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The Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111
2To whom correspondence should be addressed. E-mail: tucker{at}hnrc.tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • vitamin B-12 • homocysteine • ethnicity • elderly • Hispanic • Puerto Rican • Dominican
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
). It is well documented that an inadequate supply of vitamin B-12 is associated with megaloblastic anemia and neurologic symptoms, often occurring in the absence of clinically apparent vitamin B-12 deficiency. The scientific and medical community has witnessed a renewed interest in vitamin B-12 because of more recent evidence that homocysteine, a major risk factor for vascular disease, accumulates in the presence of vitamin B-12 deficiency (4
,5
). Further, the recent folate fortification of the food supply raises concerns for older adults, given that exposure to high levels of dietary folate may mask vitamin B-12 deficiency by eliminating hematologic signs associated with anemia and, moreover, could exacerbate the progression of neurological disease (6
).
The main cause of impaired vitamin B-12 absorption is atrophic gastritis, which is estimated to affect 10–30% of adults aged > 65 y in the United States (7
,8
). Atrophic gastritis results in a decreased ability to absorb protein-bound vitamin B-12 attributed to the lack of pepsin activity; however, the ability to absorb crystalline or unbound vitamin B-12, found in supplements and fortified foods (e.g., fortified, ready-to-eat breakfast cereal), is not compromised. For these reasons, the recently updated Recommended Dietary Allowance (RDA) for vitamin B-12 was increased to 2.4 µg/d for adults (9
), with the suggestion that older adults obtain most of this from supplements and fortified foods (10
). Supplement users, compared to nonsupplement users, were significantly less likely to have plasma concentrations < 185 pmol/L in the Framingham Offspring Study (11
). Among nonsupplement users, more frequent consumption of fortified cereal and greater dairy intake was associated with better vitamin B-12 status (11
).
Recent reports suggest that ethnic differences in vitamin B-12 concentrations exist across elderly populations (12
,13
). Few studies have examined vitamin B-12 status in Hispanics. However, a recent study found that Mexican-Americans had lower serum vitamin B-12 concentrations than did non-Hispanic whites (13
). The Hispanic population is the fastest growing minority group in the United States, and 5.3% of Hispanics are age 65 y and over (14
). In this study, we estimated the prevalence of plasma vitamin B-12 concentrations below specified cutoffs and examined associations between plasma vitamin B-12 concentrations and dietary intake in a representative sample of elderly Puerto Ricans and Dominicans, the two largest Hispanic subgroups in Massachusetts (14
). We also examined a neighborhood comparison group of non-Hispanic whites. We hypothesized that elderly Hispanics would have a higher prevalence of low plasma vitamin B-12 concentrations compared to that of non-Hispanic whites and that vitamin B-12 intake from supplements, fortified breakfast cereal and dairy sources would be more protective against low plasma concentrations than would intake from other food sources. Because homocysteine accumulates in the presence of vitamin B-12 deficiency, we also hypothesized that low B-12 status would be associated with high homocysteine concentrations.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Subjects in this study were a subset of the 1030 members of the Massachusetts Hispanic Elders Study (MAHES), a statewide survey conducted between 1993 and 1997 (15
). For this analysis, we selected subjects aged 60–93 y, of Puerto Rican (347), Dominican (102) or non-Hispanic white ethnicity (154), with available dietary and plasma data. Puerto Ricans and Dominicans were grouped together as Hispanics of Caribbean origin after we determined that there were no significant differences in age, education, poverty level, energy intake, total vitamin B-12 intake or plasma vitamin B-12 between these groups. Remaining subjects of diverse Hispanic origin (Cuban, Mexican, Central and South American) were not included because of the small numbers in each group. This study was conducted with the approval of the Human Investigation Review Board of Tufts University/New England Medical Center and subjects gave informed consent before participation.
Field data collection
Sociodemographic and health-related information was collected at the subjects’ homes. Dietary intake was assessed with a semiquantitative food frequency questionnaire adapted and validated for use with this population (16
). The questionnaire included information on the type of breakfast cereal most frequently consumed. Dietary questionnaires were considered invalid and excluded from further analyses if total energy intake was < 2.51 MJ/d (600 kcal/d) or > 16.74 MJ/d (4000 kcal/d), or with 
12 food items (of 132) missing from the questionnaire (46 of 858 forms). Vitamin supplement use was determined in the home by observing supplement packaging. Vitamin B-12 intake from individual food sources was analyzed by examining the food contributions to total vitamin B-12 intake for each participant. Total vitamin B-12 intake was divided into vitamin B-12 intake from supplements, breakfast cereal, dairy sources, eggs, meat, poultry, fish, and all other foods.
Fasting (12 h) blood samples were drawn and collected in tubes containing 1.5 g/L EDTA and centrifuged at 2500 x g for 20 min at 4°C to separate plasma. Plasma creatinine was measured in a Cobas Mira analyzer (Roche Diagnostic Systems, Indianapolis, IN). Plasma vitamin B-12 and folate concentrations were measured using the BioRad Laboratories Quantaphase II radioassay (BioRad, Hercules, CA). Total homocysteine concentrations were measured using the method of Araki and Sako (17
). In our laboratory, the intra-assay CV for vitamin B-12, folate and homocysteine were 4.7, 4.3 and 6%, respectively.
It has been shown that the prevalence of vitamin B-12 deficiency is underestimated when using the classical clinical cutoff < 148 pmol/L (200 pg/mL) and that many individuals above this level exhibit clinical symptoms (18
,19
). Lindenbaum and colleagues (1
) also found that >15% of subjects with plasma concentrations as high as 258 pmol/L (350 pg/mL) had elevated methylmalonic acid concentrations (a metabolite highly specific to vitamin B-12 deficiency) and suggested that < 258 pmol/L may be a more appropriate cutoff for considering vitamin B-12 deficiency. Elevated methylmalonic acid concentrations have been shown to be significantly more common in subjects below vs. above < 185 pmol/L (1
). We thus report prevalences below three descriptive cutoffs: 148 pmol/L (classical clinical cutoff), 185 pmol/L (an intermediate cutoff), and 258 pmol/L (the highest cutoff proposed for vitamin B-12 deficiency).
A cutoff of > 14 µmol/L was used to define elevated homocysteine concentrations. This cutoff was previously reported to be associated with low plasma folate, vitamin B-12 or vitamin B-6 concentrations in a representative sample of the elderly adult population in Framingham, Massachusetts (20
).
Statistical analysis
Statistical analysis was completed with SPSS for Windows (version 10.0.7; SPSS, Chicago, IL). All plasma and dietary intake measures were positively skewed and we used logarithmic transformations to normalize distributions. Descriptive means were adjusted for age and sex. Dietary variables were also adjusted for total energy intake. Prevalence of plasma vitamin B-12 concentrations below defined cutoffs and vitamin B-12 dietary intake defined by percentage < 2/3 RDA were estimated by ethnic group. Linear regression analyses of plasma vitamin B-12 concentrations on dietary intake were performed to determine associations between intake and plasma concentrations. Mean (±SEM) plasma concentrations, adjusted for age, sex and energy intake, were determined for each quintile of vitamin B-12 intake and plotted against the median intake/d for each corresponding intake quintile group; for all subjects and for nonsupplement users, by each ethnic group. Food sources were identified and ranked for subjects who had plasma concentrations above and below 258 pmol/L. General linear models were performed to test for significant differences in supplement use, cereal consumption and intake from dairy and meat sources (defined by tertile categories). Logistic regression was used to estimate the prevalence of high homocysteine in subjects with plasma vitamin B-12 concentrations above and below defined cutoffs, adjusted for age, sex, plasma folate, and plasma creatinine.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). This was true for total vitamin B-12 intake and for vitamin B-12 intake among nonsupplement users only. Fifteen percent of Hispanic subjects consumed < 2/3 the RDA for vitamin B-12 compared to approximately 5% for non-Hispanic whites. Plasma vitamin B-12 concentrations for Hispanics and non-Hispanic whites were 308 ± 7 and 343 ± 12 pmol/L, respectively (P < 0.01). In addition, Hispanics were significantly more likely to have plasma vitamin B-12 concentrations < 258, <185 and < 148 pmol/L than were non-Hispanic whites.
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and 2
for Hispanics and non-Hispanic whites, respectively. For Hispanics, the curve in Figure 1
demonstrates a strong association between plasma vitamin B-12 concentrations and total intake through approximately 7 µg/d, where it appears to level off.
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258 pmol/L and < 258 pmol/L (Table 2
). Hispanic subjects with concentrations above this cutoff tended to obtain more of their vitamin B-12 intake from supplements and cereal (P < 0.10) and significantly less from poultry and eggs than did those with lower B-12 concentrations. Similarly, non-Hispanic whites with higher plasma concentrations obtained significantly more B-12 from supplements, and less from meat, compared to non-Hispanic whites with lower concentrations.
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). Among nonsupplement users, plasma concentrations of vitamin B-12 were higher (P < 0.01), and vitamin B-12 intake tended to be greater (P < 0.15) in subjects that consumed cereal > 4 times/wk compared to those who did not consume cereal. The 22% of Hispanics who did not take supplements or use breakfast cereal had the highest prevalence of plasma vitamin B-12 concentrations < 185 pmol/L (24%). In contrast, only 8% of nonsupplement users who ate cereal > 4 times/wk had low plasma concentrations.
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. Despite these differences in vitamin B-12 intake across tertiles, there were no differences in plasma concentrations. However, the proportion of subjects with plasma vitamin B-12 concentrations < 185 pmol/L was 16% for the upper tertile and 14% for the middle tertile, compared to 24% for the lower tertile (P < 0.05). In contrast, although subjects in the highest tertile of meat intake consumed more than twice as much vitamin B-12 than did those in the lowest tertile (P < 0.001), there were no differences in plasma vitamin B-12 concentrations across tertiles.
Among non-Hispanic whites, 32% consumed supplements containing vitamin B-12, and these subjects had higher plasma concentrations than did nonsupplement users (P < 0.001) (Table 3)
. Moreover, only 2% of supplement users, compared to 13% of nonsupplement users, had plasma vitamin B-12 concentrations < 185 pmol/L (P < 0.01). Non-Hispanic whites consuming cereal at least 4 times/wk were only half as likely to have low vitamin B-12 concentrations relative to noncereal consumers. A similar ratio was seen for the highest vs. lowest tertile of dairy consumption, although the difference was not significant (P = 0.21).
Because homocysteine, a risk factor for vascular disease, accumulates in the presence of vitamin B-12 deficiency, we examined whether significant differences in homocysteine were present with varying plasma concentrations (with cutoffs of 258, 185 and 148 pmol/L). After adjusting for age, sex, plasma folate and creatinine concentrations, significant differences were found in all comparisons, with the exception of the two lowest cutoff points for non-Hispanic whites, where there were too few subjects to accurately estimate this association (Table 4
). Approximately 40% of subjects in both groups with plasma vitamin B-12 < 185 pmol/L had high homocysteine concentrations.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Another study found that elderly Hispanic and non-Hispanic whites had lower cobalamin concentrations than did African- or Asian-Americans (12
).
These results are also consistent with our recent study of Framingham, MA adults, where plasma vitamin B-12 concentrations were associated with B-12 dietary intake, although plasma concentrations in that adult population leveled off at a higher value (approximately 10 µg/d) (11
). A study in Dutch elderly individuals, however, did not find that dietary intake differed by cobalamin status group (3
), nor did another U.S. study that compared dietary intakes in the elderly with low cobalamin status to those with normal cobalamin status (21
). It is likely that the sample sizes available in the Framingham Offspring study (n = 2999) and the currently reported group of Hispanics (n = 449) allowed us to detect associations between vitamin B-12 intake and plasma concentrations, whereas others, with smaller sample sizes, did not.
Analyses of sources of vitamin B-12 intake revealed that the Hispanics with lower vitamin B-12 concentrations consumed less vitamin B-12 from supplements and fortified, ready-to-eat breakfast cereal and more from poultry and eggs. Use of breakfast cereal > 4 times/wk tended to preclude lower plasma vitamin B-12 concentrations compared to consuming no cereal. We previously showed that Framingham subjects who consumed cereal > 4 times/wk were less likely to have vitamin B-12 concentrations below the cutoffs than those who consumed no cereal (11
). Unbound vitamin B-12 found in supplements and as added to fortified breakfast cereal has been shown to be more bioavailable than vitamin B-12 from naturally occurring sources (22
,23
). Protein-bound sources of vitamin B-12 may be poorly absorbed because of the prevalence of atrophic gastritis in the elderly population (7
, 8
). Our findings, therefore, lend support to previous work demonstrating the beneficial effects of vitamin B-12 dietary supplements (3
,24
,25
) and fortified cereal consumption (11
) against vitamin B-12 deficiency. Because the plasma response to diet curve appeared to level off at approximately 7 µg/d, a daily multivitamin supplement (that typically contains about 6 µg) or a serving of breakfast cereal fortified at 100% of the daily value (also 6 µg) appears to be sufficient. It is important to note, however, that this amount is considerably greater than the current RDA for vitamin B-12 intake (9
).
Our Framingham analyses (11
) also found that intake from dairy sources was more protective of vitamin B-12 status than was meat. Patterns of plasma vitamin B-12 concentrations in the current study were in the expected direction, but did not differ significantly among tertile categories of vitamin B-12 intake from dairy sources, with the exception that Hispanics in the middle tertile were significantly less likely to have low plasma vitamin B-12 than those in the lowest intake tertile. This may be attributable to the low dairy intake in this group and lack of variability, thus making it difficult to detect associations. The upper and middle tertiles of vitamin B-12 intake from meat consumed considerably more vitamin B-12 compared to the lowest tertile. However, no differences in plasma concentrations were found, again suggesting that the vitamin B-12 availability from meat may be low.
We also found that high homocysteine concentrations (> 14 µmol/L) were common in this population and were strongly associated with low vitamin B-12 concentrations in both Hispanic and non-Hispanic whites. Despite more frequent vitamin B-12 deficiency among Hispanics, the prevalence of high homocysteine was similar in the two ethnic groups, and this was consistent across cutoff points. Hispanics and non-Hispanic whites had overall prevalences of high homocysteine of 20 and 18%, respectively, which increased to almost 40% among those with vitamin B-12 concentrations < 185 pmol/L. Because homocysteine is increasingly accepted as a potent risk factor for vascular disease (26
,27
), the associations shown here are important. Although the recently implemented folic acid fortification is likely to have lowered the prevalence of high homocysteine overall, it will not lower that proportion that is attributed to low vitamin B-12 (20
,24
). These results confirm the findings of several previous studies that have documented the association between low vitamin B-12 status and elevated homocysteine, and its greater importance in explaining the prevalence of high homocysteine that remains despite folic acid fortification (20
,28
,29
).
The strong association between reported intake and plasma concentration suggests that this food frequency questionnaire captures vitamin B-12 intake well in this Hispanic group. However, this food frequency questionnaire, which was modified for use with both Hispanics of Caribbean origin and non-Hispanic whites, could be more limited in capturing vitamin B-12 intake in the non-Hispanic group. Unlike the Hispanics, the association between intake and plasma concentration was not significant for non-Hispanic, white nonsupplement users. Alternatively, these elderly non-Hispanic whites may have poorer absorption from foods because of possible differences in medication use or prevalence of atrophic gastritis. Previous studies report no association between dietary vitamin B-12 and plasma concentrations among elderly subjects (3
, 21
). Further investigation of these differential results is needed.
One limitation of this study was that we did not obtain data from which to quantify effects of medication or prevalence of atrophic gastritis. On the other hand, the non-Hispanic whites appeared to have greater response to supplement use, with higher plasma concentrations among users than among Hispanics, despite similar reported intakes among supplement users. Lack of compliance with regular supplement use among Hispanics may explain this result. Because this is a cross-sectional study, it is also possible that recent prescription ascribed to deficiency may have affected the association between intake from supplements and plasma concentrations in this group. Finally, statistical power was limited for comparisons of intake subgroups because of limited sample size, particularly among the non-Hispanic whites.
In this study, elderly Hispanics had a higher prevalence of low plasma vitamin B-12 concentrations than did neighborhood-matched non-Hispanic whites. Inadequate vitamin B-12 intake in the Hispanic diet appears to be an important contributing factor to the low plasma status. As in other populations, sources of unbound vitamin B-12 such as supplements and fortified breakfast cereal appear to be more protective than naturally occurring sources of vitamin B-12. These sources were not widely used by these elderly Hispanics. Culturally sensitive dietary intervention programs targeted to the Hispanic population should promote these vitamin B-12–rich sources.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 8 March 2002. Initial review completed 21 March 2002. Revision accepted 24 April 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Lindenbaum, J., Rosenberg, I. H., Wilson, P. W., Stabler, S. P. & Allen, R. H. (1994) Prevalence of cobalamin deficiency in the Framingham elderly population. Am. J. Clin. Nutr. 60:2-11.
2. Joosten, E., van den Berg, A., Riezler, R., Naurath, H. J., Lindenbaum, J., Stabler, S. P. & Allen, R. H. (1993) Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people. Am. J. Clin. Nutr. 58:468-476.
3. van Asselt, D. Z., de Groot, L. C., van Staveren, W. A., Blom, H. J., Wevers, R. A., Biemond, I. & Hoefnagels, W. H. (1998) Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older Dutch subjects. Am. J. Clin. Nutr. 68:328-334.[Abstract]
4. Clarke, R., Daly, L., Robinson, K., Naughten, E., Cahalane, S., Fowler, B. & Graham, I. (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N. Engl. J. Med. 324:1149-1155.[Abstract]
5. Stabler, S. P., Marcell, P. D., Podell, E. R., Allen, R. H., Savage, D. G. & Lindenbaum, J. (1988) Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J. Clin. Invest. 81:466-474.
6. Savage, D. G. & Lindenbaum, J. (1995) Folate-cobalamin interactions. Bailey, L. B. eds. Folate in Health and Disease 1995 Marcel Dekker New York, NY. .
7. Hurwitz, A., Brady, D. A., Schaal, S. E., Samloff, I. M., Dedon, J. & Ruhl, C. E. (1997) Gastric acidity in older adults. JAMA 278:659-662.[Abstract]
8. Krasinski, S. D., Russell, R. M., Samloff, I. M., Jacob, R. A., Dallal, G. E., McGandy, R. B. & Hartz, S. C. (1986) Fundic atrophic gastritis in an elderly population. Effect on hemoglobin and several serum nutritional indicators. J. Am. Geriatr. Soc. 34:800-806.[Medline]
9. Institute of Medicine (1998) Dietary reference intakes: thiamin, riboflavin, niacin, vitamin B-6, folate, vitamin B-12, pantothenic acid, biotin and choline 1998 National Academy Press Washington, DC. .
10. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes (1998) Folate, other B vitamins and choline 1998 National Academy of Science Washington, DC. .
11. Tucker, K. L., Rich, S., Rosenberg, I., Jacques, P., Dallal, G., Wilson, P. W. & Selhub, J. (2000) Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am. J. Clin. Nutr. 71:514-522.
12. Carmel, R., Green, R., Jacobsen, D. W., Rasmussen, K., Florea, M. & Azen, C. (1999) Serum cobalamin, homocysteine, and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities. Am. J. Clin. Nutr. 70:904-910.
13. Lindeman, R. D., Romero, L. J., Koehler, K. M., Liang, H. C., LaRue, A., Baumgartner, R. N. & Garry, P. J. (2000) Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: correlations with cognitive and affective functions. J. Am. Coll. Nutr. 19:68-76.
14. U.S. Census Bureau (2000) Census 2000 2000 Washington, DC. .
15. Tucker, K. L., Falcon, L. M., Bianchi, L. A., Cacho, E. & Bermudez, O. I. (2000) Self-reported prevalence and health correlates of functional limitation among Massachusetts elderly Puerto Ricans, Dominicans, and non-Hispanic white neighborhood comparison group. J. Gerontol. A Biol. Sci. Med. Sci. 55:M90-M97.[Abstract]
16. Tucker, K. L., Bianchi, L. A., Maras, J. & Bermudez, O. I. (1998) Adaptation of a food frequency questionnaire to assess diets of Puerto Rican and non-Hispanic adults. Am. J. Epidemiol. 148:507-518.
17. Araki, A. & Sako, Y. (1987) Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J. Chromatogr. 422:43-52.[Medline]
18. Carmel, R. (1988) Pernicious anemia. The expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch. Intern. Med. 148:1712-1714.[Abstract]
19. Lindenbaum, J., Healton, E. B., Savage, D. G., Brust, J. C., Garrett, T. J., Podell, E. R., Marcell, P. D., Stabler, S. P. & Allen, R. H. (1988) Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N. Engl. J. Med. 318:1720-1728.[Abstract]
20. 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. JAMA 270:2693-2698.[Abstract]
21. Howard, J. M., Azen, C., Jacobsen, D. W., Green, R. & Carmel, R. (1998) Dietary intake of cobalamin in elderly people who have abnormal serum cobalamin, methylmalonic acid and homocysteine levels. Eur. J. Clin. Nutr. 52:582-587.[Medline]
22. Miller, A., Furlong, D., Burrows, B. A. & Slingerland, D. W. (1992) Bound vitamin B12 absorption in patients with low serum B12 levels. Am. J. Hematol. 40:163-166.[Medline]
23. Scarlett, J. D., Read, H. & O’Dea, K. (1992) Protein-bound cobalamin absorption declines in the elderly. Am. J. Hematol. 39:79-83.[Medline]
24. Koehler, K. M., Baumgartner, R. N., Garry, P. J., Allen, R. H., Stabler, S. P. & Rimm, E. B. (2001) Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use. Am. J. Clin. Nutr. 73:628-637.
25. McKay, D. L., Perrone, G., Rasmussen, H., Dallal, G. & Blumberg, J. B. (2000) Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet. J. Nutr. 130:3090-3096.
26. Boushey, C. J., Beresford, S. A., Omenn, G. S. & Motulsky, A. G. (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274:1049-1057.[Abstract]
27. Refsum, H., Ueland, P. M., Nygard, O. & Vollset, S. E. (1998) Homocysteine and cardiovascular disease. Annu. Rev. Med. 49:31-62.[Medline]
28. Jacques, P. F., Bostom, A. G., Wilson, P. W., Rich, S., Rosenberg, I. H. & Selhub, J. (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am. J. Clin. Nutr. 73:613-621.
29. Selhub, J., Jacques, P. F., Rosenberg, I. H., Rogers, G., Bowman, B. A., Gunter, E. W., Wright, J. D. & Johnson, C. L. (1999) Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991–1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann. Intern. Med. 131:331-339.
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