychiatric course of persons with clinically apparent and inadequately treated vitamin B12 deficiency.1 The asymptomatic (preclinical) cases of “pernicious anemia” described by Carmel2 should not be used as an argument against increased folic acid fortification, but they do suggest that population-based screening and treatment of preclinical disease should be considered.
I agree with Dr. Pérez-Escamilla that we should use existing data to formulate the best policy. I conclude from the existing data that a recommended daily allowance of approximately 200 μg of food-derived folate is too low and that even if all Americans ate five servings of fruits and vegetables a day, most women of reproductive age would have insufficient blood folate levels to be afforded full protection against having a child with a folic acid–preventable birth defect. I also conclude that people over 50 years of age should be consuming supplemental B12 because of the possibility of malabsorption of food-derived cobalamin.
In April, the Food and Nutrition Board of the Institute of Medicine issued recommendations consistent with these inferences.3 It recommended that all women capable of becoming pregnant consume 400 μg of synthetic folic acid from fortified food or supplements per day in addition to eating a varied diet, that the recommended daily allowance for folate be increased to 400 μg per day, and that persons over the age of 50 consume 2.4 μg of synthetic vitamin B12 from supplements or fortified foods per day.
To improve the health of the public, I believe that we should move as rapidly as possible to get most women of reproductive age and most people over the age of 50 to consume the recommended amounts of the synthetic vitamins. The most efficient and effective means of achieving these goals would be through a fortification program.4 The current level of fortification of enriched cereal grains provides only about 100 μg of folic acid a day and no vitamin B12. There is an urgent need here and around the world for fortification programs that would result in the consumption of folic acid and vitamin B12 at the levels recommended by the Food and Nutrition Board. Until there is sufficient fortification, people can easily consume the amounts of folic acid and vitamin B12 recommended by the board by taking vitamin supplements and eating certain breakfast cereals.
“Eat right and take a multivitamin” remains good advice.
4 ReferencesGodfrey P. Oakley, Jr., M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30341-37241
Dickinson CJ . Does folic acid harm people with vitamin B12 deficiency? QJM 1995;88:357-364
Medline2
Carmel R . Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 1996;156:1097-1100
CrossRef | Web of Science | Medline3
Institute of Medicine, Food and Nutrition Board. Dietary reference intakes: thiamine, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, D.C.: National Academy Press (in press).
4
Oakley GP Jr . Let's increase folic acid fortification and include vitamin B-12. Am J Clin Nutr 1997;65:1889-1890
Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
N. B. TUTUNCU, T. ERBAS, M. ALIKASIFOGLU, E. TUNCBILEK. (2005) Thermolabile methylenetetrahydrofolate reductase enzyme genotype is frequent in type 2 diabetic patients with normal fasting homocysteine levels. Journal of Internal Medicine 257:5, 446-453
CrossRef2
FIGEN NARIN, NAZMI NARIN, MUSTAFA AKCAKUS, MUZAFFER USTDAL, INCI KARAKÜÇÜK, CANAN HALICI. (2002) The Effect of Folic Acid, Vitamin B6 and Vitamin B12 on the Homocysteine Levels in Rabbits Fed by Methionine-Enriched Diets.. The Tohoku Journal of Experimental Medicine 198:2, 99-105
CrossRef3
Rick L. Smith. (2001) Evaluation of Vitamin B12 and Folate Status in the Nursing Home. Journal of the American Medical Directors Association 2:5, 230-238
CrossRef
