Nutrtion

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

7.12

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

7.13

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,

7.14

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

Only about 10% of phylloquinone is absorbed from boiled spinach, suggesting that the

vitamin K1 from natural plant sources may be poorly absorbed. Purified K1 is absorbed at a rate

of about 80%. 107

Except for oysters, fish and shellfish contain virtually no vitamin K; 38

see Table 7.11

below. Full-fat dairy from grass-fed cows, including cheeses, yogurts and kefir, and eggs from

free-range chickens contain much more K2 than typical grain-fed sources. 151

Table 7.10. Representative Foods High in Vitamin K1 (Phylloquinone). 38

Food mcg Food mcg Kale, frozen, boiled, chopped (1 cup) 1146.6 Dandelion greens, raw, chopped (1 cup) 482.0

Collards, frozen, boiled, chopped (1cup) 1059.4 Brussel sprouts, frozen, boiled (1 cup) 300.0

Spinach, canned, drained (1 cup) 987.8 Broccoli, frozen, boiled, chopped (1 cup) 162.0

Spinach, fresh, boiled (1 cup) 888.4 Asparagus, frozen, boiled, chopped (1 cup) 144.0

Turnip greens, frozen, boiled (1 cup) 851.0 Coleslaw (1/2 cup) 67.7

Mustard greens, boiled (1 cup) 829.8 Plums, dried (prunes), uncooked (1/2 cup) 51.8

Beet greens, boiled (1 cup) 697.0 Radicchio, raw (1 cup) 102.0

Dandelion greens, boiled (1 cup) 579.0 Broccoli, raw, chopped (1 cup) 92.0

Swiss chard, boiled (1 cup) 572.8 Soup, split pea (1 cup) 92.0

Table 7.11. Representative Foods High in Vitamin K2 (Menaquinone-4, except as

indicated). 38,100

Food mcg Food mcg Natto (3 oz) (as MK-7) 850 Cheese, cheddar , diced (1/2 cup) 5.6

Chicken, back meat only, rotisserie (1 back) 26.1 Oysters, eastern, cooked moist heat (3.0 oz) 4.2

Italian meat balls, frozen (3 oz) 23.9 Cheese, parmesan, grated (1/2 cup) 3.6

Chicken, thigh meat only, rotisserie (1 thigh) 21.4 Cheese, mozzarella, diced (1/2 cup) 2.6

Chicken, drumstick, rotisserie (1 drumstick) 18.9 Pulled pork in barbecue sauce (1/2 cup) 1.9

Kielbasa, kolbasy, pork, beef (1 link) 12.2 Beef, shoulder steak (3 oz) 1.7

Frankfurter, chicken (1 link) 11.3 Milk, whole (3.25%) (1 cup, 8 oz) 2.4

Pork sausage, smoked (1 link) 9.3 Milk, low-fat (2%) 1.0

Corn dog (1 dog) 8.7 Turkey breast, sliced, prepackaged (1 slice) 1.4

Ham, pork rump, cured (3 oz) 8.2 Cottage cheese (1/2 cup, 4 oz) 1.0

Chicken liver, braised (3 oz) 6.0 Salmon, sockeye, smoked (3 oz) 0.8

Ground beef, broiled (3 oz) 6.0 Catfish, channel cat, cooked, dry heat (3 oz) 0.6

Deficiency

Infants are especially at risk for vitamin K-deficiency problems for the following reasons: 1)

Vitamin K does not transfer across the placenta well, and neonates have about ½ the amount of

vitamin K as their mothers; thus, they are born deficient. 2) Neonates are born without the gut

bacteria necessary to synthesize vitamin K. 3) The liver cannot make sufficient clotting factors in

neonates; the concentration of plasma clotting factors is about ¼ that of the mother. 4) Breast

7.18

milk does not contain sufficient vitamin K; thus, neonates are deficient vitamin K and are at risk

of hemorrhagic disease. 107

Overt vitamin K deficiency is exceedingly rare in adults. 126

A higher than normal time for

blood to clot is a symptom. 100

The NHANES 2011-2012 study indicated that males 20-29 and >

70 years of age consumed, on the average, slightly insufficient amounts of vitamin K, but the

other age classes of males, and all age classes of women, starting at 0 years of age to > 70, were

not at risk for vitamin K deficiency. 153

The 2015 USDA Scientific Report of the Dietary

Guidelines Advisory Committee determined that Vitamin K intake for all age classes of both

males and females were above RDA or AI amounts. 158

A healthy pancreas and liver for the production of bile is necessary for the absorption of

vitamin K. 107

Liver disease may reduce the amount of vitamin K-produced clotting factors and

increase the risk of uncontrolled bleeding. 101

Antibiotic use is associated with vitamin K deficiency. Virtually any orally-administered

antibiotics reduce the numbers of K2-producing gut bacteria, thus markedly reduce the amount of

menaquinones in the blood. 110,141,142,143,144

High amounts of vitamin A and vitamin E reverse the effects of vitamin K. 101,154

Vitamin

A blocks vitamin K absorption leading to deficiency and vitamin E blocks the formation of

vitamin K-dependent clotting factors. 114

Individuals taking anticoagulant drugs such as warfarin

(Coumadin), which blocks the action of vitamin K, increase their risk of hemorrhage by taking

vitamin E supplements. 115

Vitamin K and vitamin D deficiency is associated with inflammatory bowel disease,

especially Crohn’s disease. 122,157

Low vitamin K status is associated with pathologies caused by

inflammation such as osteoarthritis; one study linked osteoarthritis of the hand and knee

specifically to vitamin K deficiency. 156

Vitamin K deficiency is associated with an increased risk of uncontrolled bleeding and an

increased risk of bone loss and calcification of the arteries, especially in postmenopausal women,

diabetics and individuals with kidney disease. 126

The risk of osteoporosis increases with vitamin

K deficiency. 100

Excessive bleeding from wounds, easy bruising, heavy menstrual periods

(menorrhagia), blood in the urine or stools all may be signs of vitamin K deficiency. 147

Vitamin K deficiency is also associated with increased risk of developing type 2

diabetes 133

and increased risk of heart disease in individuals with type 2 diabetes. 132

Low vitamin K status increases the risk of vascular calcification, leading to

atherosclerosis, heart disease, kidney disease, and other vascular pathologies. About 30% of

adults have vascular calcification. 155

Toxicity and Supplementation

There are no known toxic effects associated with high dietary or supplemental amounts of

vitamins K1 (phylloquinone) or K2 (menaquinones) in adults. 101

Vitamin K3 (menadione),

though, has been shown to be toxic, and is not used to treat vitamin K deficiency and is not

recommended as a supplement. 101

When injected, menadione has been shown to oxidatively

damage cell membranes, resulting in liver damage and the destruction of red blood cells,

characterized by jaundice and hemolytic anemia. 101

As recommended by the American Academy of Pediatrics, vitamin K supplements are

given to newborns as a single injection to promote normal blood clotting, preventing Vitamin K

Deficiency Bleeding (also termed, “Hemorrhagic Disease of the Newborn”); 145

follow-up

7.19

supplementation is given orally. 126

Vitamin K injections in infancy have been shown to not

increase the risk of childhood cancers, including leukemia. 126,145

Vitamin K is used to counter the effects of medications that inhibit blood clotting such as

salicylates (aspirin), sulfonamides and quinine. 111

Since antibiotics inhibit the production of

vitamin K from gut bacteria, vitamin K supplements may be given to individuals who are on

antibiotics. 111

Individuals at high risk for osteoporosis may be given vitamin K to increase bone

mineralization; 112

the use of steroid medications may increase bone loss, so vitamin K may be

given to these individuals. 111

Vitamin K injections are clinically given to individuals with blood

clotting problems. 111

Vitamin K is given to lower blood cholesterol. 111

Cancer treatment using

vitamin K have been shown to be effective. 112

Topically, vitamin K is used to resolve bruises, stretch marks, scars, and spider veins;

surgical scars are often treated with vitamin K. 111

Vitamin K2 has been shown to induce apoptosis (cell death) in cancer cells including

those involved in leukemia, ovarian, liver, pancreatic, lung, stomach 134

and colorectal cancer. 136

However, alpha-tocopherol (vitamin E) inhibits the mechanism that vitamin K2 uses to do this,

so, in general, it is advisable not to take vitamin E supplements. 134

Vitamin K2 has also been

shown to inhibit the proliferation of liver cancer cells, but K1 showed no such effect. 135

Vitamin

K2, especially K2 from dairy, but not K1, has been shown to significantly reduce the risk of

prostate cancer and to significantly inhibit advanced stages of prostate cancer. 149

In individuals with high cardiovascular disease risk, increased dietary intake of vitamin K

reduces the risk of heart disease, cancers, kidney disease and all-cause mortality. 124,128

Menaquinone (K2) supplementation reduces aortic and coronary calcification, which contribute

to heart disease, by 57%; phyllaquinone showed no such effect. 100,130

Supplementation also

reduces the calcification of arteries in the kidneys in individuals with chronic kidney disease. 128

Vitamin K2 (MK-7) has been shown to significantly reduce inflammation, thereby

contributing another mechanism that reduces the risk of heart disease, bone loss and other

pathologies. 150,152

Vitamin K1 (phylloquinone) has also been shown to reduce inflammatory

markers by 30%. 123

Increased dietary intake of phylloquinone (K1) markedly reduces the risk of developing

type 2 diabetes 133

and reduces the risk of heart disease in people with type 2 diabetes. 132

Vitamin

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

and vitamin K2

(menatretrenone) supplementation has been shown to significantly improve blood glucose and

insulin levels, 131

so may be of benefit to diabetics.

Vitamin K supplementation has been approved in Europe and Japan for the treatment of

osteoporosis. 100

Vitamin K2 supplements including MK-4 and MK-7 are optimal, and should be taken

with fat to increase absorption. Vitamin D and calcium should be ingested with vitamin K. 151,152

 Water-Soluble Vitamins

The water soluble vitamins are those that can freely mix with water and not with oil. Because of

this, they generally do not bioaccumulate in fat tissues or in the liver, 162

vitamin B12 being the

exception (see below). This means that toxic levels are generally difficult to ingest as amounts

taken in that are not used by the body are flushed out with in the urine. This also means they

must be replaced daily, 162

preferably through the consumption of nutrient-dense, whole foods.

7.20

Vitamin C and the B vitamins are the water-soluble vitamins. They are chemically fragile

vitamins, easily destroyed by cooking 162

or easily washed out of foods into the water used to

cook them; the water used to cook foods should be consumed. The B vitamins in fresh fruits and

vegetables begin to decompose at the time of harvest, so fresh fruits and vegetables should either

be immediately consumed or frozen. 162

Vitamin C (Ascorbic Acid)

Vitamin C, otherwise known as L-ascorbic acid or ascorbate, and dehydroascorbic acid, 159,162

was one of the first vitamins discovered. Sailors of the 14 th

to 18 th

centuries generally ate a

closely-rationed diet of hardtack; salted beef, pork or fish; a bit of cheese; possibly beans or

peas; some oil; water; and ale/beer or wine. Hardtack was unleavened biscuits, usually moldy or

covered with beetles called weevils. Water was often stale, so beer and wine were carried as

standard beverages, and rat urine and feces often contaminated ship’s stores. 178,179,180

The beer

and wine undoubtedly served to keep the crew amiable. On shorter voyages, fresh foods could be

carried aboard ship; 180

but on long voyages, this kind of diet greatly increased the risk of

developing bleeding swollen gums, tooth loss, hemorrhaging under the skin and wounds that

healed slowly, a pathology called scurvy; it also increased the risk of death. 165

During the “Age

of Exploration,” some two thirds of Vasco da Gama’s crew (1499) died from scurvy while

crossing the Indian Ocean and 80% of Magellan’s crew (1520) died from scurvy while crossing

the Pacific. 182

Some of the first clear records describing scurvy were written during the

Crusades. 165

A Scottish physician, James Lind, in 1747, experimented with different foods that might

affect scurvy, and found that oranges, lemons and other citrus were effective in treating the

pathology. 164

In 1795, the British Navy began allocating, by law, lemon or lime juice from

Jamaica, a British colony, to all sailors, 165

giving British seamen the nickname, “limeys.” 181

Lemon juice contains more vitamin C than lime juice and is less susceptible to losses in vitamin

C caused by ship-board storage; lime juice, though, was less expensive. 183

By the way, well

before this, Danish sailors knew that citrus would prevent this pathology, so included citrus in

their provisions. 165

In 1933, Joseph Svirbely and Albert Szent-Györgyi published their work

demonstrated that ascorbic acid deficiency caused scurvy. 166

Characterization and Function

Most mammals can synthesize vitamin C, from glucose; 168

humans and other primates, guinea

pigs, some bats, some bird species, most fishes and a few other species have lost the ability. 161

Thus, those of us who cannot make vitamin C must get it from foods that contain vitamin C.

Dietary vitamin C, both ascorbic acid and dehydroascorbic acid, is taken in the entire

length of the small intestine, with three times the absorption near the end. 168

Ascorbic acid is

absorbed by sodium-dependent transporters. 168

Some ascorbic acid in the gut is oxidized to

dehydroascorbic acid, which is absorbed by glucose transporters. 107

About 80%-90% of vitamin

C is normally absorbed at doses up to about 1,000 mg. 107

High dietary iron concentration in the

gut may oxidize vitamin C, destroying its biological activity; 177

too much iron in the diet,

generally only derived through supplementation, is toxic (see Chapter 8).

Inside the cells lining the small intestine, dehydroascorbic acid is converted to ascorbic

acid and released. 107

Some 80%-90% of vitamin C is transported in the plasma as ascorbic acid,

7.21

the rest as dehydroascorbic acid. 107

From the blood, cells take up ascorbic acid and

dehydroascorbic acid by sodium-dependent transporters and glucose transporters, respectively. 107

Insulin increases the absorption of dehydroascorbic acid, and glucose decreases it by

competition; thus diabetics may have high plasma levels of dehydroascorbic acid. 107

Human (and animal) tissues do concentrate levels of ascorbic acid. The pituitary gland

accumulates 40-50 mg/100 g and the adrenal glands 30-40 mg/100 g of tissue; bovine adrenal

glands have ascorbic acid concentrations of up to 168 mg/100 g of tissue. The human liver

contains up to 16 mg; thymus gland, pancreas, heart, kidneys and brain up to 15 mg/100 g of

tissue; lens of the eyes, up to 31 mg, muscle, 3-4 mg, and lungs, 7 mg/100 g of tissue. 107

Vitamin C ingested in excess of 500 mg/day is excreted, intact, in the urine. Thus, mega

doses are not absorbed by the cells. 107

Vitamin C is needed for the synthesis of collagen, 159

the most common protein in the

body, found in all connective tissues; thus, it is needed to maintain the structure of blood vessels,

provide the protein component of bone, maintain ligaments and tendons, hold muscles together,

keep teeth in their sockets, is an essential component in wound healing 159

and promotes healthy

skin. 162,163,165

It is also involved in making L-carnitine, the transporter that moves fatty acids into

mitochondria for the production of ATP (energy), and it’s needed to synthesize some

neurotransmitters. 159

Vitamin C promotes the absorption and use of both non-heme iron, 162,163

and heme

iron. 107

Non-heme iron is derived from plants, dairy and eggs, and is poorly-absorbed; heme iron

comes from meats and is better absorbed; see Chapter 8.

Vitamin C reduces blood cholesterol levels and inhibits the formation of

nitrosamines. 162,163

Vitamin C enhances the functioning of the immune system. 162,163

Research suggests that vitamin C reduces the risk of arteriosclerosis, heart disease and

some types of cancer 163

and cataracts. 162

Vitamin C is the most powerful water-soluble antioxidant, 107,163,165,167

and works with

vitamin E to neutralize free radicals, 162

slowing oxidative damage. It works with vitamin E to

inhibit the oxidation of LDLs. 107

And it helps to recharge vitamin E. 167

Vitamin C helps protect

proteins from oxidation, thereby reducing the risk of cataracts, and helps protect DNA from

oxidation during times of inflammation. 107

Nitric oxide is a hormone that causes dilation of

arteries and arterioles, thereby lowering blood pressure; vitamin C helps protect nitric oxide from

oxidation, thus helping to normalize blood pressure. 107

At least 8 enzymes use vitamin as a cofactor, activating them. 107,167

These enzymes are

involved in collagen synthesis; the synthesis of the neurotransmitter, dopamine; carnitine

synthesis; cholesterol and tyrosine metabolism. 107

RDI and UL

Males, 19 years of age and over, require 90 mg of vitamin C daily and females, 19 years of age

and over, require 75 mg of vitamin C daily. 138,139

Although non-toxic, an upper limit has been set

for adults, 19 years of age and over, of 2,000 mg/day; see Table 7.12 below. Once saturated with

vitamin C, the body does not absorb more, so much of what is consumed in supplement doses

over about 500 mg/day is excreted out into the urine (see below).

7.22

Table 7.12. DRI and UL for Vitamin C (ascorbic acid) in mg/day. 138,139

(Upper limits in parentheses.)

Age Male Female Pregnancy Lactation

0-6 months 40 (ND) 40 (ND) - -

6-12 months 50 (ND) 50 (ND) - -

1-3 years 15 (400) 15 (400) - -

4-8 years 25(650) 25(650) - -

9-13 years 45 (1,200) 45 (1,200) - -

14-18 years 75 (1,800) 65 (1,800) 80 (1,800) 115 (1,800)

19-50 years 90 (2,000) 75 (2,000) 85 (2,000) 120 (2,000)

> 50 years 90 (2,000) 75 (2,000) - -

ND = not determined

Dietary Sources

Vitamin C (ascorbic acid) is the most important vitamin required for human nutrition found in

fruits and vegetables. 163

The best source of vitamin C is freshly-picked, raw or steamed, whole,

fruits and vegetables.

Post harvest, the longer fruits and vegetables rich in vitamin C are stored and the higher

the temperature of storage, the more vitamin C is lost. 163

Leafy green vegetables lose more

vitamin C when subjected to drying conditions; 163

leafy greens should be kept moist until

consumed to maximize vitamin C content. During the preparation of fruits and vegetables,

conventional heating damages more vitamin C than microwaving; 163

cooking in copper pots is

particularly damaging to vitamin C. 165

Boiling destroys vitamin C. 165

Irradiation, used to inhibit

the spoilage of fresh fruits and vegetables, has no significant affect on vitamin C content. 163

Foods that are particularly high in vitamin C include fruits such as West Indian cherries,

peaches, currants, kiwis and guavas; oranges, lemons, limes, grapefruit and other citrus; broccoli,

and other green vegetables; tomatoes and peppers; 165

see Table 7.13 below.

Table 7.13. Representative Foods High in Vitamin C (Ascorbic Acid). 38

Food mg Food mg Acerola (West Indian cherry) juice (1/2 cup) 1936.0 Broccoli, raw, chopped (1 cup) 81.2

Guava (1 cup) 376.6 Pineapple, chunks, raw (1 cup) 79.0

Rose hips, wild (1/2 cup) 270.5 Peas, boiled (1 cup) 76.6

Peaches, frozen, sliced (1 cup) 235.5 V8 vegetable juice, low sodium (1 c) 72.0

Currants, European black, raw (1 cup) 202.7 Sweet potato, canned (1 cup) 67.4

Peppers, sweet, yellow, raw (1/2 pepper) 170.7 Broccoli, flower clusters, raw (1 cup) 66.2

Kiwifruit, green, raw, sliced (1 cup) 167.0 Cantaloupe, balls, raw (1 cup) 65.0

Oranges, navels, raw, sections (1 cup) 97.6 Orange juice, raw (1/2 cup, 4 oz) 62.0

Peppers, sweet, red, raw, chopped (1/2 cup) 95.0 Lemons, raw, without peel, sections (1/2 c) 56.2

Strawberries, frozen, unsweetened (1 cup) 91.2 Lemon juice, raw (1/2 cup, 4 oz) 47.2

Strawberries, raw (1 cup) 89.4 Grapefruit juice, white or pink, raw (1/2 cup) 47.0

Papayas, raw, 1” pieces (1 cup) 88.4 Orange juice (1/2 cup, 4 oz) 45.1

Grapefruit, pink and red, raw sections (1 c) 87.6 Pineapple juice, with added C (1/2 cup) 39.1

Kale, scotch, raw, chopped (1 cup) 87.1 Lime juice, raw (1/2 cup, 4 oz) 36.3

Mandarin oranges, canned (1 cup) 85.2 Peppers, jalapeno, raw, sliced (1/4 cup) 26.7

Tomato juice, canned (1/2 cup, 4 oz) 85.2 Peppers, banana, raw (1/4 cup) 25.6

7.23

Deficiency

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee determined

that overall Vitamin C intake was insufficient. 158

Cases of overt vitamin C deficiency are not

common, however, but are sometimes seen in infants not given any source of vitamin C and in

the elderly, usually males, who do not consume foods containing vitamin C. 165

Alcoholics and

those who smoke tobacco are at a greater risk of vitamin C deficiency; 162

children who breathe in

second-hand tobacco smoke has lower serum levels of vitamin C. 107

Individuals who are

subjected to air and noise pollution; women who use oral, estrogen-based contraceptives; 160

individuals who are recovering from trauma, or who have fever and infection; people who

consume aspirin daily; and children and pregnant women as growth requires extra vitamin C, all

are at a higher risk of vitamin C deficiency. 160

Vitamin C deficiency causes scurvy, characterized by fatigue, bleeding and swollen

gums, loss of teeth, red blotched beneath the skin, bones that are broken easily, and wounds that

heal slowly. 159,162

Poor bone growth is especially noticeable in children. 173

Toxicity and Supplementation

Vitamin C is nontoxic, but very high doses are associated with increased risk of nausea,

vomiting, diarrhea, heartburn, cramps and possibly kidney stones, especially in individuals who

already have problems with high oxalic acid in their urine; 159

one study showed that men who

took > 1,000 mg/day of vitamin C per day over a course of 14 years, increased their risk of

kidney stones by 41%. 175

In supplement doses up to 10 g/day, there are no reliable human studies indicating that

vitamin C increases the risk of birth defects, cancers, excess iron absorption, 176

or reduces the

absorption of vitamin B12. 160

In postmenopausal women who have diabetes, vitamin C supplements were found to be

associated with increased risk of dying from heart disease. 174

Besides increasing the absorption of iron (see above), high doses of vitamin C increase

the absorption of manganese, increase the use of selenium, but decrease the absorption of

copper. 107

In general, vitamin C supplementation higher than the RDI, has not been shown to

provide additional protective benefits or lower the risk of many pathologies. 167

As indicated

above, saturation levels occur at about 500 mg, with anything above that simply being excreted

in the urine. 107

The key is to make sure that enough vitamin C is ingested daily.

It was thought that vitamin C supplementation might benefit cataracts; however, it has

been found to have no effect on the risk of developing cataracts or the treatment of cataracts. 169

Vitamin C supplementation has been found to reduce glycosylation of plasma proteins in

diabetics, and has been shown to reduce arterial damage in individuals with high blood sugar. 107

Neurologically, vitamin C increases memory in individuals with dementia, and generally

increases cognition in older individuals. 107

Vitamin C supplementation can reduce the symptoms

of schizophrenia. 170

Topically, vitamin C has been found to help with the repair of sun-damage skin, as well

as skin inflammation caused by acne and eczema. 107

Long-term use of vitamin C supplements is generally associated with positive bone

density, especially in women; 171,172

very few studies have examined this association in males.

7.24

The B Vitamins

The B vitamins, also known as the B-complex group, include vitamins B1 (thiamin), B2

(riboflavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B7 (biotin), B9 (folate), and B12

(cobalamin). They are water soluble, which means that they are generally nontoxic and generally

are not stored in the body, with important exceptions. In general, they function as coenzymes,

activating enzymes that are especially used to metabolize carbohydrates, fats and proteins for the

production of ATP energy; B vitamins do not themselves contain energy, despite the adverts

associated with so-called “energy drinks” that contain high amounts of the B vitamins. 162

The B

vitamins are also involved in the synthesis of proteins and hormones, the maintenance of the

immune, nervous and muscular systems and the control of cell replication, growth and

differentiation. A normal appetite, vision, healthy skin and the production of red blood cells all

depend on the B vitamins. 162

B vitamin deficiencies are associated with nausea, loss of appetite and weight loss; lack

of energy; cracks at the corners of the mouth and skin rashes; muscle pain; anemia; neurological

problems such as irritability and depression, memory loss, loss of the ability to think clearly, and

the inability to control and coordinate the muscles. 162

Note that the amino acid adenine, and the compounds carnitine and choline each were

variously given the B4 designation; none of these are considered vitamins, though choline is

considered a “near vitamin, and is explored at the end of this chapter. 187,188

 Vitamin B1 (Thiamine)

Kanehiro Takaki (1849-1920) was a physician and Executive Officer with the Naval Medical

Bureau with the Imperial Japanese Navy, who had studied Western medicine in Tokyo, and then

at St. Thomas’ Hospital Medical School in London, 1875-1880. In 1888, he was the first

Japanese to receive the degree of Doctor of Medical Sciences.

Between the years 1878-1881, over 1/3 of the sailors in the Japanese Navy experienced

beriberi, called kak’ke in Japanese, on the average of four times a year, a disease common

throughout Eastern Asia. 189

He noted that ship’s officers, who ate varied, whole-food diets,

rarely developed beriberi; sailors, who depended more on polished, white rice for their diet,

developed beriberi more commonly; and prisoners, who were fed almost exclusively polished,

white rice, developed beriberi most commonly. In 1883, Takaki proposed that something lacking

in the food caused beriberi, as opposed to the current scientific though that an unknown

bacterium must be the cause. 189

In 1884, Takaki convinced the authorities to provision a ship

with meat and vegetables and no polished, white rice. At the end of a nine-month voyage, not a

single case of beriberi was noted, whereas the same voyage, run the previous year with polished,

white rice as the main provision for sailors, resulted in 169 of 370 sailors contracting beriberi,

with 25 deaths. 189

As a boy, Christiaan Eijkmann (1848-1930) wanted to be a physician. Eijkmann’s family

could not pay for his medical education, so the Dutch military sponsored him in return for his

eventual service as an army surgeon in the Dutch East Indies. 190

In the East Indies, Eijkmann

contracted malaria and was sent back to Europe where he worked in Germany with Robert Koch,

who had demonstrated the bacterial cause of many diseases. In the 1880s, an epidemic of

beriberi seized the Dutch colonies, and actually spread throughout Southeast Asia, due to the

advent in the 1870s of new rice processing mills producing a rice that was considered preferable

7.25

to the unrefined brown rice. A research station was set up by the army in Java in 1886, and

Eijkman went there to discover the bacterium that caused beriberi. 190

Experiments to infect experimental chickens with various bacteria isolated from

organisms with beriberi were inconclusive. By luck, he noted that if his assistant in charge of

feeding the chickens fed them left-over, cooked white rice from the hospital next door, they

developed beriberi, but chickens that were fed uncooked, unpolished rice did not develop the

disease. 190

Through a series of experiments, Eijkman concluded that starch was poisonous,

because polished white rice caused beriberi, and something in the brown skin of unpolished rice

inhibited beriberi, something he called an “anti-beriberi factor.” 190

In 1895, after nine years of working with animals, Eijkman, and his colleague, A. G.

Vorderman, fed human prisoners polished, white rice and other prisoners unpolished, brown rice;

the prisoners fed the polished rice contracted beriberi, those fed brown rice, did not. Eijkman left

the Dutch East Indies in 1896, but his research was continued by Gerrit Grinjs, who realized that

white rice was not toxic, but it lacked a “vital substance,” that was present in brown rice. 190

Eijkman won the Nobel Prize in 1929 largely for his rigorous experimental techniques,

which did clearly suggest that a substance in brown rice, and in other whole foods as well,

prevented beriberi. 190

Thiamin was the first B vitamin discovered. 220

Characterization and Function

In low doses, such as those obtained in food, thiamin is absorbed from the intestine by active

transport using transporters, and is absorbed by passive diffusion in high doses. 184

Absorption

occurs mainly in the intermediate region of the small intestine. 220

High doses of thiamin result in

only a small amount being absorbed, and what is absorbed beyond physiological need is rapidly

excreted in the urine, with peak urinary concentrations about 2 hours after ingestion. 220

Ingestion,

carry, absorption 220

Very small amounts of thiamin may be stored in the liver, but it is rapidly

cleared, so daily ingestion of thiamin is necessary. 184

In the blood, thiamin is carried by red blood cells and freely, in the plasma. 220

In cells,

thiamin is found mainly as thiamin pyrophosphate, its coenzyme form. 184,220

A recent study (2015) showed that 56% of 256 specifies of common gut bacteria have the

ability to produce thiamin, 218

but the amount of thiamin they contribute to human nutrition is

unknown. 184

Vitamin B1 helps metabolize carbohydrates, fats and proteins, producing ATP energy.

Thiamin pyrophosphate is the major coenzme that activates pyruvate dehydrogenase, the

mitochondrial enzyme that splits pyruvate into CO2 and acetate, allowing acetate’s components

to be used in the Kreb’s cycle and electron transport chain to produce ATP. Pyruvate is the end

product of glycolysis, the digestion of glucose (Chapter 4). Fats produce glycerol, that can enter

glycolysis, and fatty acids that can be turned into acetyl (Chapter 5). Amino acids from proteins

can form either glucose or acetyls (Chapter 6). Essentially, with insufficient vitamin B1, not

enough ATP is produced to provide cells with the energy they need.

Thiamin is needed to degrade the branched-chain amino acids (leucine, isoleucine and

valine) into components that can enter the Kreb’s cycle for the production of ATP, the

production of cholesterol and the synthesis of the neurotransmitters GABA (gamma-amino

butyric acid) and glutamate. 185

The enzyme, transketolase, depends on thiamin. Transketolase is needed to make the

7.26

structure of ATP and a similar, high-energy molecule, GTP. It’s also needed to make DNA,

RNA and fatty acids. 185

RDI and UL

Males, 19 years of age and over, require 1.2 mg of thiamin daily; females, 19 years of age and

over, require 1.1 mg of thiamin daily. 138,139

Thiamin is nontoxic and upper limits have not been

determined; see Table 7.12 below.

Table 7.14. DRI and UL for Vitamin B1 (Thiamin) in mg/day. 138,139

(Upper limit for thiamin has not been determined.)

Age Male Female Pregnancy Lactation

0-6 months 0.2 0.2 - -

6-12 months 0.3 0.3 - -

1-3 years 0.5 0.5 - -

4-8 years 0.6 0.6 - -

9-13 years 0.9 0.9 - -

14-18 years 1.2 1.0 1.4 1.4

19-50 years 1.2 1.1 1.4 1.4

> 50 years 1.2 1.1 - -

Table 7.15. Representative Foods High in Vitamin B1 (Thiamin). 38

Food mg Food mg Morningstar Farms garden veggie patties (1) 7.502 Cereals, Kellogg’s Rice Krispies (1.25 cup) 0.577

Pork loin, backribs, lean (1 rib) 5.312 Cereal, Cream of Wheat, instnt, cooked (1 c) 0.559

Morningstar Frms breakfast sausage patty (1) 4.180 Cereals, Kellogg’s Frosted Flakes (3/4 cup) 0.571

Worthington dinner roast, meatless (1 slice) 1.785 Sausage, Italian, pork, cooked (1 link, 4 oz) 0.517

Cereals, Kellogg’s Product 19 (1 cup) 1.500 Game meat, raccoon, roasted (3 oz) 0.502

Morningstar Farms Grillers, ¼ lb (1 burger) 1.368 Fish, salmon, sockeye, smoked (3 oz) 0.420

Wheat flour, white, cake, enriched (1 cup) 1.222 Pork, ground, 4% fat (4 oz) 0.468

Oats (1 cup) 1.190 Macadamia nuts, dry roasted (1/2 cup) 0.469

Wheat flour, white, bread, enriched (1 cup) 1.112 Macaroni, dry, enriched (1/2 cup) 0.468

Liver, New Zealand lamb (3 oz) 1.025 Egg noodles, cooked (1 cup) 0.462

Wheat four, white, all-purpose, enriched (1 c) 0.981 Bacon, meatless (2 strips) 0.440

Pork, cured, ham, extra lean, canned (3 oz) 0.880 Cereals, Quaker, Cap’n Crunch (3/4 cup) 0.436

Cornmeal, degermed, white or yellow (1 c) 0.865 Game meat, deer, ground, pan-broiled (3 oz) 0.428

Pork tenderloin, lean only, broiled (3 oz) 0.840 Pistachio nuts, dry roasted (1/2 cup) 0.428

Cereals, General Mills, Corn Chex (1 cup) 0.744 Bagels, enriched (1 medium, 3.7 oz) 0.392

Cereals, General Mills, Wheaties (1 cup) 0.756 Pasta, macaroni or spaghetti, enrichd, cooked (1 c) 0.384

Burger King Double Whopper, no cheese (1) 0.722 Cereals, General Mills, Cheerios (1 cup) 0.372

Tomatoes, red, ripe, canned (1/2 cup) 0.690 Peas and carrots, frozen, boiled (1 cup) 0.360

Navajo frybread, made with lard (1 piece) 0.654 Soybeans, green, boiled (1/2 cup) 0.234

Beef kidney, New Zealand (4 oz) 0.632 Sunflower seeds, toasted (1/2 cup) 0.218

Oatmeal, instant, plain, cooked (1 c) 0.608 Beans, pink, boiled (1/2 cup) 0.217

Pizza Hut 14” pepperoni pizza (1 slice) 0.605 Beans, navy, boiled (1/2 cup) 0.216

Wheat flour, whole grain (1 cup) 0.602 Beans, small white, boiled (1/2 cup) 0.211

Fish, pompano, cooked, dry heat (3 oz) 0.578 Beans, black, boiled (1/2 cup) 0.210

Cereals, General Mills, Kix (1.25 cup) 0.586 Peas, green, boiled (1/2 cup) 0.207

Pretzels, soft, unsalted (1 large) 0.586 Rice, white, long-grain, parboiled (1/2 cup) 0.207

7.27

Dietary Sources

Good sources of vitamin B1 include pork products, legumes, nuts, seeds, and any grain products

as these are fortified with thiamin 38,186

by FDA recommendation, but the amount of fortification

is not governed by Federal law, only by “good manufacturing practice.” Individual states have

various laws, though, governing which grain products must be enriched and by how much. 248

Dairy products are relatively low in vitamin B1, as is the meat from chicken, turkey and

beef, although all of these foods do contain some thiamin, and organ meats are high in B1; 38

see

Table 7.15 above. In fact, most whole foods do contain some thiamin.

Deficiency

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee determined

that vitamin B1 (thiamin) intake for all age classes of both males and females were above RDA

or AI amounts. 158

Deficiencies in vitamin B1 are rare, due to the wide availability of thiamin in

foods and due to the supplementation of grain products with thiamin. 107

People on low-calorie diets that do not stress whole foods may be at risk for thiamin

deficiency. 107

Some 20%-30% of elderly people, especially those at long-term care facilities, are

at a higher risk of thiamin deficiency. 184,193

Individuals with HIV are at a higher risk for thiamin

deficiency. 194

Type 1 diabetics have plasma thiamin levels up to 76% lower and type 2 diabetics

have plasma thiamin levels up to 75% lower than in healthy individuals, for reasons

unknown. 184,195,196

Globally, thiamin deficiencies are seen most commonly in countries where

unenriched, polished, white rice is a dietary staple. 186

In the West, including in the United States,

thiamin deficiency is most often seen in alcoholics 184,191

and is manifested as Wernicke-

Korsakoff syndrome. Alcohol inhibits the absorption of thiamin from food in the gut and

increases the excretion of thiamin from the kidneys into the urine. 186

Alcohol also does not

contain thiamin, and since it often replaces food, the diet of alcohols tends to be thiamin

deficient. 107,186

Lack of coordination, mental confusion and the involuntary movement of the eyes are

general symptoms of Wernicke-Korsakoff syndrome; 186

however, the syndrome can present in

two stages. The first stage is Wernicke’s encephalopathy. Peripheral neuropathies are usually

seen during Wernicke’s encephalopathy, and, without treatment, up to 20% of individuals

exhibiting Wernicke’s encephalopathy die. The 80% who survive develop Korsakoff’s

psychosis, characterized by disorientation, short-term memory loss and confusion between

memories that are real and imagined. About ¼ of patients exhibiting Korsakoff’s psychosis do

not respond to treatment. Some individuals may present with Korsakoff psychosis without

having first presented with Wernicke’s encephalopathy. 184

Thiamin deficiency causes wet and dry beriberi. Dry beriberi damages the nervous

system, affecting arm and leg coordination, and causing lethargy and confusion. Wet beriberi

affects the cardiovascular system and causes swelling in the arms and legs, particularly the

ankles, wasting of muscles, enlargement of the heart and congestive heart failure. 186

A rare, inherited condition, genetic beriberi is characterized by the inhibition of thiamin

absorption. 191

Wet beriberi, even heart damage, is usually reversible. If caught early, some of the

neurological damage of dry beriberi is also reversible. Thiamin supplementation, either oral or

via injection, is used to reverse thiamin deficiency and to cure beriberi. 191

7.28

By the way, “beriberi” means “sheep-sheep” in low Malay, referring to the way people

with dry beriberi walk, with a “stiff, tripping gait,” similar to the way sheep walk. 192

Toxicity and Supplementation

Thiamin is nontoxic. 162

Supplemental thiamin is used to cure beriberi and to treat Wernicke-

Korsakoff syndrome. 184

To treat mild thiamin deficiency, WHO recommends 10 mg/day for a

week, then 3-5 mg/day for 6 weeks. Severe deficiencies are treated with 50-100 mg intravenous

injections, followed by 10 mg/day intramuscular injections for one week, then 3-5 mg/day orally

for 6 weeks or longer. 184

It is clear that both type 1 and type 2 diabetes are associated with thiamin deficiency. It is

theorized that thiamin supplementation may reduce the risk of heart disease in diabetics. 197

Small

studies have shown that thiamin supplementation lowers blood glucose, but more research is

needed before thiamin can be recommended to diabetics for this purpose. 198

Animal studies show

that thiamin deficiency causes the pancreas to produce less insulin. 199

Current thought is that high thiamin supplementation in individuals with cancer may

stimulate the growth of malignant tumors, so is not recommended. 200

 Vitamin B2 (Riboflavin)

Riboflavin is a yellow-green, fluorescent, water-soluble pigment that was first discovered in milk

in 1879. 215

It was the second vitamin to be isolated. 215

Characterization and Function

Riboflavin is essential in the production of ATP energy by mitochondria in the cells. Riboflavin

is the major structural component of the coenzymes, FAD (flavin adenine dinucleotide) and

FMN (riboflavin-5’-phosphate). 203

FAD and FMN are electron carriers, thus fundamental to the

production of energy from carbohydrates, lipids and proteins. 202

FAD is one of the molecules,

along with NAD, which carry high-energy electrons from the Kreb’s cycle into the electron

transport chain, resulting in the production of large amounts of ATP. Besides being an electron

carrier, FAD is also essential for the synthesis of niacin (vitamin B2) from tryptophan, niacin

being used to make NAD. Thus, both FAD and NAD are directly or indirectly dependent on

riboflavin.

FAD and FMN also play a role in the metabolization of drugs and toxins. 202

Besides being needed for the formation of niacin, riboflavin, as FMN, is needed for the

activation of pyridoxine (vitamin B6). 217

Riboflavin is involved in the synthesis of red blood cells, the making of antibodies by the

immune system, growth and reproduction. It is needed to maintain the health of skin, hair and

nails; to regulate the functioning of the thyroid gland; and it is involved in maintaining the health

of the eyes. 203

Riboflavin is essential in the production of the glutathione peroxidases, major antioxidant

enzymes. 203

Deficiency in riboflavin has been linked to oxidative stress as it affects the

formation of glutathione peroxidases; selenium is also needed to form these important enzymes

(see Chapter 8). 204

7.29

Hemoglobin is the iron-rich molecule found in great amounts inside red blood cells that is

responsible for the transport of oxygen. Riboflavin helps maintain hemoglobin and play a role in

the use of iron by hemoglobin and in the prevention of iron-deficiency anemia. 202,211

Dietary riboflavin, as FAD and FMN, is generally complexed with proteins. Stomach

acids begin the digestion of proteins, release FAD and FMN. In the first part of the small

intestine, enzymes (pyrophosphatases and phosphatases) hydrolyze FAD and FMN to

riboflavin. 217

Riboflavin is easily absorbed by the small intestine. 203

Primary absorption of small

amounts of riboflavin occurs in the first part of the small intestine using transporters via active

transport, that use ATP to power the transporters, or facilitated transport, that use the

concentration gradient of the riboflavin itself to power the transporters; sodium is not involved in

riboflavin transport. High levels of riboflavin can be absorbed by simple diffusion, without

transporters. The presence of food and bile salts facilitate absorption. 217

Some riboflavin

absorption also occurs in the colon. 216

In the blood, albumin and other blood proteins complex with riboflavin and facilitate its

transport. 217

Riboflavin ingested in excess of dietary need is excreted in the urine; very little riboflavin

is stored by the cells. 217

Bacteria in the colon also produce riboflavin that can be absorbed. Diets that are higher in

plant-based foods stimulate the production of more riboflavin than diets that are higher in

animal-based foods. 201

A recent study (2015) showed that 65% of 256 specifies of common gut

bacteria have the ability to produce riboflavin. 218

The production of riboflavin by gut bacteria

benefits the immune system by enhancing T-cell activation. 219

RDI and UL

Males, 14 years of age and over, require 1.3 mg of riboflavin daily; females, 14 years of age and

over, require 1.1 mg of riboflavin, daily. 138,139

Riboflavin is nontoxic and upper limits have not

been determined; see Table 7.16 below.

Table 7.16. DRI and UL for Vitamin B2 (Riboflavin) in mg/day. 138,139

(Upper limit for riboflavin has not been determined.)

Age Male Female Pregnancy Lactation

0-6 months 0.3 0.3 - -

6-12 months 0.4 0.4 - -

1-3 years 0.5 0.5 - -

4-8 years 0.6 0.6 - -

9-13 years 0.9 0.9 - -

14-18 years 1.3 1.1 1.4 1.6

19-50 years 1.3 1.1 1.4 1.6

> 50 1.3 1.1 1.1 1.6

Dietary Sources

Riboflavin is found in a wide variety of animal- and plant-sourced foods; see Table 7.17 below.

Foods particularly rich in vitamin B2 include liver and other organ meats, dairy, eggs, malted

7.30

barley and leafy vegetables. 203

Grain products such as breads, flours and cereals are also a good

source of riboflavin as they are fortified with riboflavin 38,186

by FDA recommendation, but the

amount of fortification is not governed by Federal law, only by “good manufacturing practice.”

Individual states have various laws, though, governing which grain products must be enriched

and by how much. 248

Riboflavin is broken down by bright light; 50% of the riboflavin in a clear, glass

container of milk is destroyed after two hours of bright sunlight. 210

So, if you do purchase your

milk in glass containers, make sure it gets into the darkness of the fridge quickly!

Table 7.17. Representative Foods High in Vitamin B2 (Riboflavin). 38

Food mg Food mg Lamb liver, New Zealand, soaked/fried (3 oz) 4.480 Tomato sauce (1 cup) 0.300

Spaghetti with meat sauce, frozen (1 serving) 3.772 Mollusks, squid, fried (3 oz) 0.389

Pork loin, backribs, lean (1 rib) 3.545 Kielbasa, pan-fried (1/2 link, 6.5 oz) 0.387

Beef liver, pan-fried (3 oz) 2.913 Tempeh (1/2 cup) 0.297

Algae, spirulina, dried (1/2 cup) 2.055 Mushrooms, oyster, raw (3 oz, ~1 cup slices) 0.297

Chicken liver, pan-fried (3 oz) 1.967 Hotdog (1) 0.274 Cereals, General Mills, Whole Grain Total (3/4 cup) 1.710 Fish, shad, cooked with dry heat (3 oz) 0.262

Cereals, Kellogg’s Product 19 (1.0 cup) 1.701 Egg, hardboiled (1) 0.256

Vegetarian stew (1.0 cup, 8 oz) 1.482 Waffles, buttermilk (1) 0.253

Mollusks, cuttlefish, moist heat (3 oz) 1.470 Game meat, bison, lean (3 oz) 0.230

Milk, chocolate, reduced fat (1.0 cup, 8 oz) 1.412 Lamb, broiled (3 oz) 0.230

Yeast extract spread (1 tsp) 1.050 Sweet potato, canned (1 cup) 0.230

Maple syrup, Canadian (1/4 cup) 1.002 Blackberries, raw (1 cup) 0.226

Corn flour, masa, enriched (1 cup) 0.918 Egg, whole, scrambled (1) 0.229 McDonald’s Double Quarter Pounder w/ Cheese (1) 0.848 Spaghetti, cooked, enriched (1 cup) 0.225

Cereals, General Mills, Wheaties (3/4 cup) 0.837 Fish, Pacific herring, dry heat (3 oz) 0.218

Almonds, dry roasted (1/2 cup) 0.826 Noodles, egg, cooked (1 cup) 0.218

Beet greens, boiled (1 cup) 0.816 Chili beans, barbecue, ranch style (1/2 cup) 0.190

Game meat, caribou, roasted (3 oz) 0.765 Salami, pork, dry or hard (2 oz) 0.187

Beef steak, lean, grilled (3 oz) 0.721 Chicken breast, rotisserie (3 oz) 0.176

Wheat flour, white, bread, enriched (1 cup) 0.701 Plums, dried (prunes) (1/2 cup) 0.162

Game meat, bear, simmered (3 oz) 0.697 Turkey breast, roasted (3 oz) 0.161

Feta cheese (1/2 cup) 0.633 Raisins (1/2 cup) 0.150

Cereal, Kellogg’s Special K (1 cup) 0.595 Cheddar cheese (1 oz) 0.123

Game meat, deer, shoulder, roasted (3 oz) 0.558 Beans, black beans, canned (1/2 cup) 0.144

Buttermilk, low-fat, cultured (1 cup, 8 oz) 0.514 Pistachio nuts, dry roasted (1/2 cup) 0.144

Silk plain soymilk (1 cup, 8 oz) 0.510 Peanuts, dry roasted (1/2 cup) 0.144

Cream of Wheat, instant, cooked (1 cup) 0.506 Blackeyed peas, boiled (1/2 cup) 0.122

Oatmeal, instant, cooked (1 cup) 0.503 Green peas, boiled (1/2 cup) 0.119

Mushrooms, portabella, grilled, sliced (1 c) 0.488 Monterey jack cheese (1 oz) 0.111

Yogurt, Greek, plain, nonfat (6 oz) 0.473 Split peas, boiled (1 cup) 0.110

Salmon, sockeye, smoked (3 oz) 0.462 Orange juice (1 cup, 8 oz) 0.097

Milk, 1% fat (1 cup, 8 oz) 0.451 Avocado, California (1/2) 0.097

Whale, beluga (3 oz) 0.441 Banana, medium (1) 0.086

Braunschweiger, Oscar Mayer (1 oz) 0.439 Oranges, Valencia, segments (1 cup) 0.072

Cereals, Kellogg’s Rice Krispies (1.25 cup) 0.426 Apricot halves (1 cup) 0.062

Spinach, boiled (1 cup) 0.426 Blueberries (1 cup) 0.061

Cereals, Post Alpha Bits (1 cup) 0.420 Navy beans, boiled (1/2 cup) 0.060

Mollusks, clams, steamed (3 oz) 0.362 Kidney beans, California red, boiled (1/2 c) 0.055

Pretzel, soft (4 oz) 0.333 Meatless bacon (2 strips) 0.048

Pork, ham, roasted (3 oz) 0.322 Cereals, Cheerios (1 cup) 0.028

7.31

Deficiency

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee determined

that vitamin B2 (riboflavin) intake for all age classes of both males and females were above RDA

or AI amounts. 158

Riboflavin deficiency is exceedingly rare in the United States, but has been given the

general name of ariboflavinosis. 202

Ariboflavinosis usually occurs with deficiencies in other

water-soluble vitamins besides riboflavin. Symptoms of ariboflavinosis include cracks or sores at

the corners of the mouth and around the outside the outside of the lips; redness and inflammation

of the tongue and inside the mouth; a sore throat; and anemia. 202,217

Acute riboflavin deficiency

can result in the decreased conversion of tryptophan to niacin by vitamin B6 (see below under

vitamin B6). 202

In pregnant women, riboflavin deficiency increases the risk of preeclampsia by 4.7 times.

Preclampsia is characterized by high blood pressure, swelling and protein in the urine.

Preclampsia develops into eclampsia 5% of the time, associated with high blood pressure,

hemorrhage and seizures, and significantly increasing the risk of fetal death. 205

Athletes and laborers, individuals who are physically active, may require more riboflavin,

thus may be at a slight risk for riboflavin deficiency. 202

People who are on very low calorie diets or anorexic may not consume enough

riboflavin. Individuals who are lactose intolerant may not consume dairy, an important source of

riboflavin, thus may be deficient. In hypothyroidism, riboflavin may not be metabolized to form

FAD or FMN. 202

Riboflavin deficiency appears to inhibit the absorption of iron, increase the loss of iron

into the gut, and inhibit the use of iron in the production of hemoglobin. 211

Iron-deficiency

anemia is a global problem, especially during pregnancy, resulting in high infant death rates. 212

Toxicity and Supplementation

Riboflavin is nontoxic. There are no known toxic effects associated with taking high levels of

riboflavin supplements; the only known effect is coloring the urine bright yellow, which is

harmless. 202

There are no upper limits set; see Table 7.16. Excess riboflavin is simply removed

from the body into the urine. 217

Riboflavin supplementation is used in the treatment of riboflavin deficiency. 203

The frequency of migraine headaches is reduced in adults through the supplementation of

400 mg/day of riboflavin; 202

the severity or duration of headaches were not affected. Further,

studies have shown that riboflavin has no affect on migraine headaches in children. 208,209

There is some experimental evidence that riboflavin supplementation may reduce the risk

of cataracts in older people. 202

Riboflavin supplementation lowers blood pressure, and works with folate to activate an

enzyme that is associated with reducing the risk of stroke. 206

Riboflavin supplementation (with vitamin B6) is associated with a reduced risk of

colorectal cancer; 207

however, other studies have shown riboflavin supplementation to have little

to no affect on esophageal, lung, breast, prostate and stomach cancers. 202

With folic acid, iron and vitamin A, riboflavin supplementation has been shown to

increase hemoglobin levels and decrease rates of iron-deficiency anemia better than simple folic

acid-iron supplementation, in pregnant women in Southeast Asia. 213

7.32

Of note, riboflavin supplementation does not increase athletic performance, nor does it

increase stamina. 214

 Vitamin B3 (Niacin)

When Europeans “discovered” the New World, the natives shared with them the foods they ate,

and the Europeans shared with the natives diseases, mostly smallpox, influenza and measles, that

wiped out 90% of the native population. 225

One of the foods that was brought back to Europe was corn (maize). Corn grew well in

southern Europe and many Europeans, especially the poor, made it a staple of their diet. People

who ate diets rich in corn, tended to develop red, blistering lesions on the skin exposed to the

sun, mental confusion, digestive system problems and other symptoms. The condition was first

described by Gasper Casal y Julian in Spain in 1735, but was named “pellagra” by Francesco

Frapoli in 1771; “pellagra” means “rough skin,” in Italian vernacular. 226

In 1902, pellagra was reported in the United States. There were some three million cases

and 400,000 deaths in the first half of the twentieth century in 15 southern states due to

pellagra. 226,227

It was thought that corn might be toxic; however, in 1927, Joseph Goldberger of

the U.S. Public Health Service showed that pellagra could be cured and prevented by an

unknown B vitamin that he and his colleagues termed, “pellagra-preventive factor,” found in

dried yeast. 226

In 1937, Conrad Elehjem of the University of Wisconsin demonstrated that this

“pellagra-preventive factor” was niacin. 228

The reason for the epidemic of pellagra cases in the

U.S. stems from the new (1901) technology of degerminating corn, which removed much of the

nutrients, but also allowed corn meal to be stored without spoiling. 222

So, why is it that Latin Americans and American Indians, who eat tremendous amounts

of corn, have very low rates of pellagra? Corn essentially contains inadequate amounts of

tryptophan, which turns into niacin, and the niacin found in corn is strongly bound to the outer

shell of the kernel. In Latin American cuisine, corn is soaked in lime (calcium oxide), before

being used to make tortillas; American Indians used a similar process in the preparation of corn.

The soaking in the alkaline lime solution releases the niacin, making it available for

absorption. 221,228

They also didn’t eat degerminated corn.

Characterization and Function

Niacin, also called nicotinamide or nicotinic acid, 222

makes up part of the two molecules NAD

(nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide

phosphate). 228

As indicated above under the section dealing with riboflavin, NAD is one of two

molecules that carry electrons and hydrogens from the Kreb’s cycle to the electron transport

chain in mitochondria, allowing for the generation of most of the ATP energy used by cells. 228

Thus, niacin, as with riboflavin, is essential in the metabolization of carbohydrates, fats and

proteins for energy.

NADP is involved in the detoxification of free radicals, the metabolization of drugs, in

pathways involved in the synthesis of fats, 228

and in the synthesis and repair of DNA. 221,222

In its role of DNA repair, niacin inhibits cancer. DNA and chromosome damage are

linked to cancer, and DNA damage stimulates the synthesis of NAD. 232

NAD is involved in the

formation of tumor suppressor protein p53, in human breast, skin and lung cancer cells, 232

which

inhibits cancer.

7.33

Small amounts of nicotinamide and nicotinic acid are rapidly absorbed through the walls

of the small intestine by a sodium-dependent transporter, and in high concentrations by way of

passive diffusion. 222,229

Up to 3 to 4 mg of niacin can be absorbed at a time, 222

The amino acid tryptophan can be turned into niacin, but it takes about 60 g of tryptophan

to produce 1 g of niacin, so it’s not an efficient source of niacin; 221,222

there is some evidence that

the conversion rate isn’t even this high. 231

The conversion requires vitamins B6 (pyridoxine), B2

(riboflavin) and heme. 221

As an interesting side note, tryptophan helps stimulate T-lymphocytes,

which are essential to the immune system; in pregnancy, the oxidation of tryptophan in the

placenta depletes tryptophan concentrations, thus inhibiting material T-lymphocytes, preventing

the attack of the fetus by the mother’s immune system. 230

Some niacin is stored in the liver; excess niacin is processed by the liver, deposited into

the blood and removed by the kidneys into the urine. 222

RDI and UL

Males, 14 years of age and over, require 16 mg of niacin daily; females, 14 years of age and

over, require 14 mg of niacin, daily. 138,139

Toxic amounts have been determined; for both males

and females, 14-18 years of age, 30 mg/day are toxic, and for both males and females over the

age of 19 years, 35 mg/day are toxic. See Table 7.18 below.

Table 7.18. DRI and UL for Vitamin B3 (Niacin) in mg/day. 138,139

(Upper limits in parentheses.)

Age Male Female Pregnancy Lactation

0-6 months 2 (ND) 2 (ND) - -

6-12 months 4 (ND) 4 (ND) - -

1-3 years 6 (10) 6 (10) - -

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

9-13 years 12 (20) 12 (20) - -

14-18 years 16 (30) 14 (30) 18 (30) 17 (30)

19-50 years 16 (35) 14 (35) 18 (35) 17 (35)

> 50 years 16 (35) 14 (35) - -

ND = not determined

Dietary Sources

Grain products such as breads, flours and cereals are fortified with niacin by FDA

recommendation, but the amount of fortification is not governed by Federal law, only by “good

manufacturing practice.” Individual states have various laws, though, governing which grain

products must be enriched and by how much. 248

The importance of this in eliminating pellagra is

discussed below.

Most whole foods contain niacin; see Table 7.19 below. Fish, crustaceans and mollusks

of all types, and beef, pork, chicken and turkey meat are high in niacin. Liver of all types is high

in niacin. Whole grains, fruits and vegetables contain niacin. Even fast food contains niacin; a

McDonald’ Big Mac has about half of the niacin an adult female needs. A cup of coffee contains

78% of the niacin needed by an adult male. A varied diet is the key to getting enough niacin!

7.34

Table 7.19. Representative Foods High in Vitamin B3 (Niacin). 38

Food mg Food mg Vegetarian stew (1 cup) 29.640 Pasta sauce, tomato-based (marinara) (1 cup) 5.172

Cereals, Kellogg’s Product 19 (1 cup) 20.010 Peanuts, dry roasted (1 oz) 4.070

Salmon, sockeye, smoked (3 oz) 19.349 Russet potato, baked, flesh and skin (1 large) 4.031

Salmon, sockeye, cooked w/ dry heat (3 oz) 8.243 Rice, white, long-grain, parboiled (1 cup) 3.648

Tuna, yellowfin, cooked w/ dry heat (3 oz) 18.760 Mushrooms, white, boiled (1/2 cup pieces) 3.479

Tuna, skipjack, cooked w dry heat (3 oz) 15.943 Noodles, egg, cooked (1 cup) 3.323

Fish, shad, cooked w/ dry heat (3 oz) 15.507 Crustaceans, blue crab, boiled (1 cup) 3.241

Pork chops, lean, pan-broiled (1 chop) 15.484 Pearled barley, cooked (1 cup) 3.240

Beef liver, pan-fried (3 oz) 14.863 Green peas, boiled (1 cup) 3.234

Whale, beluga, meat, dried (3 oz) 12.927 Mollusks, octopus, boiled (3 oz) 3.213

Coffee, brewed, restaurant-prepared (1 cup) 12.496 Pancakes, plain, reduced fat (3) 3.000

Chicken liver, pan-fried (3 oz) 11.843 Rice, brown, long-grained, cooked (1 cup) 2.980

Corn flour, masa, enriched, yellow (1 cup) 11.322 Sweet potato, baked in skin, flesh (1 cup) 2.974

Tuna, light, canned in water (3 oz) 11.288 Mollusks, clams, moist heat (3.0 oz) 2.851

Turkey, ground, fat-free, pan-broiled (3 oz) 10.668 Macaroni, cooked, enriched (1 cup) 2.635

Wheat flour, white, bread, enriched (1 cup) 10.349 Corn, canned (1 cup) 2.452

Morningstar Farms, Veggie Dog (1) 10.280 Tomatoes, sun dried (1/2 cup) 2.444

Rice flour, brown (1 cup) 10.017 Mollusks, squid, fried (3 oz) 2.212

Cereals, General Mills, Wheaties (3/4 cup) 9.990 Catfish, channel, farmed, cooked w/ dry heat (3 oz) 2.166

Turkey breast, meat only, roasted (3 oz) 9.988 Tortilla, flour (1, 1.7 oz) 2.054

Wheat flour, white, cake, enriched (1 cup) 9.302 Cereals, corn grits, enriched, cooked (1 cup) 2.053

Burger King, Whopper w/ cheese (1) 8.090 Seeds, sunflower kernels, dry roasted (1 oz) 1.996

Game meat, deer, ground, pan-broiled (3 oz) 7.868 Prunes, dehydrated (1/2 cup) 1.977

Chicken breast, meat only, rotisserie (3 oz) 7.853 Biscuit, plain or buttermilk (1) 1.919 Lamb tenderloin, New Zealand, fast fried (3 oz) 7.713 Asparagus, frozen, boiled (1 cup) 1.868

Yeast extract spread (1 tsp) 7.650 Peas and carrots, frozen, boiled (1 cup) 1.846

Beef, top sirloin steak, lean, broiled (3 oz) 7.596 Blackberries, frozen, thawed (1 cup) 1.824

Portabella mushrooms, sliced, grilled (1 cup) 7.569 Squash, acorn, cubes (1 cup) 1.806

Cereals, Cream of Wheat, cooked (1 cup) 7.454 Guavas (1 cup) 1.788

McDonald’s Big Mac (1) 7.411 Nectarines, slices (1 cup) 1.610

Cereals, Kellogg’s Special K (1 cup) 7.006 Split peas, boiled (1 cup) 1.744

Frybread, Navajo, made w/ lard (1, 5.36 oz) 6.997 Bread, wheat (1 oz) 1.593

Kielbasa, pan-fried (1/2 link) 6.834 Dinner roll (1 oz) 1.503

Fish, halibut, cooked w/ dry heat (3 oz) 6.724 Avocado, California (1/2) 1.300

Fish, mahi-mahi, cooked w/ dry heat (3 oz) 6.315 Blackeyed peas, boiled (1/2 cup) 1.158

Pork, ham, roasted (3 oz) 6.327 Cod, Pacific, cooked w/ dry heat (3 oz) 1.142

Salmon, coho, cooked w/dry heat (3 oz) 6.284 Soybeans, boiled (1/2 cup) 1.125

Pork loin, boneless, lean, roasted (3 oz) 6.185 Lentils, boiled (1/2 cup) 1.050

Game meat, muskrat, roasted (3 oz) 6.111 Macadamia nuts, dry roasted (1 oz) 0.645

Beef, tenderloin, steak, broiled (3 oz) 6.094 Carrot, raw, medium (1) 0.600

Cereals, Kellogg’s Rice Krispies (1.25 cup) 5.929 Beans, kidney, boiled (1/2 cup) 0.512

Cereals, General Mills Cheerios (1 cup) 5.871 Beans, black, boiled (1/2 cup) 0.434

Cereals, Quaker, Cap’n Crunch (3/4 cup) 5.796 Beans, garbanzos (1/2 cup) 0.431

Lamb chop, New Zealand, fried (3 oz) 5.653 Broccoli, boiled (1/2 cup) 0.431

Rye flour, dark (1 cup) 5.466 Pistachio nuts, dry roasted (1 oz) 0.389

Soft pretzel (1 medium, 4 oz) 4.910 Yogurt, Greek, plain, nonfat (6 oz) 0.354 Trout, rainbow, wild, cooked w/dry heat (3 oz) 4.904 Feta cheese (1 oz) 0.239

Eggo waffles, frozen (2 waffles) 4.270 Egg, cooked (1) 0.235

Peanut butter, smooth style (2 tbsp) 4.196 Strawberries, sliced (1 cup) 0.640

Crustaceans, spiny lobster, boiled (3 oz) 4.163 Milk, 1% fat (1 cup, 8 oz) 0.227

Potatoes, hash browns (1 cup) 4.151 Cheddar cheese (1 oz) 0.123

7.35

Deficiency

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee determined

that Vitamin B3 (niacin) intake for all age classes of both males and females were above RDA or

AI amounts. 158

In the United States, niacin deficiency is seen mostly in alcoholics, or individuals

who follow diets that are not nutritionally sound. 228

Acute niacin deficiency results in pellagra, 221

and, based on mortality statistics, it resulted

in the most severe nutritional deficiency in U.S. history. 246

Clinically, pellagra is defined by “the

three Ds,” diarrhea, dermatitis and dementia. 228

The first signs of pellagra include apathy,

malaise and weakness; inflammation and atrophy (shrinkage) of the tissues lining the gut,

leading to abdominal discomfort (gastritis) and malabsorption of food, with symptoms similar to

irritable bowel syndrome. The tongue becomes swollen, “beefy red,” and tender. Inflammation

of the small intestine and colon are common. 228

Areas of the skin exposed to the sun are sharply

distinct, and are characterized by redness and a burning sensation, initially resembling a sunburn,

but developing into skin overgrowth and thickening, dark pigmentation, and blistering and

lesions, which become disfiguring. 221,228

Neurological signs include headaches, depression,

anxiety, hallucinations, delusions and insomnia. 228

If untreated, pellagra results in “the fourth

D,” death. 221

Pellagra is generally not seen in infants or children; it is most likely seen in adults. 228

In individuals who consume diets that lack niacin or tryptophan plus vitamin B6, the

symptoms of pellagra can begin to appear in 6 to 8 weeks. 228

Diets that are low in animal

proteins and high in unlimed corn are at a high risk for developing pellagra; animal proteins are

rich in niacin. 38

Niacin deficiency is commonly associated with homeless and malnourished

individuals. 221

Vitamins B6 (pyridoxine), B2 (riboflavin) and heme are required for the conversion of

tryptophan to niacin. 221

Acute riboflavin deficiency can result in the decreased conversion of

tryptophan to niacin (see below under vitamin B6). 202

Individuals with diets high in the branched-chain amino acid leucine and low in

tryptophan are at a higher risk to develop pellagra as leucine blocks the conversion of tryptophan

to niacin; body builders who take large amounts of leucine daily might fall into this category. 228

Diabetics are at a higher risk of niacin deficiency. 228

Insufficient dietary niacin, because DNA and chromosome damage is not being

adequately addressed, may increase cancer risk. 221,233

Lowered levels of NAD, resulting from

insufficient dietary niacin, decreases the concentration of tumor suppressor protein p53, in

human breast, skin and lung cancer cells, 232

which increases cancer risk.

Toxicity and Supplementation

Niacin that occurs naturally in foods is not toxic. 221,222

However, at high (pharmacological)

doses, niacin is toxic. Moderate niacin supplementation can result in skin rashes, itching,

headache, nausea, vomiting, low blood pressure and peptic ulcers. Liver damage, as indicated by

jaundice and elevated liver enzymes, has been noted in doses of timed-release niacin as little as

500 mg/day for two months. At higher doses, timed-release niacin appears to be more toxic than

immediate release, although immediate release shows toxic effects as well. Acute hepatitis is

most commonly seen in individuals who have taken timed-release niacin at doses of 3 to 9 g/day

for months to years. 221

7.36

Niacin flush has been noted in some individuals at moderate doses of 30 to 1,000 mg

within as little as 30 minutes of ingestion. 222

It is characterized by a burning feeling and

reddening of the skin, mainly on the face, arms and chest, due to vasodilation of dermal

capillaries under the epidermis. Gradually increasing niacin dosage can increase niacin tolerance,

minimizing niacin flush. 222

It caused by the release of prostaglandins; taking an aspirin about 20

minutes before taking niacin blocks the release of prostaglandins and alleviates niacin flush.

Very high doses of niacin inhibit glucose tolerance, most likely by way of reducing

insulin sensitivity, causing elevated blood glucose. Pre-diabetic individuals are at a risk of

becoming diabetic at high doses of niacin, 222

but this risk is considered acceptable, and the

slightly elevated glucose levels, 8.7 mg/dL or less, with no change in HbA(1c) in diagnosed

diabetics is considered acceptable, when evaluated against the significant decrease in

cardiovascular disease risk high-dose niacin supplements provide. 243,244

Nicotinamide supplementation appears to be better tolerated than niacin. The risk of

niacin flush is reduced, but at doses of 3 g/day, it can cause nausea, vomiting, and liver

damage. 221

The major use of niacin supplementation, particularly nicotinamide to reduce niacin flush

symptoms, is in the prevention and treatment of pellagra. The voluntary fortification of foods,

particularly bread, with niacin in 1938, markedly reduced the incidence of pellagra-caused

mortality in the United States, ending the worst nutritional problem in U.S. history. 246

Regarding

treatment of pellagra, the World Health Organization suggests 300 mg/day, along with B-

complex vitamins as patients with pellagra are generally deficient many of these vitamins as

well. 249

Following the established RDIs prevents pellagra in healthy individuals.

Niacin supplements reduce the risk of heart attack. Very high doses of niacin

significantly increase HDLs, reduce small LDLs for large LDLs and reduce atherosclerosis; 221,223

niacin is the most effective drug available for increasing HDLs. 224

Niacin is prescribed by

physicians to lower the risk of heart disease. 224

In one large study of 8,000 men who had already

experienced heart attacks, 3 grams (3,000 mg) of niacin taken daily reduced total blood

cholesterol an average of 10%, decreased triglycerides 26%, and decreased stroke and heart

attacks 26%. 240

Niacin therapy has been shown to benefit both males and females with

unfavorable blood lipid values. 241,242

Niacin may play a role in the prevention and treatment of cancer. 232

Studies indicate

niacin supplementation may decrease mouth, throat and esophageal cancer by 40%, 221

and may

help protect the skin from cancers triggered by ultraviolet light as NAD-dependent enzymes are

needed to protect against and repair damage done to the skin by ultraviolet radiation. 236

Niacin supplementation does not decrease the risk of genetic damage in individuals who

smoke cigarettes, 234

but does reduce genetic damage in individuals exposed to ionizing

radiation. 235

In type 1 diabetes, niacin supplementation has been shown to be beneficial. High

supplementation of nicotinamide helps protect the insulin-producing beta-cells of the pancreas

from destruction by the immune system, 239

but does not improve blood sugar control, 237

possibly

because it decreases insulin sensitivity. 238

Niacin supplementation does not inhibit the onset of

type 1 diabetes in children. 221

Nicotinamide fortification may increase the risk of obesity and type 2 diabetes. Niacin

(nicotinamide) fortification of flours and cereals has been used to markedly reduce global rates

of pellagra. By decreasing glucose control, thus increasing appetite, nicotinamide may increase

obesity, and certainly exacerbate type 2 diabetes. Increased levels of type 2 diabetes are seen in

7.37

third-world and developed countries, including the U.S., where flours and cereals have been

fortified with nicotinamide. 245

Of course, along with increased niacin, we see the increased

consumption of refined carbohydrates (ready-to-eat cereals, soda-pop), which may play a more

significant role; still, this argues for the basic dietary principle that, in general, small amounts of

vitamins that are essential, but high, supplemental doses may have health risks.

By the way, excess nicotinamide can be removed from the body through sweat produced

by physical exercise; thus, one reason exercise is very good for all of us, including diabetics. 245

 Vitamin B5 (Pantothenic acid)

In 1930, Norris and Ringrose at Cornell University were studying a “growth factor” called

“vitamin B2” that was needed to prevent pellagra-like lesions on chicks. At the same time, Roger

J. Williams at the University of Texas, isolated a “growth factor” from a diverse number of

plants and animals that was essential to yeasts and bacteria; it had the same properties as Norris’

and Ringrose’s “growth factor.” Since it could be isolated from so many different organisms,

Williams’ research group named it “pantothene,” which means, “found everywhere.” The

Williams lab determined its chemical structure in 1939. 107

Characterization and Function

Vitamin B5, pantothenic acid, is an essential component of two important substances, coenzyme

A and acyl-carrier protein. 250,251

Coenzyme A is the molecule that carries acetyl, as acetyl-CoA, from pyruvate into the

Kreb’s cycle in mitochondria enabling the production of ATP from the energy stored in

carbohydrates, fats and some amino acids, 254

and is needed in the reverse processes, the synthesis

of carbohydrates, fatty acids and amino acids. 251

Coenzyme A is also involved in the synthesis

and degradation of fatty acids, again in mitochondria. 251,253

It is needed to synthesize cholesterol

and steroid hormones. 186,250

Coenzyme A is involved in the production of the heme component

of hemoglobin, so is essential in the production of red blood cells, along with folate, B6 and

B12. 186,250

Needed for the synthesis of the common neurotransmitter, acetylcholine, and hormone,

melatonin. 250

The enzymatic digestion in the liver of many drugs and toxins, including alcohol,

requires Coenzyme A, hence pantothenic acid. 186,250

Of special note, pantothenic acid is needed in the synthesis of vitamins A and D. 251

Coenzyme A works by “tagging” proteins with acetyl groups; this is what is does when it

brings acetyl from pyruvate into the Kreb’s cycle—it “tags” one of the compounds in the cycle

with its acetyl, the acetyl is then degraded, allowing its components to be carried into the

electron transport chain where ATP is made. Most of the proteins in cells that have added acetyls

have been acetylated by coenzyme A. Acetylated proteins are involved in the replication of

DNA, cell division and the control of genes, hence, are involved in growth and development. 250

Acyl-carrier protein is an enzyme that requires a form of pantothenic acid, 4’-

phosphopantetheine, to work. Both coenzyme A and acyl-carrier protein are needed for the

synthesis of fatty acids, including the phospholipids that make up most of the lipid component of

cell membranes, and the lipids that make up the myelin sheaths of nerve cells, allowing them to

function optimally. 250,251

Pantothenic acid in food generally exists as coenzyme A. 256

Coenzyme A is

enzymatically hydrolyzed in the small intestine into pantethine, which is then split by a specific

7.38

enzyme into pantothenic acid and beta-mercaptoethylamine. Absorption of pantothenic acid

occurs throughout the small intestine, but mostly in the middle section (jejunum). 256

Pantothenic acid is absorbed from the gut into the cells lining the small intestine by the

sodium-dependent multivitamin transporter, SMVT. Biotin (vitamin B7) and lipoate (alpha-

lipoic acid) share the SMVT with pantothenic acid; excess pantothenic acid can inhibit biotin

absorption. 257

Lipoate has several functions in the body, one of its chief roles its involvement as

a cofactor of the enzyme system that processes pyruvate into acetyl, which coenzyme-A

transports into the Kreb’s cycle, as described above. We’ll look at vitamin B7 below. Evidence

suggests that all cells have the SMVT, so are able to absorb pantothenic acid (as well as biotin

and lipoate) from the blood. 256

High levels of pantothinic acid are absorbed by passive

transport, 251

which does not use ATP. A higher absorption efficiency exists at lower

concentrations than at higher concentrations, meaning a higher percentage of pantothenic acid is

absorbed with smaller amounts than high doses, but the exact percentages are not known for

humans. 251

Most of the pantothenic acid in the blood is carried by red blood cells. 107

A recent study (2015) showed that 71% of 256 specifies of common gut bacteria have the

ability to produce pantothenic acid, 218

and do produce it, but the amount that is absorbed and

utilized is not known. 250,251,256

However, cells of the colon do have SMVTs, so can absorb

pantothenic acid (and biotin). 257

As indicated above, and elsewhere throughout this text, coenzyme A is an essential

molecule for the generation of ATP energy; thus, one might think that the consumption of more

pantothenic acid would produce more coenzyme A, thus giving one an energy boost. Such is not

the case. The enzyme, pantothenate kinase, converts pantothenate into coenzyme A, and when

sufficient amounts of coenzyme A are produced, it binds to pantothenate kinase, turning it off.

Because of this, high amounts of dietary or supplementary pantothenic acid do not result in high

amounts of coenzyme A. 251

Excess pantothenic acid is excreted in the urine as free pantothenic acid, 251

with 15%

being metabolized to CO2 and exhaled and 15% being removed in the feces. 107,258

RDI and UL

Both males and females, 14 years of age and over, require 5 mg of pantothenic acid daily; 138,139

pantothenic acid is nontoxic and upper limits have not been determined; 251

see Table 7.20 below.

Table 7.20. DRI and UL for Vitamin B5 (Pantothenic Acid) in mg/day. 138,139

(Upper limits not determined.)

Age Male Female Pregnancy Lactation

0-6 months 1.7 1.7 - -

6-12 months 1.8 1.8 - -

1-3 years 2 2 - -

4-8 years 3 3 - -

9-13 years 4 4 - -

14-18 years 5 5 6 7

19-50 years 5 5 6 7

> 50 years 5 5 - -

7.39

Dietary Sources

All plant and animal cells contain pantothenic acid. 251

Foods that are high in vitamin B5 include

meats, fish and shellfish; liver and other organ meats; fruits, vegetables, legumes and dairy.

Essentially, all whole foods, and even fast foods, contain vitamin B5.

Keeping in mind that 5 mg/day is the recommended dose of pantothenic acid for an adult,

a quick perusal of Table 7.21 suggests that anything that approaches a balanced diet will supply

sufficient vitamin B5.

Table 7.21. Representative Foods High in Vitamin B5 (Pantothenic Acid). 38

Food mg Food mg Cereals, Total Raisin Bran (1 cup) 10.000 Milk, 0% fat (1 cup, 8 oz) 0.875

Beef liver, New Zealand, boiled (3 oz) 8.330 Crustaceans, blue crab, boiled (3 oz) 0.847

Chicken liver, pan-fried (3 oz) 7.072 Chicken breast, roasted (3 oz) 0.795

Beef liver, braised (3 oz) 5.988 Beef chuck steak, lean, braised (3 oz) 0.790

Pork liver, braised (3 oz) 4.030 Catfish, channel, wild, dry-heat cooked (3 oz) 0.774

Mushrooms, shiitake, cooked (1/2 cup) 2.606 Fish, shad, dry-heat cooked (3 oz) 0.735

Mollusks, abalone (3 oz) 2.440 Fish, striped bass, dry-heat cooked (3 oz) 0.735

Game meat, caribou, roasted (3 oz) 2.278 Oatmeal, prepared (1 cup) 0.728

Seeds, sunflower kernels, dry roasted (1 oz) 1.996 Cream of wheat, prepared (1 cup) 0.721

Pork chop, pan-fried (1 chop) 1.930 Egg, large, hard-boiled (1 egg) 0.699

Sweet potato, boiled, mashed (1 cup) 1.906 Beans, garbanzos, canned (1/2 cup) 0.670

Rye flour, dark (1 cup) 1.864 Lentils, boiled (1/2 cup) 0.632

Taco Bell Enchirito (1) 1.834 Fish, herring, dry-hat cooked (3 oz) 0.629

Chili with beans, canned (1/2 cup) 1.818 Macaroni or spaghetti, whole wheat, cooked (1 c) 0.587

Mushrooms, white, boiled (1/2 cup) 1.685 Yogurt, Greek, plain, nonfat (6 oz) 0.563

Sweet breads (beef thymus), braised (3 oz) 1.676 Split peas, boiled (1/2 cup) 0.558

Potatoes, hash-browns, home prepared (1 c) 1.394 Kellogg’s Raisin Brain (1 cup) 0.544

Corn, canned (1 cup) 1.336 Succotash (corn and lima beans), boiled (1/2 c) 0.544

Peas, frozen, boiled (1 cup) 1.372 Turkey breast, roasted (3 oz) 0.539

Scalloped potatoes, made w/ butter (1 cup) 1.260 Eggnog (1/2 cup) 0.530

Tomato puree, canned (1 cup) 1.100 Cottage cheese, 1% fat (1/2 cup) 0.486

Acorn squash, baked, cubes (1 cup) 1.035 Noodles, egg, boiled (1 cup) 0.421

Potatoes, mashed (1 cup) 1.018 Shredded wheat, spoon-sized (1 cup) 0.392

Pumpkin, canned (1 cup) 0.980 Rice, white or brown, boiled, med-grain (1/2 cup) 0.382

Broccoli, boiled (1 cup) 0.960 Beans, great northern, canned (1/2 cup) 0.364

Game meat, bison, roast, braised (3 oz) 1.377 Beans, blackeyed peas, boiled (1/2 cup) 0.351

McDonald’s Hot Fudge Sundae (1) 1.341 Crustaceans, spiny lobster (3 oz) 0.343

Pork loin, roasted (3 oz) 1.276 Cashews, dry roasted (1 oz) 0.345

Kielbasa, cooked, pan-fried (1/2 link) 1.171 Mixed nuts, with peanuts, dry roasted (1 oz) 0.342

Salmon, sockeye, dry-heat cooked (3 oz) 1.165 General Mills Cheerios (1 cup) 0.300

Potato, Russet, flesh and skin, baked (1 large) 1.136 Peanuts, dry roasted (1 oz) 0.287

Salmon, coho, dry-heat cooked (3 oz) 1.082 Beans, navy, boiled (1/2 cup) 0.242

Avocado, Californian (1/2 fruit) 0.995 Orange juice (1/2 cup, 4 oz) 0.236

Herring, Pacific, dry-heat cooked (3 oz) 0.981 Refried beans, canned, fat-free (1/2 cup) 0.225

Braunschweiger, Oscar Mayer (1 oz) 0.966 Oranges, navels, sections (1/2 cup) 0.215

Milk, whole, 3.25% fat (1 cup, 8 oz) 0.910 Strawberries (1 cup) 0.208

Soymilk (1 cup, 8 oz) 0.906 Bread, whole wheat (1 oz) 0.183

Rainbow trout, wild, dry-heat cooked (3 oz) 0.905 Cheese, cheese (1 oz) 0.135

Pork, cured, ham, roasted (3 oz) 0.892 Cheese, mozzarella, low moisture (1 oz) 0.118

Milk, 1% fat (1 cup, 8 oz) 0.881 Apples, medium (1 fruit) 0.111

Turkey breast, roasted (3 oz) 0.880 Almonds, dry roasted (1 oz) 0.091

7.40

Deficiency

Deficiencies of pantothenic acid are very rare, 252

but may occur in individuals who are

malnourished. During World War 2, Allied POWs in prison camps in Burma, the Philippines and

Japan often experienced numbness, tingling and burning in their feet; these symptoms,

collectively termed “burning feet syndrome,” cleared up when given pantothenic acid, but not

the other B-complex vitamins. 250,251

Vitamin B5 deficiency has been experimentally induced in test subjects by giving them a

pantothenic acid blocker and putting them on a diet lacking pantothenic acid; this resulted in

excess fatigue, apathy and insomnia, loss of appetite, nausea, vomiting, gastritis, 186,259

personality changes, emotional disorders, irritability, as well as numbness of the hands, burning

of the hands and feet and muscle weakness. Interestingly, insulin sensitivity increased

significantly in these experimental subjects, inducing hypoglycemia. 259

Animal studies show that deficiencies in pantothenic acid cause anemia, low blood

glucose, skin irritation, neurological problems including spinal cord damage and convulsions,

rapid breathing and heart rate, decreased glycogen storage, decreased stamina, and other

symptoms. 250

Enlargement of the adrenal glands and spleen, and atrophication of the thymus

have been noted. 260

Pantothenic acid deficiency increases triglyceride and free fatty-acid levels

in the blood. 255

The metabolic degradation product of alcohol, acetaldehyde, inhibits the conversion of

pantothenic acid into coenzyme A, thus pantothenic acid deficiency may be seen in alcoholics. 258

Toxicity and Supplementation

There is no known toxicity of pantothenic acid to humans or animals. 251

Doses up to 1200

mg/day are considered safe, but may cause nausea and heartburn in higher doses. Doses of 10 to

20 grams/day of calcium D-pantothenate may cause diarrhea. 250

Pantothenic acid, topically applied, has been shown to be effective against acne. 260

Pantethine, a derivative of pantothenic acid, but not pantothenic acid itself, when given

two to three times per day for a total of 900 mg, significantly lowers, LDLs, total cholesterol and

triglyceride levels, 260

and increases HDLs, without the side effects of niacin. 250,261,262

Pantethine

is of particular use to diabetics. 250

 Vitamin B6 (Pyridoxine)

In the early 1930s, scientists were working on the identification and characterization of the B

vitamins. A condition in rats called acrodyna, very similar to pellagra in humans, could be

induced by feeding rats a synthetic diet including thiamin (B1) and riboflavin (B2), but lacking an

unknown factor.

One of the scientists working on B vitamins was Paul György, a Hungarian-born

pediatrician and researcher working in Heidelberg, Germany. After having left Germany in 1933

with his family, Paul György, while working at Cambridge University, England, in 1934, named

the unknown factor in yeast extract that cured acrodyna, vitamin B6; in 1938, György, now at

Western Reserve University at Cleveland, and several others, isolated vitamin B6, and in 1939,

György named it, “pyridoxine.” 266,267,268,269

7.41

Characterization and Function

Vitamin B6 is a group of three vitamers, with their phosphate forms: pyridoxine, pyridoxine 5’-

phosphate, pyridoxal, pyridoxal 5’-phosphate, pyridoxamine and pyridoxamine 5’-

phosphate. 263,264

Pyridoxal 5’-phosphate is the metabolically-active form, participating in over

4% of enzymatic reactions in the body; more than 100 enzyme systems involved in the

metabolism of amino acids use pyridoxal 5’-phosphate. 264,265

Pyridoxine is the form most

commonly seen in supplements. 263

All of the forms of B6 are interconvertible; 270

riboflavin

(vitamin B2) is needed to convert pyridoxine 5’-phosphate into pyridoxal 5’-phosphate. 202

Vitamin B6 is essential for the optimal functioning and development of the brain. 287

The

synthesis of several neurotransmitters of the brain requires pyridoxal 5’-phosphate. 287

These

include serotonin, dopamine, glycine, D-serine, glutamate, histamine and gamma-aminobutyric

acid (GABA). 264

The formation of functioning red blood cells depends of vitamin B6. Heme is the iron-

containing component of hemoglobin that allows it to bind to oxygen, and heme synthesis

requires pyridoxal 5-phosphate. 264,265

Niacin and NAD (nicotinamide adenine dinucleotide) formation from tryptophan

involves enzymes that use pyridoxal 5’-phosphate; thus vitamin B6 helps maintain this process

that is essential in the generation of ATP energy for cells. 264

Steroid hormones include estrogens, testosterone, progesterone, cortisone, and others.

The effects of steroid hormones may be inhibited by pyridoxal 5’-phosphate, which may play a

role in inhibiting cancers that are exacerbated by steroid hormones such as breast and prostate

cancers. 264

Research suggests that high dietary intake of B6 lowers the risk of various cancers. 271

The synthesis of some amino acids and proteins requires pyridoxal 5’-phosphate. The

enzymes that synthesize serine from glycine requires pyridoxal 5’-phosphate, 264

as do those that

make cysteine from homocysteine. 265

Vitamin B6 is needed for the formation of collagen. 289

Nucleic acid synthesis requires pyridoxal 5’-phosphate. 264

Vitamin B6 is important in the maintenance and function of the immune system as it is

involved in the synthesis of antibodies. 284

Vitamin B6 is involved in the stabilization of blood glucose levels. 284

The release of

glucose from stored glycogen in muscle tissue and the generation of glucose from glucogenic

amino acids requires pyridoxal 5’-phosphate. 264

Adequate levels of B6 are needed to synthesize

insulin, 162

maintain healthy insulin activity and lower blood glucose levels. 289

Homocysteine is a risk factor for vascular diseases including heart failure, coronary

artery disease, myocardial infarction and stroke (blockage of brain arteries). 274

Blood

homocysteine levels are inhibited by vitamin B6, as well as vitamins B9 (folate) and B12

(cobalamin). 264

There is evidence that inflammation may inhibit B6 status and metabolism. 264

Vitamin B6 is required to digest proteins; higher intake of protein necessitates a higher

intake of pyridoxine. 284

The vitamers of vitamin B6 found in food are usually the phosphorylated forms, and they

are generally attached to proteins; the acidic environment of the stomach detaches them. 286

When the vitamin B6 vitamers enter the small intestine, phosphatase enzymes remove the

phosphates. 283

The nonphosphorylated molecules attach to specific transporters and are moved

into the cells lining the small intestine; unlike most vitamin transporters, these are not sodium-

dependent. 265

Pyridoxal 5’-phosphate and pyridoxamine 5’-phosphate, the principal forms of B6

7.42

found in animal tissues, are absorbed the best of the various forms. 265

Most B6 is absorbed in the

middle portion (jejunum) of the small intestine. 263,286

The cells lining the intestines release the nonphosphorylated B6 vitamers into the blood

where they are picked up and carried by blood albumin proteins in the plasma, by hemoglobin

inside red blood cells, or are transported freely in the plasma. From the intestines, they are taken

to and absorbed by the liver, where they are phosphorylated and converted into pyridoxal 5’-

phosphate. 286

The liver attaches this molecule to albumin and releases it back into the blood,

where it is delivered to tissues that require it. 265

Proteins in tissues can bind to pyridoxal 5’-phosphate, allowing the tissues to accumulate

the vitamin to saturation, with muscle containing about 80% of the body’s B6. 265

Once saturation

is reached, the liver converts excess pyridoxal 5’-phosphate into 4-pyridoxic acid. 265

About half

of the B6 in plasma is 4-pyridoxic acid, with nonphosphorylated forms of B6 making up the rest.

The kidneys remove the excess B6 from the plasma into the urine, the major excretory product

being 4-pyridoxic acid. 265,270

Some 50% of 256 specifies of common gut bacteria have the ability to produce pyridoxal

5’-phosphate, 218

and do produce it, and some of it is absorbed in the colon, 285

but the amount that

is absorbed and utilized in humans is not known. 285,286

RDI and UL

Males, 14 to 50 years of age, require 1.3 mg of pyridoxine daily, with older males needing 1.7

mg daily; females, 14 to 18 years of age, require 1.2 mg of pyridoxine daily, with older females

needing 1.5 mg daily. 138,139

Upper limits for individuals 14 to 18 years have been set at 80 mg

daily, and 100 mg daily for individuals 19 years and older; see Table 7.22 below. The upper limit

cannot be attained through whole foods; only by taking supplements. 263,293

Table 7.22. DRI and UL for Vitamin B6 (Pyridoxine) in mg/day. 138,139

(Upper limits in parentheses.)

Age Male Female Pregnancy Lactation

0-6 months 0.1 (ND) 0.1 (ND) - -

6-12 months 0.3 (ND) 0.3 (ND) - -

1-3 years 0.5 (30) 0.5 (30) - -

4-8 years 0.6 (40) 0.6 (40) - -

9-13 years 1.0 (60) 1.0 (60) - -

14-18 years 1.3 (80) 1.2 (80) 1.9 (80) 2.0 (80)

19-50 years 1.3 (100) 1.5 (100) 1.9 (100) 2.0 (100)

> 50 years 1.7 (100) 1.5 (100) - -

Dietary Sources

Animal tissues contain mainly pyridoxal 5’-phosphate and pyridoxamine 5’-phosphate, whereas

plant tissues contain mainly pyridoxine and pyridoxine 5’-phosphate. 265

Note that the plant forms

of vitamin B6 require niacin for conversion into pyridoxal 5’-phosphate, whereas the animal

forms do not; this should not be a problem, though, in a balanced diet. The bioavailability of

vitamin B6, assuming a mixed diet, is about 75%. 265

Fish, organ meats including liver, starchy vegetables, including white potatoes, and fruit,

7.43

other than citrus, are good, whole-food sources of B6; see Table 7.23 below. In the United States,

most adults get their vitamin B6 by eating ready-to-eat cereals, beef, poultry, starchy vegetables,

and non-citrus fruits (bananas). 263

Table 7.23. Representative Foods High in Vitamin B6 (Pyridoxine). 38

Food mg Food mg Kellogg’s All Bran (0.5 cup) 3.720 Herring, Pacific, dry-heat cooked (3 oz) 0.441

Vegetarian stew (1 cup) 2.717 Banana, raw (1 medium) 0.433

General Mills, Total Raisin Bran (1 cup) 2.000 Pork, ham, roasted (3 oz) 0.426

Kellogg’s Special K (1 cup) 2.000 Garlic, raw (1/4 cup) 0.420

T.G.I. Friday’s classic sirloin steak (10 oz) 1.301 Rice, long-grain white, parboiled (1/2 cup) 0.418

Wendy’s, Jr. Hamburger, with cheese 1.233 Spanish mackerel, dry-heat cooked (3 oz) 0.391

Kellogg’s Raisin Bran (1 cup) 1.087 Chicken, dark meat (thigh), roasted (3 oz) 0.377

Kellogg’s Frosted Flakes (3/4 cup) 1.072 Squash, Hubbard, baked, cubes (1 cup) 0.353

Russet potato, baked (1 large) 1.058 Green peas, boiled (1 cup) 0.346

Ground turkey, fat free, pan-broiled (3 oz) 0.918 Chili beans, barbecue, cooked (1/2 cup) 0.342

Yellowfin tuna, dry-heat cooked (3 oz) 0.882 Tomato sauce, canned (1/2 cup) 0.327

Beef liver, pan fried (3 oz) 0.873 Waffle, frozen, 4” (1) 0.325

Kellogg’s Rice Krispies (1.25 cup) 0.776 Nuts, pistachios, dry roasted (1 oz) 0.318

Potatoes, hash browns, home-prepared (1 cup) 0.756 Broccoli, boiled (1 cup) 0.312

Cream of Wheat, instant, cooked (1 cup) 0.745 Apricots, dried, sulfured (1/2 cup) 0.310

Beef, tenderloin steak, boneless, lean (3 oz) 0.738 Mahi-mahi, dry-heat cooked (3 oz) 0.303

Beef, eye of round steak, grilled (3 oz) 0.711 Sunflower seed kernels, toasted (1 oz) 0.228

Sockeye salmon, smoked (3 oz) 0.694 Prune juice, canned (1/2 cup) 0.279 KFC chicken breast, original recipe (1 breast) 0.691 Carrot juice, canned (1/2 cup) 0.256

Turkey, white meat, roasted (3 oz) 0.686 Peppers, sweet red, raw, chopped (1/2 cup) 0.217

Oatmeal, instant, cooked (1 cup) 0.679 Pinto beans, boiled (1/2 cup) 0.196

New England clam chowder, canned (1 can) 0.675 Avocado, California (1/2) 0.195

Beef, top round roast, lean, roasted (3 oz) 0.673 Soybeans, roasted (1/2 cup) 0.179

General Mills, Cheerios (1 cup) 0.669 Lentils, boiled (1/2 cup) 0.176

Subway, tuna sub on Ital, lettuce/tomato (6 “) 0.642 Raisins, seeded (1/2 cup) 0.155 Game meat, deer, top round steak, broiled (3 oz) 0.603 Walnuts, English (1 oz) 0.152

General Mills Corn Chex (1 cup) 0.600 Corn, sweet, yellow, boiled, medium ear (1) 0.143

Sweet potato, canned (1 cup) 0.600 Peanut butter, smooth style (2 tbsp) 0.141 Sockeye salmon, dry-heat cooked (3 oz) 0.589 Chestnuts, European, roasted ( 1 oz) 0.141

Wendy’s Classic Double, w/ cheese (1) 0.586 Peanuts, dry roasted (1 oz) 0.132

Garbanzo beans (chickpeas), canned (1/2 cup) 0.568 Dole pineapple juice (1/2 cup, 4 oz) 0.125

Quaker, Cap’n Crunch cereal (3/4 cup) 0.577 Feta cheese (1 oz) 0.120

Sweet potato, baked in skin (1 cup) 0.572 Oranges, navel , 2 7/8” diameter (1) 0.111

Game meat, bison steak, top round, lean (3 oz) 0.558 Banana peppers (1/4 cup) 0.111

Beef strip steaks, grass-fed, lean (3 oz) 0.553 Macadamia nuts, dry roasted (1 oz) 0.102

Mollusks, whelk, moist-heat cooked (3 oz) 0.552 Milk, whole (3.25 fat) (1 cup, 8 oz) 0.088

Mollusks, octopus, moist-heat cooked (3 oz) 0.551 Carrot, medium (1) 0.084

Halibut, dry-heat cooked (3 oz) 0.537 Egg, scrambled, large (1) 0.082

Post Shredded Wheat, big biscuits (2 biscuits) 0.531 Apple, medium, 3” diameter (1) 0.075 Post Alpha-Bits (1 cup) 0.510 Cashews, dry roasted (1 oz) 0.073

Chicken breast, meat only, roasted (3 oz) 0.510 Spaghetti and other pasta, cooked (1 cup) 0.069

Pork chop, boneless, lean, pan-fried (3 oz) 0.492 Bread, whole wheat (1 oz, 1 slice) 0.061

Coho salmon, farmed, dry-heat cooked (3 oz) 0.483 Egg, hard boiled, large (1) 0.060

Plaintains, cooked, mashed (1 cup) 0.480 Spinach, raw (1 cup) 0.058

Pork chop, boneless, lean, braised (3 oz) 0.477 Bread, rye (1 oz, 1 slice) 0.021

Spinach, boiled (1 cup) 0.436 Cheddar cheese (1 oz) 0.014

7.44

Deficiency

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee determined

that vitamin B6 (pyridoxine) intake for all age classes of both males and females were above

RDA or AI amounts, 158

and deficiency in only B6 without being deficient other nutrients is

rare. 263

Deficiency in B6 usually occurs with low levels of other B vitamins such as B9 (folate)

and B12 (cobalamin) deficiency. 263

Alcoholics, those who are obese, diabetics and individuals with absorption problems such

as those with celiac disease, Crohn’s disease and ulcerative colitis are at particular risk for B6

deficiency. 263,283

Excess consumption of alcohol replaces foods that contain B6 with alcohol that does not

contain B6, so alcoholics tend to ingest insufficient nutrients, including B6; further, acetaldehyde,

the degradation product of alcohol decomposition, inhibits the production of pyridoxal 5’-

phosphate by cells 263

and facilitates the release of pyridoxal 5’-phosphate from binding proteins,

allowing excess hydrolysis of the released vitamer. 265,286

Ethanol may also increase the removal

of nonphosphorylated B6 vitamers by the kidneys into the urine. 286

Individuals with liver disease may also be at risk for B6 deficiency as they may be unable

to produce pyridoxal 5’-phosphate from the other forms of B6. 286

Vitamin B6 deficiency is seen in individuals with autoimmune diseases such as

rheumatoid arthritis; note, though, that B6 deficiency does not cause the inflammatory reactions

associated with autoimmune diseases. 263

Women who are taking high levels of contraceptives exhibit decreased levels of

pyridoxal 5’-phosphate, but the decrease is not significant. 265

Symptoms of B6 deficiency may include irritability, depression and confusion, 263

insomnia, 186

sores of the mouth and tongue, 284

also called “burning mouth syndrome,” 288

swollen

tongue, 263

scaling on the lips and cracks at the corners of the mouth, 162,263

a seborrheic dermatitis,

anemia, 265

and convulsions. 186

The pellagra-like sores associated with pyridoxine deficiency are due, in part, to inhibited

collagen synthesis in the skin. 289

B6 deficiency decreases the formation of NAD from tryptophan, 264

which may result in

the production of insufficient amounts of ATP, should niacin levels also be insufficient.

Besides anemia, 229

an inhibition of blood clotting mechanisms is associated with

inadequate dietary B6. 265

Problems with the central nervous system are associated with pyridoxine deficiencies. 229

Low blood levels of pyridoxal 5’-phosphate are associated with elevated homocysteine

levels and a near doubling of the risk of heart disease. 264,273

Low vitamin B6 levels are associated with depression in the elderly. 277

Vitamin B6 deficiency increases the risk of some cancers, especially among elderly

individuals and alcoholics, 271

especially colorectal cancer, 278

but has been shown to be not

associated with risk of cancer of the esophagus, stomach 280

or pancreas, 281

In infants, B6 deficiency may cause irritability and convulsive seizures; 263

breast milk,

however, generally contains adequate B6 to supplement what baby has stored during

development until about 6 months, when foods containing B6 need to be added; 294

see Chapter

12 for more on this.

7.45

Toxicity and Supplementation

Vitamin B6 in supplements is mainly in the form of pyridoxine, but pyridoxyl 5’-phosphate is

available. Although the body absorbs large, pharmacological doses of B6 well, it rapidly excretes

excess into the urine. 263

Individuals at risk for low blood B6 levels such as alcoholics, the obese,

diabetics, and those with absorption and liver disease, may be advised to take B6 supplements. 263

High intake of pyridoxine over time may lead to irreversible sensory neuropathy (nerve

damage), but has not been clearly shown to cause other effects such as dermatological lesions. 265

Symptoms of B6 toxicity may include numbness, sensory changes and coordination

difficulties. 284

Cases of B6 toxicity are rare. 162

Neurological symptoms seen in doses of 1,000 to

6,000 mg of pyridoxine taken orally for 12-40 months include inability to control body

movements, stop when high doses are discontinued. 263

Other symptoms of high intake include

nausea and heartburn; painful, disfiguring skin lesions; and sensitivity to light. 263

High intakes by

adults of 200 mg/day for up to five years have shown no evidence of toxic effects. 263

B6 from whole foods may be good for the heart. In one large study (n = 40,000) that ran

for 11.5 years, individuals who obtained 1.6 mg B6/day in their diet had a 48% lower risk of

myocardial infarction than those who obtained only 1.3 mg B6/day; note that this was B6

obtained through foods, not through supplementation. 242

Other large studies support the inverse

association between blood B6 levels and myocardial infarction risk. 273

However, no improvement

in cardiovascular disease risk factors has been found with B6 supplementation. 263,264,295

Vitamin B6 supplementation, along with B9 and B12, have been shown to improve

symptoms of depression in otherwise healthy elderly people, 275

as well as in individuals

recovering from a stroke. 276

Although B6 supplementation is used to correct low blood levels in individuals with

autoimmune diseases, 263

it does not inhibit inflammation reactions. 264

Although higher B6 blood levels have been associated with higher memory scores in

elderly men, 297

there is no evidence that B6 supplementation benefits individuals with

Alzheimer’s or general cognitive decline. 263,264

There is no evidence to date showing that B6 supplements reduce the risk of cancer. 264,296

There is some evidence that high blood levels of B6 inhibits colorectal cancer 264

and breast

cancer in postmenopausal, but not premenopausal women. 279

The key is eating a whole-food diet

that includes adequate B6.

There is conflicting evidence as to whether B6 supplementation inhibits the development

of calcium oxalate kidney stones by reducing urinary oxalate levels; more research is needed

here. 264

Vitamin B6 in the form of pyridoxine hydrochloride (10 mg) has been shown to be

effective, along with doxylamine succinate (10 mg) for the treatment of morning sickness during

pregnancy, and is recommended for such by the American and Canadian Colleges of Obstetrics

and Gynecology. 292

Some evidence suggests that B6 supplementation may help the moodiness, irritability,

anxiety and bloating associated with premenstrual syndrome, although more research is needed

to verify this. 263

In type 2 diabetics, pyridoxine supplementation (150 mg/day) significantly improve

blood glucose (HbA1c) levels. 290

Diabetes plays a major role in damaging kidneys. Simultaneous supplementation of B6

with vitamins B9 (folate) and B12 (cobalamin) have been used to decrease homocystein levels and

7.46

the risk of cardiovascular disease in diabetics. However, in individuals who already have diabetic

nephropathy (kidney disease), this combination of vitamins appears to worsen the nephropathy

and increase the risk of vascular disease. 291

A large-scale review of the literatures shows that

vitamin B supplementation therapy for diabetic kidney disease, including therapy with B6, has

not been shown to be effective. 292

 Vitamin B7 (Biotin)

In 1901, French biochemist E. Wilders discovered a substance in yeast water that was used up as

yeast grew and was essential to the growth of yeast; he called it “bios.” After determining many

of the physical and chemical properties of this substance, he further determined that it was found

in wort, meat extracts and other substances. 303

In 1906, Devloo found “bios” in opium,

belladonna, ergot, bile, and other researchers found it in protein-free milk and wheat germ. 304

In 1927, biochemist Margaret A. Boas, working in London, discovered that rats fed

uncooked egg white as their dietary protein source developed an “eczematous dermatitis,”

whereby red, scaly patched appear at the corners of the mouth, the coat loses hair, skin

hemorrhaging occurs, and neurological condition develops characterizes by a kangaroo-like

posture and motion of the front limbs, eventually resulting in paralysis and death. 301,302

If the egg

protein were cooked, these symptoms did not occur. Boas postulated there was a water-soluble,

heat-resistant, B-vitamin-like substance in egg and other proteins she called “factor X,” that was

essential to prevent these symptoms.

Working independently of Boas, in 1931, Paul György (see vitamin B6 above),

discovered a substance with the same properties as factor X which he isolated from liver and

named “vitamin H.” 305

Root nodules are structures developed by legumes in response to infection by Rhizobium

bacteria. But these infections are beneficial, as they allow plants, such as beans, peanuts, clover

and alfalfa, to fix nitrogen from the atmosphere into biologically-usable compounds, fertilizing

the soil. In 1933, Allison, Hoover and Burk named Allison reported on a factor needed by

Rhizobium for respiration and secondarily for growth found in yeast, molasses, humic acid and

egg albumen, which they termed “coenzyme R,” that was essential for the growth of

Rhizobium. 307,308

In 1936, German biochemists, Kögl and Tönnis, isolated the substance needed for yeast

growth from egg yolk and called it “biotin.” In 1940, György’s research group discovered that

bios, factor X, vitamin H and coenzyme R were all the same substance, biotin. 305,306

Also in 1940,

it was shown that the egg protein, avidin, formed a complex with biotin inhibiting its

absorption. 302

Characterization and Function

Biotin, also called vitamin B7 or vitamin H, is a cofactor for five enzymes involved in the

catabolism (digestion) of amino acids and fatty acids, the formation of glucose

(gluconeogenesis), and the synthesis of fatty acids. 283

Two of the enzymes that depend on biotin are involved in the synthesis of fatty acids

from acetyls 298,299

and the oxidation of fatty acids to make ATP. 298

Another enzyme helps make

oxaloacetate from pyruvate, oxaloacetate can then form components of the Kreb’s cycle or can

be turned into glucose in the liver, kidneys and other tissues; 299

in this way, glucose can be

7.47

formed from various compounds other than carbohydrates, including amino acids. 298

The fourth

enzyme is involved in the metabolism of odd-chain amino acids, cholesterol, and amino acids. 298

A fifth biotin-dependant enzyme is needed for the metabolization of the branch-chain amino

acid, leucine. 299

Biotin is thus needed in energy metabolism, to produce ATP from carbohydrates. 162,186

Biotin also helps to regulate oncogenes, genes that induce the formation of cancer; 283

is probably

involved in the regulation of other genes, needed for the immune system, and cell growth and

proliferation. 312,298

Biotin is needed for normal growth, maintenance of the skin, nervous system

function and fetal development. 283

Replication, which is the duplication of DNA, so that each new cell product of cell

division can have a complete set of genes, requires biotin, as does the process of transcription,

the reading of the genetic message encoded on DNA molecules. 298

In food, biotin exists both unattached and complexed with proteins. 283,299,312

The

digestion of proteins that bind biotin begins in the stomach, and continues with proteases

attached to the walls of the small intestine, producing biotin with one or a few amino acids

attached. 283

An enzyme called biotinidase completes the formation of free biotin. 283,299,312

At low concentrations, biotin is absorbed from the small intestine by SMVTs (sodium-

dependent active transporters), 312

and at high amounts, by simple diffusion. 229,283

Recall that

biotin shares the SMVTs with pantothenic acid (vitamin B5) and lipoate. 283

From the absorptive

cells lining the small intestine, another sodium-dependent transporter moves biotin into the

interstitial fluid. 283

Biotin is absorbed mainly in the first part of the small intestine

(duodenum), 313

but is also absorbed in the first and middle parts of the colon. 315

Regulation of biotin uptake is associated with the amount of dietary biotin. High amounts

of biotin in the diet causes a deactivation (down-regulation) of receptors, so less biotin is

absorbed; low amounts of biotin in the diet causes an activation (up-regulation) of receptors, so

more biotin is absorbed. 283,312

About 81% of the biotin in the blood is free in plasma, 7% is reversibly bound to plasma

proteins and 12% covalently bound to plasma proteins. The plasma proteins involved appear to

be albumins, which are the most common plasma proteins and can bind to many substances in

the blood, and biotinidase, which binds only to biotin. 309

Some biotin is, of course, filtered out of

the blood into the urine by the kidneys; a significant amount of biotin, though, is removed from

urine by transporters and returned to the blood. 309

After being absorbed by the intestines and released into the blood, biotin is carried to the

liver. With low concentrations of biotin, sodium-dependent transporters move biotin into the

liver; with high concentrations, diffusion appears to be the mechanism. 309

Once in the liver,

biotin binds to storage proteins. Biotin eventually enters mitochondria, where it used. 309

Various metabolic byproducts of biotin metabolism are released into the blood and

filtered out by the kidneys into the urine. 299

Some 40% of 256 specifies of common gut bacteria have the ability to produce biotin. 218

Biotin is produced by these bacteria and a “substantial amount” is released in its free form, 312

but

it is not known how much of this biotin is absorbed and utilized. 283,300

Cells of the colon have

SMVTs, so absorption of significant amounts of biotin (and pantothenic acid) is possible. 257,283

RDI and UL

Males and females, 19 years of age and over, require 30 mcg of biotin daily. 138,139

Biotin toxicity

7.48

has not been reported and upper limits have not been determined; see Table 7.24 below.

Table 7.24. DRI and UL for Vitamin B7 (Biotin) in mcg/day. 138,139

(Upper limits have not been determined.)

Age Male Female Pregnancy Lactation

0-6 months 5 5 - -

6-12 months 6 6 - -

1-3 years 8 8 - -

4-8 years 12 12 - -

9-13 years 20 20 - -

14-18 years 25 25 30 35

19-50 years 30 30 30 35

> 50 years 30 30 - -

Dietary Sources

Good sources of biotin include organ meats, egg yolk, yeast breads, cereals, and most

vegetables. 162,312

Biotin in meats is more bioavailable than biotin in cereals. Raw egg white binds

to biotin, inhibiting its absorption. 299

The amount of biotin in most foods has not been yet

determined. A varied and balanced diet is likely to supply adequate amounts of biotin.

Table 7.25. Representative Foods Containing Vitamin B7 (Biotin). 319

Food mcg Food mcg Chicken liver, cooked (3 oz) 158.51 Noodles (1 cup) 0.28

Beef liver, cooked (3 oz) 35.40 Milk, 2% fat (1 cup, 8 oz) 0.26

Egg, whole, cooked (1 egg) 10.00 French fries (3 oz) 0.27

Salmon, pink, canned in water (3 oz) 4.98 Macaroni and cheese (1 cup) 0.24

Peanuts, roasted (1 oz) 4.97 Raspberries, raw (1 cup) 0.22

Sweet potato, cooked (1 cup) 4.76 Milk, 3.25% fat, whole (1 cup, 8 oz) 0.21

Hamburger patty, cooked (3 oz) 3.79 Pizza, pepperoni, 3.5 oz slice (1 slice) 0.21

Pork chop, cooked (3 oz) 3.79 Salad, mixed green (2 cups) 0.20

Strawberries, raw, sliced (1 cup) 2.50 Hamburger bun 0.17

Sunflower seeds, roasted (1 oz) 2.21 Raisins (1/4 cup, packed) 0.16

Mushrooms, canned (1/2 cup) 1.68 Banana, raw, medium (1 fruit) 0.16

Almonds, roasted (1 oz) 1.25 Spaghetti sauce, with beef (1 cup) 0.16

Spinach, frozen (1 cup) 1.10 Grits (1 cup) 0.14

Avocado, raw (1/2 fruit) 0.97 Pizza, cheese, 3.5 oz slice (1 slice) 0.11

Broccoli, fresh, chopped (1 cup) 0.86 Plain yogurt (1/2 cup, 4 oz) 0.09

Tomatoes, raw, chopped (1/2 cup) 0.63 Orange, raw, 2 5/8” diameter (1 fruit) 0.06

Catfish, breaded, fried (3 oz) 0.63 Apple juice, canned from concentrate (1/2 c) 0.06

Tuna, canned in water (3 oz) 0.58 Kellogg’s Frosted Flakes (3/4 cup) 0.04

Orange juice, canned from concentrate (1/2 c) 0.47 Provolone cheese (1 oz) 0.04

Oatmeal (1 cup) 0.44 Corn, whole kernel, canned (1 cup) 0.08

Beer (1½ cup, 12 oz) 0.41 Apple, raw, medium (1 fruit) 0.04

Cheddar cheese, milk (1 oz) 0.40 Crackers, saltine (5 crackers, ½ oz) 0.04

Chicken strips, breaded, fried (3 oz) 0.37 General Mills, Cheerios (1 cup) 0.03

Milk, 0% fat, skim (1 cup, 8 oz) 0.30 Bread, whole wheat (1 oz) 0.02

Mashed potatoes, with brown gravy (1 cup) 0.28 Dinner roll (1 oz) 0.01

7.49

Deficiency

Isolated biotin deficiencies are rare, 229,252

because most foods contain significant amounts of

biotin, and probably because we absorb biotin produced by friendly gut bacteria, but may occur

in conjunction with deficiencies of other B-vitamins. 309

Individuals who consume raw egg white for long periods of time (weeks) are at a high

risk of biotin deficiency. 298,299

The egg protein, avidin, binds the biotin found in eggs and in

other foods consumed with raw eggs, making it unavailable for absorption. The cooking of eggs

denatures some avidin, liberating biotin. 300

Egg whites have to be boiled for at least 4 minutes to

completely denature avidin and release bound biotin; 311

a source cited in Chapter 6 states that

avidin must be heated to 120°C (higher than boiling) for 15 minutes for avidin’s complete

denaturation. 310

Frying eggs reduces avidin activity to 33%, poached eggs have 71% avidin

activity and boiling eggs for 2 minutes leaves 40% avidin activity in egg whites. 311

Other people at particular risk for biotin deficiency include women who are pregnant,

alcoholics and those with inflammatory bowel disease. 283

The developing fetus takes biotin from

mom, so a pregnant women needs to make sure she’s getting adequate biotin; biotin deficiency

may lead to birth defects. 298

Alcohol inhibits the operation SMVTs in both the small intestine and

in the colon. 283

Individuals who take large supplement doses of pantothenic acid (vitamin B5) or

lipoic acid might be at risk for biotin deficiency as biotin, pantothenic acid and lipoic acid

compete for the same SMVT transporters, thus inhibit the absorption of the other; 298,314

this has

been shown to be the case in animal studies, but so far has not been seen in humans. 298

Biotin deficiency is associated with a red, scaly rash around the eyes, nose, mouth,

especially at the corners of the mouth, and genitals; 298

hair loss and the loss of hair color;

conjunctivitis; growth retardation, and nervous system problems. 283,298,299

Nervous system

problems include depression, lethargy, hallucinations and tingling of the hands and feet. 298,299

Biotin deficiency can lead to glucose intolerance, 255

high blood cholesterol and increased

risk of heart disease. 316

Toxicity and Supplementation

Biotin is nontoxic. Oral doses of up to 200 mg daily and intravenous injections of up to 20 mg

daily to treat specific problems in biotin metabolism have not been shown to be toxic. 309

Even

daily doses of 200,000 mg have not been shown to be toxic. 298

Biotin supplementation is used for confirmed biotin deficiency. 309

Biotin supplementation may help lower blood glucose in both type 1 and 2 diabetics, as

suggested by several small studies. It is clear that biotin deficiency does inhibit glucose

utilization, but the effect of supplementation has not yielded consistent results. Biotin does

stimulate for formation of fatty acids and glycogen from glucose, and increase the release of

insulin from the pancreas, thus lowering blood glucose levels. More studies are needed to

recommend biotin supplementation as a treatment for diabetes. 298

The risk of heart disease may be reduced through biotin supplementation. 317

Biotin has

been shown to lower blood triglycerides, and overall cholesterol levels by decreasing

VLDLs. 317,318

Biotin deficiency causes hair loss and the loss of color in hair, but there are no studies

that I am aware of that shows biotin supplementation, other than to make up for biotin

deficiency, can be effectively used to prevent or treat hair loss. 298

7.50

Biotin supplementation has been shown, in small studies, to significantly strengthen and

thicken fingernails in women with brittle fingernails. Large, controlled studies are needed before

biotin can be clinically recommended for this. 298

 Vitamin B9 (Folate)

Folate was first isolated from spinach leaves in 1941, and was given its name from the Latin,

“folium,” meaning “leaf.” Folic acid was synthesized in 1943. 324

After it had been synthesized,

folic acid was found be effective as a cure for various anemias, but was found to be effective

against pernicious anemia for only a limited period of time; 324

for more on this, read the section

dealing with cobalamin, vitamin B12.

Lucy Wills was an English physician. She went to Bombay, India, in 1928, to study

anemia, common in textile workers who consumed diets low in protein, fruits and vegetables. 324

Wills thought it might be a vitamin deficiency. 325

In 1930, after trying many different

compounds, by chance, she cured a monkey with anemia by feeding it marmite, an inexpensive

yeast extract; the monkey recovered. 325

Wills and coworkers discovered that marmite as well as

liver extract prevented anemia in rats fed a deficient diet. She then discovered, in 1931, that

marmite and liver extract prevented anemia in pregnant women fed a diet that was deficient B

vitamins. 324,326

She suggested, in 1933, that an “extrinsic factor” in yeast extract and animal

protein, something others were calling “Wills’ factor,” prevented/cured anemia. Wills’ factor

turned out to be folate. 325,326

Characterization and Function

Folate is the general term for any of a number of natural folates found in foods and folic acid,

which is added to some foods and available as a dietary supplement. 320,323

Folate activates enzymes that are involved in the synthesis of DNA and RNA, and in

amino acid metabolism. 320,322

DNA and RNA synthesis and amino acid metabolism are needed

for cell division, hence needed for growth and development. 322

One of the earliest signs of folate

deficiency is anemia, the reduction in formation of red blood cells. 320

Folate helps regenerate the amino acid methionine from homocysteine, producing

compounds that are involved in methylation reactions; 320

note that the synthesis of methionine

also requires vitamin B12. 321

DNA, RNA, proteins, hormones, lipids and other molecules may be

methylated. 323,348

Methylation reactions add a single-carbon methyl group to target molecules.

This process helps control the replication of DNA, which is needed for cell growth, and the

control and expression of genes and protein metabolism, needed for growth and development. 348

Folate assures that there is always a supply of methionine with attached methyl groups for

methylation reactions. 323

Besides the interconversion of homocysteine into methionine, other amino acid

conversions that depend on folate include the catabolism of histidine to glutamic acid and the

interconversion of serine and glycine. 322

Adequate levels of folate appear to be necessary to maintain optimal cognitive

functioning, memory and good mental health. 320

Folates found in food are enzymatically hydrolyzed in the intestine to what is called the

monoglutamate form. 320,322,323

They then attach to transport proteins in the first part of the small

intestine 322

and are actively moved into the cells lining the intestine. Large amounts of folate or

7.51

folic acid can also cross directly into the blood 229

by passive diffusion. 322

Before being released

into the blood, folate and folic acid 340

are generally further modified, mostly into 5-

methyltetrahydrofolate (= L-methylfolate), by the enzyme MTHFR (methylenetetrahydrofolate

reductase); 321

5-methyltetrahydrofolate is the major, biologically-active form of folate found in

plasma; 320

and is capable of being moved across cell membranes into tissues, including across

the blood brain barrier into brain cells. Note that riboflavin is also needed for the synthesis of 5-

methyltetrahydrofolate. 229,321

From the cells lining the small intestine, 5-methyltetrahydrofolate is transported to the

liver, 322

where it is modified and stored, or released back into the blood or into bile. 322

About ½

of the folic acid in the body is found in the liver. 320,322

Some 2/3 of plasma folate is carried by

blood proteins, mainly by albumin, 322

the remaining being free in the plasma. 326

Most folate in

the blood is carried in red blood cells. 320

Plasma folate is easily removed from the blood by the kidneys, which then reabsorb it

back into the blood, so not much folate is lost in urine. Some folate does end up in bile, thus goes

into the feces, but much of this is picked up by the small intestine; again, loss of folate in the

feces is small. 322

Natural folates lose biological activity very rapidly during the harvesting of fruits and

vegetables, but also during storage and preparation, with biological activity lasting only days to

weeks. Further, the bioavailability of natural folates may be as little as 25-50%. On the other

hand, folic acid is stable for months to years, with a bioavailability approaching 100%. 323

Some 43% of 256 specifies of common gut bacteria have the ability to produce folate. 218

RDI and UL

Males and females, 14 years of age and over, require 400 mcg-DFEs of folate daily. 138,139

Folate

is considered nontoxic and upper limits have not been determined; see Table 7.26 below.

Units of folate are given in mcg of DFE, or “Dietary Folate Equivalents,” which equate

the bioavailability of the various forms of folate to food folate, with 1 mcg of food folate being

equal to 1 mcg of DFE; 1 mcg of folic acid in a fortified food or taken as a supplement with

meals has the biological activity of 1.7 mcg of DFE; and 1 mcg of folic acid taken as a

supplement on an empty stomach has the biological activity of 2.0 mcg of DFEs. 321

The USDA

nutrient listings for folate are listed in mcg of DFE; see Table 7.27.

Table 7.26. DRI and UL for Vitamin B9 (Folate) in mcg-DEFs/day. 138,139

(Upper limits in parentheses.)

Age Male Female Pregnancy Lactation

0-6 months 65 (ND) 65 (ND) - -

6-12 months 80 (ND) 80 (ND) - -

1-3 years 150 (300 150 (300) - -

4-8 years 200 (400) 200 (400) - -

9-13 years 300 (600) 300 (600) - -

14-18 years 400 (800) 400 (800) 600 (800) 500 (800)

19-50 years 400 (1,000) 400 (1,000) 600 (1,000) 500 (1,000)

> 50 years 400 (1,000) 400 (1,000) - -

ND = not determined

7.52

Dietary Sources

In 1998, the Federal Drug Administration required that all cereal-grain products in the United

States be fortified with folate. 247

(See below.)

Foods that are particularly high in folate include fortified cereals and grain products;

liver; yeast; legumes, grains and seeds; and spinach, asparagus and other green vegetables.

Meats, poultry, fish and dairy are not particularly high in folate, although some shellfish contain

significant amounts; see Table 7.27.

Table 7.27. Representative Foods High in Vitamin B9 (Folate). 38

Values are listed as mcg of DFE.

Food mcg of

DFE

Food Mcg of

DFE Quaker, Cap’n Crunch w/ Crunchberries (¾ cup) 717 Navy beans, boiled (1/2 cup) 128

Kellogg’s All Bran (1/2 cup) 681 Split peas, boiled (1 cup) 128

Kellogg’s Special K (1 cup) 676 Animal crackers (1 box, 2.4 oz) 123

Chicken liver, simmered (3 oz) 491 Cream of Wheat, 2 ½ min prep (1 cup) 106

Yeast extract spread (Marmite) (1 tsp) 353 Great northern beans, canned (1/2 cup) 106

Kellogg’s Rice Krispies (1.25 cup) 341 Corn, canned (1 cup) 104

General Mills, Wheaties (3/4 cup) 336 Green peas, boiled (1 cup) 102

General Mills Cheerios (1 cup) 336 Focaccia bread (1 piece, 2 oz) 100

Post Alpha Bits (1 cup) 336 Taco with beef, cheese and lettuce (1) 98

Frybread, Navajo, made with lard (1 piece) 298 Corn grits, prepared with water (1 cup) 98

Farina, water cooked (1 cup) 286 Pan dulce (1 piece) 98

Veal liver, braised (3 oz) 282 Conch, baked or broiled (3 oz) 91

Asparagus, boiled (1 cup) 268 Boysenberries, frozen (1 cup) 84

Spinach, boiled (1 cup) 264 Biscuit, buttermilk (1) 81

Vegetable stew (1 cup) 254 Black turtle beans, boiled (1/2 cup) 80

Asparagus, frozen, boiled (1 cup) 244 Potatoes, Russet, baked (1 large) 78

Burger King Whopper, with cheese (1) 228 Orange juice (1 cup, 8 oz) 74

Spinach, frozen, chopped or leaf (1 cup) 226 Beets, canned (1 cup) 72

Egg noodles, prepared (1 cup) 221 Sunflower seeds, toasted (1 oz) 67

Long-grain rice, parboiled (1 cup) 216 Refried beans, canned, fat free (1/2 cup) 66

Beef liver, braised (3 oz) 215 Pretzels (1 oz) 66

Soybeans, mature seeds, roasted (1/2 cup) 182 California avocados (1/2 fruit) 61

Lentils, boiled (1/2 cup) 179 King crab, moist heat (3 oz) 45

Blackeyed peas, boiled (1/2 cup) 178 Quinoa, boiled (1/2 cup) 39

Pizza Hut, 14” pepperoni pizza (1 slice) 175 Peppers, red, sweet, raw (1/2 cup) 35

Turnip greens, boiled (1 cup) 175 Peanuts, dry roasted (1 oz) 27

Broccoli, boiled, chopped (1 cup) 168 Guava (1) 27

Pasta (spaghetti, macaroni), cooked (1 cup) 167 Bread stick, plain (1/3 oz) 26

Oatmeal (1 cup) 166 Egg, hard boiled or scrambled, large (1) 22

Brussels sprouts, frozen boiled (1 cup) 158 Shrimp, moist heat (3 oz) 20

Pinto beans, boiled (1/2 cup) 147 Almonds, dry roasted (1 oz) 16

Tortilla, flour, 10” (1, 2.5 oz) 145 Pistachios, dry roasted (1 oz) 14

Pink beans, boiled (1/2 cup) 142 Bread, whole wheat (1 slice) 12

Garbanzo beans (chickpeas), boiled (1/2 cup) 141 Milk, whole, 3.25% fat (1 cup, 8 oz) 12

Lima beans, boiled (1/2 cup) 137 Yogurt, Greek, nonfat, plain (6 oz) 12

Corndog 135 Turkey breast, roasted (3 oz) 8

Ramen noodles, w/o flavor packet (1 packet) 134 Cheese, cheddar (1 oz) 7

Black beans, boiled (1/2 cup) 128 Steak, tenderloin, broiled (3 oz) 7

7.53

Deficiency

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee determined

that Americans were not getting enough Vitamin B9 (folate) in their diet. 158

Of particular concern

are women of childbearing age, with 19% of females, age 14 to 18 years, and 17% of women age

19-30 getting insufficient folate. Overall, 13% of non-Hispanic white women and 23% of non-

Hispanic black women do not get enough folate. Individuals over the age of 51 tend to consume

folate over the upper limit. 320,327

Folate deficiency is associated with poor diet, tobacco smoking, 321

alcoholism and

pathologies that inhibit the absorption of folate. Alcohol inhibits the absorption of folate 321

and

increases its breakdown. 320

Further, alcoholics, as they obtain most of their calories from alcohol,

tend to be nutrient deficient and not ingest sufficient folate in the first place. 320,321

Individuals

with celiac disease and inflammatory bowel diseases such as Crohn’s disease and ulcerative

colitis are at an increased risk for folate deficiency. 320,321

Another cause of folate deficiency is genetic variations in the gene that produces the

enzyme MTHFR (methylenetetrahydrofolate reductase) that turns inactive folate, including folic

acid, into active folate (5-methyltetrahydrofolate, = L-methylfolate). 339,340

These gene variations

code for enzymes with decreased activity, resulting in the formation of less active folate. 336

If an

individual has one defective gene for this enzyme, folate activation may be reduced by 40%; if

both genes are affected, folate activation may drop to by 70%. 336

This results in significantly

lower levels of folate in red blood cells and plasma. 337

One genetic variation is seen in over 20%

of U.S. Hispanics, 8-20% of whites, and less than 2% of blacks; another variation is seen in 4-

5% of Hispanics, 7-12% of whites, 1-4% of Chinese and other Asian populations. 337

One

estimation is that 40-60% of the population is affected by MTHFR gene variations. 340

The primary symptom of folate deficiency is megaloblastic anemia, 321,322

a type of

anemia characterized by very large, nonfunctioning red blood cells. These cells crowd out the

functioning red blood cells resulting in the blood not being able to carry enough oxygen to the

tissues; this causes shortness of breath, lack of energy, headache, irritability and heart

palpations. 320,321,322

Note that megaloblastic anemia can also be a sign of vitamin B12

deficiency. 320

Because red blood cells live about 120 days, it may take four months or more of

folate deficiency for the first megaloblastic red blood cells to appear. 321

Other signs of folate deficiency include shallow ulcerations in the tongue and lining of

the mouth; changes in the pigmentation of the skin, hair and fingernails; and elevated

homocysteine levels. 320

Insufficient dietary folate in women is associated with an increased risk of preterm

delivery and spontaneous abortion, giving birth to babies with low birth weight, inhibited growth

and neural tube defects such as spina bifida. 328

In order to reduce the risk to baby, women must

have adequate folate levels at conception. 329

Neural tube defects may result in spina bifida and/or anencephaly. 320

Spina bifida is the

incomplete formation and closure of the vertebrae, allowing the membranes covering the spinal

cord to balloon out of the body, often resulting in paralysis. Anencephaly occurs when the brain

does not form. Hispanic women have the highest rates of giving birth to children with neural

tube defects; black and Asian women have the lowest rates. 341

Folate deficiency is associated with the development of several cancers including lung,

esophageal, stomach, pancreatic, breast, cervical and breast cancers. 320

7.54

Although folate supplementation does not increase cognitive function or memory in

individuals with adequate folate levels (see below), folate deficiency is associated with cognitive

decline, reduced memory and depression. 320

The presence of variations in the gene that activates

folic acid, MTHFR (see above), is directly related to various psychiatric disorders including

depression, schizophrenia and bipolar disorder. 337

Variations in the gene that activates folate are also associated with an increased risk of

peripheral neuropathy and retinopathy, a major cause of blindness, in individuals with

diabetes. 338

Toxicity and Supplementation

Folate is considered non-toxic. 346

In studies where subjects were given 40,000 mcg doses of folic

acid, no increased health risks were noted. 347

Most dietary supplements are available as folic acid, usually in 400 mcg doses. When

taken with food, some 85% of folic acid is bioavailable; if taken without food, the bioavailability

of folic acid rises to about 100%. 320

However, it is suggested that L-methylfolate may be the

preferred supplement to folic acid, especially for individuals who possess the gene variations that

do not allow for the full conversion of folic acid into L-methylfolate (5-methyltetrahydro-

folate). 340

Beginning in January of 1998, U.S. food manufacturers have been required by the U.S.

Food and Drug Administration (FDA) to fortify cereal-grain products such as breads, cereals,

flour, cornmeal, pastas and rice with folate, which has significantly increased the blood folate

status of the average American. 247,320

However, folate supplements are still recommended for

women of childbearing age. 247

Folate supplementation has reduced the incidence of neural tube

defects (spina bifida and anencephaly) in U.S. infants 2

by 25-30%, 342

and have the estimated

potential to reduce neural defects by as much as 50-60%. 342

Rates in spina bifida and

anencephaly have been decreasing significantly in babies born to Hispanic and non-Hispanic

white women, but not in babies born to black women. 343

Most countries do not require folate

supplementation. Australia, 335

Canada, Costa Rica, Chile and South Africa are among the few

countries, beside the U.S., that do. 320

The mechanism by which folate reduces neural tube defects

has not been determined. 349

Prenatal folic acid supplementation has also been associated with reducing the incidence

of premature birth 344

and, when included with other prenatal vitamins, congenital heart

defects. 320

Supplementation using folic acid is successfully used to treat megaloblastic anemia

caused by folate deficiency. 321

Several studies suggest that folic acid supplementation reduces the risk of colorectal

cancer, 320

in one study, about 2% for every 100 mcg ingested. 321

In the NIH-AARP Diet and

Health Study of 525,488 individuals age 50-71, those who took 900 mcg or more of folic acid

had a 30% lower risk of colorectal cancer than those who took only 200 mcg. 330

Regarding

colorectal and other cancers, folic acid supplementation increases the development of cancerous

cells in individuals who already have cancerous or precancerous conditions. 320,321

One theory

suggests that moderate folate intake promotes the development of normal cells in precancerous

conditions, but once cancer begins, folic acid supplements promote the development of more

cancerous cells. 320,321

Consuming whole fruits and vegetables has been shown to reduce cancer

risk; it is thought that the folate in fruits and vegetables plays a major role in reducing this

7.55

risk. 321

A 2013 meta-analysis of all relevant studies came to the conclusion that folic acid

supplementation had no significant effect on cancer risk, particularly on colorectal, prostate,

lung, breast or blood cancers, but does lower the risk of melanomas; 345

another 2013 meta-

analysis came to a similar conclusion that folic acid supplements taken for up to 5.2 years had no

significant affect on the development of any specific type of cancer including colorectal,

prostate, lung or breast cancer. 347

Recent studies show that folic acid supplementation reduces the risk of stroke, but does

not reduce the risk of heart disease, 206

even though it does reduce homocysteine levels. It was

once thought that lowering homocysteine levels reduced the risk of heart disease, but current

research does not support this. 320

Moderate to high supplementation of folic acid (to 2,500 mcg) has been shown to have no

affect on cognitive functioning in individuals with Alzheimer’s disease or other forms of

dementia. 320,321

Moderate folic acid supplementation (400 mcg) has been shown to improve

cognitive functioning and memory in individuals who are deficient folate, 332

but otherwise does

not improve cognitive functioning and memory. 333

Moderate folic acid supplementation increases

the efficacy of antidepressant medications and may help reduce depression, but the research to

test this has not yet been done. 320,334

One concern about long-term folic acid supplementation is that vitamin B12 deficiency

causes megaloblastic anemia and neurological damage; folic acid reverses the megaloblastic

anemia but not the neurological damage, thus decreasing the likelihood of discovering B12

deficiency until irreversible neurological damage has taken place. Since megaloblastic anemia is

no longer used to diagnose B12 deficiency, this is no longer a major concern. 320

The conclusion I get from this is that moderate supplementation, within the ranges set by

the USDA (see Table 7.26), is beneficial, but high supplementation is generally not beneficial,

except in specific cases, and may have negative health effects for some individuals.

 Vitamin B12 (Cobalamin)

By the 1930s, folate had been shown to temporarily reverse the anemia seen in pernicious

anemia, but the anemia would always relapse, and folate was of no use against the neuropathy of

pernicious anemia. 324

In 1926, in England, George Whipple, George Minot and William Murphy

found that lightly-cooked (raw) liver could be used to successfully treat both the anemia and

neuropathy of pernicious anemia, suggesting that it contained an “antipernicious anemia

factor;” 107

they won the Nobel Prize in 1934 for this work.

107

In 1928, William Castle found an “intrinsic factor” that was missing from people with

pernicious anemia that was necessary for the absorption of an “extrinsic factor” found in liver.

The extrinsic factor turned out to be vitamin B12, and the intrinsic factor, still called by that

name, is a glycoprotein that combines with B12 and activates B12 receptors; in pernicious anemia,

the immune system destroys the cells that make intrinsic factor, so patients don’t absorb B12.

Castle found that pernicious anemia could be successfully treated by giving patients predigested

meat, which contains vitamin B12, and animal stomach lining extract, which contains intrinsic

factor. Castle was nominated twice for the Nobel Prize. 353

Interestingly, work with animals at about the same time in the United States, identified a

factor, needed for growth in rats, that was produced by a bacterium that grew in poultry manure;

this factor was also successfully used to treat pernicious anemia. The factor was vitamin B12, and

7.56

bacterial synthesis of cobalamin became a very inexpensive way to produce large quantities of

the vitamin. 107

Characterization and Function

Vitamin B12 is also called cobalamin. There are several cobalamin compounds, all of which

contain the element, cobalt. In humans, methylcobalamin and 5-deoxyadenosylcobalamin are the

biologically-active forms; 350,351

these are freely formed from cyanocobalamin or

hydroxocobalamin. 381

Cobalamin is used as a cofactor to activate enzymes involved in only two chemical

reactions. 354

In one reaction, methylmalonic acid is turned into succinyl-CoA; in the second,

cobalamin works with folate to turn homocysteine into the amino acid, methionine. 354

Succinyl-CoA is used both in the Kreb’s cycle and in the formation of hemoglobin. 350

Methionine is needed to form S-adenosylmethionine, a major source of methyl groups for the

methylation of DNA, RNA, proteins and lipids; this is needed in the synthesis of DNA, which, in

turn, is needed to form normal red blood cells, and in the maintenance and functioning of the

nervous system. 352

Without adequate B12 (or folate), the red blood cells that are formed are

oversized and reduced in function. 352

Dietary cobalamin is complexed with animal-sourced protein, which must be digested in

the stomach by pepsin, a protein-digesting enzyme, activated by hydrochloric acid. This

digestion of the protein that binds to cobalamin is needed to liberate it. Cyanocobalamin, which

is synthetic, found in foods that are fortified with vitamin B12 as well as in supplements, is

already in the free form and is not complexed with protein, 350

so it is more easily absorbed than

protein-complexed B12. Once liberated from protein, however, all forms of cobalamin absorb

about the same. 350

The cells that produce hydrochloric acid in the stomach also produce a glycoprotein

called intrinsic factor. Intrinsic factor binds to free cobalamin in the first part of the small

intestine, 354

and activates the cobalamin transporters located at the very end of the small

intestine, 350

where cobalamin and intrinsic factor are absorbed together. In the blood, cobalamin

binds to a protein, transcobalamin, for transport. 229

With normal intrinsic factor produced, absorption of cobalamin is at about 56% with a 1

mcg oral dose; 350

this is factored into DRI calculations. 352

At higher doses, absorption decreases

markedly as there is insufficient intrinsic factor and transporters to accommodate additional

B12. 350

However, without intrinsic factor, about 1% of free cobalamin is absorbed throughout the

small intestine. 354,355

It takes 3-4 hours for B12 to cross the cells lining the gut and enter the

blood. 352

In the blood, all B12 attaches to the plasma binding proteins, transcobalamin I, II or III. 352

These proteins deliver about 50% of B12 to the liver, the rest to the tissues. 352

Most of the vitamin

B12 that is bound and transported in the plasma is methylcobalamin. 107

Vitamin B12 is unusual in that humans can store, in the liver, enough B12 to last from 3 to

5 years. 354

The liver constantly secretes small amounts of B12 in the bile; but this B12 is virtually all

reabsorbed in healthy individuals. 352

In people with pernicious anemia, the B12 secreted in the

bile apparently is not reabsorbed, thus contributing to B12 deficiency. 352

7.57

B12 that is not bound to transcobalamin in the plasma is removed by the kidneys into the

urine; this generally only happens after B12 injections. 352

Some 42% of 256 specifies of common gut bacteria have the ability to produce

cobalamin, 218

but it is apparently not absorbed. 358

One study showed that the water extract of the

feces of vegans, who do not consume any vitamin B12, contained enough bacteria-produced B12

to cure the megaloblastic anemia of other vegans, if ingested. 358

Human feces contain large

amounts of high-quality B12. 358

RDI and UL

Males and females, 14 years of age and over, require 2.4 mcg of vitamin B12 (cobalamin)

daily. 138,139

Cobalamin is generally nontoxic and upper limits have not been determined; see

Table 7.28 below.

Table 7.28. DRI and UL for Vitamin B12 (Cobalamin) in mcg/day. 138,139

(Upper limits not determined.)

Age Male Female Pregnancy Lactation

0-6 months 0.4 0.4 - -

6-12 months 0.5 0.5 - -

1-3 years 0.9 0.9 - -

4-8 years 1.2 1.2 - -

9-13 years 1.8 1.8 - -

14-18 years 2.4 2.4 2.6 2.8

19-50 years 2.4 2.4 2.6 2.8

>50 years 2.4 2.4 -- -

Dietary Sources

Bacteria are the only natural sources of vitamin B12, 351,371

particularly the lactic- and propionic-

acid bacteria; 369

for this reason, fermented dairy products are a good source of B12, and the other

B-vitamins as well. 370

Meats and dairy products are the primary dietary sources of vitamin B12, 354

and individuals who do not consume animal products must take supplements as there are no

adequate, clearly-demonstrated, non-animal, non-fortified sources. The average diet in the U.S.

includes 5-15 mcg of B12, which is more than adequate. 354

There are very few non-animal B12 sources, other than supplements. B12-enriched

vegetables fermented with lactic- or propionic-acid bacteria may contain up to 8.5 mcg bacteria-

produced B12 per 3 oz. 371

For instance, 3 oz of tempeh, which is fermented soybean paste,

contains 0.6-6.8 mcg of bioavailable B12; 371

other fermented soybean products contain only trace

(insignificant) amounts of B12. 371

Kimchi, a Korean dish of fermented vegetables, contains only

trace amounts of B12 (< 0.1 mcg/100 g). 371

There are some fermented black teas that contain B12,

but since 1 L of this tea contains only 20 ng of B12, 371

one would have to consume 120 L, almost

32 gallons, to get the recommended 2.4 mcg dose. However, there are very few studies to date

that show these products improve B12 status in humans; more research is needed, and vegans are

cautioned to take supplements and not to rely on these sources for their B12. 375

One Korean

study, though, suggested that elderly Koreans who ate very few animal products, obtained about

30% of their B12 from algae, kimchi that was allowed to ferment for some 8 months, and other

7.58

fermented foods, which is plausable. 376

Some mushrooms do contain B12, some don’t, and some contain B12 analogs that inhibit

B12 absorption. 371

Mushrooms can’t synthesize B12 themselves, but absorb it from the bacteria in

the medium in which they grow. 373

Virtually no B12 is found in black, porcini, parasol or oyster

mushrooms. 371

Dried shitaki mushrooms average 1.40 mcg B12 per 1 ounce, 373

which is

significant; however, the consumption of nearly 1.8 oz of dried or 1.1 pounds of fresh shitaki

mushrooms daily to make the 2.4 DRI minimum might be difficult, but this could be a significant

part of “natural” B12 for a vegan. A small German study showed that the regular consumption of

dried mushrooms did not increase B12 status in vegans. 378

Enjoy eating mushrooms, but don’t

count on them to provide significant B12.

Of the edible algae, only green laver (Enteromorpha) and nori (Porphyra), also called

purple laver, contain significant amounts of B12. 371

Dried green laver contains about 18.03 mcg

B12 per ounce, 371

whereas dried nori contains about 9.16 mcg B12 per ounce. 374

Due to its

versatility, nori appears to be the best potential whole food vegans could incorporate into their

diets to provide B12. About 0.26 oz of dried nori can supply 2.4 mcg of B12; this is around 25

sheets, with one sheet being 0.3 g. 371

Nori is used to wrap rice, vegetables and other ingredients

into sushi and spring rolls, and both nori and green laver can be shredded and used in Italian,

French, Spanish, Greek and other cuisines as a vegetable. However, no studies to date have

shown that algal-sourced B12 improves B12 status, and nori, in particular, has been shown to not

improve B12 status 378

and to possibly reduce it. 375

Table 7.29. Representative Foods High in Vitamin B12 (Cobalamin). 38

Food Mcg Food mcg Clams, mixed species, moist-heat cooked (3 oz) 84.06 General Mills, Wheaties (3/4 cup) 3.00

Beef liver, New Zealand, boiled (3 oz) 81.60 Silk Light Vanilla soymilk (1 cup, 8 oz) 2.99

Beef liver, domestic braised (3 oz) 60.02 Lamb, Australian, 1/8” fat, broiled (3 oz) 2.80

Octopus, moist-heat cooked (3 oz) 30.60 Crayfish, moist-heat cooked (3 oz) 2.64

Pacific oysters, moist-heat cooked (3 oz) 24.48 Catfish, channel, wild, dry-heat cooked (3 oz) 2.46

Mussels, blue, moist-heat cooked (3 oz) 20.40 Bison, lean, roasted (3 oz) 2.43

Salmon, sockeye, smoked (3 oz) 15.17 Kellogg’s Rice Krispies (1.25 cup) 2.39

Pork liver, braised (3 oz) 15.87 Beef, ground, 95% lean, pan browned (3 oz) 2.38

Clams, canned (3 oz) 15.84 Tuna, light, canned in water (3 oz) 2.17

Whelk (mollusk), moist-heat cooked (3 oz) 15.42 Cod, Pacific, dry-heat cooked (3 oz) 1.96

Clam chowder, New England, canned (1 c) 12.20 General Mills, Cheerios (1 cup) 1.90

Herring, Atlantic, dry-heat cooked (3 oz) 11.17 Turkey breast, roasted (3 oz) 1.50

King crab, Alaskan, moist-heat cooked (3 oz) 9.78 Cottage cheese, 1% milkfat (1 cup) 1.42

Sardines, canned in oil (1 can, 3.75 oz) 8.22 Yogurt, Greek, plain, nonfat (6 oz) 1.28

Liverwurst (1/4 cup) 7.40 Milk, 1% milkfat (1 cup, 8 oz) 1.15

Beef, skirt steak, 0% fat, grilled (3 oz) 6.73 Milk, whole, 3.25% milkfat (1 cup, 8 oz) 1.10

Kellogg’s Special K (1 cup) 6.01 Swiss cheese (1 oz) 0.94

Juice Smoothie, Naked Juice Blue Machine (8 oz) 6.00 Egg, whole, large, boiled (1) 0.56

Wendy’s Classic Double burger, w/ cheese (1) 5.95 Buttermilk, cultured, low-fat (1 cup, 8 oz) 0.54

Braunschweiger (1 oz) 5.72 Egg, whole, large, scrambled (1) 0.46

Caribou, roasted (3 oz) 5.64 Blue cheese (1 oz) 0.35

Rainbow trout, dry-heat cooked (3 oz) 5.36 Chicken breast, meat only, roasted (3 oz) 0.29

Salmon, sockeye, dry-heat cooked (3 oz) 4.82 Cheddar cheese (1 oz) 0.25

Pickled herring, Atlantic (3 oz) 3.63 Egg noodles, cooked (1 cup) 0.14

Spiny lobster, moist-heat cooked (3 oz) 3.43 Tempeh (1 cup, 8 oz) 0.13

Taco, ground beef, lettuce, cheese (1) 3.43 Mushrooms, brown, Italian or crimini, raw, whole (1 c) 0.09

Top sirloin steak, 0% fat, grilled (3 oz) 3.11 Portabella mushrooms, diced (1 cup) 0.04

Türinger, summer sausage (2 oz) 3.08 Butter (1 tbsp) 0.02

7.59

The B12 reported for some fermented soy products such as tempeh and algae such as

Spirulina is actually B12 analogs that inhibit B12 absorption, and not vitamin B12 that is active in

human physiology. 358,371

Active B12 that is reported from some plant-based foods is generally

from bacterial contamination. 358

Yeast, itself, does not produce B12, but may contain B12 if grown

on B12-containing medium. 358

Plants such as lettuce that are grown in hydroponic media rich in B12 readily absorb B12.

In one study, lettuce was produced with so much B12 that two leaves met the 2.4 mcg DRI. 375

Similarly, plants grown with cow dung fertilizer had more B12 than those that were not. 377

I’m

not sure if these foods would qualify as “natural” foods for vegans; in any event, to my

knowledge, they are not available in markets.

Note that quite a few processed and/or packaged foods are fortified with B12. For

instance, 8 oz of Naked Juice’s Blue Machine contains 6.00 mcg and 1 cup of Cheerios contains

190 mcg of B12, both fortified, which is good! See Table 7.29.

Note that, unless fortified (and many are), or containing foods of animal origin, cereal

grains and pasta, fruits and fruit juices, legumes and legume products, nuts and seed products,

spices and herbs, sweets, and vegetables and vegetable products contain zero B12. According to

the USDA, a couple of types of mushrooms do contain trace amounts of B12, as do some

seaweeds. 38

If you don’t eat animal-sourced foods, take a supplement!

By the way, cranberries and cranberry juice increase B12 absorption in individuals who

are on medication that lowers stomach acid; 379

it is unclear whether it is an active compound in

cranberries or the acidity that is responsible. And besides containing good amounts of B12, dairy

products contain calcium, which facilitates B12 absorption. 380

Deficiency

The 2015 USDA Scientific Report of the Dietary Guidelines Advisory Committee determined

that Vitamin B12 (cobalamin) intake for all age classes of both males and females were above

RDA or AI amounts. 158

Some groups are, however, at higher risk for B12 deficiency than others.

The fact that humans can store enough B12 for 3 to 5 years, 354

and it may take 5 to 10

years for clinical signs of B12 deficiency to appear, 356

explains how severe dietary changes, such

as those seen in vegans who do not take supplements, do not result in symptoms for some time.

People at risk for B12 deficiency include those who do not get enough B12 in the diet.

Elderly individuals who do not eat a balanced diet are at particular risk, especially those in

nursing homes, 356

as are alcoholics and vegans. 354,356

A 2013 review of 18 studies showed that

among vegans and other vegetarians, 62% of pregnant women, 25-86% of children, 21-41% of

adolescents and 11-90% of elderly were deficient B12, with the highest numbers coming from

vegans. 372

The risk of vitamin B12 deficiency increases with age. About 15% of individuals over the

age of 65 have clinical signs of B12 deficiency; part of this is due to the increased use of acid-

neutralizing and acid-blocking agents with older age. 354

The chronic use of any compounds that

reduce stomach acid at any age can lead to cobalamin deficiency. 354

Vitamin B12 deficiency is seen is individuals with pernicious anemia. Pernicious anemia

is an autoimmune disease where the immune system gradually destroys the ability of the parietal

cells of the stomach to produce hydrochloric acid and intrinsic factor. Thus, not only is the

enzyme needed to free B12 from protein not activated by hydrochloric acid, so there isn’t much

free B12 being produced, the intrinsic factor necessary to move free B12 into the blood isn’t there.

7.60

Pernicious anemia is seen in 0.1% of the general population and 1.9% of individuals over 60

years of age. 355

It accounts for 20-50% of the causes of B12 deficiency in adults, 355

and is the

most common cause of B12 deficiency. 356

Type 2 diabetics are at risk for B12 deficiency because metformin, the major drug used to

treat type 2 diabetes, lowers plasma B12 levels, possibly by inhibiting B12 absorption. 365

Metformin also decreases the effect of calcium, needed to operate B12 transporters. 380

Individuals who do not consume adequate dairy may be at higher risk of B12 deficiency

because calcium is needed to operate B12 transporters. Calcium supplementation helps increase

B12 absorption, particularly in those with type 2 diabetes. 380

Individuals with a high load of tapeworms or other gut parasites may be a risk for B12

deficiency. 326,354

High serum levels of methylmalonic acid may be good early-warning signs of B12

deficiency as B12 deficiency inhibits the conversion of methylmalonic acid into succinyl Co-A. 354

Clinical deficiency symptoms include blood, neurological, psychiatric, cardiovascular

and fertility problems. 354

 Megaloblastic anemia is a common sign of B12 deficiency that can be covered up if the diet includes high amounts of folate; further, a reduction is the numbers of both red and white

blood cells (pancytopenia) may be seen in advanced B12 deficiency cases. 354

Common

symptoms of anemia include pallor of the skin, lack of energy, fatigue, shortness of breath

and heart palpations. 352

Anemia is caused by impaired DNA synthesis. 352

 Irreversible neurological damage associated with B12 deficiency includes peripheral neuropathy, resulting in a tingling of the fingers and toes,

354 and damage to the myelin of the

spinal cord causing varied neurological symptoms. 323,354,355

There is also evidence that B12

deficiency causes the brain to atrophy (shrink). 357

 Psychiatric problems noted with B12 deficiency include decreased memory, fatigue, dementia, depression, irritability, changes in personality and possibly psychoses.

354

 An increased risk of atherosclerosis, thus heart attack and stroke, have been associated with B12 deficiency.

354,355

 Women who are B12 deficient are at an increased risk of fertility problems and abortions. 355

Toxicity and Supplementation

Oral supplementation of vitamin B12 is very effective and safe, as effective as B12 injections, in

the treatment of B12 deficiency, because about 1% of free cobalamin is absorbed without intrinsic

factor. 354

Although cobalamin transporters are located only at the end of the small intestine,

about 1% of cobalamin is absorbed throughout the small intestine, 354,355

so 240 mcg doses can

supply individual with pernicious anemia with 2.4 mcg of B12. Oral doses of 1,000 mcg per day

are commonly given to treat B12 deficiency. 354,355

Supplementation completely reverses the megaloblastic anemia but not the neurological

damage associated with B12 deficiency. 352

The most common form of synthetic B12 available is cyanocobalamin. 351

It readily

converts into methylcobalamin and 5-deoxyadenosylcobalamin, 350

and is the most stable form of

cobalamin. Hydroxycobalamin is also available as a supplement 351

, as are methylcobalamin 351

and 5’-deoxyadenosylcobalamin. 381

Hydroxocobalamin binds to toxic cyanide, producing the nontoxic compound,

cyanocobalamin. It is thought that hydroxocobalamin may detoxify small amounts of “natural”

7.61

cyanide found in many fruits and vegetables; 107

in fact, hydroxocobalamin is injected in the

treatment of cyanide poisoning. 360

Cyanocobalamin contains cyanide, which is a neurotoxin. In the conversion of

cyanocobalamin to methylcobalamin, some cyanide is released. Since the amount of

cyanocobalamin that is ingested in supplement form is so small, the amount of toxic cyanide that

is liberated is considered insignificant; healthy kidneys normally detoxify small amounts of

cyanide. A study conducted in Norway showed that the average daily intake of cyanide from

whole foods is between 95 to 372 mcg per person per day. 363

The amount of cyanide in a 1,000

mcg dose of cyanocobalamin supplement is 20 mcg, 364

which is not significant to healthy

individuals, but may be significant to people with kidney disease 361

and optical neuropathy. 367

Hydroxocobalamin, which is also readily converted to the active forms of cobalamin and actually

persists longer in the body than cyanocobalamin, is recommended over cyanocobalamin by the

World Health Organization for the treatment of B12 deficiency, 367

although cyanocobalamin is

generally used in the United States and no studies to date have linked high-dose cyanocobalamin

supplementation with any health problems. 351

If active forms of cobalamin are to be given, a

combination of both methylcobalamin and adenosylcobalamin should be given, as each has

unique and essential physiological functions. 366

The B12 contained in energy drinks is utterly useless, unless one is deficient vitamin B12;

it neither contains any energy itself, nor does it facilitate the release of energy. 358

Also, snorting

B12 up the nose is also utterly useless, unless one is deficient B12, and may result in an allergic

response. 358

(Yes, some people snort B12!) B12 and other vitamins do absorb optimally through

the nasal mucosa. 358

Sublingual B12 doesn’t offer any benefits over oral supplement doses, and both are as

effective as intramuscular injections in treating B12 deficiency. 359

Data comparing the absorption

and efficacy of oral sprays, nasal gels and transdermal patches are lacking. 382

There is some evidence that topical B12 can help treat eczema and psoriasis. 368

Sublingual

B12 may help reduce the frequency, duration and pain of canker sores. 368

There is some evidence

that vitamin B12, when taken with pyridoxine (B6), folate (B9) and the amino acid methionine,

may reduce the risk of breast cancer. 368

B12 injections may help relieve fatigue. 368

Low B12

supplementation (7.5 mcg), when taken with fish oil, may help lower total cholesterol and

triglyceride levels more than fish oil alone. 368

There is insufficient evidence that Vitamin B12 is effective against allergies, aging,

diabetes, heart disease, lyme disease, memory problems, multiple sclerosis or immune system

deficiencies. 368

Research suggests that B12 is not effective against Alzheimer’s disease and

general mental function including memory, sleep disorders, lung cancer, stroke and preventing

reblockage of vessels after heart angioplasty. 368

B6 (pyridoxine), B9 (folate), B12 (cobalamine) combination therapy is used to reduce

homocysteine levels and the risk of cardiovascular disease, especially in patients with either type

1 or 2 diabetes. It has been shown, however, that high-dose therapeutic cosupplementation of

these three vitamins, 25 mg/day of B6 (pyridoxine, UL 100 mg/day), 2,500 mcg/day of B9 (folate,

UL 1,000 mcg/day), and 1,000 mcg/day of B12 (cobalamine, DRI 2.4 mcg/day), increases the

severity of kidney disease in individuals with advanced diabetic nephropathy. 383

Although other

studies do not show this result, the use of very high doses of these vitamins in combination

therapy has been questioned. 384

7.62

 Vitamin-Like Substances

Choline.

In 1850, the French pharmacist Theodore Gobley, isolated a molecule from fish eggs and brain

tissue that he named “lecithine,” from the Greek word for egg yolk, “lekithos.” 396

This molecule,

which we call “lecithin” in English, we now know is one of the main phospholipids in cell

membranes. Lecithin was found in bile, and Adolph Strecker, in 1862, at the University of

Tübingen, found that by boiling bile, a molecule that he named “choline” was produced. 396

It

turns out that choline is part of lecithin. The technical name for lecithin is, in fact,

phosphatidylcholine.

In 1921, Otto Loewi at the University of Graz, discovered a compound that he termed

“vagusstoffe” that was secreted from activated nerves. 397

Working at about the same time as Otto

Loewi, Henry Dale of the Wellcome Physiological Research Laboratories, had isolated and

determined the structure of a molecule from fungi that activated nerves, 398

which he named

acetylcholine; he realized that this was the same substance as Loewi’s vagusstoffe. 396

We now

know that acetylcholine is the major neurotransmitter in the human body. In 1936, Loewi and

Dale shared the Nobel Prize for Physiology or Medicine “for their discoveries relating to

chemical transmission of nerve impulses.” 399

In 1932, it began to be realized that choline was an essential nutrient, one that could

generally not be synthesized by the human body. It was shown by Charles Best that fatty liver

could be corrected by eating lecithin, and that the active ingredient in lecithin was choline. 400

In

1991, it was shown that men and post-menopausal women who were given diets low in choline

developed liver damage, and that the liver damage cleared up when choline was given. Further, it

was found that estrogen stimulated a gene that caused the liver to synthesize lecithin

(phosphatidylcholine), from which the body can derive choline; thus, pre-menopausal women

tend not to be choline deficient, even if they don’t get enough choline in their diet. 396

Characterization and Function

Choline is part of the phosphate group of lecithin, also called phosphatidylcholine, a major

phospholipid component of cell membranes; it makes up about 13% of the phosphatidylcholine

molecule. 292

(see Chapter 5). About 95% of the body’s total choline is found as part of

phosphatidylcholine in cell membranes, 401

where it plays a role in maintaining the membrane’s

structural integrity. 402

Choline is an essential nutrient, meaning that it is not synthesized in adequate amounts

by the human body; 403

however, humans can synthesize small amounts. 401

Choline is used to synthesize acetylcholine, a neurotransmitter associated with muscle

contraction, memory and other functions, and stimulates the synthesis and release of the

tyrosine-derived neurotransmitters of epinephrine, norepinephrine and dopamine. 401

Choline is used to synthesize phosphatidylcholine and another phospholipid,

sphingomyelin. Sphingomyelin is a component of cell membranes, plus is an important

component of the myelin sheath that insulates myelinated nerve cells, allowing neurons to work.

Phosphatidylcholine and sphingomyelin are needed to synthesize various cell signaling

molecules, 401

and choline is needed to make these molecules.

Triglyceride fats and cholesterol, either absorbed by the gut from food or synthesized by

7.63

the cells lining the gut, are transported to the liver where they are packaged into VLDLs (review

Chapter 5). Choline, as part of phosphatidylcholine, is required to package fats and cholesterol

into VLDLs. 401

In mitochondria, choline is converted into the compound, betaine, which provides up to

60% of the methyl groups needed to convert homocysteine into the amino acid methionine,

thereby lowering blood homocysteine levels and lowering cardiovascular disease risk. 401

As a

note, vitamin B12 activates an enzyme that also converts homocysteine to methionine, using a

different mechanism, and using folate as the methyl source; vitamins B2 (riboflavin) and B6

(pyridoxine) are also involved in this. 401

Methionine is the major methyl donor. 401

Methylation is

essential in the control of genes and other molecules; DNA methylation, for instance, is needed

to suppress genes that cause cancer, and needed to control the normal growth and development

of cells. 404

Besides being needed to convert homocysteine into methionine, betaine helps regulate

cell volume thereby protecting cells from osmotic stress, particularly in the kidneys. 401

Choline is essential to normal growth and development, 402

especially to the nervous

system in the child, both before and after birth, particularly to the formation of the neural tube

and in the development of the hippocampus, 403

the part of the brain responsible for memory

recall.

In food, choline is found in its free form, and as part of cell membrane components such

as phosphatidylcholine, also termed lecithin, and as part of a few other compounds. 402

Digestive

enzymes from the pancreas liberate some choline, although about 50% phosphatidylcholine is

not digested. 416

In the gut, bacteria transform some choline into betaine and some into

methylamines, while much of it remains as choline. Choline transporters in the gut then absorb

choline into the cells lining the small intestine; there, choline is either repackaged into

phosphatidylcholine or incorporated into chylomicrons and carried by the lymphatic system into

the blood. 415

Phosphatidylcholine is readily absorbed from the gut. 416

From the blood, these

choline-containing structures are transported to the liver and the kidneys where much of it is

converted into betaine. 402

All cells can absorb and store choline. 402

From the gut, betaine and

methylamines are also absorbed. 402

RDI and UL

In 1998, choline was recognized as an essential nutrient. 403

Males, 14 years of age and over,

require 550 mg of choline daily, with an upper limit of 3,500 mg; females, 14 years of age and

Table 7.30. DRI and UL for Choline in mg/day. 138,139

(Upper limits note determined.)

Age Male Female Pregnancy Lactation

0-6 months 125 (ND) 125 (ND) - -

6-12 months 150 (ND) 150 (ND) - -

1-3 years 200 (1,000) 200 (1,000) - -

4-8 years 250 (1,000) 250 (1,000) - -

9-13 years 375 (2,000) 370 (2,000) - -

14-18 years 550 (3,000) 400 (3,000) 450 (3,000) 550 (3,000)

19-50 years 550 (3,500) 425 (3,500) 450 (3,500) 550 (3,500)

>50 years 550 (3,500) 425 (3,500) -- -

7.64

over, require 425 mg of choline daily, also with an upper limit of 3,500 mg. 138,139

See Table 7.30.

Dietary Sources

Organ meats such as liver, 403

and eggs are an excellent source of choline, but be sure to eat the

egg yolk as that’s where virtually all of the choline is. Fruits and fruit juices are relatively low in

choline; see Table 7.31.

In the American diet, meats, poultry and fish, and dishes made with these foods, provide

about 30% of choline intake; grains, breads and grain-based dishes, 22%; dairy, 13%; and eggs,

12%. 405

Table 7.31. Representative Foods High in Total Choline. 38

Food mg Food mg Beef kidneys, simmered (3 oz) 436.2 Beet greens, chopped, boiled (1 cup) 61.2

Beef liver, braised (3 oz) 362.3 Granola, homemade (1 cup) 59.9

Chicken liver, pan fried (3 oz) 277.9 Sundried tomatoes (3 oz) 56.5

Veal thymus (sweetbreads), braised (3 oz) 177.9 Corn, sweet, canned (1 cup) 52.0

Fast food, biscuit, with egg and ham (1) 176.5 Asparagus, canned (1 cup) 51.8

Egg, large, hard boiled (1) 146.9 Swiss chard, boiled (1 cup) 50.2

Egg, large, fried (1) 145.9 Natto (fermented soy) (3 oz) 48.5

Egg yolk, large, raw (1) 139.4 Green peas, boiled (1 cup) 47.5

Chicken, dark meat, drumstick, roasted (1) 141.3 Cauliflower, raw, chopped (1 cup) 47.4

Beef, top round roast, braised (3 oz) 117.0 Pureed tomato (1 cup) 44.0

Shrimp, moist-heat cooked (3 oz) 115.1 Buttermilk, low fat (1 cup, 8 oz) 43.4

Oysters, Eastern, moist-heat cooked (3 oz) 110.5 Milk, 1% fat (1 cup, 8 oz) 43.3

Chocolate cake, w/o frosting (3 oz) 109.2 Quinoa, cooked (1 cup) 42.6

Soybeans, roasted (1/2 cup) 106.9 Oyster mushrooms, raw (3 oz) 41.4

Beef, top sirloin steak, broiled (3 oz) 99.7 Mollusks, conch, baked or broiled (3 oz) 41.3

Sockeye salmon, moist-heat cooked (3 oz) 95.8 Egg noodles, cooked (1 cup) 41.1

Scallops (bay and sea), steamed (3 oz) 94.1 Kielbasa, pan fried (3 oz) 35.3

Kidney beans, canned (1 cup) 89.3 Milk, whole, 3.25% milkfat (1 cup, 8 oz) 34.9

Pork chop, lean, pan fried (3 oz) 89.0 Broccoli, boiled (1/2 cup) 31.3

Beef, tenderloin steak, lean, broiled (3 oz) 85.7 Dandelion greens, chopped (1 cup) 29.0

Pickle herring (3 oz) 88.5 Portabello mushrooms, grilled (3 oz) 27.9

Soybeans, boiled (1 cup) 81.7 Yogurt, plain, nonfat (6 oz) 25.8

Navy beans, boiled (1 cup) 81.4 Raspberries, frozen/thawed, sweetened (1 cup) 25.5

Whitefish, smoked (3 oz) 80.8 Figs, dried (1 cup) 23.5

Red kidney beans, canned (1 cup) 78.1 Pearl barley, cooked (1 cup) 21.0

Collard greens, chopped, boiled (1 cup) 73.0 Pistachios, dry roasted (1 oz) 20.2

Seaweed, spirulina, dried (1 cup) 73.9 Peanuts, dry-roasted (1 oz) 18.3

Chicken breast, meat only, broiled (3 oz) 72.5 Post Grape Nuts (1/2 cup) 18.2

Pork, cured (ham) (3 oz) 73.2 Oatmeal, cooked w/ water (1 cup) 17.3

Garbanzo beans (chickpeas), boiled (1 cup) 70.2 Cashews, dry roasted (1 oz) 17.3

Soymilk (1 cup) 69.0 Pumpkin and squash seed kernels, dried (1 oz) 17.9

Atlantic sardines, canned in oil (1 can, 3.75 oz) 69.0 Post Raisin Bran (1 cup) 16.1

Lobster, northern, moist-heat cooked (3 oz) 68.8 Sunflower seed kernels, dry roasted (1 oz) 15.6

Shiitake mushrooms, cooked (3 oz) 68.0 Almonds, dry roasted (1 oz) 14.8

Fish, flounder or sole, dry-heat cooked (3 oz) 67.9 Banana (1 medium) 11.6

Pacific cod, dry-heat cooked (3 oz) 67.7 Cheese, cheddar or Swiss (1 oz) 10.3

Fish, haddock, dry-heat cooked (3 oz) 67.7 Avocado, California (1/2) 9.7

Catfish, channel, farmed, dry-heat cooked (3 oz) 66.9 Pasta (macaroni or spaghetti), cooked (1 cup) 9.0

Turkey breast, roasted, meat only (3 oz) 64.9 Red potatoes, baked, flesh and skin (3 oz) 6.6

Lentils, boiled (1 cup) 64.7 Rice, white, long-grain, cooked (1 cup) 3.5

Split peas, boiled (1 cup) 64.3 Cheese, mozzarella (1 oz) 5.2

7.65

Deficiency

Data from the NHANES 2007-2008 study indicate that on the average, Americans consume 302

mg choline per day. Adult males (> 20 years) average 396 mg and adult females (> 20 years)

average 260 mg choline, with choline intake in both males and females increasing until the 40-49

year old age group, then decreasing. 405

This suggests that, on the average, Americans are

deficient choline.

In the liver, phosphatidylcholine is required to package fats and cholesterol, brought there

by chylomicrons, into VLDLs. Without sufficient choline, low levels of VLDLs are produced,

resulting in low levels of LDLs. However, fats and cholesterol build up in the liver, 401

leading to

nonalcoholic fatty liver disease (NAFLD) and liver damage, which resolves upon the intake of

choline. 401,403

NAFLD is generally associated with metabolic syndrome disorders such as obesity

and insulin resistance, 401

not good for diabetics. The presence of NAFLD increases the risk of

cirrhosis and cancer of the liver. 406

Fat buildup in the liver may inhibit the functioning of liver

mitochondria, increasing the formation of reactive oxygen species that increase inflammation

and damage to DNA, proteins and lipids. 407

Up to 30% of Americans may be affected by

NAFLD caused by choline deficiency. 408

Choline deficiency leads to organ dysfunction, such as liver damage, 402

as indicated by

the presence of blood biomarkers. Organ dysfunction may include choline deficiency-induced

DNA damage. 401

In order to make adequate methionine, adequate levels of choline and folate are needed.

Thus individuals who are at special risk of choline deficiency include those who do not get

enough folate in their diet, those who can’t absorb adequate folate, or those who selectively

excrete folate, because low folate levels increases the demand for choline. 401,403

Individuals with

celiac disease and other malabsorption pathologies, and alcoholics are at special risk. 401,403

On

the average, men and women over the age of 71 consume about half the recommended amount of

folate, 264 mg/day, so are at special risk. Also, 90% of women do not get the recommended

amount of choline. 403

Regarding postmenopausal women, only about 2% consume the

recommended amount of choline. 417

Choline deficiency also leads muscle damage. 401,403

Because estrogen stimulates the synthesis of some phosphatidylcholine in humans, pre-

menopausal women are at about a 50% lower risk than post-menopausal women of developing

choline deficiency-induced pathologies such as NAFLD, liver damage or muscle damage. 401

This

does not suggest, however, than pre-menopausal women, on the average, consume enough

choline; they don’t.

Another group that is of particular risk of not getting enough choline is vegans. Because

meat, milk and eggs are particularly rich in choline, and most plant-based foods are not, strict

vegetarians may not get enough choline in their diet. 401

The amount of choline in the diet changes the bacterial composition of the gut. Choline-

deficient diets increase the growth of endotoxin-producing bacteria associated with metabolic

syndrome, obesity, insulin resistance and the risk of diabetes. 408

Toxicity and Supplementation

A widely-available supplemental form of choline is lecithin, but the amount of choline in lecithin

varies widely from something like 20 to 90%, depending of the type of oil from which the

7.66

lecithin is derived. 401

Citicoline (CDP-choline), choline chloride and chline bitartrate as also

available. 401

Whole foods are, of course, generally the best source of choline.

Choline toxicity is characterized by a fishy body odor, increased sweating, increased

salivation, vomiting and decreased blood pressure. 402,403

Choline deficiency symptoms resolve with the intake of choline supplements. 401

Choline intake is associated with decreased risk of breast cancer in women. 403

Several large studies suggest that dietary supplementation of choline or betaine does not

reduce the risk of cardiovascular or peripheral artery disease. 401

There is currently inadequate evidence suggesting that choline supplementation over the

DRI for pregnant women would further protect developing babies from neural tube defects such

as spina bifida. 401

Numerous animal studies show that choline supplementation of pregnant rats during

pregnancy and lactation significantly increases the cognitive function of rat pups. 409

However,

several human studies have shown that maternal supplementation of choline does not result in

the increased cognitive development in children. 401

Of course, adequate dietary choline is

essential by pregnant women to allow for the normal neural and cognitive development of the

child.

At least two large studies indicated that choline supplementation above the RDA

increases cognitive function including verbal and visual memory, sensory motor speed,

perceptual speed, executive function and global cognition. 401

More studies are needed before

firm recommendations can be made.

Several studies show that high supplement doses of citicoline, a modified form of

choline, in stroke patients significantly inhibit cognitive decline. 401,410

Citicoline, 1,000 mg/day

by injection or 2,000 mg/day orally, has also been shown to significantly improve retinal

function associated with glaucoma. 401

The use of citicoline for the treatment of traumatic brain

injury is currently being studied in humans 418

as it has been shown efficacious in animal

studies. 419

Dietary choline, phosphatidylcholine and L-carnitine have been linked to possibly

increased cardiovascular disease risk as they are all turned into TMA (trimethylamine) by gut

bacteria, which is then turned into TMAO (trimethylamine oxide) by the liver. 412,413

In one study,

volunteers were given two eggs and a capsule of choline; high levels of the compound TMAO

were measured. A second group of volunteers were given antibiotics to suppress their gut

bacteria; they then were given two eggs and a choline capsule; TMAO levels were significantly

reduced. The study concluded that gut bacteria produce TMA/TMAO from choline. 411

TMAO

stimulates the deposition of plaque-forming cholesterol and foam cells under the walls of the

arteries, contributing to coronary artery disease. 401,413

It remains unclear if all bacteria contribute

to this process, or if only certain populations of non-beneficial bacteria do so. 401,414

Further, it is

questioned if TMAO-producing foods do contribute to coronary artery disease as eggs, various

species of fish such as halibut, and whole grains increase TMAO levels, yet all are associated

with a decreased risk of heart disease. 414

7.67

 References

1. http://www.nlm.nih.gov/medlineplus/vitamins.html 2. Millen, B. E. (Chair, 2015 Dietary Guidelines Advisory Committee). 2015. Scientific

report of the 2015 Dietary Guidelines Advisory Committee. Advisory report to the

Secretary of Health and Human Services and the Secretary of Agriculture. February, 2015.

http://www.health.gov/dietaryguidelines/2015-scientific-report/PDFs/Scientific-Report-of-

the-2015-Dietary-Guidelines-Advisory-Committee.pdf

3. Johnson, L. E. 2014. Overview of vitamins. Merck Manual Professional Version. http://www.merckmanuals.com/professional/nutritional_disorders/vitamin_deficiency_dep

endency_and_toxicity/overview_of_vitamins.html

4. Higdon, J., V. J. Drake, B. Delage, A. C. Ross and L. Tan. 2015. Vitamin A. Micronutrient Information. Linus Pauling Institute of Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-A

5. Anon. 2013. Vitamin A. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminA-

HealthProfessional/

6. Tang, G. 2010. Bioconversion of dietary provitamin A carotenoids to vitamin A in humans. Am. J. Clin. Nutr. 91(5): 14685-14735. doi: 10.3945/ajcn.2010.28674G

7. Higdon, J., V. J. Drake and E. J. Johnson. 2009. Carotenoids. A-carotene, b-carotene, b- cryotpxanthin, lycopene, lutein, and zeoxanthin. Linus Pauling Institute of Oregon State

University. http://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/carotenoids

8. Michaud, D. S., D. Feskanich, E. B. Rimm, et al. 2000. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am. J. Clin. Nutr. 72(4): 990-997

9. Holick, C. N., D. S. Michaud, R. Stolzenberg-Solomon, et al. 2002. Dietary carotenoids serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-

carotene cohort study. Am. J. Epidemiol. 156(6): 536-547

10. Voorrips, L. E., R. A. Goldbohm, H. A. Brants, et al. 2000. A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol. Biomarkers

Prev. 9(4): 357-365.

11. Hennekens, C. H., J. E. Buring, J. E. Manson, et al. 1996. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and

cardiovascular disease. N. Engl. J. Med. 334(18): 1145-1149

12. Doss, R. 2013. Foods containing fat soluble vitamins. Livestrong.com (Aug 16). http://www.livestrong.com/article/31925-foods-containing-fat-soluble-vitamins/

13. Bellows, L. and R. Moore. 2015. Fat-soluble vitamins: A, D, E, and K. Colorado State University Extension (March 23). http://www.ext.colostate.edu/pubs/foodnut/09315.html

14. Brusco, J. 2015. What are the effects of a fat deficiency in humans? Livestrong.com (May 1). http://www.livestrong.com/article/503785-what-are-the-effects-of-fat-deficiencies-in-

humans/

15. Kono, N. and H. Arai. 2014. Intracellar transport of fat soluble vitamins A and E. Traffic 16(1): 19-34. doi: 10.1111/tra.12231

16. Touger-Decker, R., C. Mobley and J. B. Epstein (Eds). 2014. Nutrition and oral medicine. 2

nd ed. Humana Press.

https://books.google.com/books?id=nTu3BAAAQBAJ&pg=PA86&lpg=PA86&dq=Fat+s

oluble+vitamin+deficiencies+mineral+oil+laxatives&source=bl&ots=Tdp7K0jtGR&sig=

7.68

A5uHUcFubc1mTBbC4PCWS7-s2-o&hl=en&sa=X&ei=SO5YVbD-

JcqdygT8jIGADA&ved=0CD4Q6AEwBQ#v=onepage&q=Fat%20soluble%20vitamin%2

0deficiencies%20mineral%20oil%20laxatives&f=false

17. Booij, M. T. and P. C. Van De Kerkhof. 2011. Acitretin revisited in the era of biologics. J. Dermatolog. Treat. 22(2): 86-89. Doi: 10/3109/09546630903578582

18. Thielitz, A. and H. Gollnick. 2008. Topical retinoids in acne vulgaris: update on efficacy and safety. Am. J. Clin. Dermatol. 9(6): 369-381. doi: 10.2165/0128071-200809060-

00003

19. Berson, E. L., B. Rosner, M. A. Sandberg, et al. 1993. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch. Ophthalmol. 111(6): 761-

772.

20. Telander, D. G. 2015. Retinitis pigmentosa treatment & management. Medscape (Feb. 17). http://emedicine.medscape.com/article/1227488-treatment

21. Lo-Coco, F., G. Avvisati, M. Vignetti, et al. 2013. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 369(2): 111-121. doi:

10.1056/NJMoa1300874

22. Grune, Tilman, G. Lietz, A. Palou, et al. 2010. B-carotene is an important vitamin A source for humans. J. Nutr. 140(12): 2268S-2285S. doi: 10.3945/jn.109.11024

23. Ehrlich, S. D. 2013. Beta-carotene. University of Maryland Medical Center (June 21). http://umm.edu/health/medical/altmed/supplement/betacarotene

24. Chew, E. Y., T. E. Clemons, E. Agrón, et al. 2013. Long-term effects of vitamins C and E,

-carotene, and zinc on age-related macular degeneration: AREDS report no. 35.

Ophthalmology 120(8): 1604-1611. doi: 10.1016/j.ophtha.2013.01.021

25. Traber, M. G., S. R. Diamond, J. C. Lane, et al. 1994. Beta-carotene transport in human lipoproteins. Comparisons with a-tocopherol. Lipids 29(10): 665-669.

26. Tourniaire, F., E. Gouranton, J. von Lintig, et al. 2009. -carotene conversion products and their effects on adipose tissue. Genes Nutr. 4(3): 179-187. Doi: 10.1007/s12263-009-

0128-3

27. Bonet, M. L., J. Riot, F. Felipe and A. Palou. 2003. Vitamin A and the regulation of fat reserves. Cell Mol. Life Sci. 60(7): 1311-1321.

28. Pino-Lagos, K., M. J. Benson and R. J. Noelle. 2008. Retinoic acid in the immune system. Ann. N. Y. Acad. Sci. 1143: 170-187. doi: 10.1196/annals.1443.017

29. Germain, P., P. Chambon, G. Eichele, et al. 2006. International Union of Pharmacology. LX. Retinoic acid receptors. Pharm. Rev. 58(4): 712-725. doi: 10.1124/PR.58.4.4

30. Kam, R. K. T., Y. Deng, Y. Chen and H. Zhao. 2012. Retinoic acid synthesis and functions in early embryonic development. Cell & Biosci. 2:11. doi: 10.1186/2045-3701-

2-11

31. Anon. 2011. Retinoic acid biological activity. News Medical. (February 1). http://www.news-medical.net/health/Retinoic-Acid-Biological-Activity.aspx

32. Gibbs, S., C. Backendorf and M. Ponec. 1996. Regulation of keratinocyte proliferation and differentiation by all-trans-retinoic acid, 9-cis-retinoic acid and 1,25-dihydroxy

vitamin D3. Arch. Dermatol. Res. 288(12): 729-738.

33. Bamberger, C., Dieter Pollet and H. Schmale. 2002. Retinoid acid inhibits downregulation

of Np63 expression during terminal differentiation of human primary keratinocytes. J.

of Invest. Dermatol. 118: 133-138. doi: 10.1046/j.0022-202.2001.01649.x

7.69

34. Metzler, D. E. 2003. Biochemistry: the chemical reactions of living cells, volume 2. Academic Press.

35. Tang, X.-H. and L. J. Gudas. Retinoids retinoic acid receptors, and cancer. 2011. Ann. Rev. Pathol: Mech. Disease 6: 345-364. Doi: 10.1146/anurev-pathol-011110-130303

36. Schenk, T., S. Stengel and A. Zelent. 2014. Unlocking the potential of retinoic acid in anticancer therapy. Brit. J. Cancer 111: 2039-2045. doi: 10.1038/bjc.2014.412

37. Sherwin, J. C., M. H. Reacher, W. H. Dean and J. Ngondi. 2012. Epidemiology of vitamin A deficiency and xerophthalmia in at-risk populations. Trans.R. Soc. Trop. Med. Hyg.

106(4): 205-214. doi: 10.1016/j.trstmh.2012.01.004

38. USDA. 2011. USDA National Nutrient Database for Standard Reference. USDA Agriculture Research Service, National Agriculture Library. http://ndb.nal.usda.gov/

39. Ross, A. C., C. L. Taylor, A. L. Yaktine and H. B. Del Valle (Eds). 2011. Dietary reference intakes for calcium and vitamin D. Institute of Medicine (US) Committee to

Review Dietary Reference Intakes for Vitamin D and Calcium. National Academies Press

(US), Washington (DC). http://www.ncbi.nlm.nih.gov/books/NBK56061/

40. Drake, V. J. 2011. Vitamin D and skin health. Linus Pauling Institute, Micronutrient Information Center, Oregon State University.

http://lpi.oregonstate.edu/mic/micronutrients-health/skin-health/nutrient-index/vitamin-D

41. Anon. 2014. Vitamin D. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminD-

HealthProfessional/

42. http://www.vitamindcouncil.org/about-vitamin-d/how-do-i-get-the-vitamin-d-my-body- needs/

43. Higdon, J., V. J. Drake, B. Delgado, A F. Gombart. 2014. Vitamin D. Linus Pauling Institute Micronutrient Information Center, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-D

44. Aranow, C. 2011. Vitamin D and the immune system. J. Investig. Med. 59(6): 881-886. doi: 10.231/JIM.0b013e31821b8755

45. Heer, M. and S. Egert. 2015. Nutrients other than carbohydrates: their effects on glucose homeostasis in humans. Diabetes Metab. Res. Rev. 31(1): 14-35. doi: 10.1002/dmrr.2533

46. Wang, T. J., M. J. Pencina, S. L. Booth, et al. 2008. Vitamin D deficiency and the risk of cardiovascular disease. Circulation 117(4): 503-511. doi:

10.1161/CIRCULATIONAHA.107.706127

47. Al Mheid, I., R. S. Patel, V. Tangpricha and A. A. Quyyumi. 2013. Vitamin D and cardiovascular disease: is the evidence solid? Eur. Heart J. 34(48): 3691-3698. doi:

10.1093/eurheartj/eht166

48. Pike, J. W., N. K. Shevde, B. W. Hollis, et al. 2008. Vitamin D—binding protein influences total circulating levels of 1,25-dihydroxyvitamin D-3 but does not directly

modulate the bioactive levels of the hormone in vivo. Endocrinology 149(7): 3656-3667.

doi: 10.1210en.2008-0042

49. Martinez, M. E., M. T. Del Campo, M. J. Sanchez-Cabezudo, et al. 1995. Effect of oral calcidiol treatment on its serum levels and peritoneal losses. Peritoneal Dialysis

International 15(1): 65-70

50. Aljabri K. S., S. A. Bokhari and M. J. Khan. 2010. Glycemic changes after vitamin D supplementation in patients with type 1 diabetes mellitus and vitamin D deficiency. Ann.

Saudi Med. 30(6): 454-458. doi: 10.4103/0256-4947.72265

7.70

51. Holick, M. F. 2004. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am. J. Clin. Nutr. 79(3): 362-371

52. Hyppönen, E., E. Läärä, A. Reunanen, et al. 2001. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358(9292): 1500-1503

53. Penckofer, S., J. Kouba, M. Byrn and C. E. Ferrans. 2010. Vitamin D and depression: where is all the sunshine? Issues Ment. Health Nurs. 31(6): 385-393. Doi:

10.3109/01612840903437657

54. Shaffer, J. A., D. Edmondson, L. T. Wasson, et al. 2014. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled

trials. Psychosom. Med. 76(3): 190-196. doi: 10.1097/PSY0000000000000044

55. Anon. 2011. Vitamin D. Fact sheet for consumers. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminD-Consumer/

56. American Academy of Dermatology. 2009. Position statement on vitamin D. American Academy of Dermatology and AAD Association.

https://www.aad.org/Forms/Policies/Uploads/PS/PS-Vitamin%20D.pdf

57. Gorham, E. D., C. F. Garland, F. C Garland, et al. 2007. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta-analysis. Am. J. Prev. Med. 32(3): 210-

216.

58. Garland, C. F., E. D. Gorham, S. B. Mohr, et al. 2007. Vitamin D and prevention of breast cancer: pooled analysis. J. Steroid Biochem. Mol. Biol. 103(3-5): 708-711.

59. Munger, K. L., L. I. Levin, B. W. Hollis, et al. 2006. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296(23): 2832-2838

60. Scragg, R., M. Sowers, C. Bell, et al. 2004. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care

27(12): 2813-2818

61. Melamed, M. L., P. Muntner, E. D. Michos et al. 2008. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001-2004.

Arterioscler. Thromb. Vasc. Biol. 28(6): 1179-1185

62. Thacher, T. D., P. R. Fischer, M.A. Strand and J. M. Pettifor. 2006. Nutritional rickets around the world: causes and future directions. Ann. Trop. Paediatr. 26(1): 1-16

63. Holick, M. F. 2007. Vitamin D deficiency. N. Engl. J. Med. 357(3): 266-281 64. Cannell, J. J., R. Vieth, J. C. Umhau, et al. 2006. Epidemic influenza and vitamin D.

134(6): 1129-1140.

65. Laaksi, I., J. P. Ruohola, P. Tuohimaa, et al. 2007. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men.

Am. J. Clin. Nutr. 86(3): 714-717.

66. http://www.healthcare.siemens.com/clinical-specialities/bone-metabolism/vitamin- d/vitamin-d-deficiency

67. Ginde, A. A., M. C. Liu and C. A. Camargo. 2009. Demographic differences and trends of vitamin D insufficiency in the U.S. population, 1988-2004. Arch. Intern. Med. 169(6):

626-632. Doi: 10.1001/archinternmed.2008.604

68. Ding, C., D Gao, J. Wilding, et al. 2012. Vitamin D signaling in adipose tissue. Br. J. Nutr. 108(11): 1915-1923. doi: 10.1017/S0007114512003285

69. Chang, L. 2004. Vitamin D: vital role in your health.WebMD (http://www.webmd.com/food-recipes/vitamin-d-vital-role-in-your-health

70. Mathur, R. 2015. Hypercalcemia. MedicineNet.

7.71

http://www.medicinenet.com/hypercalcemia/page3.htm

71. Anon. 2014. Vitamin E. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminE-

HealthProfessional/#h4

72. Klein, E. A., I. M. Thompson, Jr., C. M. Tangen, et al. 2011. Vitamin E and the risk of prostate cancer. The selenium and vitamin E cancer prevention trial (SELECT). JAMA

306(14): 1549-1556. doi: 10.1001/jama.2011.1437

73. Higdon, J. and V. J. Drake. 2011. Vitamin E. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-E

74. Wu, J. H. 2007. Vitamin E metabolism. Molecular Aspects of Medicine 28: 437-452. https://www.researchgate.net/profile/Jason_Wu2/publication/235765736_Vitamin_E_met

abolism/links/02e7e52bb3540276ff000000.pdf

75. Preedy, V. R. and R. R. Watson. 2007. The encyclopedia of vitamin E. CABI.

76. Arita, M., K. Nomura, H. Arai and K. Inoue. 1997. -tocopherol transfer protein

stimulates the secretion of -tocopherol from a cultured liver cell line through a brefeldin

A-insensitive pathway. Proc. Nat. Acad. Sci. U.S.A. 94(23): 12437-12441.

http://www.pnas.org/content/94/23/12437.full

77. Traber, M. G. 2007. Vitamin E regulatory mechanisms. Ann. Rev. Nutr. 27: 347-362. http://www.ncbi.nlm.nih.gov/pubmed/17439363?dopt=Abstract

78. Liou, S. 2001. Free radical damage. Huntington’s Outreach Project for Education, at Stanford. http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/about-free-radical-

damage/

79. Bruno, R. S., S. W Leonard, J. Atkinson, et al. 2006. Faster plasma vitamin E disappearance in smokers is normalized by vitamin C supplementation. Free Radic. Biol.

Med. 40(4): 689-697. http://www.ncbi.nlm.nih.gov/pubmed/16458200

80. Freedman, J. E. and J. F. Keaney, Jr. 2001. Vitamin E inhibition of platelet aggregation is independent of antioxidant activity. J. Nutr. 131(2): 374S-377S.

81. Kang, J.-H. 2014. Protein kinase C (PKC) isozymes and cancer. New Journal of Science 2014(2014), Article ID 231418, 36 pp. http://dx.doi.org/10.1155/2014/231418.

82. Evert, A. 2013. Vitamin E. MedlinePlus. NIH and the U.S. National Library of Medicine. http://www.nlm.nih.gov/medlineplus/ency/article/002406.htm

83. Lonn, E., J. Bosch, S. Yusuf, et al. 2005. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 293(11): 1338-

1347.

84. Anon. 2015. Can antioxidants in fruits and vegetables protect you and your heart? American Heart Association.

http://www.heart.org/HEARTORG/GettingHealthy/NutritionCenter/HealthyEating/Can-

antioxidants-in-fruits-and-vegetables-protect-you-and-your-

heart_UCM_454424_Article.jsp

85. Kris-Etherton, P. M., A. H. Lichtenstein, B. V. Howard, et al. 2004. Antioxidant vitamin supplements and cardiovascular disease. Circulation 110(5): 637-641.

86. Sesso, H D., J. E. Buring, W. G. Christen, et al. 2008. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled

trial. JAMA 300(18): 2123-2133. doi: 10.101/jama.2008.600

87. Chong, E. W., T. Y. Wong, A. J. Kreis, et al. 2007. Dietary antioxidants and primary

7.72

prevention of age related macular degeneration: systematic review and meta-analysis.

BMJ 335(7623): 755. Doi: http://dx.doi.org/10.1136/bmj.39350.500428.47

88. Christen, W. G., R. J. Glynn, E. Y. Chew and J.E. Buring. 2010. Vitamin E and age- related macular degeneration in a randomized trial of women. Ophthalmology

117(6):1163-1168. doi: 101016/j.ophtha.2009.10.043

89. Christen, W. G., R. J. Glynn, E. Y. Chew and J. E. Buring. 2008. Vitamin E and age- related cataract in a randomized trial of women. Ophthalmology 115(5): 822-829.e1

90. Dysken, M. W., M. Sano, S. Asthana, et al. 2014. Effect of vitamin E and memantine on functional decline in Alzheimer disease. The TEAM-AD VA Cooperative Randomized

Trial.JAMA 311(1): 33-44. doi: 10.1001/jama.2013.282834

91. Blacker, D. 2005. Mild cognitive impairment—no benefit from vitamin E, little from donepezil. N. Engl. J. Med. 352(23: 2439-2441.

92. Petersen, R. C., R. G. Thomas, M. Grundman, et al. 2005. Vitamin E and donepezil for the treatment of milk cognitive impairment. N. Engl. J. Med. 352(23): 2379-2388.

93. Lock, M. and A. Loblaw. 2005. Vitamin E might increase risk of death. Can. Fam. Physician 51(6): 829-831

94. Etminan, M., S. S. Gill and A. Samii. 2005. Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson’s disease: a meta-analysis. Lancet Neurol. 4(6): 362-

365

95. Weber, C. A. and M. E. Ernst. 2006. Antioxidants, supplements, and Parkinson’s disease. Ann. Pharmacother. 40(5): 935-938.

96. Miller, A. E., K. W. Dodd and A. F. Subar. Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: the 1987, 1992, and 2000 National Health

Interview Survey results. J. Am. Diet. Assoc. 104(6): 942-950.

97. Ascherio, A., M. G. Weisskopf, E. J. O’reilly, et al. 2005. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann. Neurol. 57(1): 104-110.

98. Orrell, R. W., R. J. Lane and M. Ross. 2007. Antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst. Rev. Jan 24(1): CD002829.

99. Fulgoni III, V. L., D. R. Keast, R. L. Baily and J. Dwyer. 2011. Foods, fortificants, and supplements: where do Americans get their nutrients? J. Nutr. 141(10): 1847-1854. doi:

10.3945/jn. 111.142257

100. Anon. 2015. Vitamin K. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/

101. Higdon, J., V. J. Drake, B. Delage and S. L. Booth. 2014. Vitamin K. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-K

102. Ferland, G. 2012. Vitamin K. In: Erdman, J.W., I. A. Macdonald and S. H. Zeisel, Eds. Present knowledge in nutrition. 10

th ed. Washington, DC. Wiley-Blackwell.

103. Ke, B. 2003. Photosynthesis: photobiochemistry and photobiophysics. Volume 10. Kluwer Academic Publishers, New York.

104. Suttie, J. W. 2014. Vitamin K. In: Ross, A. C., B. Caballero, R. J. Cousins, et al. Eds. Modern nutrition in health and disease. 11

th ed. Lippincott, Williams & Wilkins,

Baltimore.

105. Conly, J. M., K. Stein, L. Worobetz and S. Rutledge-Harding. 1994. The contribution of vitamin K2 (menaquiones) produced by the intestinal microflora to human nutritional

requirements for vitamin K. Am. J. Gastroenterol. 89(6): 915-923.

7.73

106. Conly, J. M. and K. Stein. 1992. The production of menaquinones (vitamin K2) by intestinal bacteria and their role in maintaining coagulation homeostasis. Prog. Food Nutr.

Sci. 16(4): 307-343.

107. Combs, G. F., Jr. 2008. The vitamins; fundamental aspects in nutrition and health. 3rd ed. Elsevier Academic Press, Burlington, MA.

108. Nakagawa, K., Y. Hirota, N Sawada, et al. 2010. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 468(7320): 117-121. doi:

10.1038/nature09464

109. Olson, J. 1987. Recommended dietary intakes (RDI) of vitamin K in humans. Am. J. Clin. Nutr. 45(4): 687-692.

110. Anon. 2013. Vitamin K deficiency associated with antibiotic use. Provet Healthcare Information. http://www.provet.co.uk/health/diseases/vitkantibiotics.htm

111. Anon. 2009. Find a vitamin or supplement. Vitamin K. WebMD. http://www.webmd.com/vitamins-supplements/ingredientmono-983-

vitamin%20k.aspx?activeingredientid=983&activeingredientname=vitamin%20k

112. Shearer, M. J. and P. Newman. 2008. Metabolism and cell biology of vitamin K. Thromb. Haemost. 100(4): 530-547.

113. Mathers, J. C., F. Fernandez, M. J. Hill, et al. 1990. Dietary modification of potential vitamin K supply from enteric bacterial menaquinones in rats. Brit. J. Nutr. 63: 639-652.

114. Traber, M. G. 2008. Vitamin E and K interactions—a 50-year-old problem. Nutr. Rev. 66(11): 624-629. doi: 10.1111/j.1753-4887.2008.00123.x

115. Pastori, D., R. Carnevale, R. Cangemi, et al. 2013. Vitamin E serum levels and bleeding risk in patients receiving oral anticoagulant therapy: a retrospective cohort study. J. Am.

Heart Assoc. 2(6): e000364. doi: 10.1161/JAHA/113.000364

116. Gundberg, C. M., J. B. Lian and S. L. Booth. 2012. Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv. Nutr. 3(2): 149-157. doi: 10.3945/an.112.001834

117. Schlieper, G., R. Westenfeld, T. Krüger, et al. 2011. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J. Am. Soc. Nephrol. 22(2):

387-395. doi: 10.1681/ASN.210040339

118. Vanakker, O. M., L. Martin, L. J. Shurgers, et al. 2010. Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX

mutations in the PXE-like syndrome. Lab Invest. 90(6): 895-905. doi:

10.1038/labinvest.2010.68

119. Robins, R. S., C. A. Lemarié, S. Laurance, et al. 2013. Vascular Gas6 contributes to thrombogenesis and promotes tissue factor up-regulation after vessel injury in mice. Blood

121(4): 692-699. doi: 10.182/blood-2012-05-433730

120. Rothlin, C. V., J. A. Leighton and S. Ghosh. Tyro3, Axl, and Mertk receptor signaling in inflammatory bowel disease and colitis-associated cancer. Inflamm. Bowel Dis. 20(8):

1472-1480. Doi: 10.1097/MIB.0000000000000050

121. Tjwa, M., L. Moons and E. Lutgens. 2009. Pleiotropic role of growth arrest-specific gene 6 in atherosclerosis. Curr. Opin. Lipidol. 20(5): 386-392. doi:

10.1097/MOL.0b013e32830982e

122. Nakajima, S., H. Lijima, S. Egawa, et al. 2011. Association of vitamin K deficiency with bone metabolism and clinical disease activity in inflammatory bowel disease. Nutrition

27(10): 1023-1028. doi: 10.1016/j.nut/2010.10.021

123. Juanola-Falgarona, M., J. Salas-Salvadó, R. Estruch, et al. 2013. Association between

7.74

dietary phylloquinone intake and peripheral metabolic risk markers related to insulin

resistance and diabetes in elderly subjects at high cardiovascular risk. Cardiovasc.

Diabetol. 12: 7. doi: 10.1186/1475-2840-12-7

124. Juanola-Falgarona, M., J. Salas-Salvadó, M. A. Martínez-González, et al. 2014. Dietary intake of vitamin K is inversely associated with mortality risk. J. Nutr. 144(5): 743-750.

doi: 10.3945/jn. 113.187740

125. Laurance, S., C. A. Lemarié and M. D. Blostein. 2012. Growth arrest-specific gene 6 (gas6) and vascular hemostasis. Adv. Nutr. 3: 196-203.

126. Lippi, G. and M. Franchini. 2011. Vitamin K in neonates: facts and myths. Blood Transfus. 9(1): 4-9. doi: 10.2450/2010.0034-10

127. Usui, Y., H. Tanimura, N. Nishimura, et al. 1990. Vitamin K concentration I the lasma and liver of surgical patients. Am. J. Clin. Nutr. 51(5): 846-852.

128. Schurgers, L. J. 2013. Vitamin K: key vitamin in controlling vascular calcification in chronic kidney disease. Kidney Int. 83(5): 782-784. doi: 10.1038/ki.2013.26

129. Schurgers, L. J., I. A. Josen, E M. Laufer, et al. 2012. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PLoS One 7(8):

e43229. doi: 10.1371/journal.pone.0043229

130. Beulens, J. W., M. L. Bots, F. Atsma, et al. 2009. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 203(2): 489-493. doi:

10.1016/j.atherosclerosis.2008.07.010

131. Choi, H. J, J. Yu, H. Choi, et al. 2011. Vitamin K2 supplementation improves insulin sensitivity via osteocalcin metabolism: a placebo-controlled trial. Diabetes Care 34(9):

e147. doi: 10.2337/dc11-0551

132. Dalmeijer, G. W., Y. T. van der Schouw, E. J. Magdeleyns, et al. 2013. Matrix gla protein species and risk of cardiovascular events in type 2 diabetic patients. Diabetes Care

36(11): 3766-3771. doi: 10.2337/dc13-0065

133. Ibarrola-Jurado, N., J. Salas-Salvadó, M. A. Martínez-González, et al. 2012. Dietary phylloquinone intake and risk of type 2 diabetes in elderly subjects at high risk of

cardiovascular disease. Am. J. Clin. Nutr. 96(5): 1113-1118. doi:

10.3945/ajcn.111.033498

134. Litwack, G. (Ed.) 2008. Vitamin K. Vitamins and hormones, volume 78. Academic Press. 135. Hitomi, M., F. Yokoyama, Y. Kita, et al. 2005. Antitumor effects of vitamin s K1, K2

and K3 on hepatocellular carcinoma in vitro and in vito. Int. J. Oncol. 26(3): 713-720.

136. Ogawa, M., S. Nakai, A. Dequchi, et al. 2007. Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells.

Int. J. ONcol. 31(2): 323-331.

137. Prasad, K. N., B. Kumar, X. D. Yan, et al. 2003. Alpha-tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment: a review. J. Am. Col. Nutr.

22(2): 108-117.

138. Anon. 2015. Dietary reference intakes: RDA and AI for vitamins and elements. DRI tables and application reports. United States Department of Agriculture National

Agricultural Library.

http://www.nal.usda.gov/fnic/DRI/DRI_Tables/RDA_AI_vitamins_elements.pdf

139. Anon. 2015. Dietary refrence intakes: tolerable upper intake level values for vitamins and elements. DRI tables and application reports. United States Department of Agriculture

National Agricultural Library.

7.75

http://www.nal.usda.gov/fnic/DRI/DRI_Tables/UL_vitamins_elements.pdf

140. Conly J. and K. Stein. 1994. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin. Invest. Med. 17(6): 531-

539.

141. Suttie, J. W. 2009. Vitamin K in health and disease. CRC Press. 142. Bhat, R. V. and C. T. Deshmukh. 2003. A study of vitamin K status in children on

prolonged antibiotic therapy. Indian Pediatr. 40(1): 36-40.

143. Shirakawa, H., M. Komai and S. Kimura. 1990. Antibiotic-induced vitamin K deficiency and the role of the presence of intestinal flora. Int. J. Vitam. Nutr. Res. 60(3): 245-251.

144. Ehrlich, S. D. 2007. Possible interactions with: vitamin K. (May 31). http://umm.edu/health/medical/altmed/supplement-interaction/possible-interactions-with-

vitamin-k

145. Blackmon, L. (Chair), et al. 2003. Policy statement, American Academy of Pediatrics. Controversies concerning vitamin K and the newborn. 112(1): 191- 192.

http://pediatrics.aappublications.org/content/112/1/191.full.pdf

146. Aziz, F. and P Patil. 2015. Role of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia. Indian J. Pediatr. 82(4): 363-367. doi: 10.1007/s12098-

014-1584-3

147. Anon. 2013. Vitamin K deficiency. Lab Tests Online. American Associatino for Clinical Chemistry. https://labtestsonline.org/understanding/conditions/vitamink/start/2/

148. Walther, B., J. P. Karl, S. L. Booth and P. Boyaval. 2013. Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin K

requirements. Adv. Nutr. 4(4): 463-473. doi: 10.3945/an.113.003855

149. Nimptsch, K., S. Rohrmann and J. Linseisen. 2008. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into

Cancer and Nutrition (EPIC-Heidelberg). Am. J. Clin. Nutr. 87(4): 985-992

150. Ravishankar, B., Y. A. Dound, K. S. Behta, et al. 2015. Safety assessment of menaquinone-7 for use in humans. J. of Food and Drug Anal. 23(1): 99-108. doi:

http://dx.doi.org/10.1016/j.jfda.2014.03.001

151. Guyenet, S. 2008. Vitamin K2, menatetrenone (MK-4). Whole Health Source. Nutrition and Health Science. http://wholehealthsource.blogspot.com/2008/06/vitamin-k2-

menatetrenone-mk-4.html

152. Shea, M. K., S. L. Booth, J. M. Masaro, et al. 2008. Vitamin K and vitamin D status: associations with inflammation markers in the Framingham Offspring Study. Am. J.

Epidemiol. 167(3): 313-320. doi: 10.1093/aje/kwm306

153. Anon. 2014. Table 1. Nutrient intakes from food and beverages: mean amounts consumed per individual, by genera and age, in the United States, 2011-2012. What We

Eat In America, NHANES 2011–2012. U.S. Dept. of Agriculture, Agricultural Research

Service.

http://www.ars.usda.gov/SP2UserFiles/Place/80400530/pdf/1112/Table_1_NIN_GEN_11.

pdf

154. Booth, S. L., I. Golly, J. M. Sacheck, et al. 2004. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am. J. Clin. Nutr. 80(1): 143-

148.

155. Shea, M. K. and R. M. Holden. 2012. Vitamin K status and vascular calcification: evidence from observational and clinical studies. Adv. Nutr. 3: 158-165. doi:

7.76

10.3945/an.111.001644

156. Neogi, T., S. L. Booth, Y. Q. Zhang, et al. 2006. Low vitamin K status is associated with osteoarthritis in the hand and knee. Arthritis & Rheumatism 54(4): 1255-1261. doi:

10.1002/art.21735

157. Duggan, P., M. O’Brien, M. Kiely, et al. Vitamin K status in patients with Crohn’s Disease and relationship to bone turnover vitamin K status and bone turnover in Crohn’s

disease patients. Am. J. Gastroenterology 99: 2178-2185. doi: 10.1111/j.1572-

0241.2004.40071.x

158. Millen, B. E. 2015. Scientific report of the 2015 Dietary Guidelines Advisory Committee. Advisory report to the Secretary of Health and Human Services and the Secretary of

Agriculture. United States Department of Agriculture.

http://www.health.gov/dietaryguidelines/2015-scientific-report/PDFs/Scientific-Report-of-

the-2015-Dietary-Guidelines-Advisory-Committee.pdf

159. Anon. 2015. Vitamin C. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminC-

HealthProfessional/

160. Higdon, J., V. J. Drake, G. Angelo, B. Frei and A. J. Michels. 2014. Vitamin C. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-C

161. Drouin, G., J.-R. Godin and B. Pagé. 2011. The genetics of vitamin C loss in vertebrates. Curr. Genomics 12(5): 371-378. Doi: 10.2174/138920211796429736

162. Bellows, L. and R. Moore 2012. Water-soluble vitamins: B-complex and vitamin C. Colorado State University Extension.

http://www.ext.colostate.edu/pubs/foodnut/09312.html

163. Lee, S K. and A. A. Kader. 2000. Preharvest and postharvest factors influencing vitamin C content of horticultural crops. Postharvest Biology and Technology 20: 207-220.

164. Carpenter, K. J. 2012. The discovery of vitamin C. Ann. Nutr. Metab. 61(3): 259-264. doi: 10.1159/000343121

165. Schultz, J. 2002. The discovery of vitamin C by Albert Szent-Györgyi. American Chemical Society National Historic Chemical Landmarks.

http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/szentgyorgyi.htm

l

166. Svirbely, J. L. and A. Szent-Györgyi. 1933. The chemical nature of vitamin C. Biochem. J. 27(1): 279-285.

167. Jacob, R. A. and G. Sotoudeh. 2002. Vitamin C function and status in chronic disease. Nutr. Clin. Care 5(2): 66-74

168. Malo, C. and J. X. Wilson. 2000. Glucose modulates vitamin C transport in adult human small intestinal brush border membrane vesicles. J. Nutr. 130(1): 63-69.

169. Christen, W. G., R. J. Glynn, H. D. Sesso, et al. 2010. Arch. Ophthalmol. 128(11): 1397- 1405. doi: 10.1001/archophthalmol.2010.266

170. Dakhale, G. N., S. D. Khanzode, S. S. Khanzode and A. Saoji. 2005. Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome

of schizophrenia. Psychopharmacology 182(4): 494-498.

171. Simon, J. A. and E. S. Hudes. 2001. Relation of ascorbic acid to bone mineral density and self-reported fractures among US adults. Am. J. Epidemiol. 154(5): 427-433

172. Morton, D. J., E. L. Barrett-Conner and D. L. Schneider. 2001. Vitamin C supplement

7.77

use and bone mineral density in postmenopausal women. J. Bone Miner. Res. 16(1): 135-

140

173. Johnson, L. E. 2014. Vitamin C. Merck Manual Professional Version. http://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency-

dependency-and-toxicity/vitamin-c

174. Lee, D. H., A. R. Folsom, L. Harnack, et al. 2004. Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Am. J. Clin. Nutr 80(5): 1194-1200.

175. Taylor, E. N., M. J. Stampfer and G. C. Curhan. 2004. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J. Am. Soc.

Nephrol. 15(12): 3225-3232.

176. Gerster, H. 1999. High-dose vitamin C: a risk for persons with high iron stores? Int. J. Vitam. Nutr. Res. 69(2): 67-82.

177. Groff, J. L., S. S. Gropper and S. M. Hunt. 1995. The water soluble vitamins. In: Advanced nutrition and human metabolism. West Publishing Company.

178. http://www.rmg.co.uk/explore/sea-and-ships/facts/ships-and-seafarers/life-at-sea-in-the- age-of-sail

179. http://www.pbchistoryonline.org/page/what-did-sailors-eat 180. http://www.sca.noaharney.com/a-meal-onboard-ship-in-the-16th-century/ 181. Oxford Dictionary.

http://www.oxforddictionaries.com/us/definition/american_english/Limey

182. Lamb, J. 2011. Captain Cook and the scourge of scurvy. BBC History. http://www.bbc.co.uk/history/british/empire_seapower/captaincook_scurvy_01.shtml

183. Lewis, D. 2013. Don’t forget the lime. Now I Know (October 10). http://nowiknow.com/dont-forget-the-lime/

184. Anon. 2015. Thiamin. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/Thiamin-

HealthProfessional/

185. Higdon, J., V. J. Drake, B. Delage and C. Bates. 2013. Thiamin. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/thiamin

186. Anon. 2014. Vitamin B. Better Health Channel, State Government of Victoria, Australia, in association with Deakin University, Australia.

http://www.betterhealth.vic.gov.au/bhcv2/bhcsite.nsf?open

187. Whelan, W. J. 2005. What’s in a name? Vitamin B4. IUBMB Life 57(2): 125. http://onlinelibrary.wiley.com/doi/10.1080/15216540500078939/pdf

188. Navarra, T. 2004. Encyclopedia of vitamins, minerals, and supplements. Infobase Publishing.

189. Itokawa, Y. 1976. Kanehiro Takaki (1849-1920): a biohgraphical sketch. J. Nutr. 106(5): 581-588.

190. http://www.nobelprize.org/educational/medicine/vitamin_b1/eijkman.html 191. Vorvic, L. J. 2014. Beriberi. MedlinePlus (August 17).

http://www.nlm.nih.gov/medlineplus/ency/article/000339.htm

192. Bruyn, G. W. and C. M. Poser. 2003. The history of tropical neurology: nutritional disorders. Science History Publications.

193. O’Rourke, N. P., V. W. Bunker, A. J. Thomas, et al. 1990. Thiamine status of healthy and institutionalized elderly subjects: analysis of dietary intake and biochemical indices. Age.

7.78

Ageing 19(5): 325-329.

194. Larsen, T. R., D. Draqu and M. Williams. 2013. Wernike’s encephalopathy: an unusual consequence of the acquired immune deficiency syndrome-case report and literature

review. Case Rep. Med. 2013: 709474. doi: 10.1155/2013/709474

195. Al-Attas, O. S., N. M. Al-Daghri, A. A. Alfadda, et al. 2012. Blood thiamine and its phosphate esters as measured by high-performance liquid chromatography: levels and

associations in diabetes mellitus matients with varying degrees of microalbuminuria. J.

Endocrinol. Invest. 35(11): 951-956. doi: 10.3275/8126

196. Pácal, L., K. Kuricová and K. Kaňková. 2014. Evidence for altered thiamine metabolism in diabetes: is there a potential to oppose gluco- and lipotoxicity by rational

supplementation? World J. Diabetes 15(5): 288-295. doi: 10.4239/wjd.v5.i3.288

197. Page, G. L., D. Laight and M. H. Cummings. 2011. Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular

disease. Int. J. Clin. Pract. 65(6): 684-690. doi: 10.1111/j.1742-124120011.02680.x

198. González-Ortiz, M. E. Martínez-Abundis, J. A. Robles-Cervantes, et al. 2011. Effect of thiamine administration on metabolic profile, cytokines and inflammatory markers in

drug-naïve patients with type 2 diabetes. Eur. J. Nutr. 50(2): 145-149. doi:

10.1007/s00394-010-0123-x

199. Rathanaswami, P., A. Pourany and R. Sundaresan. 1991. Effects of thiamine deficiency on the secretion of insulin and the metabolism of glucose in isolated rat pancreatic islets.

Biochem. Int. 25(3): 577-583.

200. Boros, L. G., J. L. Brandes, W. N. Lee, et al. 1998. Thiamine supplementation to cancer patients: a double edged sword. Anticancer Res. 18(1B): 595-602.

201. Anon. 2015. Riboflavin. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/Riboflavin-

HealthProfessional/

202. Higdon, J., V. J. Drake, B. Delage, H. McNulty and A. McCAnn. 2013. Riboflavin. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/riboflavin

203. Anon. 2013. Riboflavin. DrugBank. Canadian Institutes of Health Research. http://www.drugbank.ca/drugs/DB00140

204. Powers, H. J. 1999. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc. Nutr. Soc. 58(2): 435-440.

205. Wacker, J., J. Frühauf, M. Schulz, et al. 2000. Riboflavin deficiency and preeclampsia. Obstet. Gynecol. 96(1): 38-44.

206. McNulty, H., J. J. Strain, K. Pentieva and M. Ward. 2012. C(1) metabolism and CVD outcomes in older adults. Proc. Nutr. Soc. 71(2): 213-221. doi:

10.1017/S0029665111003387

207. Zschäbitz, S., T. Y. Cheng, M. L. Neuhouser, et al. 2013. B vitamin intakes and incidence of colorectal cancer: results from the Women’s Health Initiative Observational

Study cohort. Am. J. Clin. Nutr. 97(2): 332-343. doi: 10.3945/ajcn.112.034736

208. MacLennan, S. C., F. M. Wade, K. M. Forres, et al. 2008. High-dose riboflavin for migraine prophylaxis in children: a double-blind, randomized, placebo-controlled trial. J.

Child. Neurol. 23(11): 1300-1304. doi: 10.1177/08830873808318053

209. Bruijn J., H. Duivenvorden, J. Passchier, et al. 2010. Medium-dose riboflavin as a prophylactic agent in children with migraine: a prelmininary placebo-controlled,

7.79

randomised, double-blind, cross-over trial. Cephalalgia. 30(12): 1426-1434. doi:

10.1177/0333102410365106

210. Böhles, H. 1997. Antioxidative vitamins in prematurely and maturely born infants. Int. J. Vitam. Nur. Res. 67(5): 321-328.

211. Powers, H J., L. T. Weaver, S. Austin and J. K. Beresford. 1993. A proposed intestinal mechanism for the effect of riboflavin deficiency on iron loss in the rat. Br. J. Nutr. 69(2):

553-561.

212. de Benoist, B., E. McLean, I Egli, M. Cogswell (Eds). 2008. Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia. World Health Organization Press.

213. Ma, A. G., E. G. Schouten, F. Z. Zhang, et al. 2008. Retinol and riboflavin supplementation decreases the prevalence of anemia in Chinese pregnant women taking

iron and folic acid supplements. J. Nutr. 138(10): 1946-1950.

214. Soares, M. J., K. Satyanarayana, M. S. Bamji, et al. 1993. The effect of exercise on the riboflavin status of adult men. Br. J. Nutr. 69(2): 541-551.

215. Northrop-Clewes, C. A. and D. I. Thurnham. 2012. The discovery and characterization of riboflavin. Ann. Nutr. Metab. 61(3): 224-230. doi: 10.1159/000343111

216. Sorrell, M. F., O. Frank, A. D Thompson, et al. 1971. Absorption of vitamins from the large intestine in vivo. Nutr. Rep. Int. 3: 143-148.

217. Pitkin, R. M. (Chair). 1998. Chapter 5—riboflavin. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

National Academy Press. http://fnic.nal.usda.gov/dietary-guidance/dri-nutrient-

reports/thiamin-riboflavin-niacin-vitamin-b6-folate-vitamin-b12

218. Magnúsdóttir, S., D. Ravcheev, V. de Crécy-Lagard and I. Thiele. 2015. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes.

Front. Genet. 6: 148. doi: 10.3389/fgene.2015.001500148

219. Kjer-Nielsen, L., O. Patel, A. J. Corbett, et al. 2012. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491(7426): 717-723. 10.1038.nature11605

220. Pitkin, R. M. (Chair). 1998. Chapter 5—thiamin. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

National Academy Press. http://fnic.nal.usda.gov/dietary-guidance/dri-nutrient-

reports/thiamin-riboflavin-niacin-vitamin-b6-folate-vitamin-b12

221. Higdon, J., V. J. Drake, B. Delage and E. L. Jacobson. 2013. Riboflavin. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/niacin

222. Pitkin, R. M. (Chair). 1998. Chapter 6—niacin. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

National Academy Press. http://fnic.nal.usda.gov/dietary-guidance/dri-nutrient-

reports/thiamin-riboflavin-niacin-vitamin-b6-folate-vitamin-b12

223. Villines, T. C., A. S. Kim, R. S. Gore and A. J. Taylor. 2012. Niacin: the evidence, clinical use and future directions. Curr. Atheroscler. Rep. 14(1): 49-59. doi:

10.1007/s11883-011-0212-1

224. Hochhotzer, W, D. D. Berg and R P Guigliano. 2011. The facts behind niaci. Ther. Adv. Cardiovasc. Dis. 5(5): 227-240. doi: 10.1177/1753944711419197

225. Hays, J. N. 2005. Epidemics and pandemics: their impacts on human history. Santa Barbara, CA: ABC-CLIO

226. Rajakumar, K. Pellagra in the United States: a historical perspective. Southern Medical

7.80

Journal 93(3): 272-277.

227. Bollet, A. J. 1992. Politics and pellagra: the epidemic of pellagra in the U.S. in the early twentieth century. Yale J. Biol. Med. 65(3): 211-221.

228. Rabinowitz, S. S. and N. Unnikrishnan. 2014. Pediatric pellagra. Medscape Drugs & Diseases. http://emedicine.medscape.com/article/985427-overview

229. Rhoades, R. A. and D. R. Bell. (Eds.) 2013. Medical physiology: principles for clinical medicine. 4

th Ed. Lippincott, Williams & Wilkins.

230. Hao, K., Q. Zhou W. Chem, et al. 2013. Possible role of the ‘IDO-AhR axis’ in maternal- foetal tolerance. Cell. Biol. Int. 37(2): 105-108. doi: 10.1002/cbin.10023.

231. Jacob, R. and M. Swenseid. 1996. Niacin. In: Ziegler, E. and L. Filer, Eds. Present knowledge in nutrition. 7

th Ed. ILSI Press, Washington. Pgs. 185-190.

232. Jacobson, E. L.,W. M. Shieh and A. C. Huang. 1999. Mapping the role of NAD metabolism in prevention and treatment of carcinogenesis. Mol. Cell. Biochem. 193(1-2):

69-74.

233. Kirkland, J. B. 2003. Niacin and carcinogenesis. Nutr. Cancer 46(2): 110-108 234. Hageman, G. J., R. H. Stierum, M. H. van Herwijnen, et al. 1998. Nicotinic acid

supplementation: effects on niacin status, cytogenetic damage and poly(ADP-ribosylation)

in lymphocytes of smokers. Nutr. Cancer 32(2): 113-120.

235. Yong, L. C. and M. R. Petersen. 2011. High dietary niacin intake is associated with decreased chromosomes translocation frequency in airline pilots. Br. J. Nutr. 105(4): 496-

505. doi: 10.1017/S000711451000379X

236. Benavente, C. A., S. A. Schnell and E. L. Jacobson. 2012. Effects of niacin restriction on sirtuin and PARP responses to photodamage in human skin. PLoS One 7(7): e42276. doi:

10.1371/journal.pone.0042276

237. Hedman, M., J. Ludvigsson and M. K. Faresjö. 2006. Nicotinamide reduces high secretion of IFN-gamma in high-risk relaties even though it does not prevent type 1

diabetes. J. Interferon Cytokine Res. 26(4): 207-213.

238. Greenbaum, C. J., S. E. Kahn and J. P. Palmer. 1996. Nicotinamide’s effects on glucose metabolism in subjects at risk for IDDM. Diabetes 45(11): 1631-1634.

239. Lampeter, E. F., A. Klinghammer, W. A. Scherbaum, et al. 1998. The Deutsche nicotinamide intervention study: an attempt to prevent type 1 diabetes. DENIS Group.

Diabetes 47(6): 980-984.

240. Canner, P. L., K. G. Berge, N. K. Wenger, et al. 1986. Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J. Am. Coll. Cardiol. 8(6): 1245-1255.

241. Guyton, J. R. and D. M. Capuzzi. 1998. Treatment of hyperlipidemia with combined niacin-statin regimens. Am. J. Cardiol. 82(12A): 82U-84U.

242. Ito, M. K. 2002. Niacin-based therapy for dyslipidemia: past evidence and future advances. Am. J. Manag. Care 8(12 Suppl): S315-S322.

243. Sazonov, V., D. Maccubbin, C. M. Sisk and P. L. Canner. 2013. Effects of niacin on the incidence of new onset diabetes and cardiovascular events in patients with

normoglycaemia and impaired fasting glucose. Int. J. Clin. Pract. 67(4): 297-302. doi:

10.111/ijcp.12089

244. Elam, M. B., D. B. Hunninghake, K. B. Davis, et al. 2000. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial

disease: the ADMIT study: a randomized trial. Arteral Disease Multiple Intervention Trial.

JAMA 284(10): 1263-1270.

7.81

245. Li, D., W.-P. Sun, Y.-M. Zhou, et al. 2010. Chronic niacin overload may be involved in the increase prevalence of obesity in US children. World J. Gastroenterol. 16(19): 2378-

2387. doi: 10.3748/wjg.v16.i19.2378

246. Park, Y. K., C. T. Sempos, C. N. Barton, et al. 2000. Effectiveness of food fortification in the United States: the case of pellagra. Am. J. Public Health 90(5): 727-738.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1446222/

247. Dietrich, M., C. J. Brown and G. Block. 2005. The effect of folate fortification of cereal- grain products on blood folate status, dietary folate intake, and dietary folate sources

among adult non-supplement users in the United States. J.Am. Coll. Nutr. 24(4): 266-274.

248. Schmidt, R. H. and G. E. Rodrick. 2003. Food safety handbook. John Wiley & Sons, Inc. 249. Prinzo, Z. W. 2000. Pellagra and its prevention and control in major emergencies. World

Health Organization.

http://apps.who.int/iris/bitstream/10665/66704/1/WHO_NHD_00.10.pdf?ua=1

250. Higdon, J., V. J. Drake and N. Plesofsky. 20108. Pantothenic acid. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/pantothenic-acid

251. Pitkin, R. M. (Chair). 1998. Chapter 10—pantothenic acid. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and

choline. National Academy Press. http://www.nal.usda.gov/fnic/DRI//DRI_Thiamin/357-

373_150.pdf

252. Johnson, L. E. 2014. Biotin and pantothenic acid. Merck Manual Professional Edition. http://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency-

dependency-and-toxicity/biotin-and-pantothenic-acid

253. Berg, J. M., J. L. Tymoczko and L. Stryer. 2002. Section 22.5. Acetyl coenzyme A carboxylase plays a key role in controlling fatty acid metabolism. Biochemistry. 5

th Ed.

W. H. Freeman. http://www.ncbi.nlm.nih.gov/books/NBK21154/

254. Berg, J. M., J. L. Tymoczko and L. Stryer. 2002. Section 17.1. The citric acid cycle oxidizes two-carbon units. Biochemistry. 5

th Ed. W. H. Freeman.

http://www.ncbi.nlm.nih.gov/books/NBK22427/

255. Bender, D. A. 1999. Optimum nutrition: thiamin, biotin and pantothenate. Proc. Nutr. Soc. 58(2): 427-433.

256. Ball, G. F. M. 2004. Vitamins: their role in the human body. Blackwell publishing. 257. Said, H M., A. Ortiz, E. McCloud, et al. 1998. Biotin uptake by human colonic epithelial

NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J. Physiol.

275(5 Pt 1): C1365-1371.

258. Friedrich, W. 1988. Vitamins. Walter de Gruyter & Co. 259. Hodges, R. E., M. A. Ohlson and W. B. Bean. 1958. Pantothenic acid deficiency in man.

J. Clin. Invest. 37(11): 1642-1657. doi: 10.1172/JCI103756

260. Kelly, G. S. 2011. Pantothenic acid. Altern. Med. Rev. 16(3): 263-274. http://www.altmedrev.com/publications/16/3/263.pdf

261. Gaddi, A., G. C. Descovich, G. Noseda, et al. 1984. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of

hyperlipoproteinemia. Atherosclerosis 50(1): 73-83.

262. Evans, M., J. A. Rumberger, I. Azumano, et al. 2014. Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate

cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-

7.82

controlled investigation. Vasc. Health Risk Manag. 10: 89-100. doi:

10.2147/VHRM.S57116

263. Anon. 2011. Vitamin B6. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/VitaminB6-

HealthProfessional/

264. Higdon, J., V. J. Drake, B. Delage and J. F. Gregory. 2014. Vitamin B6. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-B6

265. Pitkin, R. M. (Chair). 1998. Chapter 7—vitamin B6. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and

choline. National Academy Press. http://www.nal.usda.gov/fnic/DRI//DRI_Thiamin/150-

195_150.pdf

266. György, P. 1934. Vitamin B2 and the pellagra-like dermatitis in rats. Nature 133: 498- 499.

267. György, P. 1938. Crystalline vitamin B5. J. Am. Chem. Soc. 60: 983-984. 268. György, P. and R. E. Eckardt. 1939. Vitamin B6 and skin lesions in rats. Nature 144:

512-512.

269. Barness, L. A. and R. M. Tomarelli. 1979. Paul György (1893-1976): a biographical sketch. J. Nutr. 109(1): 17-23. http://jn.nutrition.org/content/109/1/17.full.pdf+html

270. Johansson, S., S. Lndstedt and H.-G. Tiselius. 1974. Metabolic interconversions of different forms of vitamin B6. J. Biol Chem. 249(19): 6040-6046.

271. Choi, S. W. and S. Friso. 2012. Vitamins B6 and cancer. Subcell. Biochem. 56: 247-264. doi: 10.1007/978-94-007-2199-9_13

272. Ishihara J., H. Iso, M. Inoue, et al. 2008. Intake of folate, vitamin B6 and vitamin B12 and the risk of CHD: the Japan Public Health Center-Based Prospective Study Cohort I. J.

Am. Coll. Nutr. 27(1): 127-136.

273. Page, J. H., M. Jing, S. E. Chiuve, et al. 2009. Plasma vitamin B6 and risk of myocardial infarction in women. Circulation 120: 649-655. doi:

10.1161/CIRCULATIONAHA.108.809038

274. Gerhardt, G. T. and P. B. Duell. 1999. Homocysteine and atherosclerosis. Curr. Opin. Lipidol. 10(5): 417-428.

275. Skarupski, K. A., C. Tangney, H. Li, et al. 2010. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am. J.

Clin. Nutr. 92(2): 330-335. doi: 10.3945/ajcn.2010.29413

276. Almeida, O. P., K. Marsh, H. Alfonso, et al. 2010. B-vitamins reduce the long-term risk of depression after stroke: the VITATOPS-DEP trial. Ann. Neurol. 68(4): 503-510. doi:

10.1002/ana.22189

277. Merete, C., L. M. Falcon and K. L. Tucker. 2008. Vitamin B6 is associated with depressive symptomatology in Massachusetts elders. J. Am. Coll. Nur. 27(3): 421-427.

278. Larsson, S. C., N. Orsini and A. Wolk. 2010. Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA 303(11): 1077-1083. doi:

10.1001/jama.2010.263

279. Wu, W., S. Kang and D. Zhang. 2013. Association of vitamin B6, vitamin B12 and methionine with risk of breast cancer: a dose-response meta-analysis. Br. J. Cancer

109(7): 1926-1944. Doi: 10.1038/bjc.2013.438

280. Xiao, Q., N. D. Freedman, J. Ren, et al. 2014. Intakes of folate, methionine, vitamin B6,

7.83

and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. Br. J.

Cancer 110(5): 1328-1333. doi: 10.1038/bjc.2014.17

281. Ong, Z., E. A. Holly and P M. Bracci. 2009. Intake of folate, vitamins B6, B12 and methionine and risk of pancreatic cancer in a large population-based case-control study.

Cancer Causes Control 20(8): 1317-1325. doi: 10.1007/s10552-009-9352-9

282. Maltepe, C. and G. Koren. 2013. The management of nausea and vomiting of pregnancy and hyperemesis gravidarum—a 2013 update. J. Popul Ther. Clin. Pharmacol. 20(2):

e184-192.

283. Said, H. M. 2011. Intestinal absorption of water-soluble vitamins in health and disease. Biochem. J. 437(3): 357-372. doi: 10.1042/BJ20110326

284. Evert, A. 2013. Vitamin B6. MedlinePlus. U.S. National Library of Medicine (February 18). http://www.nlm.nih.gov/medlineplus/ency/article/002402.htm

285. Feldman, M., L. S. Friedman and L. J. Brandt. (Eds.) 2016. Sleisenger and Fordtran’s gastrointestinal and liver disease, 10

th edition. Elsevier, Saunders.

286. Ball, G. F. M. 2006. Vitamins in foods. Analysis, bioavailability, and stability. CRC Press.

287. Albersen, M., F. Groenendaal, van der Ham, M., et al. 2012. Vitamin B6 vitamer concentrations in cerebrospinal fluid differ between preterm and term newborn infants.

Pediatrics 230(1): e191-e198. doi: 10/1542/peds.2011/3751

288. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/61064 289. Inubushi, T., T. Takasawa, Y. Tuboi, et al. 2005. Changes of glucose metabolism and

skin-collagen neogenesis in vitamin B6 deficiency. Biofactors. 23(2):59-67.

290. Solomon, L. R. and K. Cohen. 1989. Erythrocyte O2 transport and metabolism and effects of vitamin B6 therapy in type II diabetes mellitus. Diabetes 38(7): 881-886. doi:

10.2337/diab.38.7.881

291. House, A. A., M. Eliasziw, D. C. Cattran, et al. 2010. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA 303(16): 1603-

1609. doi: 10.1001/jama.2010.490

292. Raval, A. D., D. Thakker, A. N. Rangoonwala, et al. 2015. Vitamin B and its derivatives for diabetic kidney disease. Cochrane Database Syst. Rev. 1:CD009403. Doi:

1002/14651858.CD009403

293. http://www.hsph.harvard.edu/nutritionsource/vitamin-b/ 294. Heiskanen, K., M. A. Siimes, J. Perheentupa and L. Salmenperä. 1996. Risk of low

vitamin B6 status in infants breast-fed exclusively beyond six months. J. Pediatr.

Gastroenterol. Nutr. 23(1): 38-44.

295. Ebbing, M., K. H. Bønaa, E. Arnesen, et al. 2010. Combined analyses and extended follow-up of two randomized controlled homocyteine-lowering B-vitamin trials. J. Intern.

Med. 268(4): 367-382. doi: 10.1111/j.1365-2796.2010.02259.x

296. Ebbing, M., K. H. Bønaa, O. Nygård, et al. 2009. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 302(19): 2119-2126. doi:

10.1001/jama.2009.1622

297. Riggs, K. M., A. Spiro 3rd, K. Tucker and D. Rush. 1996. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging

Study. Am. J. Clin. Nutr. 63(3): 306-314.

298. Higdon, J., V. J. Drake and D. Mock. 2008. Biotin. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

7.84

http://lpi.oregonstate.edu/mic/vitamins/biotin

299. Pitkin, R. M. (Chair). 1998. Chapter 11—biotin. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

National Academy Press. http://www.nal.usda.gov/fnic/DRI//DRI_Thiamin/374-

389_150.pdf

300. Said, H. M. 2002. Biotin: the forgotten vitamin. Am. J. Clin. Nutr. 75(2): 179-180. http://ajcn.nutrition.org/content/75/2/179.full

301. Boas, M. A. 1927. The effect of desiccation upon the nutritive properties of egg-white. Biochem. J. 21(3): 712-725.

302. Liener, I. E. (Ed.) 1974. Toxic constituents of animal foodstuffs. Academic Press. 303. Wildiers, E. 1901. Nouvelle substance indispensable au développement de la levure. La

Cellule 18: 313-332. http://202.114.65.51/fzjx/wsw/newindex/wswfzjs/pdf/1901p240.pdf

304. Clark, N. A. 1922. The rate of formation and the yield of yeast in wort. J. Phys. Chem. 26: 42-60.

305. McDowell, L. 2013. Vitamin history, the early years. University of Florida, IFAS. 306. György, P., D. B. Melville, D. Burk and V. DuVigneaud. 1940. The possible identity of

vitamin H with biotin and coenzyme R. Science 91(2358): 243-245.

307. Allison, F. E. and S. R. Hoover. 1934. An accessory factor for legume nodule bacteria. Sources and activity. J. Bact. 27: 561-581.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC533652/pdf/jbacter00814-0022.pdf

308. Allison, F. E., S. R. Hoover and D. Burk. 1933. A respiration coenzyme. Science 78: 217-218.

309. Coates, P. M., M. R. Blackman, G. M Cragg, et al. (Eds.) 2005. Encyclopedia of dietary supplements. CRC Press.

310. Yamamoto, T., R. Juneja, I. Hatta and M. Kim. (Eds.) 1997. Hen eggs: their basic and applied science. CRC Press, LLC.

311. Durance, T. D. 1991. Residual avid in activity in cooked egg white assayed with improved sensitivity. J. Food Sci. 56(3): 707-709. doi: 10.111/j.1365-

2621.1991.tb05361.x

312. Said, H. M. 2009. Cell and molecular aspects of human intestinal biotin absorption. J. Nutr. 139(1): 158-162. doi: 10.3945/jn. 108.092023.

313. Said, H. M., R. Redha and W. Nylander. 1988. Biotin transport in the human intestine: site of maximum transport and effect of pH. Gastroenterology 95(5): 1312-1317.

314. Barrett, K. E. and M. Donowitz. (Eds.) 2001. Gastrointestinal transport: molecular physiology, vol. Academic Press.

315. Gropper, S. S. and J. L. Smith. 2013. Advanced nutrition and human metabolism 6th Ed. Wadsworth, Cengage Learning.

316. Anon. 2015. Drugs and supplements: biotin (oral route). Mayo Clinic (April 1). http://www.mayoclinic.org/drugs-supplements/biotin-oral-route/description/drg-20062359

317. Wasserman, R. 2015. The benefits of biotin for lowering cholesterol. Livestrong.org (Jan. 28). http://www.livestrong.com/article/279189-the-benefits-of-biotin-for-lowering-

cholesterol/

318. Revilla-Monsalve, C., I. Zendejas-Ruis, S. Islas-Andrade, et al. 2006. Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and

in nondiabetic subjects with hypertriglyceridemia. Biomed. Pharmacother. 60(4): 182-184.

319. Staggs, C. G., W. M. Sealey, B. J. McCabe, et al. 2004. Determination of the biotin

7.85

content of select foods using accurate and sensitive HPLC/avidin binding. J. Food.

Compost. Anal. 17(6): 767-776. doi: 10.1016/j.jfca.2003.09.015.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1450323/

320. Anon. 2012. Folate. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

321. Higdon, J., V. J. Drake, B. Delage and H. McNulty. 2014. Folate. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/folate

322. Pitkin, R. M. (Chair). 1998. Chapter 8—folate. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

National Academy Press. http://www.nal.usda.gov/fnic/DRI//DRI_Thiamin/196-

305_150.pdf

323. McCormick, D. B. (Chair) 2002. Chapter 4. Folate and folic acid. In: Human vitamin and mineral requirements. Report of a joint FAO-WHO expert consultation, Bangkok,

Thailand. World Health Organization, Food and Agriculture Organization of the United

Nations, Rome. http://www.fao.org/docrep/004/y2809e/y2809e0a.htm#TopOfPage

324. Hoffbrand, A. V. and D. G. Weir. 2001. Historical review: the history of folic acid. Brit. J. Haematology 113(3): 579-589. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-

2141.2001.02822.x/pdf

325. Bastian, H. 2007. Lucy Wills (1888-1964), the life and research of an adventurous independent woman. JLL Bulletin: Commentaries on the history of treatment evaluation.

James Lind Library. http://www.jameslindlibrary.org/articles/lucy-wills-1888-1964-the-

life-and-research-of-an-adventurous-independent-woman/

326. Semba, R. D. 2007. Handbook of nutrition and ophthamalogy. Humana Press. 327. Bailey, R. L., K. W. Dodd, J. J. Gahche, et al. 2010. Total folate and folic acid intake

from foods and dietary supplements in the United States: 2003-2006. Am. J. Clin. Nutr.

91(1): 231-237. doi: 10.3945/ajcn.2009.28427

328. Scholl, T. O. and W. G. Johnson. Folic acid: influence on the outcome of pregnancy. Am. J. Clin. Nutr. 71(5 Suppl): 1295S-303S. http://ajcn.nutrition.org/content/71/5/1295s.full

329. Junod, S. W. 2009. Folic acid fortification: fact and folly. About FDA. History of Product Regulation. U.S. Food and Drug Administration.

http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromF

DLIUpdateseriesonFDAHistory/ucm091883.htm

330. Gibson, T. M., S. J. Weinstein, R. M. Pfeiffer, et al. 2011. Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the

United States. Am. J. Clin. Nutr. 94(4): 1053-1062. doi: 10.3945/ajcn.110.002659

331. Figueiredo, J. C., M. V. Gau, R. W. Haile, et al. 2009. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J. Natl. Cancer Inst. 101(6): 432-435. doi:

10.1093/jnci/djp019

332. Walker, J. G., P. J. Batterham, A. J. Mackinnon, et al. 2012. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults

with depressive symptoms—the Beyond Ageing Project: a randomized controlled trial.

Am. J. Clin. Nutr. 95(1): 194-203.

333. Van der Zwaluw, N. L., R. A. M. Dhonukshe-Rutten, J. P. van Wijngaarden, et al. 2014. Results of 2-year vitamin B treatment on cognitive performance. Neurology 83(23): 2158-

2166. doi: 10.1212/WNL.0000000000001050

7.86

334. Coppen, A. and J. Bailey. 2000. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J. Affect. Disord. 60(2): 121-130.

335. Hickling, S., J. Hung, M. Knuiman, et al. 2005. Impact of voluntary folate fortification on plasma homocysteine and serum folate in Australia from 1995 to 2001: a population

based cohort study. J. Epidemiol. Community Health 59: 371-376.

336. Garilli, B. 2012. MTHFR mutation: a missing piece in the chronic disease puzzle. Holistic Primary Care 13(2). http://holisticprimarycare.net/topics/topics-a-g/functional-

medicine/1353-mthfr-mutation-a-missing-piece-in-the-chronic-disease-puzzle

337. Gilbody, S., S. Lewis and T. Lightfoot. 2014. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am. J.

Epidemiology 165(1): 1-13. http://aje.oxfordjournals.org/content/165/1/1.long

338. Yigit, S., N. Karakus and A. Inanii. 2013. Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Mol. Vis. 19: 1626-1630.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724957/

339. Födinger, M., W. H. Hörl and G. Sunder-Plassmann. 2000. Molecular biology of 5,10- methylenetetrahydrofolate reductase. J. Nephrol. 13(1): 20-33.

340. Greenberg, J. and S J. Bell. 2011. Multivitamin supplementation during pregnancy: emphasis on folic acid and L-methylfolate. Rev. Obstet. Gynecol. 4(3-4): 126-127.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250974/

341. Rader, J. I. and B. O. Schneeman. 2006. Prevalence of neural tube defects, folate status, and folate fortification of enriched cereal-grain products in the United States. Pediatrics

117(4): 1394-1399.

342. Pitkin, R. M. 2007. Folate and neural tube defects. Am. J. Clin. Nutr. 85(1): 285S-288S. 343. Williams, L. J., S. A. Rasmussen, A. Flores, et al. 2005. Decline in the prevalence of

spina bifida and anencephaly by race/ethnicity: 1995-2002. Pediatrics 116(3): 580-586.

344. Czeizel, A. E., E. H. Puho, Z. Langmar, et al. 2010. Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based

study. Eur. J. Obstet. Gynecol. Reprod. Biol. 148(2): 135-140.

345. Qin, X., Y. Cui, L. Shen, et al. 2013. Folic acid supplementation and cancer risk: a meta- analysis of randomized control trials. Int. J. Cancer 133(5): 1033-1041. doi:

10.1002/ijc.28038

346. Johnson, L. E. 2014. Folate. Merck Manual Professional Version. http://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency-

dependency-and-toxicity/folate

347. Wollset, S. E., R. Clarke, S. Lewington, et al. 2013. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analysis o

data on 50 000 individuals. Lancet 381: 1029-1036.

http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2812%2962001-7.pdf

348. Crider, K. S., T. P. Yang, R. J. Berry and L. B. Bailey. 2012. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv.

Nutr. 3: 21-38. doi: 10.3945/an.111.000992

349. Crider, K. S., O. Devine, L Hao, et al. 2014. Population red blood cell folate concentrations for prevention of neural tube defects: bayesian model. BMJ 2014;

349:g4554. doi: http://dx.doi.org/10.1136/bmj.g4554

350. Anon. 2011. Vitamin B12. Fact sheet for health professionals. National Institutes of Health, Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/VitaminB12-

7.87

HealthProfessional/

351. Higdon, J., V. J. Drake, B. Delage and J. W. Miller. 2014. Vitamin B12. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/vitamins/vitamin-B12

352. Pitkin, R. M. (Chair). 1998. Chapter 9—vitamin B12. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and

choline. National Academy Press. http://www.nal.usda.gov/fnic/DRI//DRI_Thiamin/306-

356_150.pdf

353. Carpenter, K. J. 2004. The Nobel Prize and the discovery of vitamins. Nobelprize.org. http://www.nobelprize.org/nobel_prizes/themes/medicine/carpenter/

354. Oh, R. C. and D. L. Brown. 2003. Vitamin B12 deficiency. Am. Fam. Physician. 67(5): 979-986. http://www.aafp.org/afp/2003/0301/p979.html

355. Andres, E. and K. Serraj. 2012. Optimal management of pernicious anemia. J. Blood Med. 3: 97-103. doi: 10.2147/JBM.S25620

356. Sethi, N., E. Robilotti and Y Sadan. 2004. Neurological manifestations of vitamin B-12 deficiency. The Internet Journal of Nutrition and Wellness 2(1).

http://ispub.com/IJNW/2/1/4476

357. Tangney, C. C., N. T. Aggarwal, H. Li, et al. 2011. Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination. Neurology 77(13): 1276-1282. doi:

10.1212/WNL.0b013e3182315a33

358. Herbert, V. 1988. Vitamin B-12: plant sources, requirements, and assay. Am. J. Clin. Nutr. 48: 852-858.

359. Sharabi, A., E. Cohen, J. Sulkes and M. Garty. 2003. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br. J. Clin. Parmacol.

56(6): 635-638. doi: 10.1046/j.1365-2125.2003.01907.x

360. Dart, R. C. 2006. Hydroxocobalamin for acute cyanide poisoning: new data from preclinical and clinical studies; new results from the prehospital emergency setting.

44(s1): 1-3. doi: 10.1080/15563650600811607.

361. Dubois, S. 2013. Kidneys & B12. Livestrong.com (March 10). http://www.livestrong.com/article/562157-kidneys-b12/

362. Koyama, K., A. Yoshida, A. Takeda, et al. 1997. Abnormal cyanide metabolism in uraemic patients. Neph. Dial. Transplant. 12(8): 1622-1628.

363. Anon. 2004. Opinion of the scientific panel on food additives, flavourings processing aids and maerals in contact with food (AFC) on hydrocyanic acid in flavourings and other

food ingredients with flavouring properties. Question number EFSA-Q-2003-145. The

EFSA Journal 105: 1-28. doi: 10.2903/j.efsa.204.105

364. Norris, J. 2012. Side effects of B12 supplements. VeganHealth.org. http://veganhealth.org/b12/toxicity#7

365. Hermann, L. S., B. Nilsson, S. Wettre. 2004. Vitamin B12 status of patients treated with metformin: a cross-sectional cohort study. Brit. J. Diabetes & Vascular Disease 4(6): 401-

406. doi: 10.1177/14746514040040060701

366. Thakkar, K. and G. Billa. 2015. Treatment of vitamin B12 deficiency-methylcobalamine? Cyanocobalamine? Hydroxocobalamine? –clearing the confusion. Eur. J. Clin. Nutr.

69(1): 1-2. doi: 101038/ejcn.2014.165

367. Van Asselt, D. Z. B., F. W. H. M Merkus, F. G. M. Russel and W. H. L. Hoefnagels. 1998. Nasal absorption of hydroxocobalamin in healthy elderly adults. Br. J. Clin.

7.88

Pharmacol. 45(1): 83-86. doi: 10.1046/j. 1365-2125.1998.00642.x

368. Anon. 2015. Vitamin B12. MedlinePlus. U.S. National Library of Medicine, National Institutes of Health. http://www.nlm.nih.gov/medlineplus/druginfo/natural/926.html

369. LeBlanc, J. G., J. E. Laiño, M. J. del Valle, et al. 2011. B-group vitamin production by lactic acid bacteria—current knowledge and potential applications. J. Appl. Microbiol.

111(6): 1297-1309. doi: 10.1111/j.1365-2672.2011.05157.x

370. LeBlanc, J. G., C. Milani, G. S. de Giori, et al. 2013. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr. Opin. Biotechnol. 24(2): 160-168. doi:

10.1016/j.copbio.2012.08.005

371. Watanabe, F., Y. Yabuta, T. Bito and F. Teng. 2014. Vitamin B12-containing plant food sources for vegetarians. Nutrients 6(5): 1861-1873. doi: 10.3390/nu6051861

372. Pawlak, R., S. J. Parrott, S. Raj, et al. 2013. How prevalent is vitamin B(12) deficiency among vegetarians? Nutr. Rev. 71(2): 110-117. doi: 10.1111/nure.12001

373. Bito, T., F. Teng, N. Ohishi, et al. 2014. Characterization of vitamin B12 compounds in the fruiting bodies of shiitake mushroom (Lentinula edodes) and bed logs after fruiting of

the mushroom. Mycoscience 55(6): 462-468. doi: 10.1016/j.myc.2014.01.008

374. Watanabe, F., S. Takenaka, H. Katsura, et al. 2000. Characterization of a vitamin B12 compound in the edible purple laver, Porphyra yezoensis. Biosci. Biotechnol. Biochem.

64(12): 2712-2705. doi: 10.1271/bbb.64.2712

375. Norris, J. and G. Messina. 2015. B12 in plant foods. VeganHealth.org. http://www.veganhealth.org/b12/plant#mush

376. Kwak, C. S., M. S. Lee, S. I. Oh and S. C. Park. 2010. Discovery of novel sources of vitamin b(12) in traditional Korean foods from nutritional surveys of centenarians. Curr.

Gerontol. Geriatr. Res. 2010: 374897. doi: 10.1155/2010/374897

377. Mozafar, A. 1994. Enrichment of some B-vitamins in plants with application of organic fertilizers. Plant & Soil 167: 305-311.

http://link.springer.com/article/10.1007%2FBF00007957#page-1

378. Donaldson, M. S. 2000. Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann. Nutr. Metab.

44(5-6): 229-234. http://www.ncbi.nlm.nih.gov/pubmed/11146329

379. Saltzman, J. R., J. A. Kemp, B. B. Golner, et al. 1994. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J.

Am. Coll. Nutr. 13: 584-591.

380. Bauman, W. A., S. Shaw, E. Jayatilleke, et al. 2000. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 23: 1227-1231.

http://care.diabetesjournals.org/content/23/9/1227.full.pdf

381. Aguilar, F., U. Charrondiere, B. Dusemund, et al. 2008. Scientific opinion on 5’- deoxyadenosylcobalamin and metnylcobalamin as sources for vitamin B12 added as a

nutritional substance in food supplements. Scientific opinion of the Panel on Food

Additives and Nutrient Sources added to food. The EFSA Journal 815: 1-21.

382. Stabler, S. P. 2013. Vitamin B12 deficiency. N. Engl. J. Med. 368: 149-160. doi: 10.1056/NEJMcp1113996

383. House, A. A., M. Eliasziw, D. C. Cattran, et al. 2010. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA 303(16): 1603-

1609. doi: 10.1001/jama.2010.490

384. Thornalley, P. J. and N. Rabbini. 2010. Vitamin B6, B9 and B12 in diabetic nephropathy.

7.89

Medscape. http://www.medscape.com/viewarticle/731177

385. Semba, R. D. 2012. On the ‘discovery’ of vitamin A. Ann. Nutr. Metab. 61(3): 192-198. doi: 10.1159/000343124

386. Mandal, A. 2014. Vitamin A history. News Medical (Oct. 9). http://www.news- medical.net/health/Vitamin-A-History.aspx

387. Prengman, K. 2013. The birth of vitamin A. On Wisconsin Magazine, University of Wisconsin-Madison. http://onwisconsin.uwalumni.com/features/the-birth-of-vitamin-a/

388. Wolf, G. The discovery of vitamin D: the contribution of Adolf Windaus. J. Nutr. 134(6): 1299-1302. http://jn.nutrition.org/content/134/6/1299

389. Guy, R. A. 1923. The history of cod liver oil as a remedy. Am. J. Dis. Child. 26: 112-116. 390. Rajakumar, K. 2003. Vitamin D, cod-liver oil, sunlight and rickets: a historical

perspective. Pediatrics 112(2): e132-e135. http://www.direct-

ms.org/sites/default/files/RicketsHistory.pdf

391. Chesney, R. W. 2012. Theobald Palm and his remarkable observation: how the sunshine vitamin came to be recognized. Nutrients 4(1): 42-51. doi: 10.3390/nu4010042

392. Dunn, P. M. 1999. Professor Armand Trousseau (1801-67) and the treatment of rickets. Arch. Dis. Child. Fetal. Neonatal Ed. 80: F155-F157.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1720912/pdf/v080p0F155.pdf

393. Papas, A. 2001. The vitamin E factor-summary and review. NOHA News 26(2). http://americannutritionassociation.org/newsletter/vitamin-e-factor-summary-review

394. Almquist, H. J. 1975. The early history of vitamin K. Am. J. Clin. Nutr. 28: 656-659. http://ajcn.nutrition.org/content/28/6/656.full.pdf

395. Anon. 2015. The Nobel Prize in Physiology or Medicine in 1943. Nobelprize.org. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1943/

396. Zeisel, S. H. 2012. A brief history of choline. Ann. Nutr. Metab. 61(3): 254-258. doi: 10.1159/000343120

397. Loewi, O. Űber humoral Űbertragbarkeit der Herznervenwirkung. Pflügers Archiv. 189: 239-242.

398. Dale, H. 1914. The action of certain esters and ethers of choline and their relation to muscarine. J. Pharm. Exp. Ther. 6: 147-190.

399. Anon. 2015. The Nobel Prize in Physiology or Medicine 1936. Nobelprize.org. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1936/

400. Best, C. H. and M. E. Huntsman. 1932. The effects of the components of lecithine upon the deposition of fat in the liver. J. Physiol 75: 405-412.

401. Higdon, J., V. J. Drake, B. Delage and S. H. Zeisel. 2015. Choline. Micronutrient Information Center, Linus Pauling Institute, Oregon State University.

http://lpi.oregonstate.edu/mic/other-nutrients/choline

402. Pitkin, R. M. (Chair). 1998. Chapter 12—Choline. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

National Academy Press. http://www.nal.usda.gov/fnic/DRI//DRI_Thiamin/390-

422_150.pdf

403. http://www.cholineinfo.org/for_media/expert_q_a.asp 404. Mandal, A. 2015. What is DNA methylation? News-Medical (March 16).

http://www.news-medical.net/health/What-is-DNA-Methylation.aspx

405. Chester, D. N., J. D. Goldman, J. K. Ahuja and A. J. Moshfegh. 2011. Dietary intakes of choline. What we eat in America, NHANES 2007-2008. Food Surveys Research Group,

7.90

Dietary Data Brief No. 9. U.S. Department of Agriculture, Agriculture Research Service.

http://www.ars.usda.gov/SP2UserFiles/Place/80400530/pdf/DBrief/9_choline_intakes_07

08.pdf

406. Michelotti, G. A., M. V. Machado and A. M. Diehl. 2013. NADLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10(11): 656-665. doi: 10.1038/nrgstro.2013.183

407. Rolo, A. P., J. S. Teodoro and C. M. Palmeira. 2012. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Redic. Biol. Med. 52(1): 59-69. doi:

10/1016/j.freeradbiomed.2011.10.003

408. Spencer, M. D., T. J. Hamp, R. W. Reid, et al. 2011. Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline

deficiency. Gastroenterology 140(3): 976-986. doi: 10.1053/j.gastro.2010.11/049

409. McCann, J. C., M. Hues and B. N. Ames. 2006. An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive

function in offspring. Neurosci. Biobehav. Rev. 30(5): 696-712.

410. Alvarez-Sabín, J., G. Ortega, C. Jacas, et al. 2013. Long-term treatment with citicoline may improve poststroke vascular cognitive impairment. Cerebrovasc. Dis. 35(2): 146-154.

doi: 10.1159/000346602

411. Tang, W. H., Z. Wang, B. S. Levison, et al. 2013. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl. J. Med. 368(17): 1575-1584. doi:

10.1056/NEJMoa1109400

412. Tang, W. H. W. and S. L. Hazen. 2014. The contributory role of gut microbiota in cardiovascular disease. J. Clin. Invest. 124(10): 4204-4211. doi: 10.1172/JCI72331

413. Anon. 2015. Gut flora-dependent TMAO: New studies extend its reach beyond the arteries to the heart and kidneys. Consult QD—Heart & Vascular (Feb 12). Cleveland

Clinic. http://consultqd.clevelandclinic.org/2015/02/gut-flora-dependent-tmao-new-

studies-extend-its-reach-beyond-the-arteries-to-the-heart-and-kidneys/

414. Kresser, C. 2013. Choline and TMAO: eggs still don’t cause heart disease. https://chriskresser.com/choline-and-tmao-eggs-still-dont-cause-heart-disease/

415. Niculescu, M. D. 2013. Choline and brain development. In: Coulston, A. M., C. Boushey and Mario Ferruzzi. 2013. Nutrition in the prevention and treatment of disease. Academic

Press.

416. Chan, M. M. 1991. Choline and carnitine. In: Machlin, L. J. (Ed.). 1991. Handbook of vitamins. 2

nd Ed. Marcel Dekker, Inc., N.Y.

417. Fischer, L. M., K.-A. da Costa, L. Kwock, et al. 2010. Dietary choline requirements of women: effects of estrogen and genetic variation. Am. J. Clin. Nutr. 92(5): 1113-1119.

doi: 10.3945/ajcn. 2010.30064

418. http://www.cochrane.org/CD011217/INJ_citicoline-cdp-choline-for-traumatic-brain- injury

419. Guseva, M. V., D. M. Hopkins, S. W. Scheff and J. R. Pauly. 2008. Dietary choline supplementation improves behavioral, histological, and neurochemical outcomes in a rat

model of traumatic brain injury. J. Neurotrauma 25(8): 975-983. doi:

10.1089/neu.2008.0516

© Barry Putman, August 7, 2015