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Department of Public Health, POB 41
University of Helsinki
Helsinki FIN-00014
Finland
E-mail: harri.hemila{at}helsinki.fi
Johns Hopkins University School of Medicine
Baltimore, MD 21205
Dear Sir:
In a recent editorial in the Journal, Traber (1) recommended vitamin E supplementation for most adults in the United States. The logic behind her recommendation was as follows. First, Wright et al (2) reported in the same issue of the Journal that the lowest overall risk for mortality in the 19-y follow-up of the Alpha-Tocopherol Beta-Carotene (ATBC) Study occurred at serum vitamin E concentrations of 13–14 mg/L, and Traber labels that as an optimal concentration for reducing the risk of chronic disease. Second, 75% of men in the United States have serum vitamin E concentrations of <14.6 mg/L, which suggests widespread vitamin E deficiency in her opinion. Third, "given the dietary habits of most Americans," "optimal" concentrations of serum vitamin E are achievable only with vitamin E supplements (1).
We believe that Traber's recommendation for vitamin E supplementation in the general population is unjustified. Inferring cause and effect and making such broad public health recommendations for supplements on the basis of observational data violate the established principles of evidence-based medicine. In fact, her recommendations are not aligned with those based on systematic reviews of large clinical trials of vitamin E supplementation, which do not recommend vitamin E supplement use (3) and discourage the use of high-dose vitamin E supplements (4).
The risks of recommending dietary supplements on the basis of observational studies are well documented. The classic example is the divergence between the finding of an inverse association between serum concentrations of ß-carotene and lung cancer risk and the finding of increased risk of lung cancer in subjects assigned ß-carotene supplements in controlled clinical trials (as reviewed in reference 5). The lesson of the ß-carotene example is that the unreliability of drawing strong cause-and-effect conclusions from correlation data has evolved into an important teaching example for students of epidemiology.
Recommendations for vitamin E supplementation are not supported by findings from the trial period of the ATBC Study. In subjects in the lowest quintile of plasma -tocopherol concentration, the similar mortality in the groups with supplement intakes of 50 and 0 mg -tocopherol (n = 1628 and 1610, respectively; see Table 3 in reference 2) refutes the notions that a low -tocopherol intake—ie, 9.4 mg/d—is the specific cause of high mortality and that correction of this "deficiency" with 50 mg -tocopherol/d would affect mortality in this high-risk quintile.
Other clinical outcomes reported from the ATBC Study show that supplementation with 50 mg vitamin E/d has divergent relations with the incidence of pneumonia and the common cold. Although vitamin E showed no overall benefit against pneumonia, the age at smoking initiation significantly modified the effect of vitamin E, so that it was harmful or beneficial, depending on this characteristic in each participant (6). The effect of vitamin E on common cold incidence was significantly modified by smoking level at baseline, age, and residential neighborhood (7). It is worth noting that, in both of these cases, smoking-related variables modified the effect of vitamin E. Although it is not reasonable to assume that the factors that modify the effect of vitamin E on respiratory infections identically modify the effect of vitamin E on cancer, coronary heart disease, or total mortality, the possibility that the effect on these latter outcomes is also modified by various factors should not be ignored. Because of this heterogeneity in the effects of vitamin E, it is possible that supplementation of a wide population may cause harm to some restricted population groups, as indicated by a recent meta-analysis (4).
These results highlight the misconception that supplementing to correct "deficiencies" of a single micronutrient is an inaccurate interpretation of the relation between nutritional markers and the risk of chronic disease in epidemiologic studies. Most blood concentrations of micronutrients, including antioxidants, are collinear. High concentrations of antioxidants reflect an antiatherogenic diet (lower in fat and saturated fat and higher in fruit, vegetables, nuts, whole grains, and low-fat dairy), which also has beneficial effects on traditional cardiovascular disease risk factors, including blood pressure, lipid concentrations, and glucose metabolism. Supplementing with vitamin E has no effect on traditional cardiovascular disease risk factors and does not lower the risk of chronic disease by other proposed mechanisms, such as by reducing oxidative stress.
Traber (1) argued that 93% of men and 96% of women in the United States do not consume the recommended amount of vitamin E. However, the current US recommendation for vitamin E is based on peroxide-dependent erythrocyte hemolysis, a surrogate endpoint that has not been validated against any clinically relevant outcome (8, 9). Furthermore, according to the current nutritional recommendations, there is no evidence that, among free-living persons, dietary vitamin E intake may meaningfully correlate with plasma -tocopherol concentrations (8). We are not aware of any reasonable evidence indicating that 93% of men and 96% of women in the United States may suffer any harmful effect on health because of their "low" vitamin E intake.
In our opinion, the attitude toward vitamin E supplementation should be based on randomized controlled trials, which have not shown a benefit in preventing or treating chronic diseases, and not on observational studies, which are highly susceptible to biases that may remain even after statistical adjustment for confounders (5, 10). Although it is possible that some population groups may benefit from vitamin E supplementation, the evidence is so equivocal that it is inappropriate to make the sweeping recommendation for vitamin E supplementation in the United States that Traber makes. Implying health benefits of supplementation in the general population is contrary to the evidence; moreover, it puts people at risk if excess use occurs and will benefit only the industry that produces, promotes, and protects the continued sale of supplement products.
ACKNOWLEDGMENTS
Neither author had a personal or financial conflict of interest with respect to the study by Wright et al or the editorial by Traber.
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