questions - asu college of health solutions · meta-analysis examining the effect of dietary...

4/8/2016

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Dietary cholesterol: The good,

the bad, and the egg?

Sonia Vega-López, PhD

March 19, 2016

How much cholesterol can be part of a

healthful diet?

Are there specific foods that should be

limited because of their cholesterol content?

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

Lipid, member of sterol family

Cholest-5en-3b-ol; C27H46O

Derived from cyclopentano phenanthrene

Branched hydrocarbon chain at C17

Esterifies fatty acids in C3 (mainly C18:2n-6)

Highly hydrophobic

3

5

17

Figure from: Katan 2003 Mayo Clin Proc.

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

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We need cholesterol for survival.

Take home message #1:

Cholesterol Metabolism

Intestine

Extrahepatic tissues

(e.g. arterial walls)

Liver

LDL-R

LDL-R

LDL-R

LDL-R

SR-B1

Dietary

cholesterol

Bile acids

Fecal neutral

sterols

Chylomicrons

Chylomicron

remnants

HDL

VLDL

IDL

LDL

Cholesterol

Acetyl CoA

Cholesterol

Cholesterol

“Bad cholesterol”

“Good cholesterol” Acetyl CoA

If we do not eat cholesterol, our body

makes it.


Dietary cholesterol: 400 mg/d

60% absorbed = 240 mg/d

Endogenous synthesis: 850 mg/d

Total 1090 mg/d

78% synthesis

22% dietary

Cholesterol in the body

Once in our body, cholesterol is cholesterol,

no matter where we got it

from (diet vs. synthesis).


Cholesterol in the diet

Dietary contribution: 250 – 700 mg/d

Only synthesized by animals. Thus,

only present in foods of animal origin

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Cholesterol in the diet

Dietary contribution: 250 – 700 mg/d

Only present in foods of animal origin

Sources:

Eggs

Shellfish

Meat products

Dairy products

Recommendation: < 300 mg/d

*Daily Value: 300 mg/d

408 mgCholesterol in

Selected Foods

408

mg

Early evidence for cholesterol and CVD riskAnimal studies

Historical evidence for dietary

cholesterol and atherosclerosis 1910 – Windaus – aortas of patients with

atherosclerosis had higher cholesterol concentrations

1913 – Anitschkow – showed that cholesterol feeding caused “fatty streaks” in rabbits

1951-53 Eder, Nikkila & Gofman relate heart disease to high LDL and low HDL cholesterol

1960s – Klimov et al. – attribution of atherosclerotic lesion to increase in circulating lipoproteins

1976 - Strong & Gresham – cholesterol feeding and atherosclerotic lesions in primates

Steinberg, J. Lipid Res, 2004, 2005, 2006

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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 2,500 to 10,000 mg/d

Different distribution of cholesterol in

lipoproteins

The majority have more HDL-C than LDL-C

Limitations of early animal studies

Early evidence from animal

studies indicating an association

between dietary cholesterol

and atherosclerosis is not

translatable to humans.


Early evidence for cholesterol and CVD riskProspective studies

Western Electric Study

20-y follow-up of 1900 middle-aged men

Positive association between diet score and serum

cholesterol

Positive prospective association between dietary

cholesterol and Keys/Hegsted diet scores and the

19-year risk of death from CHD

Diet score included cholesterol, saturated

fatty acids and polyunsaturated fatty acids

Shekelle 1981 NEJM

Honolulu Heart Program

Prospective 10-year follow-up of 8006 men of Japanese ancestry

Positive association between cholesterol intake and risk of CHD and MI

McGee DL et al. Am J Epidemiol, 1984

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 16 cohorts in seven countries with

diverse lifestyle, eating habits, and risk factor

levels

USA, Finland, Yugoslavia, Japan, Grece, Italy,

Netherlands

25-year follow-up

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Kromhout et al. 1995 Prevent Med


Kromhout et al. 1995 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:

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.

Dietary Guidelines

Original AHA guidelines (1961)

Reduce intake of total fat, saturated fat, and

cholesterol. Increase intake of polyunsaturated

fat.

1970s guidelines specifically stating

“avoid eggs”

“No more than 3 yolks a week”

1973 AHA guidelines set cholesterol intake

limit at 300 mg/d

Kritchevsky, 2004, J Am Coll Nutr

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“…there was no scientific rationale or

justification for selecting 300mg/d as the limit

for dietary cholesterol (other than that the

average US intake at the time was 580mg/d

and that 300mg/d would represent a

significant decrease in consumption).”

McNamara DJ, 2014, Proc Nutr Soc

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.

More recent epidemiological

evidenceDietary cholesterol

Framingham Study

16-y follow-up of middle-aged men

420 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. 1991, Arch Intern Med

Health Professionals’ Study

Ascherio, et al. 1996 BMJ

43,757 health professional males, 40-75 years

Six-year follow-up

Health Professionals’ Study

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Quintile 1 (132

mg/1000 kcal)

Quintile 2 (163

mg/1000 kcal)

Quintile 3 (188

mg/1000 kcal)

Quintile 4 (217

mg/1000 kcal)

Quintile 5 (273

mg/1000 kcal)

Re

lativ

e R

isk fo

r C

HD

Age-adjusted Multivariate Multivariate + dietary fat

Ascherio, et al. 1996 BMJ

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Nurses’ Health Study

Hu FB, et al. 1997 NEJM

80,082 women, 34 to 59 years

14-year follow-up

Nurses’ Health Study

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Quintile 1 (132

mg/d)

Quintile 2 (163

mg/d)

Quintile 3 (188

mg/d)

Quintile 4 (217

mg/d)

Quintile 5 (273

mg/d)

Re

lativ

e R

isk fo

r C

HD

Age-adjusted Multivariate Multivariate + dietary fat

Hu FB, et al. 1997 NEJM

ATBC Cancer Prevention Study

Pietinen et al. 1997 Am J Epidemiol 145:876-887.

Alpha-tocopherol, beta-carotene cancer

prevention study

21,930 smoking men, 50-69 years

6.1 years follow-up

ATBC Cancer Prevention Study

0

0.2

0.4

0.6

0.8

1

768 621 543 477 390

Re

lati

ve

Ris

k

Dietary Cholesterol (mg/d)

CHD Death CHD Event

Pietinen et al. 1997 Am J Epidemiol 145:876-887.

MRFIT

Multiple Risk Factor Intervention Trial

Primary prevention trial for 12,847 high-risk

men, 35-57 years

Inverse relations between serum cholesterol

and dietary cholesterol at baseline

MRFIT

360

380

400

420

440

460

480

500

<220 220-239 240-259 260-279 280-299 >300

Die

tary

ch

ole

ste

rol (

mg

/da

y)

Serum cholesterol (mg/dL)

P<0.001

Tillotson et al. 1997 Am J Clin Nutr 65(suppl):228S-257S.

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More recent epidemiological

evidenceDeviled eggs or evil eggs?

NHANES III: Egg intake and serum

cholesterol

Song, WO, J Am Coll Nutr, 2000.

Weekly Egg Consumption and

CHD Risk

0

0.2

0.4

0.6

0.8

1

1.2

Rela

tive R

isk

Males Females

<1 1 2-4 5-6 >7

Hu F, et al. 1999 JAMA

Nurses Health and Health Professionals Follow-up Studies

37, 851 men; 80, 082 women

8-14 years of follow-up

Other epidemiological studies

reporting no association: Posner et al, Arch Intern Med 1991; Framingham Study

Esrey, J Clin Epidemiol 1996; Lipid Research Clinics Study.

Gramenzi, BMJ, 1990; no increased risk of CHD with eggs, Italian women.

Dawber, Am J Clin Nutr, 1982; no increased risk with eggs

Fraser, Am J Clin Nutr, 1999; 7th day adventist study no increased risk with eggs

Djousse Am J Clin Nutr, 2008. Physician’s Health Study; not associated with CHD Death

Qureshi, Med Sci Monit, 2007; NHANES I 20 years of follow up no increased risk CVD with eggs

Meta-analysis examining the association between dietary cholesterol and ischemic and

hemorrhagic stroke.

Samantha Berger et al. Am J Clin Nutr 2015;102:276-294

©2015 by American Society for Nutrition

Epidemiological evidence

shows that no association

exists between dietary cholesterol and/or eggs and

heart disease risk.


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Concepts DO Change 1984 1999

Clinical evidenceEgg feeding studies in humans

Feeding studies – Fernandez et al.

Randomized crossover studies

4 weeks per phase:

3 eggs/d (+ 640 mg cholesterol/d)

Equivalent amount of egg substitute (egg whites)

Feeding studies – Fernandez et al.

51 premenopausal women

Herron, Vega-López, Conde, et al. J. Am. Coll.

Nutr. 2002

40 men

Herron, Vega-López, Conde, et al. J. Nutr. 2003

42 older adults

Greene, Zern, Wood, et al. J Nutr. 2005

54 children (2 eggs/d)

Ballesteros, Cabrera, Saucedo, et al. Am J Clin

Nutr. 2004

Response to dietary cholesterol

A 100 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 640 mg/d of additional

dietary cholesterol

(2.2 x 640)/100 = 14 mg/dL

Individuals who experienced an increase in

total cholesterol greater than 14 mg/dL were

classified as hyperresponders

Generally 30% of the population

*McNamara DJ, Am J Clin Nutr, 2000

Cholesterol intake

0

200

400

600

800

1000

Ch

ole

ste

rol

Inta

ke

(m

g/d

ay) Egg Placebo

Hyper-responders Hypo-responders

*** ***

Herron et al. J Am Coll Nutr, 2002; 21:250-258.

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Men Women Men Women

0

30

60

90

120

150

Ch

ole

ste

rol (m

g/d

L)

Hyper-Responders Hypo-Responders

LDL-Egg LDL-placebo HDL-Egg HDL-placebo

NS

NS

NS

NS**

**

****

Lipid responses

Herron et al. JN 2003;133:1036-1042 & J. Am. Coll. Nutr.2002; 21:250-258.

LDL/HDL Ratio

Men Women Men Women0.00

0.70

1.40

2.10

2.80

3.50

LD

L/H

DL R

atio

Hyper-Responders Hypo-Responders

LDL/HDL-Egg LDL/HDL-placebo

NS

NS

NS

**

Herron et al. JN 2003;133:1036-1042 & J. Am. Coll. Nutr.2002; 21:250-258.

Feeding studies

Children

0

0.5

1

1.5

2

2.5

3

3.5

Hyperresponders Hyporesponders

Total:HDL

Egg Substitute

Older adults

Ballesteros et al. 2004 Am J Clin Nutr & Greene et al. 2005 J Nutr

0

0.5

1

1.5

2

2.5

3

Men Women

LDL:HDL

Egg Substitute

N.S. N.S.

Meta-analysis examining the effect of dietary cholesterol on LDL cholesterol concentration by

strata of intervention dose.



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.



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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

6 g protein (12% DV)

All essential amino acids

Highly digestible

5 g fat/1.5 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 70 kcal

Eggs

Very high cholesterol

(212 mg/egg)

Low saturated fat

Rare combination

(high cholesterol

and low saturated

fat)

McNamara, BBA, 2000

Vit A- 18%

Thiamine- 6%

Riboflavin-42%

B5-28%

Folate-11%

Choline-46%

Vit D- 15%

Calcium-5%

Iron-9%

Magnesium-3%

Phosphorus-25%

Potassium-3%

Zinc-11%

Biotin

Egg Nutrition Center

Cost

$2.50/12 eggs

6.3g protein each

~3-4 cents/g

Very inexpensive source of high quality

protein and other nutrients

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Eggs and dietary quality

Nutrient intake (NHANES III)

Eggs provided 7% of the meat/beans

servings

Compared to egg consumers, non-

consumers had higher rates of inadequate

intake for:

Vitamin B12 (10% vs. 21%)

Vitamin A (16% vs. 21%)

Vitamin E (14% vs. 22%)

Vitamin C (15% vs. 20%)

Song, WO, J Am Coll Nutr, 2000.

Nutrient intake (postpartum women)

Nutrient DRI b Egg non-consumers

(n=57)

Egg

consumers

(n=81)

P value

Vitamin A (mg) c 500 563 ± 401 668 ± 389 0.126

Vitamin C (mg) 60 54.0 ± 44.2 68.2 ± 59.2 0.128

Vitamin D (mg) 10 4.19 ± 3.39 5.48 ± 3.55 0.033

Vitamin E (mg) 12 4.48 ± 3.21 5.22 ± 2.87 0.159

Vitamin K (mg) 90 38.6 ± 34.8 45.2 ± 47.2 0.375

Thiamin (mg) 0.9 1.16 ± 0.54 1.26 ± 0.58 0.268

Riboflavin (mg) 0.9 1.43 ± 0.76 1.83 ± 0.90 0.006

Niacin (mg) 11 15.9 ± 7.9 17.3 ± 8.0 0.328

Vitamin B6 (mg) 1.1 1.44 ± 1.00 1.70 ± 1.14 0.165

Total folate (mg) 320 295 ± 197 357 ± 217 0.090

Vitamin B12 (mg) 2.0 3.98 ± 3.00 5.27 ± 3.70 0.031

Choline (mg) 425 176 ± 79 279 ± 110 0.0001

Sodium (mg) 1500 2266 ± 945 2780 ± 1206 0.008

Potassium (mg) 4700 1587 ± 629 1927 ± 848 0.011

Calcium (mg) 800 735 ± 301 826 ± 390 0.142

Phosphorus (mg) 580 913 ± 349 1091 ± 443 0.012

Iron (mg) 8.1 11.4 ± 6.4 13.4 ± 7.3 0.091

Lutein + Zeaxanthin (mg) 547 ± 648 773 ± 1150 0.181

Vega-López et al. Nutrients 2015

Eggs can be an important component of

a healthful dietary

pattern.


2015 Dietary Guidelines

“Previously, the Dietary Guidelines for

Americans recommended that cholesterol

intake be limited to no more than 300 mg/day.

The 2015 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.”

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