How much cholesterol can be part of a healthful diet? Dietary cholesterol: The good, the bad, and the egg? Are there specific foods that should be limited because of their cholesterol content? Sonia Vega-López, PhD March 9, 26 Questions Does dietary cholesterol increase plasma LDL cholesterol levels? Is dietary cholesterol related to increased heart disease risk? Do people respond differently to dietary cholesterol? Do eggs, as a source of dietary cholesterol, increase CHD risk? Cholesterol overview Cholesterol chemistry 3 Lipid, member of sterol family Cholest-5en-3b-ol; C 27 H 46 O Derived from cyclopentano phenanthrene Branched hydrocarbon chain at C7 Esterifies fatty acids in C3 (mainly C8:2n-6) Highly hydrophobic 5 7 Cholesterol biological functions Component of biological membranes Helps moderate cell membrane fluidity and strength Provides insulation Precursor of vitamin D Precursor of steroid hormones (sex hormones and corticosteroids) Substrate for bile acid synthesis Figure from: Katan 23 Mayo Clin Proc.
Cholesterol Metabolism Acetyl CoA Liver LDL-R VLDL Take home message #: Dietary cholesterol Bile acids Cholesterol LDL-R IDL SR-B LDL LDL-R Bad cholesterol We need cholesterol for survival. Intestine Cholesterol Chylomicron remnants HDL LDL-R Cholesterol Chylomicrons Good cholesterol Acetyl CoA Fecal neutral sterols Extrahepatic tissues (e.g. arterial walls) Cholesterol in the body Dietary cholesterol: 4 mg/d Take home message #2: If we do not eat cholesterol, our body makes it. 6% absorbed = 24 mg/d Endogenous synthesis: 85 mg/d Total 9 mg/d 78% synthesis 22% dietary Cholesterol in the diet Dietary contribution: 25 7 mg/d Take home message #3: Once in our body, cholesterol is cholesterol, no matter where we got it from (diet vs. synthesis). Only synthesized by animals. Thus, only present in foods of animal origin 2
Cholesterol in the diet Cholesterol in Selected Foods 48 mg mg Dietary contribution: 25 7 mg/d Only present in foods of animal origin Sources: Eggs Shellfish Meat products Dairy products *Daily Value: 3 mg/d Recommendation: < 3 mg/d Early evidence for cholesterol and CVD risk Animal studies Historical evidence for dietary cholesterol and atherosclerosis 9 Windaus aortas of patients with atherosclerosis had higher cholesterol concentrations 93 Anitschkow showed that cholesterol feeding caused fatty streaks in rabbits 95-53 Eder, Nikkila & Gofman relate heart disease to high LDL and low HDL cholesterol 96s Klimov et al. attribution of atherosclerotic lesion to increase in circulating lipoproteins 976 - Strong & Gresham cholesterol feeding and atherosclerotic lesions in primates Steinberg, J. Lipid Res, 24, 25, 26 3
Limitations of early animal studies Rabbits are highly susceptible to atherosclerosis and responsive to cholesterol Many species, including primates need extremely high doses of cholesterol to induce atherosclerosis Equivalent to 2,5 to, mg/d Different distribution of cholesterol in lipoproteins The majority have more HDL-C than LDL-C Take home message #4: Early evidence from animal studies indicating an association between dietary cholesterol and atherosclerosis is not translatable to humans. Western Electric Study Early evidence for cholesterol and CVD risk Prospective studies 2-y follow-up of 9 middle-aged men Positive association between diet score and serum cholesterol Positive prospective association between dietary cholesterol and Keys/Hegsted diet scores and the 9-year risk of death from CHD Diet score included cholesterol, saturated fatty acids and polyunsaturated fatty acids Shekelle 98 NEJM Honolulu Heart Program Prospective -year follow-up of 86 men of Japanese ancestry Positive association between cholesterol intake and risk of CHD and MI Seven Countries Study Led by Dr. Ancel Keys First major prospective study exploring associations of lifestyle (particularly diet) and other risk factors with cardiovascular disease Included 6 cohorts in seven countries with diverse lifestyle, eating habits, and risk factor levels USA, Finland, Yugoslavia, Japan, Grece, Italy, Netherlands 25-year follow-up McGee DL et al. Am J Epidemiol, 984 4
Seven Countries Study Seven Countries Study Kromhout et al. 995 Prevent Med Kromhout et al. 995 Prevent Med Limitations of early epidemiological studies Co-linearity of saturated fat and cholesterol Diet high in animal products usually a diet low in fruits, vegetables and fiber Analyses of dietary cholesterol and CHD were not properly adjusted Birth of dietary guidelines Conventional Wisdom: Dietary Guidelines If dietary cholesterol increases blood cholesterol levels, and increased blood cholesterol levels increase heart disease risk, then reductions in dietary cholesterol should lower heart disease risk. Original AHA guidelines (96) Reduce intake of total fat, saturated fat, and cholesterol. Increase intake of polyunsaturated fat. 97s guidelines specifically stating avoid eggs No more than 3 yolks a week 973 AHA guidelines set cholesterol intake limit at 3 mg/d Kritchevsky, 24, J Am Coll Nutr 5
Relative Risk for CHD 4/8/26 there was no scientific rationale or justification for selecting 3mg/d as the limit for dietary cholesterol (other than that the average US intake at the time was 58mg/d and that 3mg/d would represent a significant decrease in consumption). Dietary Cholesterol Eggs became the icon for both dietary cholesterol and blood cholesterol and egg restrictions to less than 3 per week became known worldwide. McNamara DJ, 24, Proc Nutr Soc Framingham Study More recent epidemiological evidence Dietary cholesterol 6-y follow-up of middle-aged men 42 aged 45-55 years Positive associations between incident CHD and %E from total fat %E from MUFA %E from SFA 393 aged 56-65 years No associations between dietary lipids and incident CHD No associations with dietary cholesterol Posner et al. 99, Arch Intern Med Health Professionals Study Health Professionals Study 43,757 health professional males, 4-75 years Six-year follow-up.4.2.8.6.4.2 Quintile (32 Quintile 2 (63 Quintile 3 (88 Quintile 4 (27 Quintile 5 (273 mg/ kcal) mg/ kcal) mg/ kcal) mg/ kcal) mg/ kcal) Age-adjusted Multivariate Multivariate + dietary fat Ascherio, et al. 996 BMJ Ascherio, et al. 996 BMJ 6
Relative Risk for CHD Relative Risk Dietary cholesterol (mg/day) 4/8/26 Nurses Health Study Nurses Health Study 8,82 women, 34 to 59 years 4-year follow-up.4.2.8.6.4.2 Quintile (32 mg/d) Quintile 2 (63 mg/d) Quintile 3 (88 mg/d) Quintile 4 (27 Quintile 5 (273 mg/d) mg/d) Age-adjusted Multivariate Multivariate + dietary fat Hu FB, et al. 997 NEJM Hu FB, et al. 997 NEJM ATBC Cancer Prevention Study ATBC Cancer Prevention Study Alpha-tocopherol, beta-carotene cancer prevention study CHD Death CHD Event 2,93 smoking men, 5-69 years.8 6. years follow-up.6.4.2 768 62 543 477 39 Dietary Cholesterol (mg/d) Pietinen et al. 997 Am J Epidemiol 45:876-887. Pietinen et al. 997 Am J Epidemiol 45:876-887. MRFIT MRFIT Multiple Risk Factor Intervention Trial Primary prevention trial for 2,847 high-risk men, 35-57 years 5 48 P<. Inverse relations between serum cholesterol and dietary cholesterol at baseline 46 44 42 4 38 36 <22 22-239 24-259 26-279 28-299 >3 Serum cholesterol (mg/dl) Tillotson et al. 997 Am J Clin Nutr 65(suppl):228S-257S. 7
NHANES III: Egg intake and serum cholesterol More recent epidemiological evidence Deviled eggs or evil eggs? Song, WO, J Am Coll Nutr, 2. Weekly Egg Consumption and CHD Risk Relative Risk.2.8.6.4.2 Males Females < 2-4 5-6 >7 Nurses Health and Health Professionals Follow-up Studies 37, 85 men; 8, 82 women 8-4 years of follow-up Other epidemiological studies reporting no association: Posner et al, Arch Intern Med 99; Framingham Study Esrey, J Clin Epidemiol 996; Lipid Research Clinics Study. Gramenzi, BMJ, 99; no increased risk of CHD with eggs, Italian women. Dawber, Am J Clin Nutr, 982; no increased risk with eggs Fraser, Am J Clin Nutr, 999; 7 th day adventist study no increased risk with eggs Djousse Am J Clin Nutr, 28. Physician s Health Study; not associated with CHD Death Qureshi, Med Sci Monit, 27; NHANES I 2 years of follow up no increased risk CVD with eggs Hu F, et al. 999 JAMA Meta-analysis examining the association between dietary cholesterol and ischemic and hemorrhagic stroke. Take home message #5: Epidemiological evidence shows that no association exists between dietary cholesterol and/or eggs and heart disease risk. Samantha Berger et al. Am J Clin Nutr 25;2:276-294 25 by American Society for Nutrition 8
Cholesterol Intake (mg/day) 4/8/26 Concepts DO Change 984 999 Clinical evidence Egg feeding studies in humans Feeding studies Fernandez et al. Feeding studies Fernandez et al. Randomized crossover studies 4 weeks per phase: 3 eggs/d (+ 64 mg cholesterol/d) Equivalent amount of egg substitute (egg whites) 5 premenopausal women Herron, Vega-López, Conde, et al. J. Am. Coll. Nutr. 22 4 men Herron, Vega-López, Conde, et al. J. Nutr. 23 42 older adults Greene, Zern, Wood, et al. J Nutr. 25 54 children (2 eggs/d) Ballesteros, Cabrera, Saucedo, et al. Am J Clin Nutr. 24 Response to dietary cholesterol Cholesterol intake A mg/d increase in dietary cholesterol is expected to result in a modest increase in serum total cholesterol by about 2.2 mg/dl* Participants received 64 mg/d of additional dietary cholesterol (2.2 x 64)/ = 4 mg/dl 8 6 Egg *** *** Placebo Individuals who experienced an increase in total cholesterol greater than 4 mg/dl were classified as hyperresponders Generally 3% of the population 4 2 Hyper-responders Hypo-responders *McNamara DJ, Am J Clin Nutr, 2 Herron et al. J Am Coll Nutr, 22; 2:25-258. 9
Cholesterol (mg/dl) LDL/HDL Ratio 4/8/26 Lipid responses LDL/HDL Ratio LDL/HDL-Egg LDL/HDL-placebo LDL-Egg LDL-placebo HDL-Egg HDL-placebo 5 ** ** 2 3.5 2.8 ** 9 6 ** ** 2..4 3.7 Men Women Men Women Hyper-Responders Hypo-Responders. Men Women Men Women Hyper-Responders Hypo-Responders Herron et al. JN 23;33:36-42 & J. Am. Coll. Nutr.22; 2:25-258. Herron et al. JN 23;33:36-42 & J. Am. Coll. Nutr.22; 2:25-258. Feeding studies Meta-analysis examining the effect of dietary cholesterol on LDL cholesterol concentration by strata of intervention dose. Children Older adults Total:HDL LDL:HDL 3.5 3 N.S. 3 2.5 N.S. 2.5 2 2.5.5.5.5 Hyperresponders Hyporesponders Men Women Egg Substitute Egg Substitute Samantha Berger et al. Am J Clin Nutr 25;2:276-294 Ballesteros et al. 24 Am J Clin Nutr & Greene et al. 25 J Nutr 25 by American Society for Nutrition Meta-analysis examining the effect of dietary cholesterol on HDL cholesterol concentration by strata of intervention dose. Meta-analysis examining the effect of dietary cholesterol on the LDL to HDL ratio. Samantha Berger et al. Am J Clin Nutr 25;2:276-294 Samantha Berger et al. Am J Clin Nutr 25;2:276-294 25 by American Society for Nutrition 25 by American Society for Nutrition
Take home message #6: Magnitude of effects from feeding studies suggest a small increase in cholesterol but no change in risk (LDL:HDL). Nutritional quality of eggs Nutrition one large egg Eggs 6 g protein (2% DV) All essential amino acids Highly digestible 5 g fat/.5 g SFA (8% DV for both) 2 g MUFA Trace amounts of carbohydrates Most vitamins (except C) Most minerals Good source of I, P, Zn, Se, Ca, Fe Choline and lecithin Carotenoids (highly bioavailable) Only 7 kcal Very high cholesterol (22 mg/egg) Low saturated fat Rare combination (high cholesterol and low saturated fat) McNamara, BBA, 2 Vit A- 8% Thiamine- 6% Riboflavin-42% B5-28% Folate-% Choline-46% Vit D- 5% Calcium-5% Iron-9% Magnesium-3% Phosphorus- 25% Potassium-3% Zinc-% Biotin Cost $2.5/2 eggs 6.3g protein each ~3-4 cents/g Very inexpensive source of high quality protein and other nutrients Egg Nutrition Center
Nutrient intake (NHANES III) Eggs provided 7% of the meat/beans servings Eggs and dietary quality Compared to egg consumers, nonconsumers had higher rates of inadequate intake for: Vitamin B2 (% vs. 2%) Vitamin A (6% vs. 2%) Vitamin E (4% vs. 22%) Vitamin C (5% vs. 2%) Song, WO, J Am Coll Nutr, 2. Nutrient intake (postpartum women) Nutrient DRI b Egg non-consumers (n=57) Egg consumers (n=8) P value Vitamin A (mg) c 5 563 ± 4 668 ± 389.26 Vitamin C (mg) 6 54. ± 44.2 68.2 ± 59.2.28 Vitamin D (mg) 4.9 ± 3.39 5.48 ± 3.55.33 Vitamin E (mg) 2 4.48 ± 3.2 5.22 ± 2.87.59 Vitamin K (mg) 9 38.6 ± 34.8 45.2 ± 47.2.375 Thiamin (mg).9.6 ±.54.26 ±.58.268 Riboflavin (mg).9.43 ±.76.83 ±.9.6 Niacin (mg) 5.9 ± 7.9 7.3 ± 8..328 Vitamin B6 (mg)..44 ±..7 ±.4.65 Total folate (mg) 32 295 ± 97 357 ± 27.9 Vitamin B2 (mg) 2. 3.98 ± 3. 5.27 ± 3.7.3 Choline (mg) 425 76 ± 79 279 ±. Sodium (mg) 5 2266 ± 945 278 ± 26.8 Potassium (mg) 47 587 ± 629 927 ± 848. Calcium (mg) 8 735 ± 3 826 ± 39.42 Phosphorus (mg) 58 93 ± 349 9 ± 443.2 Iron (mg) 8..4 ± 6.4 3.4 ± 7.3.9 Lutein + Zeaxanthin (mg) 547 ± 648 773 ± 5.8 Take home message #7: Eggs can be an important component of a healthful dietary pattern. Vega-López et al. Nutrients 25 25 Dietary Guidelines Previously, the Dietary Guidelines for Americans recommended that cholesterol intake be limited to no more than 3 mg/day. The 25 DGAC will not bring forward this recommendation because available evidence shows no appreciable relationship between consumption of dietary cholesterol and serum cholesterol, consistent with the conclusions of the AHA/ACC report. Cholesterol is not a nutrient of concern for overconsumption. 2
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