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Dietary cholesterol does not increase biomarkers for chronic disease in a pediatric population from northern Mexico

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British Nutrition Foundation

Dietary cholesterol, eggs and coronary heart disease risk in perspective

A. Lee and B. Griffin
Centre for Nutrition & Food Safety, School of Biomedical & Molecular Sciences, University of Surrey, Guildford, Surrey, UK

Summary

The idea that dietary cholesterol increases risk of coronary heart disease (CHD) by turning into blood cholesterol is compelling in much the same way that fish oil improves arthritis by lubricating our joints! Dietary cholesterol, chiefly in the form of eggs, has long been outlawed as a causative agent in CHD through its association with serum cholesterol. However, the scientific evidence to support a role for dietary cholesterol in CHD is relatively insubstantial in comparison with the incontrovertible link between its circulating blood relative in low density lipoprotein (LDL) cholesterol and CHD. Interpretation of the relationship between dietary cholesterol and CHD has been repeatedly confounded by an often inseparable relationship between dietary cholesterol and saturated fat. It has also been exaggerated by the feeding of unphysiologically high intakes of eggs. Nonetheless, numerous studies have shown that dietary cholesterol can increase serum LDL-cholesterol, but the size of this effect is highly variable between individuals and, according to over 30 years of prospective epidemiology, has no clinically significant impact on CHD risk. Variation in response to dietary cholesterol is a real phenomenon and we can now identify nutrient–gene interactions that give rise to this variation through differences in cholesterol homeostasis. More importantly, to view eggs solely in terms of the effects of their dietary cholesterol on serum cholesterol is to ignore the potential benefits of egg consumption on coronary risk factors, including obesity, diabetes and metabolic syndrome. Cardiovascular risk in these conditions is largely independent of LDL-cholesterol.

These conditions are also relatively unresponsive to any LDL-cholesterol raising effects of dietary cholesterol. Treatment is focused primarily on weight loss, and it is in this respect that eggs may have a new and emerging role in facilitating weight loss through increased satiety.

Dispelling the mythology

A myth can be defined as a popular idea on a natural phenomenon. The popular idea in this context has always been that dietary cholesterol is equivalent to blood cholesterol; the natural phenomenon that raised blood cholesterol increases risk of CHD. While there is no longer debate over the role of cholesterol transported in LDL in CHD, the popular idea that dietary cholesterol increases CHD by increasing LDL prevails.

The Seven Countries Study was a landmark study in the history of nutritional medicine that founded what was to later become an unequivocal relationship between dietary saturated fat and serum LDL-cholesterol. It also led Keys and Hegsted (Hegsted et al . 1965; Keys et al . 1965) to formulate equations to predict how the relative amounts of dietary saturated and polyunsaturated fats and cholesterol in our diet influence serum cholesterol. While these equations have been reworked many times over the intervening years, the later addition and quantitative contribution of dietary cholesterol in the dietary formula has always been a contentious issue, not least between the two authors. Keys acknowledged in 1965 that while dietary cholesterol should not be ignored in advice to lower serum cholesterol, attention to this factor rather than to the nature of dietary fat would accomplish little.

The proposed relationship between dietary cholesterol and CHD is indirect and mediated through increased serum LDL-cholesterol. As eggs represent the richest source of dietary cholesterol in westernised diets, a single egg yolk containing from 50 to 250 mg of cholesterol depending on its size, they have been used exclusively as a vehicle for the delivery of dietary cholesterol in human interventions and as a marker of dietary cholesterol intake in prospective cohort studies.

The endpoints from these studies have provided two important types of information: one based on changes in serum cholesterol, and thus by inference CHD risk; the other on the power of association between egg consumption and the incidence of CHD death. Since the Department of Health's 1994 COMA report on nutritional aspects of cardiovascular disease, there has been no further reference to dietary cholesterol reduction and at present, the UK recommendations still remain at 245 mg of dietary cholesterol per day.

Does dietary cholesterol raise serum cholesterol?

A host of cross-sectional, prospective cohort and intervention studies in the 1970s and 80s fuelled debate on the potential of dietary cholesterol, chiefly in the form of eggs, to raise serum cholesterol and thus, increase CHD risk (Mann 2000). However, much of the prospective epidemiology was confounded by the fact that dietary cholesterol and saturated fat occur together in the diet so that their levels in the diet are highly correlated. It later transpired that, in many cases, the methods of dietary assessment were inadequate to accurately describe dietary intakes, and that the statistical techniques were of insufficient power to distinguish between the cholesterol-raising effects of saturated fat and cholesterol.

Moreover, the majority of early human interventions were conducted against a backdrop of a high saturated fat diet (low P : S ratio), and in most cases, compared dietary extremes and unphysiologically high intakes of dietary cholesterol (>400–1000 mg/day). Data from cholesterol-feeding in animals has been used with effect to support human studies. While it is all too easy to dismiss the findings from animal studies on the grounds that extrapolation to humans is unreliable, in this particular case, this argument may be well founded. Cholesterol-feeding in animals provides more information about the experimental toxicology of what, in dietary terms, is a foreign substance to an animal adapted to a high-carbohydrate diet. It is also difficult to ignore cross-species differences in susceptibility to coronary atherosclerosis which arise, in part, from differences in lipoprotein physiology and thus the transport of serum cholesterol in LDL and high density lipoprotein (HDL). While this is exemplified between species
that are highly susceptible or resistant to dietaryinduced atherosclerosis, such as the rabbit and the rat respectively, significant differences in lipoprotein physiology also exist between non-human primates and man.

Despite the practical and statistical shortcomings of early studies, a general consensus was reached that serum cholesterol increased on average by 0.01 mmol/L for every 100 mg of added dietary cholesterol (Hegsted 1986). This increase in total serum cholesterol included elevations in both LDL and the cardioprotective HDLcholesterol, it was usually evident against a background diet that was high in saturated fat (low P : S ratio <0.5) and appeared to be highly variable between different individuals.

Some of the most scientifically rigorous studies to address the effects of dietary cholesterol on serum cholesterol and lipoproteins were to follow in the 1990s. These included two separate studies in healthy young men (Ginsberg et al . 1994) and young women consuming an American Heart Association (AHA) Step 1 diet (30% of energy as fat; 9% of energy as saturated fat) (Ginsberg et al . 1995). In the first study, 20 young men Dietary cholesterol, eggs and CHD risk 23 consumed 0, 1, 2 and 4 eggs/day in a randomised, fourway cross-over design for 8 weeks. The study examined a range of lipoprotein responses, including an assessment of postprandial response to a high-fat test meal. While there was no effect of egg-feeding on postprandial response, there was an increase in total serum cholesterol (0.038 mmol/L per 100 mg of added dietary cholesterol), that was linear for both total and LDLcholesterol across intakes of dietary cholesterol ranging from 128 to 858 mg/day. Young women showed a greater increase in serum cholesterol in response to 0, 1 and 3 eggs/day in a three-way cross-over design for 8 weeks (0.073 mmol/L per 100 mg of added dietary cholesterol). The response was again linear for total, LDL- and HDL-cholesterol across intakes of dietary cholesterol of from 125 to 745 mg. There was a greater increase in LDL-cholesterol and less individual variation in women compared with men. In each of these studies, the background diet was believed to account for the increases in LDL-cholesterol being less than that previously reported by Keys and Hegsted (Hegsted et al . 1965; Keys et al . 1965). While the artificially high intakes of dietary cholesterol will no doubt have contributed to the statistical significance of the linear responses in LDL-cholesterol in both men and women, it is still difficult to refute the effects on LDL at lower dietary intakes and the variation in response. Similar findings were reported in hyperlipidaemic patients consuming an AHA Step 1 diet and either 2 eggs/day or a placebo for 12 weeks (Knopp et al . 1997). Hypercholesterolaemic patients showed a non-significant increase in LDL-cholesterol (+0.07 mmol/L), whereas patients with combined hyperlipidaemia (raised serum cholesterol and triglyceride) were more sensitive to dietary cholesterol (+0.3 mmol/L). Both groups showed significant increases in HDL-cholesterol. It may be concluded from these carefully conducted studies with a background diet low in total and saturated fat, that dietary cholesterol can raise total serum cholesterol by increasing both LDL- and HDL-cholesterol. This effect is evident at intakes of cholesterol of less than 400 mg/day, but the effects are small and any impact of increased LDL on CHD risk is potentially countered by increases in HDL. The effects of dietary cholesterol on the ratio of total to HDL-cholesterol, a discriminating marker of CHD risk, has been addressed in a meta-analysis (Weggemans et al . 2001). While dietary cholesterol was shown to increase this ratio, the interpretation of this result was complicated by the fact that the change in the ratio was a function of the component parts, i.e. LDL andHDL. This meant that dietary cholesterol appeared
to have the most detrimental effect on LDL in subjects with the lowest total cholesterol : HDL-cholesterol ratio and thus the lowest CHD risk, a finding that was unexpected and difficult to explain.

Does dietary cholesterol or egg consumption increase CHD risk?

Having concluded that dietary cholesterol can increase serum cholesterol, the next most important question to ask is whether this increase translates into a clinically relevant increase in CHD risk? Over 30 years of prospective epidemiological surveys of CHD risk have consistently
found no independent relationship between dietary cholesterol or egg consumption and CHD risk (McNamara 2000). A more recent study that examined data from two prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study, totalling over 1 million subjects (Hu et al . 1999), could find no significant difference in cardiovascular risk between groups consuming less than one egg per day and those consuming more than one egg per day. It can therefore be concluded that dietary cholesterol, chiefly in the form of eggs, does not contribute to CHD risk. Since variation in the LDL response to dietary cholesterol may provide valuable insight into the relationship between dietary fat and CHD, and increase the potential to optimise diets for individualised nutritional health, much attention has focused on the underlying molecular basis for this phenomenon. Metabolic and genetic origins of variation in lipid response to dietary cholesterol Katan and Beynen (1983) were the first to report hyperand hypo-responsiveness to dietary cholesterol in humans. This variation was later confirmed by the same authors in response to extreme contrasts of dietary cholesterol intakes (625–989 mg/day) in relatively small groups of subjects (Beynen & Katan 1985; Katan et al . 1986). Further study of this phenomenon in a much larger group of normo- and hyper-lipidaemic subjects consuming a low saturated fat, high-fibre diet and physiologically relevant intakes of dietary cholesterol [first 2 and then 7 eggs per week (100–300 mg/day) for 4 months] could find no significant difference in serum cholesterol between the two treatments, but did identify a subgroup of 58 individuals with a mean increase in LDL-cholesterol of more than 5% (Edington et al . 1987). In a second phase of this experiment, this subgroup was re-examined on higher intakes of dietary cholesterol (no eggs and then 9 eggs per week: 100–400 mg of cholesterol/day) for a further 3 months, but once again, showed no significant increase in LDL-cholesterol (Edington et al . 1989). It was concluded that physiological intakes of dietary cholesterol in combination with a standard cholesterol-lowering diet, produce only small effects on serum cholesterol that are of negligible clinical relevance.

There was also no consistent evidence of hyper- and hypo-responsiveness to dietary cholesterol as had been previously shown under more extreme dietary conditions. Nevertheless, around 20–30% of subjects studied are commonly reported to show increased responsiveness to dietary cholesterol. This finding is not unexpected, especially in view of our increased understanding of how nutrient–gene interactions influence cholesterol homeostasis.

Effects of dietary cholesterol on cholesterol homeostasis The discovery, by Goldstein and Brown (1986), of the mechanism by which cells regulate their content of cholesterol and thus, inadvertently, regulate blood cholesterol levels via the LDL-receptor pathway, revolutionised our understanding of cholesterol homeostasis. It also unfortunately spawned a number of extreme human and animal studies designed to test how dietary constituents, including eggs, increase LDL-cholesterol by suppressing the activity of this pathway.

Cells regulate their intracellular pool of cholesterol by switching on the production of LDL receptors that migrate to the surface of cells and can then extract cholesterol from the blood in the form of LDL, and/or by increasing their own production of cholesterol. The cholesterol content in cells is also significantly influenced by the amounts of dietary and biliary cholesterol that are actively reabsorbed and excreted back into the intestinal lumen by an interplay between cholesterol transporters and cholesterol efflux proteins. Cells meet their requirements
for cholesterol by adjusting the uptake of serum LDL-cholesterol and cholesterol absorption from the intestine or by increasing cholesterol biosynthesis. Cholesterol absorption and the uptake of LDL are inversely related to rates of cholesterol biosynthesis so that cells receiving increased delivery of cholesterol from these two sources synthesise less of their own cholesterol.

Both the receptor-mediated uptake of LDL-cholesterol and cholesterol absorption are also highly sensitive to changes in dietary fat, notably saturated fat, and dietary cholesterol. As a good example of a nutrient–gene interaction, high intakes of dietary cholesterol can downregulate the LDL-receptor gene, suppress the production of LDL receptors and in doing so, raise LDL-cholesterol.

However, over a physiological range of dietary cholesterol intakes, the body compensates for this effect by decreasing the amount of dietary cholesterol that is absorbed in the intestine (Ostlund et al . 1999). Variation in the sensitivity of this compensatory reduction in cholesterol absorption is believed to account for much of the inter-individual variation seen in response to increased dietary cholesterol. Likewise, variation in the sensitivity of the LDL-receptor pathway is potentially another source of variance in response to dietary cholesterol and, more importantly, saturated fat. The best working examples of how these pathways operate are provided by the actions of LDL-lowering drugs such as the statins and blockers of cholesterol absorption such as ezetamibe, both of which result in an up-regulation of LDL-receptor activity but by inhibiting cholesterol biosynthesis and cholesterol absorption, respectively.

Dietary-induced changes that are analogous to the effects of statins and cholesterol absorption blocking drugs would be to substitute dietary saturated fats with poly- or mono-unsaturated fats and to impair cholesterol absorption in the intestine with plant sterols, respectively. Influence of genetic variation on the responsiveness to dietary cholesterol. There are a number of common polymorphic genes that code for key regulatory proteins in cholesterol metabolism that may explain variation in inter-individual response to dietary cholesterol. The most notable of these is the gene for apoprotein E (Apo E), a protein found on the surface of lipoproteins that facilitates the binding and uptake of cholesterol-carrying lipoproteins. Apo E exists in different protein isoforms (E4, E3, E2) that differ in their amino acid composition and which express variable affinity for the LDL and remnant receptors in the order of E4 > E3 > E2. As apo E4 binds with higher affinity to these receptors, it effectively overdelivers cholesterol to cells. In theory, this produces a relative suppression of the production of LDL receptors, resulting in higher serum LDL-cholesterol in individuals expressing apo E4 (approximately 10–15% of the UK population). In addition, cholesterol absorption is upregulated in the intestine so that apo E4 carriers tend to be high absorbers of dietary and biliary cholesterol, but have lower rates of endogenous cholesterol synthesis in cells (Kesaniemi et al . 1987). As a direct consequence, carriage of an apo E4 allele tends to increase responsiveness to changes in dietary cholesterol (Sarkinen et al . 1998). Another potential source of genetic variation that may contribute to variation in response to dietary cholesterol through differences in cholesterol absorption is via polymorphisms in proteins in the intestine known as ATP-binding cassette (ABC) cholesterol efflux proteins. Up-regulation of cholesterol excretion back into the intestine via these efflux proteins forms an important part of the mechanism that compensates for increased dietary cholesterol. Mice in which the gene for this protein has been deleted (ABC-1 knock-out mice) lose the ability to compensate for increased dietary cholesterol and as a result, show significant increases in serum cholesterol compared with controls (McNeish et al . 2000).
Similarly, in humans, a common genetic polymorphism coding for an efflux protein known as ABCG5-gene (G/ G variant) has been associated with reduced cholesterol excretion and increased responsiveness to dietary cholesterol (Weggemans et al . 2002).

Dietary cholesterol and eggs in perspective of other coronary risk factors

Another possible explanation for why dietary cholesterol cannot be independently associated with CHD is that the relationship is mediated through a single risk factor, LDL-cholesterol. Multiple layers of evidence exist to support the relationship between a raised LDL cholesterol and CHD, but dietary-induced changes in LDL-cholesterol have never provided an adequate explanation for the relationship between diet and CHD, perhaps because LDL-cholesterol has limited power to discriminate CHD risk within populations. It should be appreciated that LDL is just one risk factor of many that contribute to the multi-factorial aetiology of cardiovascular disease. A much more prevalent source of attributable cardiovascular risk in the UK population comes from the heterogeneous clustering of metabolic complications associated with obesity, diabetes and the metabolic syndrome (Kahn et al . 2005). The pro-atherogenic features, including dyslipidaemia (raised triglycerides, low HDL), hypertension, hyperglycaemia and proinflammatory and pro-thrombotic tendencies, arise from insulin resistance and in combination exert multiplicative effects on coronary risk that are largely independent of LDL-cholesterol. Dietary strategies to treat this risk focus on the treatment of the individual. Since fat is the most energy-dense macronutrient, its removal is fundamental to this approach.

However, there is now evidence to suggest that dietary cholesterol and eggs have a significantly reduced impact on serum LDL-cholesterol in insulin-resistant states, and may even facilitate weight loss through mechanisms of satiety. Beynen and Katan (1983) found greater LDLlowering in response to the removal of dietary cholesterol (eggs) in individuals with lower body mass index and high HDL-cholesterol. Reaven studied the effects of egg-feeding in 31 women with insulin resistance compared with 34 insulin-sensitive women (Reaven et al. 2001). The expectation at the outset of this study was that the insulin-resistant group would be more responsive to dietary cholesterol, but no significant effect on LDL-cholesterol could be shown, irrespective of insulin sensitivity, over a wide range of dietary intakes (up to 800 mg/day) (Reaven et al . 2001). Knopp et al . (2003) re-examined the interrelationships between insulin resistance, obesity and egg-feeding and found that while insulin resistance was associated with a moderately raised LDL-cholesterol at baseline, this must be for some inherent metabolic reason, as this group showed significantly lower increases in LDL-cholesterol in response to egg-feeding compared with the insulinsensitive subjects, irrespective of obesity status.

Insulin-resistant and obese subjects have been shown to express higher rates of cholesterol biosynthesis and lower levels of cholesterol absorption in comparison with lean, insulin-sensitive subjects (Berglund & Hyson 2003). In theory, these effects could arise as a consequence of the failure of insulin to stimulate the LDLreceptor pathway followed by a knock-on effect of increased cholesterol synthesis, which would be to inhibit cholesterol absorption in the intestine. Whatever the mechanism, the diminished effect of dietary cholesterol from eggs on serum LDL in this group has implications for the emerging role of eggs in the promotion of weight loss in this group.

Potential role of eggs in promoting weight loss

Weight-loss programmes, like many of the willing participants, come in all shapes and sizes. One of the most popular practices is that of a low-carbohydrate, high-fat diet that invariably leads to a raised intake of dietary cholesterol through the increased consumption of eggs and meat. While the long-term safety of these diets, that exclude important food groups, is still questionable, they are without doubt successful in promoting weight loss at least in the short-term. They also exert either no effect or potentially favourable effects on serum LDL-cholesterol
and triglycerides (Foster et al . 2003; Samaha et al . 2003). The explanation for the weight loss lies in the fact that the dieters achieve an energy deficit by simply eating less. This is most likely to occur through a combination of reduced food choice and increased satiety. Dietary protein has long been identified as the macronutrient most closely associated with satiety. Eggs, as a rich source of high-quality protein that is low in energy, fulfil this criterion very well. Eggs have been shown to have a 50% greater satiety index as compared with ready-to-eat breakfast cereals and white bread (Holt et al . 1995), and have been shown to have an overall higher satiety value than common breakfast foods in non-obese subjects (Holt et al . 2001). While the short- and longer-term efficacy of eggs in promoting weight loss has yet to be established, evidence is beginning to emerge that they may offer a viable means of sustaining an energy deficit in overweight and obese subjects (Vander Wal et al . 2005).

While it is certainly not the intention here to advocate the use of extreme diets to promote weight loss, eggs are a nutritious food that would seem appropriate for assisting weight loss in an exponentially growing proportion of the free-living population at increased CHD risk (Herron & Fernandez 2004).

Conclusion

Dietary cholesterol has been shown to produce small increases in serum LDL-cholesterol, but it should be stressed that this effect does not translate into increased CHD risk. The prevention of CHD continues to be a major public health issue in the UK population, but preventative strategies must focus on obesity, diabetes and metabolic syndrome as the most prevalent sources of increased risk. In view of the overriding importance of weight loss in reducing risk from these conditions, and evidence to suggest that people with insulin resistance are unresponsive to dietary cholesterol, the moderate consumption of eggs (1–2 eggs per day) should be actively encouraged as part of an energy-restricted, weight-losing dietary regimen. There will always be some degree of public confusion about the difference between the cholesterol that we eat and that which circulates in our blood. Take for example, the body builder eating ten eggs a day who claimed to have no fear of dietary cholesterol because he only ever eats high-density cholesterol. Unfortunately, things are not always that simple!

References

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348 : 2082–90. Ginsberg HN, Karmally W, Siddiqui M et al. (1994) A dose–response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men. Arteriosclerosis, Thrombosis and Vascular Biology 14 : 576–86. Ginsberg HN, Karmally W, Siddiqui M et al. (1995)

Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women.

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(1999) A prospective study of egg consumption and risk of cardiovascular disease in men and women. Journal of the American Medical Association 281 : 1387–94.

Kahn R, Buse J, Ferrannini E et al. (2005) The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 48 : 1684–99. Katan MB & Beynen AC (1983) Hyper-response to dietary cholesterol in man. Lancet 1 : 1213. Katan MB, Beynen AC, de Vries JH et al. (1986) Existence of consistent hypo- and hyper-responders to dietary cholesterol in man.

American Journal of Epidemiology 123 : 221–34. Kesaniemi YA, Enholm C & Miettinen TA (1987) Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype. Journal of Clinical Investigation 80 : 578–81. Keys A, Anderson JT & Grande F (1965) Serum cholesterol response to changes in diet. II. The effects of cholesterol in the diet. Metabolism 14 : 759–65. Knopp RH, Retzlaff BM, Walden CE et al. (1997) A double-blind, randomized, controlled trial of two eggs per day in moderately Dietary cholesterol, eggs and CHD risk hypercholesterolemic and combined hyperlipidemic subjects taught the NCEP step I diet. Journal of the American College of Nutrition 16: 551–61. Knopp RH, Retzlaff BM, Fish B et al. (2003) Effects of insulin resistance and obesity on lipoproteins and sensitivity to egg feeding. Arteriosclerosis, Thrombosis and Vascular Biology 23: 1437–43.

McNamara DJ (2000) Dietary cholesterol and atherosclerosis. Biochimica et Biophysica Acta 1529: 310–20. Mann J (2000) Dietary cholesterol: a review of research and practice over 30 years. In: Dietary Cholesterol as a Cardiac Risk Factor; Myth or Reality (AR Leeds & J Gray eds), pp. 000–00. Smith- Gordon: London.

McNeish J, Aiello RJ & Guyot D et al. (2000) High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proceedings of the National Academy of Sciences USA 97: 4245–50.

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Vander Wal JS, Marth JM, Khosla P et al. (2005) Short-term effect of eggs on satiety in overweight and obese subjects. Journal of the American College of Nutrition 24: 510–5.

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Eggs and Heart Disease:

A Failed Hypothesis

Donald J. McNamara, Ph.D.
Eggs for Health Consulting
Washington, DC
United States of American
d.j.mcnamara@comcast.net

Abstract

The hypothesis that dietary cholesterol raises blood cholesterol levels and thereby heart disease risk has been tried and tested for over forty years, and consistently shown to be null. Evidence from epidemiological surveys, prospective studies, and clinical trials time and again indicate that eggs and dietary cholesterol have no significant relationship to hypercholesterolemia or cardiovascular disease risk. Recent studies have even shown that components within eggs, choline and lutein, actually help lower cardiovascular disease risk as well as making important contributions to the nutritional well-being of the public. In contrast to the United States, many countries have no dietary cholesterol restrictions and inclusion of eggs is advocated by health promotion organizations for their many contributions to health promotion and disease prevention. The eggs and heart disease hypothesis has failed the test of time and should be considered null and void.

History of a Hypothesis

In 1968 the American Heart Association added to its dietary recommendations for those at high
risk for heart disease a restriction in dietary cholesterol to less than 300 mg per day,c and a specific restriction on egg consumption to no more than 3 whole eggs per week. Two points are of interest in that there was no scientific justification for selecting 300 mg per day as the limit (other than the average intake was 580 mg per day) and this was the only food specific restriction in the set of recommendations. Understandably it was difficult in 1968 to discuss total and saturated fat since consumers had little knowledge on this issue and the much simpler expressed relationship of cholesterol in food equals cholesterol in the blood would involve animal products in the diet which were the sources of dietary saturated fat. Except for the egg which, while high in cholesterol, contains a relatively modest 1.5 grams of saturated fat per 50 gram egg. One of the consequences of this focus on dietary cholesterol and eggs was that the egg became the icon for both high dietary cholesterol and high blood cholesterol and, even if the evidence was weak for a relationship, the message was simple and easily conveyed by health professionals not only to their high risk patients but to the public at large. The justification for the focus on dietary cholesterol came from three lines of research evidence– animal studies, epidemiological surveys, and clinical investigations. All of these have their strengths and weaknesses and interpretation plays a major role in how the evidence is used to set recommendations. For example, feeding cholesterol to a herbivore species like the rabbit results in pronounced hypercholesterolemia and development of atherosclerosis. In contrast, feeding cholesterol to an omnivore or carnivore species, like the dog or rat, has little effect on any of these end points. There is also the question of dosage in that feeding pharmacological levels of cholesterol to a primate species can result in hypercholesterolemia simply due to the animal's inability to metabolically compensate for such massive doses (a human equivalent of 3,500 mg/day). Similar complications are seen in the early cholesterol feeding studies where subjects are fed 1,000 to 3,000 mg per day to induce a change in plasma cholesterol levels even though the body's endogenous cholesterol production is only 850 mg per day for a 70 kg adult. The body's metabolic regulatory systems were simply overwhelmed by the excess dose. And much of the epidemiological evidence was based on simple correlations between dietary cholesterol intakes and heart disease incidence with no correction for the fact that dietary cholesterol and saturated fat, also found by simple correlation analysis to be related to heart disease risk, were correlated with each other. Even though these various arguments were raised during the discussions of recommending dietary cholesterol restrictions, it was judged that no harm would be done and some benefit might accrue. A best guess became a recommendation and today is viewed as recommendation based on sound scientific evidence. As once noted by H.L. Menckin: "For every problem, there is a solution that is simple, neat, and wrong."

The Great Tragedy of Science - The Slaying of A Beautiful Hypothesis By An Ugly Fact. (T.H. Buxley)

Once the dietary cholesterol and egg restrictions became part of the "Prudent Diet" approach to heart disease prevention there was little scientific or research room for argument or questioning of the policy. There were a number of outspoken critics of the dietary cholesterol and egg guidelines but for the most part the naysayers were marginalized and discounted (for a complete history of the diet-heart disease battles read Good Calories, Bad Calories by Gary Taubes (Taubes, 2007). For many skeptics in the scientific community the application of reverse onus (now it needed to be proven that eggs did not cause heart disease) was an insurmountable obstacle and was set aside in favor of more achievable objectives. It has taken forty years of research to begin to undo the effects of those early condemnations and the cholesterol-phobia much of the world suffered from.

The undoing of this hypothesis came about from both advances in our understanding of the
intricacies involved in the diet-heart disease relationship and progress in research defining more precisely lipoprotein risk factors for heart disease and how they were affected by dietary factors. As in all studies of the relationships between diet and health, three lines of evidence were used to test the dietary cholesterol-heart disease relationship: animal model studies, analysis of epidemiological survey data, and clinical interventions. All three lines of evidence, used initially to formulate the hypothesis, failed to validate the hypothesis over time.

A Hypothesis Based on a Best Guess

Animal Model Studies: Feeding cholesterol to rabbitts results in pronounced dyslipidemia and the development of atherosclerosis(Anitschkow and Chalatow, 1913). Feeding cholesterol to a dog or rat has little if any effect on plasma cholesterol levels. To develop hypercholesterolemia in some primate species it is necessary to feed the human dietary cholesterol equivalent of 3,000 mg per day. The majority of animal species, when fed a physiological amount of cholesterol in the diet, have little change in their plasma cholesterol profile due to appropriate metabolic feedback mechanisms. When cholesterol is fed, endogenous cholesterol synthesis is suppressed and bile acid synthesis and excretion is increased (Dietschy, 1984). These compensatory mechanisms are sufficient to maintain a steady state level of plasma cholesterol with no change in atherosclerotic risk. The quandary becomes which animal model best mimics the human condition. Many investigators would contend that probably no animal model best mimics the human response to dietary cholesterol for a number of reasons: differences in the plasma lipoprotein profile and the factors involved in lipoprotein remodeling, and differences in the tissue distribution of endogenous cholesterol synthesis and sterol excretion patterns being two major considerations, as well as species differences in the response to dietary factors (Fernandez, 2001; Fernandez et al., 1999).

Analysis of Epidemiological Survey Data: In 1968 the use of simple correlation analyses showd
that both dietary cholesterol and dietary saturated fat were related to elevated plasma cholesterol levels and heart disease risk. Unfortunately, since both are found in animal products, they are significantly related to each other. Analysis of epidemiological survey data using multivariant analysis indicated that while saturated fat was independently related to heart disease risk, the significant relationship for dietary cholesterol was lost once the covariance with saturated fat was accounted for (Hegsted and Ausman, 1988; Kromhout et al., 1995). As noted by Ravnskov (Ravnskov, 1995), in eleven reports from prospective and retrospective epidemiological studies there was no differences in dietary cholesterol intakes between cases and controls. And when applied to eggs, which have a high cholesterol content but are relatively low in saturated fat, there was no significant relationship between egg intake and heart disease risk. Across cultures there is no significant relationship between per capita egg intake and cardiovascular disease mortality rates (Lee and Griffin, 2006; McNamara, 2000a).

A number of studies have looked specifically at the relationship between egg consumption and
either plasma cholesterol levels or heart disease risk (Dawber et al., 1982; Hu et al., 1999; Nakamura et al., 2006; Qureshi et al., 2007; Song and Kerver, 2000; Tillotson et al., 1997). These studies have consistently shown that egg intake is unrelated to either plasma cholesterol levels or to heart disease risk (Kritchevsky, 2004; Kritchevsky and Kritchevsky, 2000). In these studies, the relative risk for coronary heart disease was the same whether one ate one egg a week or one egg a day. These findings are consistent with the body of epidemiological analysis reporting that dietary cholesterol is unrelated to heart disease risk within populations (Lee and Griffin, 2006; McNamara, 2000a, 1999). Recent studies investigating the effects of dietary lipids on subclincal atherosclerosis have also reported the absence of a relationship between dietary cholesterol intakes and mean carotid intimal medial thickness (Merchant et al., 2008).

Clinical Interventions: In the early days of metabolic ward studies on the effects of dietary factors on plasma cholesterol levels, patients were often fed liquid formula diets to have precise control over the composition of the dietary fat and the amount of dietary cholesterol.

Unfortunately, in many cases this led to dietary cholesterol challenges not with physiological levels but with pharmacological levels of 1,000 to 4,000 mg per day added to liquid diets with 40% of calories as coconut oil. Once the endogenous cholesterol metabolic capacity was overwhelmed, there was obviously an increase in plasma cholesterol levels as the body attempted to excrete the excess (McNamara, 1987; McNamara, 1990). In addition, virtually all of the 3 earlier studies used to justify the dietary cholesterol restriction used total plasma cholesterol levels as the surrogate marker for assumed changes in heart disease risk.

As the pattern of research studies shifted from formula feeding to solid foods and more rational
cholesterol intakes, and the variables shifted from total to lipoprotein cholesterol levels, the evidence supporting the atherogenicity of dietary cholesterol began to progressively weaken. However, a consistent finding from study after study was the high degree of variability of the plasma cholesterol responses to a dietary cholesterol challenge between patients. In order to explain this variability it is necessary to consider the inter-individual differences in cholesterol metabolism.

Cholesterol synthesis is a function of body weight, approximately 12 mg/kg-day. Therefore, changes in plasma cholesterol with the same dietary cholesterol challenge will differ for individuals having different body weights. Studies also indicate that the fractional absorption rate for cholesterol is highly variable, ranging from 20 to 80%, with an average of 55% (McNamara, 1987). Based on these considerations, it is easy to understand why feeding an additional 500 mg per of cholesterol to a 100 kg male with a fractional absorption rate of 20% will have a very different effect on plasma cholesterol levels as compared to the same dietary cholesterol challenge to a 50 kg female with an absorption rate of 80%. Only a limited number of cholesterol feeding studies have adjusted for differences in body weights and fractional absorption rates between patients (McNamara et al., 1987). Numerous analyses have shown that the average weight adjusted plasma cholesterol response to a 100 mg/day increase in dietary cholesterol in a 70 kg individual is an increase in plasma total cholesterol of 2.4 mg/dl (0.062 mmol/L) with increases in both the LDL cholesterol (1.9 mg/dl, 0.049 mmol/L) and HDL cholesterol (0.4 mg/dl, 0.010 mmol/L) (Clarke et al., 1997; Howell, 1998; McNamara, 2000b; McNamara, 1990; Weggemans et al., 2001). These studies indicate that, while adding cholesterol does have a small effect on plasma cholesterol levels, there is little if any change in the LDL:HDL cholesterol ratio, an important determinant of cardiovascular disease risk (Fernandez and Webb, 2008; Herron et al., 2002; Herron et al., 2003). Data also indicate that changes in LDL cholesterol levels are not due to changes in the number of LDL particles but rather due to changes in the cholesterol content of the LDL particles resulting in less atherogenic large, buoyant LDLs (Herron et al., 2004) rather than the more atherogenic small, dense LDL particles (Williams et al., 2003). With little effect on the LDL:HDL cholesterol ratio (Fernandez, 2006; Herron and Fernandez, 2004) or on LDL particle number (Hsia et al., 2008), dietary cholesterol has little effect on cardiovascular disease risk, as documented by the various epidemiological survey analyses (Kritchevsky, 2004; Kritchevsky and Kritchevsky, 2000).

Do No Harm

Restrictions of high quality, nutrient rich foods like eggs from the diet because of their cholesterol content is not risk free. An affordable source of high quality animal protein in the diet, especially a source that is widely available and easy to cook, chew and digest is of significant importance for growth and development as well as maintaining lean muscle tissue mass in the elderly (Houston et al., 2008). Eggs are also an excellent source of the essential nutrient choline (Zeisel, 2006) which has been shown to be inadequate in the diets of 9 out of 10 individuals. Choline plays an important role in fetal and neonatal brain development (Zeisel and 4 Niculescu, 2006) and inadequate choline intake during pregnancy increases the risk for neural tube defects such as spina bifida (Shaw et al., 2004). Choline is also related to decreased levels of plasma inflammatory factors and homocysteine which are related to increase cardiovascular disease risk (Detopoulou et al., 2008; Konstantinova et al., 2007). Eggs also provide highly bioavailable forms of the xanthophylls lutein and zeaxanthin which are related to lower risks for age-related macular degeneration and cataracts (Chung et al., 2004; Goodrow et al., 2006; Ribaya-Mercado and Blumberg, 2004; Wenzel et al., 2006) as well as some types of cancer (Huang et al., 2007; Mannisto et al., 2007; Slattery et al., 2000) and carotid artery atherosclerosis (Dwyer et al., 2001). Restricting eggs in the diet can have negative consequences and, based on the available data, little benefit in terms of cardiovascular disease risk reduction. It is essential that any food's value to health promotion – disease prevention be based on its totality of nutrients and not just a single component.

Summary

For over forty years the scientific community has debated the dietary cholesterol – blood cholesterol relationship and the rationale for restricting high cholesterol foods, like eggs, in the
diet. What the epidemiological surveys show is that there is no relationship between dietary cholesterol intakes and either blood cholesterol levels or cardiovascular disease risk between or within populations. The only group found to have an increased cardiovascular disease risk with increased egg intake are those with type II diabetes (Hu et al., 1999; Qureshi et al., 2007); however, this may relate to the degree of diabetic control in the study population. Until this question is resolved there is justification in recommending that patients with type II diabetes limit their egg intake to less than 6 per week based on the available data.

Clinical studies form the basis of continued dietary cholesterol restrictions in some populations based on dietary cholesterol induced changes in total cholesterol levels. This change does not reflect change in cardiovascular disease risk when considered in light of the lack of effect of dietary cholesterol on the LDL:HDL cholesterol ratio (Fernandez and Webb, 2008) or on the number of LDL particles (Hsia et al., 2008). There is no conflict between the observed lack of effect of dietary cholesterol on cardiovascular disease risk observed in epidemiological surveys and the small change in plasma cholesterol levels observed in clinical feeding studies when the specific effects of dietary cholesterol on the atherogenicity of the plasma lipids is fully analyzed.

The lack of evidence for a relationship between dietary cholesterol and heart disease risk is why most countries of the world do not specifically recommend dietary cholesterol restrictions. In fact, in Canada and Australia eggs carry the approval marking of their respective heart associations. Given the available evidence, it would seem that the only health risk associated with egg consumption is that associated with unnecessary restrictions on egg intake.

References

5 Anitschkow, N., and S. Chalatow. 1913. Ueber experimentelle cholesterinsteatose und ihre bedeutung fur die entstehung einiger pathologischer prozesse. Zentralbl Allg Pathol Anat 24: 1-9. Chung, H. Y., H. M. Rasmussen, and E. J. Johnson. 2004. Lutein bioavailability is higher from lutein-enriched eggs than from supplements and spinach in men. J Nutr 134: 1887-1893.

Clarke, R., C. Frost, R. Collins, P. Appleby, and R. Peto. 1997. Dietary lipids and blood cholesterol: Quantitative meta-analysis of metabolic ward studies. Bmj 314: 112-117.

Dawber, T. R., R. J. Nickerson, F. N. Brand, and J. Pool. 1982. Eggs, serum cholesterol, and coronary heart disease. Am J Clin Nutr 36: 617-625.

Detopoulou, P., D. B. Panagiotakos, S. Antonopoulou, C. Pitsavos, and C. Stefanadis. 2008. Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: The attica study. Am J Clin Nutr 87: 424-430.

Dietschy, J. M. 1984. Regulation of cholesterol metabolism in man and in other species. Klin Wochenschr 62: 338-345.

Dwyer, J. H. et al. 2001. Oxygenated carotenoid lutein and progression of early atherosclerosis: The los angeles atherosclerosis study. Circulation 103: 2922-2927.

Fernandez, M. L. 2001. Guinea pigs as models for cholesterol and lipoprotein metabolism. J Nutr 131: 10-20.

Fernandez, M. L. 2006. Dietary cholesterol provided by eggs and plasma lipoproteins in healthy populations. Curr Opin Clin Nutr Metab Care 9: 8-12.

Fernandez, M. L., and D. Webb. 2008. The ldl to hdl cholesterol ratio as a valuable tool to evaluate coronary heart disease risk No. 27. p 1-5.

Fernandez, M. L., T. A. Wilson, K. Conde, M. Vergara-Jimenez, and R. J. Nicolosi. 1999. Hamsters and guinea pigs differ in their plasma lipoprotein cholesterol distribution when fed diets varying in animal protein, soluble fiber, or cholesterol content. J Nutr 129: 1323-1332.

Goodrow, E. F. et al. 2006. Consumption of one egg per day increases serum lutein and zeaxanthin concentrations in older adults without altering serum lipid and lipoprotein cholesterol concentrations. J Nutr 136: 2519-2524.

Hegsted, D. M., and L. M. Ausman. 1988. Diet, alcohol and coronary heart disease in men. J Nutr 118: 1184-1189.

Herron, K. L., and M. L. Fernandez. 2004. Are the current dietary guidelines regarding egg consumption appropriate? J Nutr 134: 187-190.

Herron, K. L., I. E. Lofgren, M. Sharman, J. S. Volek, and M. L. Fernandez. 2004. High intake of cholesterol results in less atherogenic low-density lipoprotein particles in men and women independent of response classification. Metabolism 53: 823-830.

6 Herron, K. L. et al. 2002. Pre-menopausal women, classified as hypo- or hyperresponders, do not alter their ldl/hdl ratio following a high dietary cholesterol challenge. J Am Coll Nutr 21: 250-258.

Herron, K. L. et al. 2003. Men classified as hypo- or hyperresponders to dietary cholesterol feeding exhibit differences in lipoprotein metabolism. J Nutr 133: 1036-1042.

Houston, D. K. et al. 2008. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: The health, aging, and body composition (health abc) study. Am J Clin Nutr 87: 150-155.

Howell, W. H. 1998. Dietary cholesterol, serum cholesterol, and risks of cardiovascular and noncardiovascular diseases - reply. Am J Clin Nutr 67: 490-491.

Hsia, J. et al. 2008. Lipoprotein particle concentrations may explain the absence of coronary protection in the women's health initiative hormone trials. Arterioscler Thromb Vasc Biol 28: 1666-1671.

Hu, F. B. et al. 1999. A prospective study of egg consumption and risk of cardiovascular disease in men and women. JAMA 281: 1387-1394.

Huang, J. P., M. Zhang, C. D. Holman, and X. Xie. 2007. Dietary carotenoids and risk of breast cancer in chinese women. Asia Pac J Clin Nutr 16 Suppl 1: 437-442.

Konstantinova, S. V. et al. 2007. Dietary predictors of plasma total homocysteine in the hordaland homocysteine study. Br J Nutr 98: 201- 210.

Kritchevsky, S. B. 2004. A review of scientific research and recommendations regarding eggs. J Am Coll Nutr 23(6): 596S-600S.

Kritchevsky, S. B., and D. Kritchevsky. 2000. Egg consumption and coronary heart disease: An epidemiologic overview. J Am Coll Nutr 19: 549S- 555S.

Kromhout, D. et al. 1995. Dietary saturated and trans fatty acids and cholesterol and 25-year mortality from coronary heart disease: The seven countries study. Prev Med 24: 308-315.

Lee, A., and B. Griffin. 2006. Dietary cholesterol, eggs and coronary heart disease risk in perspective. British Nutrition Foundation Nutrition Bulletin 31: 21-27.

Mannisto, S. et al. 2007. Dietary carotenoids and risk of colorectal cancer in a pooled analysis of 11 cohort studies. Am J Epidemiol 165: 246-255.

McNamara, D. J. 1987. Effects of fat-modified diets on cholesterol and lipoprotein metabolism. Annu Rev Nutr 7: 273-290. McNamara, D. J. 1990. Relationship between blood and dietary cholesterol. Adv Meat Res 6: 63-87. McNamara, D. J. 1999. Eggs, dietary cholesterol & heart disease risk: An international perspective. In: J. S. Sim, S. Nakai and W. Guenter (eds.) Egg nutrition and biotechnology. p 55-63. CABI Publishing, New York.

7 McNamara, D. J. 2000a. Dietary cholesterol and atherosclerosis. Biochim Biophys Acta 1529: 310-320. McNamara, D. J. 2000b. The impact of egg limitations on coronary heart disease risk: Do the numbers add up? J Am Coll Nutr 19: 540S-548S.

McNamara, D. J. et al. 1987. Heterogeneity of cholesterol homeostasis in man. Response to changes in dietary fat quality and cholesterol quantity. J Clin Invest 79: 1729-1739.

Merchant, A. T. et al. 2008. Interrelation of saturated fat, trans fat, alcohol intake, and subclinical atherosclerosis. Am J Clin Nutr 87: 168-174.

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Qureshi, A. I. et al. 2007. Regular egg consumption does not increase the risk of stroke and cardiovascular diseases. Med Sci Monit 13: CR1-8. Ravnskov, U. 1995. Quotation bias in reviews of the diet-heart idea. J Clin Epidemiol 48: 713-719.

Ribaya-Mercado, J. D., and J. B. Blumberg. 2004. Lutein and zeaxanthin and their potential roles in disease prevention. J Am Coll Nutr 23: 567S- 587S.

Shaw, G. M., S. L. Carmichael, W. Yang, S. Selvin, and D. M. Schaffer. 2004.

Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol 160: 102-109.

Slattery, M. L. et al. 2000. Carotenoids and colon cancer. Am J Clin Nutr 71: 575-582.

Song, W. O., and J. M. Kerver. 2000. Nutritional contribution of eggs to american diets. J Am Coll Nutr 19: 556S-562S.

Taubes, G. 2007. Good calories, bad calories. Knopf. Tillotson, J. L., G. E. Bartsch, D. Gorder, G. A. Grandits, and J. Stamler. 1997.

Food group and nutrient intakes at baseline in the multiple risk factor intervention trial. Am J Clin Nutr 65(1) Suppl: 228S-257S. Weggemans, R. M., P. L. Zock, and M. B. Katan. 2001. Dietary cholesterol from eggs increases the ratio of total cholesterol to high-density lipoprotein cholesterol in humans: A meta-analysis. Am J Clin Nutr 73: 885-891.

Wenzel, A. J. et al. 2006. A 12-wk egg intervention increases serum zeaxanthin and macular pigment optical density in women. J Nutr 136: 2568-2573.

Williams, P. T. et al. 2003. Smallest ldl particles are most strongly related to coronary disease progression in men. Arterioscler Thromb Vasc Biol 23: 314-321.

Zeisel, S. H. 2006. Choline: Critical role during fetal development and dietary requirements in adults. Annu Rev Nutr 26: 229-250. Zeisel, S. H., and M. D. Niculescu. 2006. Perinatal choline influences brain structure and function. Nutr Rev 64: 197-203.

8 Effects of dietary cholesterol on plasma lipoprotein cholesterol levels1.
plasma cholesterol per 100 mg/day increase in dietary cholesterol

Diet2 Mean P:S < 0.7 P:S > 0.7 Total cholesterol 2.2 2.7 1.7 LDL cholesterol 1.9 2.4 1.4 HDL cholesterol 0.3 0.3 0.3 1Data from (Weggemans et al., 2001) 2P:S = ratio of polyunsaturated to saturated fat in the test diet. 9

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