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Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee (S.B.K.)
Wistar Institute, Philadelphia, Pennsylvania (D.K.)
Address reprint requests to: Stephen B. Kritchevsky, PhD, Department of Preventive Medicine, UT, Memphis, 66 N. Pauline, Suite 633, Memphis, TN 38105
| ABSTRACT |
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Key words: dietary cholesterol, eggs, coronary heart disease, epidemiology, review
Key teaching points:
Dietary cholesterol is weakly association with the risk of coronary events in epidemiologic studies.
Daily egg consumption is not associated with increased risk of coronary events after adjusting for other aspects of the diet that may predispose towards coronary disease.
| INTRODUCTION |
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Experimental feeding studies can provide only part of the evidence-base for making dietary recommendations. Epidemiologic data augment the experimental data in an important way. In controlled feeding studies, diets are constructed to differ in only the substance of interest. This design feature is essential to isolate the independent effects of individual constituents. In free-living populations diets reflect a pattern of associated choices, and increases in one food may lead to the changes in the consumption of other foods that themselves may modulate disease risk. So while dietary cholesterol increases serum cholesterol in an experiment, it does not necessarily follow that a high cholesterol food either increases serum cholesterol or disease risk in a population. The relationship of egg consumption to coronary outcomes depends not only on the cholesterol content of eggs themselves, but on the totality of the diet in which eggs are consumed. Turning to the epidemiologic evidence, the proper evaluation of the role that eggs may play in coronary risk modulation depends on being able to account for potential confounding by correlated dietary and non-dietary risk factors.
In the past several years, new epidemiologic evidence has become available that relates to both the importance of dietary cholesterol, in general, and eggs, specifically, as risk factors for coronary disease. An evaluation of the role of dietary cholesterol in determining coronary disease risk is appropriate since eggs supply approximately 30% of dietary cholesterol in the US diet. If there is no association between cholesterol and disease risk, then the relationship between eggs and risk becomes moot. Epidemiological studies of dietary cholesterol have become increasingly sophisticated in their examination of issues of confounding by other dietary factors. Two factors of particular interest are saturated fat intake and fiber intake. Many high cholesterol foods are also sources of saturated fat. High cholesterol/high fat diets are often poor in dietary fiber. Since saturated fat has been directly linked to coronary disease and fiber has been identified as a potentially protective factor, both must be considered in an evaluation of dietary cholesterol. The purpose of this review is to summarize the epidemiologic data linking dietary cholesterol to coronary heart disease risk, including more recent findings, and also to summarize recent studies that have addressed the relationship between egg-consumption per se and coronary risk.
| DIETARY CHOLESTEROL AND CORONARY DISEASE |
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The Ireland-Boston Health Study included 1001 middle-aged men, some born and living in Ireland, some recent emigrees from Ireland to Boston and some American born of Irish descent [6]. Between 1959 and 1965 the cohort provided a diet history to a study dietician. Over the next 20 years, 334 of the original cohort members died, 110 from coronary heart disease. After adjusting for many of the same factors as in the Honolulu Heart Study (alcohol consumption and place of birth/residence were also included but physical activity and weight were not), dietary cholesterol was associated with increased mortality, but the relationship was not statistically significant (p=0.11).
The Western Electric Study [7, 13, 15] included 1900 men aged 40 to 55 years employed at Western Electrics Hawthorne Works in the Chicago metropolitan area in 1957. Diet was assessed using a diet history method. Death from coronary mortality over the next 19 years was related to dietary cholesterol consumption at baseline, after adjusting for percent of calories as saturated fat and polyunsaturated fat, body mass index, ancestry, body mass index, as well as the variables adjusted for in the Ireland Boston Diet-Heart Study. Based on the statistical model, each 200 mg/1000 kcal/day increase in cholesterol was associated with a 1.9-fold increase in the risk of death from coronary disease (p=0.008). There is an issue relating the characterization of the cholesterol-disease relationship that deserves mention. The representation of dietary cholesterol in the model employed by Shekelle et al. [7] forces a log-linear relationship between intake and risk. In other words, the approach calculates an association between dietary cholesterol and mortality assuming that the elevation in risk is the same when comparing those eating 0 versus those eating 200 mg/1000 kcal/day as it is comparing those eating 250 versus those eating 450 mg/1000 kcal/day. This assumption is implicit in several other analyses discussed in this section [5,6,8,9,10]. The validity of the assumption has an important implication. If valid, then any increase in dietary cholesterol would be deleterious regardless of the absolute amount consumed. The appropriateness of this assumption can be evaluated by representing cholesterol intake as a series of variables, each indicating differing levels of cholesterol consumption (as opposed to representing it as a single continuous measure). When this is done, the shape of the exposure-disease relationship can be evaluated explicitly. Such an analysis of the 25-year follow-up data from the Western Electric Study was done by comparing coronary death rates for each quintile of cholesterol intake [15]. The analysis suggested that the assumption that the risk increases as a linear function of intake is incorrect since there was no increase in the risk of death except for those men in the highest fifth of cholesterol consumption (over 289 mg/1000 kcal/day).
The Zutphen Study which began in 1960 included 871 middle-aged men [8]. Diet was assessed using a diet history method. After 10 years of follow-up, dietary cholesterol intake was not significantly related to coronary death. At 20 years of follow-up, a positive association was noted, but the relationship was not significant after adjusting for standard risk factors and subscapular skinfolds, occupation, energy intake and fish intake [13].
From 1966 through 1969 male participants in the Framingham Study between the ages of 45 and 65 were invited to have their diet assessed by twenty-four hour recall [9]. Over the next 16 years, 123 of the 813 men, originally disease free, developed coronary disease. The investigators divided the cohort into two age strata (45 to 55 and 56 to 65). In neither age-group was there a statistically significant relationship between dietary cholesterol and incident coronary disease after adjustment for multiple confounders.
The Lipid Research Clinics Prevalence Follow-up Study included 4,546 men and women recruited from 1972 through 1976 [10]. At baseline, the study population provided a 24-hour dietary recall administered by trained nutritionists. Coronary heart disease mortality was tracked over 12 years of follow-up. In neither of the two age-strata examined (30 to 59 and 60 to 79) was dietary cholesterol significantly associated with risk of death after adjustment for energy intake and several risk factors for coronary heart disease.
The Nurses Health Study (NHS) and the Male Health Professionals Study, two large cohorts of health workers, have examined a number of issues related to diet and disease. Hu and colleagues [11] present data from the NHS based on the experience of 80,082 nurses followed for up to 14 years. Dietary data were derived from up to four food frequency questionnaires administered throughout the follow-up period during which 939 incident coronary cases were identified. After adjusting for many potential confounding factors, including energy intake, and saturated fat, polyunsaturated, mono-unsaturated and trans-saturated fat intake, dietary cholesterol was associated with an increase in coronary heart disease risk, but that increase was not statistically significant. Fiber was not considered in this analysis even though cereal fiber is associated with reduce disease risk in this population [16]. The Male Health Professionals study followed 43, 757 men for up to six years [12]. Diet was assessed similarly to the Nurses Health Study. During the follow-up period, 734 incident coronary events were ascertained. After adjusting for multiple risk factors, including dietary fat and fiber intake, there was no statistically significant relationship between dietary cholesterol intake and coronary risk. Ascherio and colleagues [12] present data that underscores the importance of adjusting for other dietary factors when considering the relationship between cholesterol and outcomes. The apparent relative risk associated with increased dietary cholesterol when neither fat nor fiber is accounted for is almost four times larger than it is after those factors are included in the statistical model (1.23 versus 1.06).
In summary, the epidemiologic data relating dietary cholesterol to coronary risk are consistent with a weak positive association with coronary risk. The observed associations are not strong and reached statistical significance in only two studies. There are a number of weaknesses in the literature. Several of the studies relied on 24-hour dietary recalls to characterize dietary cholesterol [5,9,10]. Because of high-level day-to-day intraindividual variation in cholesterol consumption, a single-recall would be expected to misclassify a considerable number of persons with respect to intake [17]. The effect of this misclassification would be to understate the actual association between cholesterol and coronary risk. While many of the studies adjusted for total energy intake [82], few adjusted for dietary saturated fat [7,11,12], and only one study accounted for fiber [12]. This study found a 6% increase in the risk of coronary heart disease associated with 200 mg/1000 kcal/day intake of dietary cholesterol.
| EGG CONSUMPTION AND CARDIOVASCULAR DISEASE |
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Studies examining the relationship between egg consumption and coronary heart disease are summarized in Table 2. Dawber and colleagues [19] examined the relationship between serum cholesterol and egg consumption among 912 male and female participants of the Framingham cohort from whom detailed diet histories were obtained. Those in the highest tertile of egg-consumption tended to be older and consume more energy. The most notable finding from this report is the complete lack of association between egg consumption and serum cholesterol levels. Men in the highest third of the egg intake distribution had identical serum cholesterol levels to men in the lowest third (235 mg/dL). Women eating fewer eggs (i.e., the first tertile) actually had slightly higher serum cholesterol levels than those at the highest intake level (245 versus 242 mg/dL). The length of follow-up was not reported, but 96 incident coronary events were ascertained in the men and 51 in the women. Those consuming more eggs were at slightly higher risk of coronary events, though the analysis did not account for any potential confounding factors, and the difference was not statistically significant.
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Between 1969 and 1972, the diet of 5,133 Finnish men and women 30 to 69 years of age was assessed [21]. Over the subsequent 12 to 16 years of follow-up, 186 of the men and 58 of the women died from coronary heart disease. After adjusting for age, those who died from coronary heart disease consumed similar amounts of egg as assessed at baseline compared to those surviving to the end of the study.
Studies of populations that include a large number of vegetarians are of special epidemiologic interest for studying diet-disease associations. In some populations there may be a narrow range of dietary intake which can inhibit the ability to demonstrate associations. Vegetarians are attractive because their patterns of intake differ considerably from non-vegetarians, and their inclusion can allow the evaluation of dietary exposures over a much greater range of intake. On the other hand, the vegetarian lifestyle may also be associated with a general level of health consciousness that may introduce confounding by non-dietary lifestyle factors. Two studies have looked at populations that included a large percentage of vegetarians. Fraser reported on the disease experience of 26,473 nondiabetic California Seventh-Day Adventists [22,23]. Thirty percent of the population reported eating no animal flesh whatsoever, an additional 21% were classified as semi-vegetarians, and 49% were classified as nonvegetarians. Over the six years of follow-up, cohort members consuming more than two eggs per week were at no different risk of incident heart disease than members consuming fewer than one egg per week (relative risk=1.01). Foods that appeared to be associated with increased coronary disease risk were beans, whole-milk and beef (among men only). Nuts and whole-wheat bread were inversely associated with risk. The Oxford Vegetarian Health Study [24] evaluated the relationship between food consumption and coronary heart disease risk in 10, 802 health conscious adults. The study volunteers were either vegetarians (54%) or non-vegetarian friends and relatives of the vegetarian participants (46%). The sample was followed for an average of 13.3 years during which time only 64 deaths from coronary disease were identified among those free of coronary disease at the outset of the study. After adjusting for age, gender, smoking and social class, foods that were associated with increased risk of coronary death were cheese, total animal fat and eggs. Those consuming six or more eggs per week were at significantly elevated risk of death compared to those consuming fewer than one egg per week (relative risk=2.68; 95% CI=1.196.02).
Only one study has set out explicitly to determine the relationship between egg consumption and cardiovascular disease risk. Hu and colleagues [25] specifically addressed the issue using data from the Nurses Health Study and the Male Health Professionals. The two cohorts have been introduced above. This report included 14 years of follow-up for the women and eight years of follow-up for the men. Because the study populations are large, the relationship between eggs and coronary heart disease could be examined over a wide range of intakes with good statistical precision. After adjusting for multiple confounders (see Table 2 for list), there was no association between egg consumption and incident coronary heart disease in either men or women. The study was large enough to examine the relationship between egg consumption and heart disease among those with low cholesterol intake from non-egg sources (less than 88.4 mg/1000 kcal for men, and 118.8 mg/1000 kcal for women). The relative risk associated with the consumption of more than one egg per day was 1.05 for the men and 0.97 for the women, compared to those consuming fewer than one egg per week. The authors considered a number of foods that could have potentially confounded the association. Only bacon qualified as a confounder and was included in the model. The primary analysis excluded participants with self-reported diabetes or hypercholesterolemia. In a secondary analysis in the diabetic sub-group, an association was found between egg consumption and heart disease risk in both men and women. Among diabetic men, the consumption of one or more eggs per day was associated with a twofold risk of heart disease (95% confidence interval, 1.03.87) compared to those consuming fewer than one egg per week. Among the diabetic women the relative risk was 1.49 (95% confidence interval: 0.882.52). The basis for this finding is unclear. It may be that diabetics are uniquely sensitive to the effects of dietary cholesterol. On the other hand, diagnosed diabetics are likely counseled to adopt a low cholesterol/low saturated fat diet because of their elevated risk for heart disease. Among diabetics, frequent egg consumption could mark non-compliance. In randomized trials non-compliant participants often have a worse disease experience compared to compliant participants even in the placebo group [26].
The epidemiologic evidence relating egg-consumption to coronary disease risk is not entirely consistent. Two of three large prospective cohort studies found no association between egg consumption and coronary risk, while one finds a rather substantial association [23,24,25]. Of the three, only one addressed confounding by other determinants of disease risk in any comprehensive fashion, and this study found no association [25]. Dietary recommendations to limit egg consumption often specify a specific number of eggs per week as an upper limit of intake. The data from Hu et al. [25] show no increase in risk at intakes up to an egg per day. The data from the Oxford Vegetarian study [24] show no significant increase in risk except for those consuming six or more eggs per week. But again, data from this study need to be interpreted with caution because a number of potentially important confounding factors were not considered. The findings of an association between egg consumption and heart disease risk among diabetics is intriguing and should be replicated.
The diet-heart hypothesis holds that a diet high in saturated fat and cholesterol and low in polyunsaturated fat leads to increased serum cholesterol levels which in turn promote the development of atherosclerosis. Eggs are of interest because, by virtue of their high cholesterol content, their consumption would be expected to raise serum cholesterol levels, a hypothesis that can be confirmed experimentally by adding eggs to an otherwise fixed diet. However, in the diets of free-living individuals, every egg consumed represents energy that is not consumed from some other source. Eggs contain less saturated fat than many other protein sources so there may be no effect on cholesterol levels when eggs are consumed in their place [27]. Hu and colleagues [25] found that frequent egg consumers consumed less energy as carbohydrates, a pattern that might lead to higher HDL cholesterol levels compared to infrequent egg eaters [28]. Whatever the exchanges may be, the data from Dawber et al. [19] suggest that the net effect leads to no differences in serum cholesterol levels.
| CONCLUSION |
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| FOOTNOTES |
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Dr. S.B. Kritchevsky is a member of the Scientific Advisory Panel of the American Egg Board/Egg Nutrition Center.
| REFERENCES |
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