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1 From the Division of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion (ESF, AHM, and UAA) and the Division of Laboratory Sciences, National Center for Environmental Health (RLS), Centers for Disease Control and Prevention, Atlanta, GA; the Division of Preventive Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA (SL); and the Department of Epidemiology, Harvard School of Public Health, Boston, MA (SL)
2 The findings and conclusions in this article are those of the authors and do not represent the views of the Centers for Disease Control and Prevention. 3 Reprints not available. Address correspondence to E Ford, Centers for Disease Control and Prevention, 4770 Buford Highway, MS K66, Atlanta, GA 30341. E-mail: eford{at}cdc.gov.
ABSTRACT
Background:Although the population distribution of serum concentrations of -tocopherol has been described in the United States, little is known about the distribution of -tocopherol or the ratio of -tocopherol to -tocopherol.
Objective:Our aim was to describe the distribution of serum concentrations of -tocopherol and -tocopherol in a nationally representative sample of US adults.
Design:We reviewed data from 4087 adults aged 20 y who participated in the National Health and Nutrition Examination Survey (1999–2000). Concentrations of -tocopherol and -tocopherol were measured by using HPLC with ultraviolet-visible wavelength detection.
Results:The arithmetic mean (±SEM) of serum concentrations of -tocopherol was 30.09 ± 0.45 µmol/L, the median was 25.94 µmol/L, and the geometric mean (±SEM) was 27.39 ± 0.38 µmol/L. The arithmetic mean of serum concentrations of -tocopherol was 5.74 ± 0.22 µmol/L, the median was 5.25 µmol/L, and the geometric mean was 4.79 ± 0.18 µmol/L. The median ratio of -tocopherol to total cholesterol was 4.93 µmol/mmol, that of -tocopherol to total cholesterol was 1.03 µmol/mmol, and that of -tocopherol to -tocopherol was 4.53 µmol/mmol. Concentrations of -tocopherol increased significantly (P for trend < 0.001) with age and were significantly (P = 0.015) lower in men than in women. African Americans and Mexican Americans had significantly (P < 0.001) lower concentrations of -tocopherol than did whites. The median concentrations of -tocopherol showed a trend with respect to age, did not differ significantly between men and women, and were slightly but nonsignificantly lower in white participants than in African American or Mexican American participants.
Conclusion:Sociodemographic variations in serum concentrations of -tocopherol and -tocopherol exist among US adults.
Key Words: -Tocopherol • ethnic groups • -tocopherol • National Health and Nutrition Examination Survey • NHANES • nutrition surveys • United States • vitamin E
INTRODUCTION
Despite mixed results of randomized clinical trials of the effect of vitamin E supplementation on cardiovascular disease [(CVD) 1-3], a great deal of interest remains in the possible beneficial effects of this vitamin on health (4). For example, vitamin E intake was inversely associated with the development of Alzheimer disease (5) and, in a long-term, randomized, placebo-controlled clinical trial, was also included in the antioxidant cocktail that delayed the progression of macular degeneration (6).
At least 8 forms of vitamin E have been described: -, ß-, -, and -tocopherol and -, ß-, -, and -tocotrienol (7). These forms differ in the number of methyl group substitutions on the chromanol ring and in the saturation of the isoprenoid side chain. Whereas -tocopherol, the major circulating form, has been the most frequently studied form of vitamin E, the other forms are receiving increasing attention. After -tocopherol, -tocopherol, the predominant form in the US diet, has perhaps received the most attention. Intriguing data showing an inverse relation between CVD and -tocopherol have yet to be explored fully.
Despite the higher dietary intakes of -tocopherol, circulating concentrations of -tocopherol are higher than those of -tocopherol. Humans appear to preferentially metabolize forms of vitamin E other than -tocopherol (8, 9). The reasons for the differential metabolism of tocopherols remain unknown, but the possibilities are that a form such as -tocopherol may have harmful effects or that its metabolites may offer physiologic benefits—eg, the ability of -2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (-CEHC) to inhibit cyclooxygenase-2 activity and the natriuretic properties of -CEHC (9-11).
Because of the continued interest in vitamin E, understanding vitamin E status in the population is of considerable interest. Relatively few studies have provided information about the status of vitamin E in nationally representative samples of countries (12-17). Although information about the distribution of serum concentrations of -tocopherol in the United States was previously published (15, 16), little is known about -tocopherol in this country. Because of the increasing attention directed toward -tocopherol (18, 19), an understanding of the distribution of this form of vitamin E in the US population should be useful to researchers and clinicians alike. Therefore, we used data from a nationally representative sample to describe the distributions of serum - and -tocopherol among US adults.
SUBJECTS AND METHODS
Subjects
This cross-sectional analysis used data from the National Health and Nutrition Examination Survey (NHANES) obtained in 1999 and 2000 (20). In this survey, a representative sample of the noninstitutionalized civilian US population was selected through a stratified multistage sampling design. Trained interviewers conducted computer-assisted personal interviews with participants at their homes. Participants were asked to visit the mobile examination center, where they were asked to complete additional questionnaires, undergo various examinations, and provide a blood sample. Details about the survey may be found elsewhere (20).
All participants gave written informed consent. The survey was approved by the Human Subjects Office at the Centers for Disease Control and Prevention and was conducted according to the principles of the Declaration of Helsinki of 1975 as revised in 1983.
Methods
Concentrations of - and -tocopherol were measured by using HPLC on a Waters Alliance system (Waters 2695 Separations Module and Waters 2996/996 Photodiode Array Detector; Waters Chromatography Division, Milford, MA) with the use of an Ultracarb 3 octadecylsilane, 15 cm x 4.6 mm, 3-µm particle size column (Phenomenex, Torrance, CA) at the National Center for Environmental Health (Centers for Disease Control and Prevention, Atlanta, GA). Modifications of the laboratory method and quality-control procedures used in the Third National Health and Nutrition Examination Survey (NHANES III) were used (21). The laboratory participates in National Institute of Standards and Technology–sponsored semiannual quality-assurance exercises for fat-soluble micronutrients. Periodically, standard reference materials (SRM968c levels 1 and 2) from the National Institute of Standards and Technology (Gaithersburg, MD) were analyzed to assess accuracy. Serum lipids (total cholesterol, triacylglycerols, and HDL cholesterol) were measured by using a Hitachi 704 automated chemistry analyzer (Roche, Indianapolis, IN) at the Lipoprotein Analytical Laboratory (Johns Hopkins University School of Medicine, Baltimore, MD; 21). We estimated the dietary intake of -tocopherol from a single 24-h recall. Intake expressed as mg -tocopherol/d was calculated by multiplying each person's intake as mg -tocopherol equivalents/d by 0.8 (7).
We included the following covariates: age, sex, race-ethnicity (ie, white, African American, Mexican American, and other), and the use of vitamin, mineral, or dietary supplements. Participants were asked the question "Have you used or taken any vitamin, minerals, or other dietary supplements in the past month?" to establish the use of such supplements.
Statistical analysis
We present the distribution of concentrations of - and -tocopherol and their ratios as well as the ratios of concentrations of - or -tocopherol to total cholesterol for all participants regardless of fasting status. Tests for linear trend used orthogonal polynomial contrasts or general linear models. For multiple comparisons, we used the Bonferroni adjustment. Moreover, in a subgroup of participants who attended the morning examination and had fasted for 8 h, we calculated the correlation coefficients between concentrations of - and -tocopherol and used analysis of covariance to calculate geometric mean concentrations of - and -tocopherol after adjustment for various concentrations of serum lipids: total cholesterol, total plus HDL cholesterol, total cholesterol plus triacylglycerols, and HDL cholesterol plus LDL cholesterol plus triacylglycerols. Percentiles were calculated by using SAS software (version 8.02; SAS Institute, Cary, NC) and weighting the data by using sampling weights. Other analyses were performed by using SUDAAN software (version 9.0.0; Research Triangle Institute, Research Triangle Park, NC) or SPSS software (version 13; SPSS Inc, Chicago, IL) to account for the complex sampling design of the survey.
RESULTS
A total of 4087 participants aged 20 y had measurements of -tocopherol, and 3580 participants had measurements of -tocopherol. The distributions of both forms of vitamin E were positively skewed (Figure 1 and Figure 2). The arithmetic mean (±SEM) of -tocopherol was 30.09 ± 0.45 µmol/L, the median was 25.94 µmol/L, and the geometric mean (±SEM) was 27.39 ± 0.38 µmol/L. The arithmetic mean of -tocopherol was 5.74 ± 0.22 µmol/L, the median was 5.25 µmol/L, and the geometric mean was 4.79 ± 0.18 µmol/L. The median -tocopherol:total cholesterol was 4.93 µmol/mmol, the median -tocopherol:total cholesterol was 1.03 µmol/mmol, and the median -tocopherol:-tocopherol was 4.53 µmol/µmol.
FIGURE 1.. Distribution of serum concentrations of -tocopherol in men, women, whites, African Americans, and Mexican Americans aged 20 y; data from the National Health and Nutrition Examination Survey (1999–2000; 20). Data for men and women are shown as lines, and the data for the 3 racial or ethnic groups are shown as columns.
FIGURE 2.. Distribution of serum concentrations of -tocopherol in men, women, whites, African Americans, and Mexican Americans aged 20 y; data from the National Health and Nutrition Examination Survey (1999–2000; 20). Data for men and women are shown as lines, and the data for the 3 racial or ethnic groups are shown as columns.
In a subgroup of participants who attended the morning examination, had fasted 8 h, and had measurements for concentrations of total, HDL, and LDL cholesterol and triacylglycerols, the concentrations of - and -tocopherol were inversely correlated (Table 1 ). Adjustment for concentrations of lipids strengthened the correlation coefficients. The magnitude of the correlation coefficients was considerably greater in users of vitamin, mineral, or dietary supplements than in nonusers of supplements.
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TABLE 1. Pearson correlations between serum concentrations of -tocopherol and -tocopherol among US adults aged 20 y in the National Health and Nutrition Examination Survey (1999–2000)1
For -tocopherol, the geometric mean concentrations increased with age (P for trend < 0.001), were lower in men than in women (P = 0.015), and were higher in white than in African American or Mexican American (P < 0.001 for both) participants (Table 2 ). For -tocopherol, the geometric mean concentrations were inversely related to age (P for trend < 0.001) and did not differ significantly between men and women (P = 0.739) or between racial-ethnic groups (P = 0.511, Wald test).
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TABLE 2. Serum concentrations of -tocopherol, the ratio of concentrations of -tocopherol to total cholesterol, concentrations of -tocopherol, the ratio of concentrations of -tocopherol to total cholesterol, and the ratio of concentrations of -tocopherol to -tocopherol in US adults aged 20 y in the National Health and Nutrition Examination Survey (1999–2000)
The patterns of sociodemographic variation for -tocopherol:total cholesterol and -tocopherol:total cholesterol are similar to those described above for concentrations of - and -tocopherol. Finally, the sociodemographic variation in the pattern for -tocopherol:-tocopherol was similar to that for concentrations of -tocopherol. (For estimates for the percentiles of the distributions for concentrations of - and -tocopherol and their ratios, see Appendixes 1–5 under "Supplemental data" in the current online issue at www.ajcn.org.)
We calculated the proportions of participants with concentrations of -tocopherol below several thresholds that have been used to identify a low concentration of vitamin E (Table 3 ). Vitamin E deficiency expressed as < 2.22 or < 2.5 µmol · L–1 · mmol total cholesterol–1 or expressed as < 1.59 µmol · L–1 · mmol total cholesterol + triacylglycerols–1 was too uncommon to report.
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TABLE 3. US adults aged 20 y who have a deficiency of serum -tocopherol calculated by using different thresholds; National Health and Nutrition Examination Survey (1999–2000)
In addition, for a subgroup of participants who attended the morning examination and had fasted 8 h, we calculated geometric mean concentrations of - and -tocopherol after adjustment for various concentrations of lipids (Table 4 ). In general, adjustment for HDL cholesterol, LDL cholesterol, and triacylglycerols provided the greatest narrowing of the differences in geometric mean concentrations. Consequently, the interpretation of statistical differences between some sociodemographic groups depended on the degree of adjustment. The effect of adjustments on P values for age trends was inconsequential for either tocopherol. However, the significance of the differences in geometric mean concentrations of -tocopherol between men and women varied according to the level of adjustment. Performing a similar set of adjustments for concentrations of -tocopherol mostly affected the interpretation of racial or ethnic differences (Table 5 ).
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TABLE 4. Serum concentrations of -tocopherol after various adjustments in US adults 20 y in the National Health and Nutrition Examination Survey (1999–2000)1
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TABLE 5. Serum concentrations of -tocopherol after various adjustments in US adults aged 20 in the National Health and Nutrition Examination Survey (1999–2000)1
Approximately 51% of adults (46% of men and 56% of women) reported using vitamin, mineral, or other dietary supplements. Among supplement users, the distribution of the serum concentration of -tocopherol was shifted to the right, whereas that of -tocopherol was shifted to the left (Figure 3 and Figure 4 ). In the users of supplements, the mean serum concentrations of - and -tocopherol were 35.57 ± 0.69 and 4.75 ± 0.17 µmol/L, respectively; the medians were 31.05 and 4.22 µmol/L; and the geometric means (±SEMs) were 32.31 ± 0.54 and 3.88 ± 0.15 µmol/L. In the supplement nonusers, the mean concentrations of - and -tocopherol were 24.01 ± 0.31 and 6.82 ± 0.23 µmol/L, the medians were 22.39 and 6.14 µmol/L, and the geometric means were 22.80 ± 0.29 and 6.05 ± 0.21 µmol/L, respectively.
FIGURE 3.. Distribution of serum concentrations of -tocopherol in adults aged 20 y by their use of vitamin, mineral, or dietary supplements; data from the National Health and Nutrition Examination Survey (1999–2000).
FIGURE 4.. Distribution of serum concentrations of -tocopherol in adults aged 20 y, by their use of vitamin, mineral, or dietary supplements; data from the National Health and Nutrition Examination Survey 1999–2000).
In those in whom we were able to measure vitamin E intake from diet and supplements, the mean unadjusted dietary intake was 7.4 ± 0.1 mg -tocopherol/d for the entire sample, 8.0 ± 0.2 mg -tocopherol/d for supplement users, and 6.7 ± 0.2 mg -tocopherol/d for supplement nonusers. Median intakes were 5.9, 6.2 and 5.4 mg -tocopherol/d, respectively. In addition, participants using any supplements consumed on average 73.7 ± 3.6 (median: 13.5) mg -tocopherol/d from supplements, assuming that the supplements contained all-rac--tocopherol. The Pearson correlation coefficient between log-transformed serum concentration of -tocopherol and the intake of vitamin E was 0.06 in supplement users and 0.04 in supplement nonusers. Mean intakes of dietary vitamin E in supplement nonusers were 6.8 ± 1.3 mg -tocopherol/d for participants with serum concentrations of -tocopherol < 14 µmol/L, 6.4 ± 0.6 mg -tocopherol/d for participants with serum concentrations 14 to <16 µmol/L, 6.5 ± 0.6 mg -tocopherol/d for participants with serum concentrations 16 to <18 µmol/L, 6.6 ± 0.3 mg -tocopherol/d for participants with serum concentrations 18 to <20 µmol/L, and 6.9 ± 0.2 mg -tocopherol/d for participants with serum concentrations 20 µmol/L. In participants who did not report using supplements, the mean dietary intakes were 6.5, 6.6, 6.7, and 7.3 mg -tocopherol/d, and the median intakes were 5.2, 5.9, 5.4, and 5.7 mg -tocopherol/d from the lowest quartile of serum vitamin E concentrations to the highest quartile.
DISCUSSION
Our results provide valuable information about the distribution of serum concentrations of - and -tocopherol in the US population. Previous studies of vitamin E in samples of the population that generally are nationally representative were conducted in the United Kingdom (12), Hungary (13), Taiwan (14), and the United States (15, 16). In NHANES III, which was conducted in the United States between 1988 and 1994, the arithmetic mean concentration of -tocopherol was 26.2 µmol/L in 7666 men aged 18 y and 27.3 µmol/L in 8629 women aged 18 y (16). After recalculating the results from the NHANES III for participants aged 20 y instead of 18 y, the arithmetic mean, median, and geometric mean for -tocopherol were 27.04 (95% CI: 26.58, 27.51), 24.38, and 25.26 (24.87, 25.65) µmol/L, respectively. For -tocopherol:total cholesterol, the same values were 5.09 (5.01, 5.18), 4.68, and 4.88 (4.81, 4.96) µmol/L, respectively. Therefore, circulating concentrations of -tocopherol in US adults have increased significantly during the period encompassed by the 2 surveys. The adults who used daily supplements of vitamin E increased from 4.1% of the US population in 1987 to 11.4% in 2000 (22).
Fewer studies that can be construed as being representative of a national population have been conducted for -tocopherol than for -tocopherol. In the National Diet and Nutrition Survey (NDNS) conducted among participants aged 65 y in the United Kingdom during 1994 and 1995, the geometric mean concentration adjusted for age, sex, domicile, and nutrient intake ranged from 1.89 to 2.02 µmol/L (12). In participants aged 19 to 85 y in 2 NDNSs conducted in the United Kingdom, -tocopherol:total cholesterol ranged from 4 to 6 mmol/mol, -tocopherol:total cholesterol ranged from 0.2 to 0.4 mmol/mol, and -tocopherol:-tocopherol ranged from 0.05 to 0.07 mmol/mmol (17). In 200 control participants aged 45 y in the Johnston County Osteoarthritis Project, the geometric mean for -tocopherol:-tocopherol was 4.4, which is lower than the 5.63 we estimated for adults in the NHANES from 1999–2000 (23).
Our results showing that the magnitude and direction of the correlations between concentrations of - and -tocopherol differed according to the use of vitamin, mineral, or dietary supplements are consistent with previous findings (24). This inverse association between the 2 forms of tocopherol has been attributed to the fact that the tocopherol transfer protein has a higher affinity for -tocopherol than for -tocopherol (24).
In the United States, the intake of -tocopherol from diet exceeds that of -tocopherol. However, the use of vitamin supplements is common in the United States: 52% of adult participants in the NHANES from 1999–2000 reported using vitamin, mineral, or dietary supplements (25). Vitamin E consumed from supplements is predominantly in the form of -tocopherol. Supplement use varies by sociodemographic characteristics, which may help to explain some of the variability in the concentrations of - and -tocopherol that we observed between groups (22). The increasing use of supplements with age may explain the age-related positive gradient in concentrations of -tocopherol and the inverse gradient with -tocopherol. The higher prevalence of supplement use by whites may explain the lower concentrations of -tocopherol, and the lower prevalence of use by African Americans may account for the higher concentrations of -tocopherol. Despite lower circulating concentrations of -tocopherol than of -tocopherol, tissue concentrations of -tocopherol can be high (26).
Because vitamin E is transported in lipoprotein fractions in the blood, concentrations of this vitamin are dependent on concentrations of lipids. Consequently, adjustment for circulating concentrations of lipids has used a variety of methods (27-30). Because researchers have not consistently used one method to adjust for concentrations of lipids, it is difficult to interpret the literature and compare findings among studies. One of the more common methods has been to calculate the ratio of vitamin E to total cholesterol concentrations.
A variety of thresholds of circulating concentrations of -tocopherol have been used to estimate deficiency of this vitamin: 7 (31, 32), 8 (33), 9 (34, 35), 12 (14, 15, 36-42), 14 (43), 15 (44), 16 (45, 46), 18 (47), 20 (16), and 28 µmol/L (48). Several medical textbooks cite a concentration of <11.6 µmol/L as indicating vitamin E deficiency. Similarly, different thresholdsof vitamin E-to-lipid concentration ratios have been used to indicate vitamin E deficiency: <2.2 (44, 49) or 2.5 (40) µmol/mmol total cholesterol and < 1.59 µmol/mmol total cholesterol and triacylglycerols (14). Furthermore, lipid-standardized threshold concentrations of >25 or >30 µmol -tocopherol/L have been proposed as providing protection against coronary heart disease or intestinal cancer (50). It is interesting that we found that vitamin E deficiency expressed as < 2.22 or < 2.5 µmol · L–1 · mmol total cholesterol–1 or as < 1.59 µmol · L–1 · mmol of total cholesterol + triacylglycerols–1 was very uncommon in US adults.
Nationally collected data on food intakes linked with serum concentrations of -tocopherol are available from NHANES. As measured by serum concentrations of -tocopherol and the most common cutoff (ie, <11.6 µmol/L), the prevalence of vitamin E deficiency was low, despite the facts that the estimated dietary intakes were low and that most of the US population did not meet dietary recommendations in 1999–2000. At least 90% of the adults had usual intakes below the estimated average requirement (51). Dietary data were derived from a single 24-h recall, and they likely underestimated the true intake of vitamin E. Currently, recommended intakes are based only on -tocopherol, whereas, in the past, other forms were used to estimate -tocopherol equivalents (7). Data on the dietary intake of -tocopherol were not released for NHANES 1999–2000, although it would be of interest to relate dietary intake to serum concentrations for this form of vitamin E, which has features distinctly different from those of -tocopherol.
Researchers continue to separate out the effects on health that are associated with the various forms of vitamin E and to attempt to establish intakes and physiologic concentrations of this vitamin that are recommended for optimal health. Given the many physiologic actions of vitamin E and the intense interest in the possible health effects of this vitamin, the distributions of circulating concentrations of vitamin E must be understood at the population level. We hope that the information in this report will prove useful to clinicians, researchers, and policy makers interested in vitamin E.
ACKNOWLEDGMENTS
We thank the staff of the Nutrition Laboratory at Centers for Disease Control and Prevention, where these measurements were made, in particular Mary Xu and Huiping Chen.
ESF conceived the study, conducted the analyses, and drafted the manuscript. RLS helped develop the analysis plan and helped write the manuscript. AHM, UAA, and SL were involved in statistical analyses, interpretation of results, and writing of the manuscript. None of the authors had a financial or personal conflict of interest.
REFERENCES