4 http www ncbi nlm nih gov books nbk21154

7.1

 What Can You Do Right Now?

In general, by eating a balanced diet, we’re getting sufficient

vitamins. If you live in the Pacific Northwest, you may need

a vitamin D supplement, especially in the winter months, due

to the low levels of sunlight. If you are a vegetarian who eats

zero animal-sourced foods, make sure you are taking vitamin

B12 supplements because you’re not getting any vitamin B12 from your diet.

Chapter 07: Vitamins

When you think of vitamins, do you think of fruits and vegetables, whole grains, dairy and

protein foods, or do you think of vitamin supplements? The 2015 Dietary Guidelines recommend

obtaining nutrients through whole foods and beverages, not through supplementation. 2

Vitamins are non-caloric, organic substances that the body can’t synthesize that are

needed in small amounts for the normal growth, maintenance and function of the body. In

general, vitamins serve as coenzymes, allowing certain enzymes to work, and as antioxidants.

Vitamins are often consumed as provitamins, which are inactive, vitamin precursors, then

converted into the active forms as the body needs them. All of the vitamins the healthy body

needs are found in sufficient quantities in whole foods.

Small amounts of vitamins are needed to prevent vitamin-deficiency diseases, and large

amounts of vitamins are not needed for this; again, whole foods provide adequate amounts. Some

vitamins, do, however, have pharmacological effects and are sometimes prescribed by doctors in

large doses. The amounts of each vitamin that 97-98% of healthy people need is termed the

Recommended Daily Allowance, or RDA. The tolerable upper intake level, or UL, is the amount

that most adults can ingest without causing negative health effects. 3

There are 13 vitamins the body needs. 1 These 13 vitamins are grouped into water soluble

and fat soluble vitamins.

 Fat-Soluble Vitamins

The fat-soluble vitamins include vitamins A, D, E and K (ADEK). These vitamins dissolve in

fats and oils, so they require fat in the diet to be optimally absorbed; low-fat diets can lead to

ADEK deficiencies. 14

ADEK must be emulsified and carried by bile in micelles though the

watery environment of the small intestine to be taken in by the cells lining the intestine, so any

pathologies that affect the production and secretion of bile will affect the absorption of ADEK. 12

Hepatitis and other liver diseases, and gall stones that block bile ducts, can reduce the amount of

bile available. Because fiber binds to and removes excess bile from the body, individuals who

consume large amounts of fiber daily over time may be at risk for ADEK deficiencies. Daily use

of mineral oil laxatives, 16

chitin and the artificial fat olestra may lead to ADEK deficiencies as

well. Individuals with Crohn’s disease may also not absorb enough ADEK. 12

Note that cooking

7.2

does not remove the fat-soluble vitamins from food. 13

However, because the fat-soluble vitamins

are stored in the liver, and because these vitamins are not excreted in the urine, only small

amounts of these vitamins are needed, and it is not absolutely necessary to ingest them every

day. 13

And, because ADEK are stored in the liver and fat cells, large doses of these vitamins,

which you can only obtain through supplements and by eating liver, can be toxic and lead to

health issues; 13

for most people, supplements of these vitamins are not needed, 13

although

specific exceptions will be discussed below.

After being absorbed by the cells lining the small intestine, ADEK are transported either

in chylomicrons or by transport proteins that allow them to mix with the watery environment of

lymph and blood.

In general, ADEK are found in high amounts in animal- and plant-sourced foods

containing fats, although some are also found in other foods, particularly dark green, leafy

vegetables.

Vitamin A

In the early 1900s, many researchers were looking into the nutritional requirements of both

humans and mammals used in agriculture. 387

Frederick Hopkins, in 1912, discovered a fat-

soluble “factor” in milk, essential for growth in rats, that was neither a carbohydrate, protein or

fat; for his work, he won the Nobel Prize in 1929. 386

In 1913, Elmer McCollum and Marguerite

Davis at the University of Wisconsin and Thomas Osborne and Lafayette Mendel of Yale

University discovered a fat-soluble accessory factor which was essential for the growth of and

prevent xerophthalmia rats 388

that was termed “fat soluble A” in butter and egg yolks, but not in

lard and olive oil. 385

The “accessory factor” was given the name, “vitamin A” in 1920. 385

By the

way, in their work toward the discovery of vitamin A, McCollum and Davis were the first to use

rats as laboratory animals. 387

Characterization

Vitamin A is a group of compounds called retinoids, which include retinal, retinol and retinoic

acid, also called “active vitamin A,” and the provitamin carotenoids, chiefly beta-carotene, also

called “inactive vitamin A.” Besides beta-carotene, the other provitamin carotenoids include

alpha-carotene and beta-cryptoxanthin, a very small number of the over 600 known carotenoids. 7

Active vitamin A is absorbed and converted into retinol inside the cells lining the gut and

incorporated into chylomicrons; carotenoids may either be split into retinol, which are packed

into chylomicrons, 15,34

or introduced into chylomicrons intact. 26

Chylomicrons are then released

into the lymph, carried into the blood, and are taken in by liver cells, resulting in the storage of

retinol and some beta-carotene in the liver; 15,26

80-90% of active vitamin A is stored in the liver. 5

Most individuals have enough retinol in their livers to last for several months. 34

Most of the beta-

carotene is stored in fat tissue. 26

Inside the liver, retinol is attached to retinol binding protein

(RBP). 15

When needed, retinol is released into the blood attached to RBP 15

or prealbumin, 3 and

delivered to where it is needed. Retinol is oxidized to retinal, which can then be converted to

retinoic acid. 5 Beta-carotene is transported through the body in VLDLs and HDLs, but

principally in LDLs. 25

7.3

Function

 Beta-carotene. The principal function of beta-carotene is as the major, non-toxic precursor for the formation of retinol and the other active forms of vitamin A.

22 It is also thought to be

an antioxidant, so normal dietary amounts may help reduce the risk of heart disease,

cancer 22,23

and other vascular diseases; diets rich in carotenoids are associated with lowered

levels of heart disease, cancers, macular degeneration and cataracts, 6

although beta-carotene

specifically has been shown to have little to no effect on macular degeneration and

cataracts. 22,24

Beta-carotene is a major skin pigment and helps protect the skin against UV

damage causing sunburn. 22

 Retinol. The chief function of retinol is to serve as the storage form of active vitamin A for later use by the body. Retinol is stored in the liver in the form of retinyl esters.

5

 Retinal is necessary for vision. It is used in the formation of rhodopsins, the photopigments that absorb light and begin the biochemical process of turning it into nerve signals that are

sent to the brain. Retinal is thus needed for dim-light and color vision, and rapid dark

adaptation. 4

Besides vision, animal studies show that retinal is essential for the production of sperm

and the fertility of the female. 34

 Retinoic acid is essential for the growth and development of the embryo,30,33 and the maintenance of normal growth in the child and adult, including that of the bones.

34 It is

responsible for most of the functions of vitamin A, 31

and is up to 1000 times more active than

the other forms of vitamin A. 34

Interestingly, retinoic acid binds to retinoic acid receptors

located on DNA molecules, functioning to turn genes on or off. 29

Retinoic acid is involved in the control of the development and keratinization of cells of

the skin 33

and the epithelial linings of the body including the lungs, digestive and urogenital

tracts, including the production of mucus. 34

Keratin is the tough protein of hair and

fingernails that helps to strengthen and waterproof the skin; a lack of retinoic acid may lead

to dryness and overgrowth of the keratin in the epithelia. 32

Retinoic acid plays a key role in the functioning of white blood cells, including T

lymphocytes, so is essential to the functioning of the immune system. 28

In fat tissue, retinoic acid appears to play a role in the formation of new fat cells, with

higher levels of retinoic acid inhibiting the formation of new fat cells and lower levels

activating the formation of new fat cells. 27

Cancer is characterized by the proliferation of cells at such a rapid rate that they don’t

have time to differentiate into functioning cells. Retinoic acid is used to treat various cancers

and pre-cancerous conditions 36

as it causes cells to differentiate, slows down proliferation, 35

and induces the death of cancerous cells via the process of apoptosis. 36

RDI and UL

Males, 19-70, require 900 mcg RAE and females, 19-70, require 700 mcg RAE of active vitamin

A (retinol) daily, with the UL set at 3000 mcg RAE. 3 (See Table 7.2.) The various sources of

inactive (provitamin) vitamin A such as beta-carotene are not absorbed and converted into

7.4

retinol as efficiently as the active forms of vitamin A—700 mcg of beta-carotene does not equal

700 mcg of retinol. For instance, 2 mcg of beta-carotene supplement or 12 mcg of beta-carotene

in foods is equivalent to 1 mcg of retinol. It is for this reason that the amount of vitamin A in

food is given in retinol activity equivalents, RAE, and not in mcg, 4 as indicated below under

“Dietary Sources.”

Table 7.1. IU to mcg RAE conversion. 5

1 IU retinol = 0.3 mcg RAE 1 IU beta-carotene from food = 0.05 mcg RAE

1 IU beta-carotene from supplements = 0.15

mcg RAE

1 IU alpha-carotene or beta-cryptoxanthin =

0.025 mcg RAE

Supplement and some food labels list vitamin A in international units, IUs. In order to

convert from IUs to mcg RAE, the source of the vitamin A must be known. For active vitamin A,

1 IU retinol = 0.3 mcg RAE and for beta-carotene from food, 1 IU = 0.05 mcg RAE. Other

values are given in Table 7.1. So, a 25 year-old male, who requires 900 mcg RAE per day, would

need 3,000 IU of active (animal-sourced) vitamin A per day, or 18,000 IU of beta-carotene from

veggies and fruits (or 6,000 IU from beta-carotene supplements). To solve these problems,

simply divide the mcg RAE by the mcg RAE per 1 IU; the first one is given as an example:

900 mcg RAE x = 3,000 IU

Fortunately, food labels report the amount of vitamin A in one serving of the product in percent

daily value.

Table 7.2. DRI and UL for Vitamin A in mcg RAE/day. 138,139

(Upper limits in parentheses.)

Age Male Female Pregnancy Lactation

0-6 months 400 (600) 400 (600) - -

6-12 months 500 (600) 500 (600) - -

1-3 years 300 (600) 300 (600) - -

4-8 years 400 (900) 400 (900) - -

9-13 years 600 (1,700) 600 (1,700) - -

14-18 years 900 (2,800) 600 (2,800) 750 (2,800) 1,200 (2,800)

19-50 years 900 (3,000) 700 (3,000) 770 (3,000) 1,300 (3,000)

> 50 years 900 (3,000) 700 (3,000) - -

Dietary Sources

Over 70% of our (U.S.) dietary vitamin A comes from animal products, with less than 30% from

carotenoids in fruits and vegetables; the reverse is true in developing countries, which consume

less than 30% of their dietary vitamin A from animal products and over 70% from plant sources. 6

 Inactive Vitamin A (Provitamin A)

Beta-carotene is a red-orange pigment found in fruits and vegetables. It is optimally absorbed

1 IU

0.3 mcg RAE

7.5

from vegetables by cooking them with a little oil or serving raw veggies that have been finely-

chopped or homogenized with a little oil; 3,7

remember that vitamin A is fat soluble!

Foods that are particularly rich in beta-carotene and the other provitamin A carotenoids

include yellow, orange and green vegetables 4 and orange fruits. Some of the foods richest in

beta-carotene are listed in Table 7.3 below.

 Active Vitamin A

Active vitamin A, in the form of retinyl esters, 4 is found in various animal-sourced foods, the

highest amounts being found in liver. Some foods richest in active vitamin A are listed in Table

7.3 below. Recall that the UL is 3000 mcg RAE.

Table 7.3. Representative Foods High in Beta-Carotene. 38

Values given in mcg retinol activity equivalents, RAE

Food RAE Food RAE Sweet potato, boiled, mashed (1cup) 2582 Turnip greens, boiled (1 cup) 549

Carrot juice, canned (1 cup) 2250 Swiss chard, boiled (1 cup) 536

Pumpkin, canned (1 cup) 1906 Peas and carrots, frozen, boiled (1 cup) 762

Squash, winter, butternut, baked (1 cup) 1144 Dandelion greens, boiled (1 cup) 359

Spinach, boiled (1 cup) 943 Cantaloupe, cubes (1 cup) 270

Carrots, raw, grated (1 cup) 918 Peanut butter (1 tbsp) 188

Kale, boiled, chopped (1 cup) 885 Apricots, dried (1/2 cup) 117

Beet greens, boiled (1 cup) 552 Red peppers, sweet, raw, chopped (1/2 cup) 117

Table 7.4. Representative Foods High in Active Vitamin A. 38

Values given in mcg retinol activity equivalents, RAE

Food RAE Food RAE Beef liver, New Zealand, boiled (2 oz) 17862 Eel, raw (3 oz) 887

Beef liver, U.S., braised (2 oz) 5329 Bluefin tuna (3 oz) [most tuna much lower] 557

Chicken liver, pan fried (2 oz) 2436 Pickled herring (3 oz) 219

Liverwurst (0.25 cup) 2250 Milk, 0%, fortified (1 cup, 8 oz) 157

Cod liver oil (1 tsp) 1350 Egg, large, scrambled 98

Braunschweiger, Oscar Mayer (1 slice, 28 g) 1322 Cheddar cheese (1 oz, 1 slice) 74

Deficiency

It is uncommon to see serious vitamin A deficiencies in the United States; 23

however it is one of

the nutrients determined by the 2015 USDA Scientific Report of the Dietary Guidelines

Advisory Committee to be a “shortfall.” 158

Clinical signs of vitamin A deficiency include slow

dark adaptation to night blindness, xerophthalmia, xerosis of the skin and of the lining of the

respiratory, GI and urinary tracts; the immune system may also be depressed. 3

Early symptoms of vitamin A deficiency include night blindness, or the inability of the

eyes to rapidly adjust from bright sunlight to darkness as one would experience in going from

outside into a darkened theater. Other symptoms may include dry skin, dry hair, dryness of the

respiratory passages and digestive tract, conjunctivitis, and frequent infections. 34

Xerophthalmia,

which is the leading preventable cause of blindness, 37

is the drying of the cornea caused by

vitamin A deficiency; it occurs late in vitamin A deficiency. 5 Other symptoms of long-term

vitamin A deficiency include iron-deficiency anemia and an increase in the severity of infections,

and an increased risk of dying from them. 5

7.6

Groups at risk for vitamin A deficiency include preterm infants, as they have not had time

to build up adequate liver stores of vitamin A; pregnant and nursing women in developing

countries as they often get insufficient vitamin A from active vitamin A sources (animals) or

beta-carotene from plant sources; infants and young children in developing countries as nursing

women are often vitamin A deficient, so their breast milk does not contain enough vitamin A. 5

Individuals with cystic fibrosis, 5 Crohn’s disease and celiac disease are at risk for vitamin A

deficiency as these pathologies inhibit fat absorption, hence affect the absorption of vitamin A,

and the other fat-soluble vitamins as well. 4

Toxicity and Supplementation

Beta-carotene is non-toxic; however, high-dose supplementation (20, 30 and 50 mg/day) has

either shown no effect on lung cancer risk in individuals who did not smoke, 8,11

or has actually

shown a significant increase in lung cancer risk in individuals who smoked. 7 High levels of beta-

carotene supplementation over long periods of time are not recommended, especially for

smokers. 7 Except for this, high doses of beta-carotene and the other provitamin A carotenoids

have not been shown to have negative health effects. 5

Although beta-carotene supplementation does not reduce lung cancer risk, 8

the

consumption of high levels of total caroteinoids, lycopene, beta-cryptoxanthin, lutein and

zeaxanthin does. 9,10

In a large, 12-year study, beta-carotene supplementation showed no effect on

heart disease, cancer, or death from all causes. 11

Beta-carotene supplementation has been shown

to help protect the skin from UV damage resulting in sunburn. 22

It was thought that beta-carotene supplementation may reduce the risk of macular

degeneration, a pathology that destroys the part of the eye responsible for focused vision;

however, beta-carotene is not found in the macula lutea of the eye, and supplementation has not

been shown to be effective in improving the condition. 22,24

All of the forms of active vitamin A have been shown to cause birth defects, 34

so

pregnant women should not take active vitamin A supplements (beta-carotene is okay); further,

since active vitamin A is stored in the liver, the risk of causing birth defects remains for several

months after discontinuing high supplementation levels. 4

Vitamin A supplementation is recommended in individuals who are vitamin A deficient,

children who have measles 4 supplementation over the RDA does not reduce the risk of cancer of

any kind further. 4

High doses of active vitamin A are used by physicians to treat leukemia, 21

retinitis

pigmentosa, 19,20

which is the major cause of inherited blindness, 4 and skin diseases such as

psoriasis 17

and acne; 18

since these treatments require doses at toxic levels, they are closely

monitored. 4

Vitamin D

Ricketts is a bone disease of children characterized by malformed bones. Cod-liver oil had been

used by coastal folk to cure rickets for centuries, and was first mentioned in the medical

literature for rickets in 1824. 389

The French physician Armand Trousseau wrote in 1861 that rickets and osteomalacia

were caused by a poor diet as well as lack of sun, and that cod-liver oil could cure it. 390,392

In

1890, Scottish physician Theobald Palm, a medical missionary to Japan and other tropical areas,

7.7

noted that British infants had a higher rate of rickets than those who lived in the tropics; he

concluded that sun was needed to prevent rickets and recommended sun exposure to cure

rickets. 391

In 1906, Frederick Hopkins theorized that rickets and scurvy were caused by deficiencies

in “essential dietary factors.” 388

In 1919, the English physician, Edward Mellanby, through

experimentation with puppies, developed four diets that caused rickets, then determined that

rickets could be cured by feeding cod-liver oil, butter or milk; Mellanby further suggested that

there was a factor in the foods that cured rickets. 390

In 1918, working at Johns Hopkins University, Elmer McCollum and colleagues found

that rickets could be induced in rats, and cod-liver oil cured it. At first, vitamin A was considered

as being the factor that cured rickets; however, because oxidized cod-liver oil no longer could be

used to treat skin and eye problems, which vitamin A does, but can still be used to cure rickets, it

was understood that there was a different vitamin at work. The new substance was termed

“vitamin D” simply because it was next in the sequence of vitamins after vitamins A, B and C

had been discovered. 390

Characterization

Vitamin D is actually a steroid hormone, technically a “prohormone,” produced from cholesterol

by skin that is stimulated by ultraviolet-B radiation. 39

Sunlight of the wavelengths 290-315 nm

(400 nm is deep blue) strike the epidermis and induces the conversion of 7-dehydrocholesterol to

cholecalciferol, otherwise known as vitamin D3. A binding protein transports cholecalciferol to

the liver, where it is turned into calcifidiol (25-hydroxycholecalciferol). Calcifidiol is then

transported in the blood to the kidneys, where it is converted into calcitriol (1,25-

dihydroxycholecalciferol). Calcifidiol is the major circulating form of vitamin D in the blood.

Cholecalciferol and calcifidiol are both biological inactive; the active form is calcitriol. 40

Ergocalciferol, or vitamin D2, is derived from artificially irradiated mushrooms and may

be added to foods as a supplement. Cholecalciferol (D3) can also be manufactured, as can

calcitriol; cholecalciferol is also commonly added to foods as supplements. Ergocalciferol is

efficiently turned into calcitriol by the kidneys, 39

but is not as biologically active as

cholecalciferol 39

and is more toxic. 3

Dietary vitamin D is absorbed with other fats in the small intestine. Thus, as with active

vitamin A, vitamin D requires bile for absorption, and any pathology of the pancreas or liver that

affects the production of bile by the liver or the secretion of fat-digesting enzymes by the

pancreas will interfere with the absorption of dietary vitamin D. Once absorbed, vitamin D is

packaged into and carried by chylomicrons to the liver. 39

Excess vitamin D is stored in fat tissue, but is not available for immediate use from tissue

when needed. It appears that vitamin D stored in fat is liberated only when fat is metabolized. 39

Function

Active vitamin D (calcitriol) stimulates the absorption of calcium and phosphorus from food in

the gut, maintaining adequate blood calcium and phosphorus levels. 41

Blood calcium and

phosphorus levels need to be sufficient to support the formation and maintenance of strong bones

and teeth, thereby preventing rickets in children, and osteomalacia and osteoporosis in adults. 41,43

Vitamin D regulates hundreds of genes, possibly as much as 5% of the human genome. 48

7.8

It is involved in the control of cell differentiation and proliferation thereby helping with healing

and inhibiting cancer of several types, 39

including prostate, colon and breast cancer. 51

It is

associated with maintaining immune function. 44

It may inhibit the development of autoimmune

diseases, including type 1 diabetes; 50,52

vitamin D deficiency is associated with increased

autoimmunity risk, 44

and vitamin D supplementation is used to treat some autoimmune

diseases. 39

Vitamin D is associated with controlling the development and inflammation of fat

cells. 68

Adequate vitamin D is essential for proper nerve and muscle function. 55

Vitamin D is a powerful anti-inflammation agent, and deficiencies are associated with

increased risk for many chronic diseases. 39

Adequate vitamin D enhances insulin and glucose control, and pancreas function, thus

reduces the risk of type 2 diabetes. 43,45

Adequate vitamin D reduces the risk of high blood pressure, markedly reducing the risks

associated with hypertension such as heart disease. 46,47

Vitamin D may help prevent kidney

disease. 43

Vitamin D plays a role in supporting cognition 43

and helps maintain good mental health. 53

It is interesting, however, that many healthy individuals have low serum vitamin D levels,

so low vitamin D levels are probably not the sole cause of many pathologies associated with low

vitamin D levels. 39

RDI and UL

Males and females, 1-70 years of age, require 600 IU (15 mcg) daily, with the UL set at 4000 IU

(100 mcg) for individuals 9 years of age and over; 41

see Table 7.5 below. Adequate vitamin D

intake and synthesis should maintain blood calcifidiol levels of 50 nmol/L, which meets the

needs of 97.5% of individuals; blood levels of 125 nmol/L cause vitamin D toxicity symptoms. 41

International units, or “IU,” are units of biological activity; 40 IU = 1 mcg. 41

IUs (and/or percent of the RDI of vitamin D) are used on food and supplement labels.

Dietary Sources

About 5-15 minutes of direct, bright-sun exposure to the arms, legs or face, at least 3 times per

week may provide enough UVB for adequate vitamin D synthesis. 3 However, the American

Academy of Dermatology does not recommend that we get increased exposure to the sun as this

Table 7.5. DRI and UL for Vitamin D in mcg/day. 138,139

(Upper limits in parentheses.)

Age Male Female Pregnancy Lactation

0-6 months 10 (25) 10 (25) - -

6-12 months 10 (38) 10 (38) - -

1-3 years 15 (63) 15 (63) - -

4-8 years 15 (75) 15 (75) - -

9-50 years 15 (100) 15 (100) 15 (100) 15 (100)

51-70 years 15 (100) 15 (100) - -

> 70 years 20 (100) 20 (100) - -

Multiple mcg given by 40 to obtain IUs; 15 mcg = 600 IU, 100 mcg = 4,000 IUs.

7.9

increases the risk of skin cancer and no amount of UVB is safe; rather, they recommend that we

obtain vitamin D through diet and supplementation. 56

It is recommended that foods rich in

vitamin D be consumed, and individuals who are at risk for vitamin D deficiency (most people)

should take supplements (see above).

Foods that are particularly rich in vitamin D are listed in Table 7.6. Generally, fatty fish,

mushrooms, especially those grown in sunlight, and fortified dairy are highest in vitamin D.

Table 7.6. Representative Foods High in Vitamin D. 38

Values given in international units (IU), with 40 IU = 1 mcg.

Food IU Food IU Greenland halibut (3 oz) 932 Pacific halibut (3 oz) 388

Carp (3 oz) 840 Coho salmon (3 oz) 383

Eel (3 oz) 792 Tuna, light, canned in oil (3 oz) 229

Maitake mushrooms (1 cup, diced) 786 Tuna, light, canned in water (3 oz) 40

Sockeye salmon, canned (3 oz) 730 Atlantic sardines, canned (1 can) 178

Portabella mushrooms, UV exposed (1 cup) 634 Morel mushrooms (1 cup) 136

Rainbow trout (3 oz) 540 Milk, whole, 3.25% milkfat (1 cup, 8 oz) 124

Cod liver oil (1 tsp) 450 Milk, nonfat (1 cup, 8 oz) 115

Whitefish, smoked (3 oz) 435 Soymilk, plain (1 cup, 8 oz) 119

Channel catfish (3 oz) 425 Orange juice, fortified with D (1 cup, 8 oz) 100

Pork loin, rib in (1 rib) 407 Egg (1 large) 41

Deficiency

Over 1 billion people are vitamin D deficient globally, 63

with 77% of the U.S. adult population

being deficient. 67

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory

Committee determined that overall Vitamin D intake was insufficient, and was a “public health

concern.” 158

Rates in vitamin D deficiency have been growing as individuals minimize their

exposure to sun due to skin cancer concerns. 67

Adequate sunlight is essential for the photosynthesis of sufficient vitamin D. Light-

skinned individuals may need as little as 5 minutes per day of bright sunlight, 41

whereas dark-

skinned individuals may require more than two hours. 42

This suggests that dark-skinned

individuals are at the highest risk for vitamin D deficiency (see below). In higher latitudes, such

as Seattle, Washington, where there is less sun, dietary supplements are recommended. 42

The use

of sunscreens, which are recommended to lower the risk of skin cancer, markedly decrease

natural vitamin D production by 99% and lead to deficiency. 56,67

One theory explaining the higher risk of heart disease, cancers, hypertension, multiple

sclerosis, type 1 and 2 diabetes, obesity, kidney and other diseases in countries at higher latitudes

compared to those closer to the equator is the lower amount of sunshine, producing vitamin D

deficiency, observed in people living at higher latitudes. 51

People who live at higher latitudes

have a higher risk of dying of colon, prostate and breast cancer, probably due to reduced UVB

exposure. 51

Vitamin D deficiency has been linked to increased risk of heart disease, 51

peripheral

arterial disease, 61

prostate, 51

colorectal, 57

breast, 58

ovarian 69

and esophageal 69

cancer, multiple

sclerosis, 59

rheumatoid arthritis, 69

type 1 diabetes 52

and other autoimmune diseases, 44

type 2

diabetes, 60

hypertension, 60

acute respiratory infections including influenza, 64,65

obesity, 68

cognitive decline 43

and depression. 53

As indicated above, vitamin D deficiency commonly causes

rickets in children, and osteomalacia and osteoporosis in adults. 41,43

Dark-skinned children,

7.10

especially those exclusively breast-fed, are at the highest risk for rickets. 62

Supplementation may

help reduce the risk of all of these pathologies.

Groups that are at a higher risk for vitamin D deficiency include the following:

 Breastfed Infants. Infants that are given only breast milk, especially those with darker skin, are at high risk. Breast milk, though the most nutritious food that can be given to baby,

contains insufficient vitamin D. Vitamin D supplement drops should be given to breast-fed

infants. 62

Breast milk contains about 7 IU vitamin D per cup (8 oz). 38

 Dark-Skinned People. Individuals with darker skin contain higher amounts of melanin in the epidermis. Melanin blocks UVB, hence reduce its ability to stimulate the photosynthesis of

vitamin D. 66

Some 97% of U.S. blacks and 90% of Mexican-Americans are vitamin D

deficient. 67

 Limited Exposure to Sun. Many people reduce their exposure to the sun to reduce the risk of skin cancer. In this case, they must obtain their vitamin D from diet and supplements. People

who live at higher latitudes are also at a higher risk for vitamin D deficiencies than those who

live closer to the equator.

 Obesity. As indicated above, vitamin D is stored in fat tissue. Overweight and obese individuals tend to have lower vitamin D levels in the blood as more of their vitamin D is

removed from the blood than in thinner individuals. 66

 Older Adults. Reduced kidney function and the reduced ability of the skin to synthesize cholecalciferol is common with older age, thus reducing naturally-produced vitamin D.

66

 Gastric Bypass Patients. Individuals who have had part of their small intestine removed absorb less vitamin D (and other vitamins) from ingested food.

66

 Kidney Disease. Kidney disease may result in a marked decrease in calcitriol production, with subsequent vitamin A deficiency symptoms.

49

 Chronic Antacid Use. Overuse of antacids can reduce blood concentrations of vitamin D.16

Toxicity and Supplementation

Toxic amounts of vitamin D can only be obtained through supplementation and not through

whole foods or sun exposure. 39

Since a significant number of people are deficient vitamin D,

supplementation to recommended levels is suggested for most people. 56

Particularly during the

winter at higher latitudes, research suggests vitamin D intake be increased to 1000 IU or more. 67

Calcium supplements are often recommended to be taken with vitamin D (see Chapter 8).

Vitamin D3 (cholecalciferol) may be less toxic than the fungus-sourced D2

(ergocalciferol), 39

and has higher biological activity, so is the supplement form preferred. 3

The main benefit to vitamin D supplementation is to restore optimal levels to the blood.

Since most Americans are deficient, vitamin D supplementation can reduce the risk of

developing the pathologies discussed above under deficiencies. In brief, supplementation may

reduce the risk of heart and other vascular diseases, reduce the risk of cancers, help increase

glycemic control both type 1 50

and type 2 diabetes, reduce the risk of developing autoimmune

disease, reduce inflammation, reduce asthma, help with weight loss and maintenance, help

improve thinking, and help treat depression, although results have been varied. 54

Of course, it is

well established that vitamin D supplementation helps with the development and maintenance of

bones and teeth, and reduces the risk of rickets, osteomalacia and osteoporosis.

It is easy to obtain toxic amounts of vitamin D from supplementation. General symptoms

of vitamin D toxicity include increased urination, anorexia and weight loss, and heart

7.11

arrhythmias. 41

A major result of excess vitamin D is hypercalcemia, very high levels of calcium

in the blood. Hypercalcemia may cause abnormal heart rhythms, heart damage and increased risk

of heart disease; 39

increased risk of lung and breast cancer; 41

digestive system disorders such as

nausea, abdominal pain, ulcers, and constipation; urinary system disorders such as increased

urination, kidney stones, kidney damage 39

and kidney failure; calcification of soft tissues; 41

brain

conditions such as confusion, memory loss, dementia and depression; hyperthyroidism; skeletal

system problems like aches and pains in the bones, increased risk of fractures and spinal

curvature. 70

Vitamin E

In 1922, Herbert Evans and Katherine Bishop at the University of California at Berkeley,

discovered that rats fed a diet of lard, they would grow, but pregnant rats would lose their pups.

When the rats’ diet was supplemented with lettuce or wheat germ, pregnant rats would give birth

to healthy pups. Oil-extract of lettuce instead of whole lettuce or wheat-germ extract would also

allow healthy rats to be born. Evans and Bishop decided to call the substance, “vitamin E” in

1925. However, in 1924, Bennett Sure at the University of Arkansas discovered a fat-soluble

factor that, when missing, would render rats sterile; he called this factor, which turned out to be

the same chemical, “vitamin E,” about one year earlier than Evans and Bishop. 393

Characterization

“Vitamin E” is the collective term for eight related antioxidants: alpha-, beta-, gamma- and

delta-tocopherol and alpha-, beta-, gamma- and delta-tocotrienols. 73

These forms of vitamin E

are absorbed and carried to the liver by chylomicrons 15,75

where all of them, except alpha-

tocopherol, are oxidized (destroyed), the components of which are excreted into the bile, released

into the small intestine, and voided with the feces. 74,75,77

Because of this, vitamin E does not

bioaccumulate to toxic levels in the liver, 77

which makes it unique among the fat-soluble

vitamins. 75

Thus, alpha-tocopherol is the only form used by the human body. 71,77

Alpha-tocopherol binds to alpha-tocophopherol transfer protein (-TTP) in the liver, 15,77

which carries it into VLDLs. 76

VLDLs, then LDLs and HDLs carry alpha-tocopherol to the

tissues. 15,75

The reason the body uses only alpha-tocopherol is -TTP only recognizes alpha-

tocopherol among the eight types of vitamin E. 15

Function

Alpha-tocopherol serves as a powerful antioxidant. Free radicals are formed by mitochondria

during normal cell metabolism, especially when cells are active, as during athletic activities; 75

they’re also formed by the smoking of tobacco, 79

fried foods, ultraviolet radiation, pesticides and

from other environmental pollutants. 71,73,78

Free radicals are chemical species that contain an odd

number of electrons. Free radicals remove electrons from the fatty acids of cell membranes and

from the fatty acids and cholesterol of LDL, oxidizing them, contributing to the narrowing and

blockage of arterioles, thus increasing the risk of heart disease and stroke. 73

Free radicals also

remove electrons from proteins and DNA, increasing the risk of cancers. 71

Alpha-tocopherol

blocks oxidation reactions by being oxidized itself, by giving an electron to the free radical, 78

thus protecting the structure of cell membranes and reducing the risk of heart disease, stroke, 73

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cancers, 71

and conditions related to aging. 82

Once alpha-tocopherol has been oxidized, vitamin C

can be used to recharge it. 79

Besides its role as an antioxidant, alpha-tocopherol helps to support the immune

system. 71

Alpha-tocopherol inhibits the various types of protein kinase C (PKC). 73

PKC promotes

the proliferation and migration of cancer cells, the development of new blood vessels to feed

tumors, and the resistance of anticancer drugs. 81

Cancers of the head and neck, thyroid, breast,

lungs, kidneys, bladder, stomach, small intestine, colon, liver, pancreas, ovaries and prostate are

related to the action of PKC, as are leukemia and melanoma. 81

The inhibition of PKC reduces the

risk of developing these cancers; 81

further, PKC inhibition suppresses platelet aggregation inside

blood vessels, further reducing risk for heart disease and other vascular diseases such as stroke. 80

Alpha-tocopherol reduces the ability of monocytes and other blood components from

sticking to the walls of arterioles, thus inhibiting the formation of atherosclerotic plaque. 75

Alpha-tocopherol inhibits inflammation by inhibiting the release of certain components of

inflammation reactions, 75

and promotes the dilation of blood vessels, again reducing the risk of

vascular diseases such as heart disease and stroke. 71

RDI and UL

Males and females, 14 years of age and over, require 15 mg (22.4 IU) of alpha-tocopherol daily,

with the UL set for all individuals, 14-18, at 800 mg (1,200 IU) and at 1,000 mg (1,500 IU) for

individuals 19 years of age and over; 71

see Table 7.7 below. International units, or “IU,” are units

of biological activity; 1 mg of natural d-alpha-tocopherol = 1.49 IU and 1 mg of synthetic alpha-

tocopherol = 2.22 IU. 71

So, for instance, a 400 IU vitamin E supplement of natural d-alpha-

tocopherol contains 268 mg of vitamin E, 12 times the recommended amount, but far below the

established ULs. But read further below for comments about the UL and the evidence suggesting

it be lowered considerably.

IUs (and/or percent of the RDI of vitamin E) are used on food and supplement labels.

Table 7.7. DRI and UL for Vitamin E (natural alpha-tocopherol) in mg/day. 138,139

(Upper limits in parentheses.)

Age Male Female Pregnancy Lactation

0-6 months 4 (ND) 4 (ND) - -

6-12 months 5 (ND) 5 (ND) - -

1-3 years 6 (200) 6 (200) - -

4-8 years 7 (300) 7 (300) - -

9-13 years 11 (600) 11 (600) - -

14-18 years 15 (800) 15 (800) 19 (800) 19 (800)

19-50 years 15 (1,000) 15 (1,000) 19 (1,000) 19 (1,000)

> 51 years 15 (1,000) 15 (1,000) - -

Multiply mg given by 1.49 to obtain IUs. ND = not determined.

Dietary Sources

The main dietary sources of d-alpha-tocopherol are nuts and seeds, seafoods, fortified cereals

and many fruits and vegetables; a perusal of Table 7.8 shows that vitamin E is found in a wide

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variety of whole foods. Note that dairy, unless fortified, meats and poultry are comparatively low

in vitamin E. Since the DRI for vitamin E is only 15 mg daily, it is clear that whole foods can

easily supply all the vitamin E most healthy people need to remain healthy.

Table 7.8. Representative Foods High in Vitamin E. 38

Values given for natural d-alpha-tocopherol.

Food mg Food mg Wheat bran flakes cereal, Ralston (3/4 cup) 23.33 Apricots, dried (1/2 cup) 2.81

Granola, homemade (1 cup) 13.55 Kiwi, sliced (1 cup) 2.62

Ovaltine beverage (1 cup) 9.57 Canola oil (1 tbsp) 2.44

Kellogg’s Rice Krispies (1.25 cup) 8.79 Broccoli, cooked (1 cup) 2.26

Conch, baked or broiled (1 cup, sliced) 8.04 Olive oil (1 tbsp) 1.94

Bagel, 4” diameter 7.83 Sardines, canned in oil (1 can, 3.75 oz) 1.88

Sunflower seed kernels, dry roasted (1 oz) 7.40 Sardines, canned in oil (1 can, 3.75 oz) 1.88

Almonds, dry roasted (1 oz) 6.78 Rye flour, dark (1/2 cup) 1.75

Soymilk (1 cup, 8 oz) 6.12 Brazilnuts (1 oz) 1.60

Hazelnuts or filberts (1 oz) 4.26 Mango, sliced (1 cup) 1.48

Tomato sauce (1 cup) 3.52 Peanuts, dry roasted (1 oz) 1.40

Abalone (3 oz) 3.40 Avocado, California (1/2) 1.34

Eel (3 oz) 3.40 Quinoa, cooked (1 cup) 1.17

Swiss chard, cooked (1 cup) 3.30 Salmon, coho, smoked (3 oz) 1.15

Sweet potato, cooked (1 cup) 3.08 Tomato, raw (1 medium) 0.66

Cranberry juice, unsweetened (1 cup, 8 oz) 3.04 Egg, large 0.52

Peanut butter (2 tbsp) 2.91 Post Shredded Wheat, spoon size (1 cup) 0.32

Deficiency

Although adequate amounts of vitamin E are easy to obtain from a balanced, whole-food diet,

over 90% of American adults do not obtain 15 mg/day of vitamin E; in fact, the average intake is

6.9 mg/day. 99

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee

determined that overall, Vitamin E was a “shortfall nutrient.” 158

Even so, symptomatic vitamin E

deficiency is rare and not seen in healthy individuals. 71,73

Vitamin E deficiency may be caused by individuals on a low-fat diet, or those with

pathologies that inhibit the absorption of fats such as cystic fibrosis, Crohn’s disease or liver

disease. 71,73

Symptoms of vitamin E deficiency include neurological problems such as damage to

the retina (retinopathy) and sensory nerves (neuropathy), balance and coordination impairment

and muscle weakness (myopathy). 73

Inhibition of the immune system with increased risk of

infections is also a symptom of vitamin E deficiency. 71

Toxicity and Supplementation

Over 1/3 of American adults take multiple vitamins daily containing 400 IU of vitamin E, 94,96

and many take an additional 400 IU, yet supplements have virtually no effect on any pathology,

except to correct nutritional deficiencies; 94

further, as indicated below, studies suggest

supplementation decreases overall health.

Studies suggest that daily vitamin E supplementation of 400 IU increases the risk of

developing prostate cancer by 17%. 72

This makes sense because alpha-tocopherol inhibits the

mechanism that vitamin K uses to cause apoptosis (cell death) in cancer cells, so by blocking the

cancer-killing action of vitamin K, vitamin E supplements increase cancer risk. 134

However,

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alpha-tocopheryl succinate, a form of vitamin E, has been shown to be a powerful anti-cancer

agent, more powerful than alpha-tocopheryl acetate or nicotinate. 137

Multiple large studies show that vitamin E supplements do not reduce the risk of heart

disease, 86

do not increase recovery from heart disease, and do, in fact, increase the risk of heart

failure. 83

The American Heart Association does not recommend taking vitamin E supplements 85

or any antioxidant supplements to prevent heart disease, but does recommend a balanced, whole-

food eating plan with physical activity to reduce the risk of heart disease. 84

Vitamin E supplements of 400 IU every other day have been shown to increase the risk of

hemorrhagic stroke, 86

with daily supplements of 150 IU and above increasing the risk of death

slightly but significantly. 94

Because supplement amounts of vitamin E inhibit the blood clotting

effects of vitamin K, 154

individuals who are taking other blood clotting agents such as vitamin D,

fish oil, aspirin, warfarin (Coumadin) 71

and other blood-thinning agents, should review what they

are taking with their doctor.

Studies suggest that vitamin E supplements do not benefit macular degeneration 87,88

or

cataracts. 89

Regarding diseases of the brain, studies have shown that vitamin E supplementation has

no effect on improving Alzheimer’s disease 92

or on improving mild cognitive impairment. 91

Recent research (2014), however, shows that high doses of vitamin E (2000 IU) reduce the

progression of functional decline in Alzheimer’s disease by 19% per year, but not cognitive

decline. 90

Regarding Parkinson’s disease, diets rich in vitamin E from whole foods decrease the

risk of developing Parkinson’s; 94

vitamin E supplements do not benefit individuals who already

have Parkinson’s. 95

Regarding amyotrophic lateral sclerosis (ALS), vitamin E supplementation

does lower the risk of developing ALS, 97

but does not benefit patients who already have ALS. 98

More research is needed.

Vitamin K

In 1929, Danish researcher Henrik Dam, while working on sterol chemistry, noted that chickens

fed a diet that did not contain foods containing cholesterol would develop symptoms including

hemorrhaging. 394

Feeding purified cholesterol to the chickens would not cure the condition; thus

he theorized that the lack of another factor was causing hemorrhaging. 394

The same symptom

was noted by other researchers in chickens fed diets that did not include greens, and could be

prevented with extracts of alfalfa meal. 394

Dam’s research group continued to work on this

substance, and published conclusive evidence that it was a new vitamin, which he named

“vitamin K,” just before an American group working out of the University of California at

Berkeley published their results. 394

In 1943, Henrik Dam and Edward Doisy were awarded the Nobel Prize for their work in

the discovery of vitamin K and determining its function. 395

Characterization and Function

Vitamin K is a group of structurally-similar compounds including vitamin K1, also called

phylloquinone, and vitamin K2, a group designation for the menaquinones, with several

subtypes. 102,107

Phylloquinone (K1) is found in green plants where it is associated with beta-

carotene and chlorophyll, participating in the process of photosynthesis; thus, it is particularly

rich is leafy green plants. 103

Phylloquinone (K1) is converted into K2 subtype MK-4 by the walls

7.15

of arteries, the pancreas and testes. 105

The MK-4 type of vitamin K2 is the most common form of

vitamin K in animals, including humans. 100

Vitamin K1 can also be converted into MK-4 or other

forms such as MK-7 to MK-11 by bacteria in the colon; 105,106

only gut bacteria can produce MK-

7 to MK-11. 105

Most of the vitamin K2 is synthesized by gut bacteria, but some is ingested from

fermented foods and animal-sourced foods. 101

Vitamin K3, menadione, is an artificially-

synthesized provitamin form of vitamin K that is commonly used for livestock. 107

Note that diets rich in soluble, fermentable fiber sources such as whole grains and

legumes, support beneficial gut bacteria that synthesize vitamin K, especially Bacteroides

fragilis and B. vulgatus, whereas very-low fiber diets do not and are associated with severe

vitamin K deficiency. 113

Evidence suggests that some of this K2 is absorbed as the unique forms

of vitamin K2, MKs 10-13, produced by these bacteria, have also been found in the liver so must

have been absorbed. 127

There is further evidence that the site of absorption of bacteria-produced

K2 is the end of the small intestine, which does harbor vitamin K-producing bacteria. 105

Since it is a fat-soluble vitamin, vitamin K is absorbed in the intestine in the same way

vitamins A, D and E are absorbed. Micelles must be formed in the aqueous environment of the

intestine with the assistance of bile, dietary fat needs to be present, and absorption occurs

through the cells lining the small intestine and colon. Absorption efficiency of vitamin K is in the

range of 40-70%. 107

There is evidence that phylloquinone (K1) is absorbed by ATP-powered active transport,

whereas K2 is absorbed by passive diffusion in the distal part of the small intestine and from the

colon, which allows for the absorption of bacteria-synthesized K2 (MK-4). 107

In the cells lining

the gut, vitamin K is packaged into chylomicrons, 107

which are released into the lymphatic

system. From the lymphatic system they enter the circulatory system and end up in the liver. In

the liver, vitamin K is either used to synthesize four of the 13 proteins essential for blood

clotting, 106

or is packaged into VLDLs for release into the blood and transportation to the

tissues, 107

where K1 and K3 are converted into K2. 108

The liver does not store vitamin K and the

half-life is about 17 hours. 107

Vitamin K2 concentrates somewhat in the brain, kidneys and

pancreas, but is found and used by many tissues such as the heart and bone. 100,107,108

Compared to the other fat-soluble vitamins, little vitamin K is stored in the body. 100

It is

quickly metablized. Some 20% of phylloquinone (K1) is excreted into the urine, with about 40-

50% dissolved in bile and released into the feces. 100

Only about 30-40% of dietary vitamin K is

kept. 100

Vitamin K is necessary for blood clotting and bone mineralization; in fact, the “K” in

vitamin K comes from the Danish word for clotting, Koagulation. 101

As stated above, four of the

13 plasma proteins that are involved in the biochemical process of blood clotting are produced

by vitamin K. 106

Vitamin K also promotes the aggregation of blood platelets by activating a

protein called Gas6 (growth arrest-specific gene 6 protein). 119

Protein S, also activated by

vitamin K, reduces coagulation. 101

Vitamin K is needed for the regulation of bone formation. Osteocalcin is one of the

proteins needed for formation of bones. Although active vitamin D (calcitriol) stimulates the

synthesis of osteocalcin by osteoblasts, which are the cells in bone tissue that form bone, a

compound formed by vitamin K2 is needed to bind calcium onto osteocalcin to form bone

crystals. 116

The matrix gla protein (MGP) works opposite osteocalcin by inhibiting bone

formation in various soft tissues such as cartilage, skin, blood vessel walls, heart, kidneys and

other sites, including bone itself. MGP is activated by vitamin K2. 100, 117

Vitamin K thus inhibits

soft tissue ossification. 118

In the heart, insufficient vitamin K does not activate enough MGP to

7.16

inhibit the calcification of the heart, increasing the risk of heart disease; thus, vitamin K inhibits

heart disease. 100

As a side note, vitamin K-antagonists are used to reduce internal clots in blood

vessels; because they also decrease the activity of MGP, they increase atherosclerotic

calcification in coronary arteries thereby contributing to heart disease. 129

The vitamin K-activated protein S, mentioned above, stimulates the breakdown of

bone, 101

thus provides another mechanism by which vitamin K helps to regulate bone formation.

Cell growth and communication between cells is regulated, in part, by vitamin K’s

activation of the Gas6 gene. As a response to injury, it promotes conditions associated with

tissue repair such as atherosclerosis 101,121

and inflammation; 125

it is also associated with the

promotion of the growth of cancer cells. 101

The overall effect of dietary menaquinone (K2),

though, is to reduce atherosclerosis 130

and inhibit the growth of cancer cells; 107

phylloquinone

(K1) reduces inflammation, 123

as does vitamin K2 (MK-7). 150

Vitamin K1 (phylloquinone) plays a role in the control of blood glucose and insulin. 123

RDI and UL

Males, 19 years of age and over, require 120 mcg of vitamin K daily and females, 19 years of

age and over, require 90 mcg of vitamin K daily. 100,138

There is no upper limit (UL) set for

vitamin K; 100,139

see Table 7.9 below.

Table 7.9. DRI and UL for Vitamin K in mcg/day. 138,139

(No upper limits have been determined for vitamin K.)

Age Male Female Pregnancy Lactation

0-6 months 2.0 2.0 - -

6-12 months 2.5 2.5 - -

1-3 years 30 30 - -

4-8 years 55 55 - -

9-13 years 60 60 - -

14-18 years 75 75 75 75

19-50 years 120 90 90 90

> 50 years 120 90 - -

Dietary Sources

It has been estimated that as much as half of the intake of vitamin K in the human diet comes

from bacterial synthesis in the gut, 109

but this value is probably significantly lower, around 10%,

due to the lack of bile in the colon needed for absorption and the fact that bacterial K2 is

complexed inside bacteria and is not freely available for absorption. 126,148

There is very good

evidence, though, that some bacteria-produced vitamin K2 is absorbed in the end of the small

intestine, 105

and that bacteria-produced vitamin K is significant as individuals on broad-spectrum

antibiotic therapy, including cephalosporins, 143,144

exhibit vitamin K deficiency

symptoms, 141,142,146

and have significantly lower amounts of K2 in the liver than individuals who

are not on antibiotic therapy. 140

Vitamin K1 is obtained from foods high in chlorophyll such as leafy green vegetables; 100

fruits and grains are not a good source, 107

although they are certainly a healthy source for other

nutrients. Vitamin K2 is found in some fermented foods 100,148

and in modest amounts in some

7.17

animal-sourced foods (see Table 7.11); note that the highest source of dietary vitamin K2 is natto,

which is fermented soybean curd.

Cooking does not significantly reduce the amount of vitamin K in foods. 126

There is commercial interest in using more bacteria that produce the various forms of

vitamin K2 to produce fermented dairy products such as cheeses to increase the amount of

menaquinones in the American diet. 148