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Research Communication

The Chilean Flour Folic Acid Fortification Program Reduces Serum Homocysteine Levels and Masks Vitamin B-12 Deficiency in Elderly People¹

Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile

²To whom correspondence should be addressed. E-mail: shirsch{at}uec.inta.uchile.cl.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Hyperhomocysteinemia is considered a risk factor for cardiovascular disease and is prevalent in the elderly. Supplementation with folic acid, vitamin B-6 and B-12 lowers homocysteine levels. In January 2000, the Chilean government initiated a flour folic acid fortification program to decrease the occurrence of neural tube defects. The aim of this study was to evaluate the effect of this program on serum homocysteine and folate levels in elderly subjects after 6 mo. A total of 108 elderly people were studied. We measured serum folate, homocysteine and vitamin B-12 levels before the fortification started and 6 mo later. At baseline, folate deficiency (<6.8 nmol/L) was present in 1.8%, vitamin B-12 deficiency (<165 pmol/L) in 27.6% and hyperhomocysteinemia (>14 µmol/L) in 31% of the sample. Six months later, serum folate levels increased from 16.2 ± 6.2 to 32.7 ± 7.1 nmol/L (P < 0.001), homocysteine levels decreased from 12.95 ± 3.7 to 11.43 ± 3.6 µmol/L (P < 0.001) and vitamin B-12 levels were unchanged. Flour fortification with folic acid had a moderate lowering effect on homocysteine levels. Given that vitamin B-12 deficiency was more common than folate deficiency, it may be more appropriate to add vitamin B-12 to food, at least in foods for this age group.

KEY WORDS: • folic acid fortification • homocysteine • elderly people • vitamin B-12

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Hyperhomocysteinemia is considered to be an independent risk factor for cardiovascular disease (1 ). Plasma levels are determined by genetic and nutritional factors. Folic acid, vitamin B-6 and B-12 levels are inversely related to homocysteine levels (2 ). Several trials have demonstrated the lowering effect of folic acid, vitamin B-6 and B-12 supplements on homocysteine levels (2 ). From a public health perspective, this is a very interesting issue because hyperhomocysteinemia in elderly people is highly prevalent (3 ,4 ). Therefore, fortified foods could prevent hyperhomocysteinemia and, in the long term, cardiovascular disease.

In the past decade, some trials showed that folic acid intake before conception reduced a woman’s risk of bearing a child with a neural tube defect (5 ). For these reasons, in January 2000, the Chilean government initiated a program of folic acid fortification, with 220 µg of synthetic folic acid/100 g of wheat flour. It is important to evaluate the effect of the national folic acid fortification program on serum homocysteine and folate levels in the elderly.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
A prospective study was performed in Santiago for 6 mo, from December 1999 to July 2000. Free-living subjects (n = 149) assigned to three public outpatients clinics near their residences, aged 70 y and with low income, were invited by telephone to participate. Exclusion criteria were as follows: vitamin supplementation, wasting chronic illness or severe cognitive impairment, defined as a score of < 20 on the Mini Mental State Examination (6). This is the most widely used test to detect dementia and a score of < 20, out of a maximum of 30, is indicative of impairment. This score has also been validated in the Chilean elderly population (7).

All individuals signed a written informed consent before entering the study, which was approved by the Institutional Review Board of the Institute of Nutrition and Food Technology of the University of Chile. Of these, 19 refused to participate, 4 subjects died and 18 subjects were lost to follow-up. Thus, the final sample studied at baseline and at 6 mo was 108 subjects (67 women), aged 74.3 ± 3.7 y.

Clinical examinations were conducted and blood samples were obtained in December 1999, before the fortification of flour with folic acid started; these procedures were repeated in July 2000. After an overnight fast, 20 mL of venous blood was drawn for routine blood chemistry assessment (packed red cell volume, creatinine, glucose, total cholesterol, HDL cholesterol, triacylglycerols), homocysteine, folate and vitamin B-12 serum levels. Folate and vitamin B-12 were measured by an anion capture technique using Abbott kits (IMX system folate and B-12_, Abbott Laboratories, Diagnostic Division, Abbott Park, IL). Serum homocysteine was also measured using an Abbott Kit (Abbott IMX homocysteine). This procedure is based on the fluorescence polarization immunoassay technology. Blood chemistry was measured using standard automated laboratory methods with Abbott commercial kits.

Statistical analysis.

Statistical analysis was done using Statistica for Windows version 4.5 (StatSoft, Tulsa, OK) Results are expressed as means ± SD. Comparison of basal data between men and women was performed using t tests for variables with normal distribution and Kruskal-Wallis ANOVA median tests for those variables with a nonnormal distribution. To evaluate the changes after folic acid fortification, paired t test and Wilcoxon matched pairs tests were performed for variables with normal and nonnormal distribution, respectively. Pearson correlation coefficient was done to evaluate the relationship between serum homocysteine and folate and vitamin B-12 levels. Proportions were compared using ² tests. Differences were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Serum HDL cholesterol was higher and vitamin B-12 levels tended to be higher (P = 0.06), whereas serum homocysteine and packed red cell volume were lower in women than in men (Table 1 ). Serum homocysteine levels were normally distributed, unlike folate and vitamin B-12 levels, which had a positive skewness, as shown in Figure 1 . Folate deficiency [<6.8 nmol/L (8 )] was observed in 1.8% and vitamin B-12 deficiency [<165 pmol/L (9 )] was present in 27.6% of the sample. Thirty-one percent of the subjects had serum homocysteine levels >14 µmol/L (10 ). Homocysteine correlated negatively with folic acid (r = -0.33, P = 0.001) and vitamin B-12 levels (r = -0.22, P = 0.024).

View larger version (26K): [in this window] [in a new window]   Figure 1. Effect of 6 mo of flour folic acid fortification on serum folate, homocysteine and vitamin B-12 levels in elderly people. Results are expressed as a frequency table before and after the folic acid fortification. The Kruskal-Wallis ANOVA median test showed an increase in serum folate (P < 0.001), and no changes in vitamin B-12 levels. Paired t test showed a decrease in serum total homocysteine levels (P < 0.001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We found that increasing the amount of folic acid in the diet was associated with a moderate decrease in homocysteine levels in older persons, even if they had normal basal serum levels of folic acid. Based on the literature, a decline of only 11% in basal serum homocysteine levels was expected (11 ).

The wheat flour in Chile is fortified with 220 µg of synthetic folic acid/100 g of flour. Our elderly subjects consumed an average of 220 g of French bread per day, equivalent to 185 g of flour, containing 410 µg folic acid. Based on data obtained from abroad, The Ministry of Health estimated that this level of fortification would cover the target population (women of childbearing age) and would not adversely affect nontarget consumers of high amounts of flour, including elderly people or young men. Ward et al. (12 ) demonstrated that 400 µg of synthetic folic acid given daily reduced homocysteine concentrations. Nevertheless, in the Framingham Offspring Study cohort, those who took vitamin B supplements had lower plasma homocysteine than people who did not take these vitamins, even after the fortification of grain products with folic acid (13 ).

Higher doses of folic acid supplements (>1000 µg) could mask hematologic signs associated with vitamin B-12 deficiency The diagnosis can be missed because irreversible neurological damage can occur even in the presence of normal hematology (14 ). In elderly people, dietary cobalamin absorption is reduced and clinical or subclinical deficiency is present in 15–30% (15 ).

In this study we observed that flour fortified only with folic acid is not appropriate for elderly people because vitamin B-12 deficiency is not corrected. Considering that one third of our subjects had a subclinical deficiency of this vitamin in the first evaluation, neurological and hematologic alterations could appear in the future. The slight increase in mean cell volume, even within the normal range, is probably an indicator of an ongoing cobalamin deficiency (14 ).

In conclusion, we demonstrated that flour fortification with folic acid in elderly people lowers homocysteine levels, but could also disguise vitamin B-12 deficiency. These results have important implications for food fortification policy.

	FOOTNOTES

 
¹ Supported by Fondecyt Grant # 1981–221, Bristol Myers-Squibb.

Manuscript received 3 August 2001. Revision accepted 12 November 2001.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

1. Danesh, J. & Lewington, S. (1998) Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies. J. Cardiovasc. Risk 5:229-232.[Medline]

2. Hankey, G. J. & Eikelboom, J. W. (1999) Homocysteine and vascular disease. Lancet 354:407-413.[Medline]

3. Selhub, J., Jacques, P. F., Wilson, P. W., Rush, D. & Rosenberg, I. H. (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J. Am. Med. Assoc. 270:2693-2698.[Abstract]

4. Bunout, D., Petermann, M., de la Maza, P., Kauffmann, R., Suazo, M. & Hirsch, S. (1998) Niveles de homocisteína en adultos sanos. Rev. Med. Chile 126:905-910.[Medline]

5. Watkins, M. L. (1998) Efficacy of folic acid prophylaxis for the prevention of neural tube defects. Ment. Retard. Dev. Dis. Res. Rev. 4:282-290.

6. Folstein, F. M., Folstein, S. E. & McHugh, P. (1975) Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. J. Psycohist. 12:189-198.

7. Amaducci, L., Baldereschi, M., Quiroga, P., Albala, C., Mamo, J., Muscat, P., Gabriel, R., Bermejo, F. & Katzman, R. (1994) Cross-cultural validation of the Mini-Mental State Examination and of the Pfeffer functional activities questionnaire. Neurol. Aging 1:281(abs.).

8. Ronnenberg, A. G., Goldman, M. B., Aitken, I. W. & Xu, X. (2000) Anemia and deficiencies of folate and vitamin B-6 are common and vary with season in Chinese women of childbearing age. J. Nutr. 130:2703-2710.[Abstract/Free Full Text]

9. Shahar, A., Feiglin, L., Shahar, D. R., Levy, S. & Seligsohn, U. (2001) High prevalence and impact of subnormal serum vitamin B12 levels in Israeli elders admitted to a geriatric hospital. J. Nutr. Health Aging 5:124-127.[Medline]

10. Hackam, D. G., Peterson, J. C. & Spence, J. D. (2000) What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below. 14 micromol/L. Am. J. Hypertens 13:105-110.[Medline]

11. Brouwer, I. A., van Dusseldorp, M., Thomas, C. M., Duran, M., Hautvast, J. G., Eskes, T. K. & Steegers-Theunissen, R. P. (1999) Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Am. J. Clin. Nutr. 69:99-104.[Abstract/Free Full Text]

12. Ward, M., McNulty, H., McPartlin, J., Strain, J. J., Weir, D. G. & Scott, J. M. (1997) Plasma homocysteine, a risk factor for cardiovascular disease is lowered by physiological doses of folic acid. Q. J. Med. 90:519-524.[Abstract/Free Full Text]

13. Jacques, P. F., Selhub, J., Bostom, A. G., Wilson, P.W.F. & Rosenberg, I. H. (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentration. N. Engl. J. Med. 340:1449-1454.[Abstract/Free Full Text]

14. Rothenberg, S. P. (1999) Increasing the dietary intake of folate: pros and cons. Semin. Hematol. 36:65-74.[Medline]

15. Scarlett, J. D., Read, H. & O’Dea, K. (1992) Protein-bound cobalamin absorption declines in the elderly. Am. J. Hematol. 39:79-83.[Medline]

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