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Vitamins

(維生素，維他命)

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單元目標 •認識維生素之定義

•認識各維生素的

• Primary roles

• Absorption

• Regulation

• Requirements

• Diseases associated with vitamins

• Factors that influence requirements

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Vitamins • Essential organic substances

• Yield no energy, but facilitate

energy-yielding chemical reactions

• If absent from a diet, it will produce

deficiency signs and symptoms

• Fat-soluble vitamins

• Water-soluble vitamins

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Fat vs. Water Soluble Vitamins

Water Soluble Fat Soluble

Absorption Directly to blood Lymph via CM

Transport free Require carrier

Storage Circulate freely In cells with fat

Excretion In urine Stored with fat

Toxicity Possible w/

supplements

Likely w/

supplements

Requirements Every 2-3 days Every week

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Roles of Vitamins

As “external” regulatory agents - the

vitamins have largely evolved to serve:

1) as specific cofactors and/or co-substrates

2) as regulatory agents

3) as antioxidants

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Common Causes of Vitamin Deficiencies

• Primary deficiencies, monotonous diets

• Disturbances of absorption,

• Antagonists,

– e.g. antibiotics, tannins, caffeic acid, alcohol

• Metabolic conditions and specific

pathologies,

– e.g. pregnancy, diabetes

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Consequence of Vitamin Deficiencies: Typical Lesions, Defects and Syndromes

• External skin lesions and rashes

• Abnormalities in epithelial differentiation

and turnover

• Faulty DNA repair and synthesis

• Perturbations in energy metabolism

• Decreased or abnormal extracellular

matrix production

• Perturbations in lipid metabolism

• Mental confusion

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The Fat-Soluble Vitamins

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Fat-Soluble Vitamins Overview

• Dissolve in organic solvents

• Not readily excreted; can cause toxicity

• Absorbed along with fat; concern for

people with fat malabsorption

• Transported like fat in chylomicrons,

VLDL, LDL

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Absorption of Vitamin A

• Requires bile, digestive enzymes,

integration into micelles

• Dependent on the fat in the diet

• 90% of retinoids can be absorbed

• Only ~3% of carotenoids are absorbed

• Intestinal cells can convert carotenoids

to retinoids

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Forms of Vit A

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β - Carotene and Retinol

CH 3

CH 3

CH 3 CH 3 CH 3

CH 3 CH 3 CH 3

H 3 C

CH 3

H 3 C CH 3

CH 3

CH 3 CH 3

H 3 C CH 3

CH 3

CH 3 CH 3

CH 2 OH

Oxidation

C H

O

Retinal

Retinol (Vitamin A)

- 2H

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Conversion of Vitamin A Activity

• Unit

• International Unit (IU)

• Retinol Equivalent (RE)

• Conversion

1 RE = 1 μg retinol = 6 μg β-carotene

= 3.33 IU retinol = 10 IU β-carotene

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Transport and Storage of Vitamin A

• Liver stores 90% of vitamin A in the body

• Reserve is adequate for several months

• Transported via chylomicrons to the liver

• Transported from the liver as retinol via

retinol-binding protein (RBP) to target tissue

• Carotenoids can be transported via VLDL

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Functions of Vitamin A

• Retinal: night and color vision

• Retinol: reproduction

• Retinoic acid: growth and cell

maturation

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Growth and Development

• Retinoic acid is necessary for cellular

differentiation

• Important for embryo development, gene

expression

• Synthesis of bone protein and

enlargement of bone

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Cell Health and Maintenance

• Epithelial cells line the outside (skin) &

external passages (mucus forming cells)

within the body

• Retinoic acid influences how epithelial cells

differentiate and mature

• W/out vitamin A, cells will deteriorate, lead to

– xerophthalmia (major cause of blindness)

– follicular hyperkeratosis (skin disorder)

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The Anti-Infection Vitamin

• Uncertain of the action of vitamin A and

resistance to disease

• Deficiency leads to poor mucus formation

• Deficiency reduces activity of some

immune-system cells

• High-dose therapy of vitamin A increase

immune response

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The DRIS (RDA) for Vitamin A

• Male adults: 600μg RE

• Female adults: 500μg RE

• 3rd trimester: +100μg RE

• Lactation: +400μg RE

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Deficiency of Vitamin A

• Night blindness

• Decrease mucus production

• Leading to bacterial invasion in the eye

– Conjunctival xerosis

– Bitot’s spots

– xerophthalmia

• Irreversible blindness

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Xerosis (Dry Eyes)

Bitot’s spots

The white of the eye

loses its shine and

begins to wrinkle

Patches of

little gray

bubbles on

the whites

of the eye

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Corneal ulceration

Keratomalcia

Dullness or

damage to

the cornea

Soft or

bulging (膨脹）cornea

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Deficiency of Vitamin A

• Follicular hyperkeratosis

• Keratin protects the inner layers of skin

and maintains moisture

• Keratinized cells replaces the normal

epithelial cells in underlying skin layers

• Hair follicles become plugged, bumpy,

rough, and dry skin

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• Risk of disease & death from severe

infections

• Pregnant women: night blindness &

risk of maternal mortality

• Public health problem in Africa and

South-East Asia

Vitamin A deficiency Leading cause of preventable blindness

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Vitamin A deficiency who is affected?

• Vitamin A deficiency

–＞100 million children suffer vitamin A

deficiency

– 2.2 million deaths from diarrhea

– 1 million deaths from measles

• Supplementing vitamin A

– Reduce deaths from diarrhea (35-50%)

– Reduce deaths from measles (50%)

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Prevention of Deficiency

• Establish an adequate liver store in

weaned infants

• Deficiency occurs most often after

baby has been weaned

• Providing a megadose of vitamin A to

at risk population may be helpful

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Vitamin A Sources

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Sources of Vitamin A

• Preformed=retinoids

• Liver, fish oils, fortified milk, eggs

• Contributes to half of all intake

• Proformed=carotenoids

– Dark leafy green , yellow-orange

vegetables/fruits

– Contributes to half of all intake

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Toxicity of Vitamin A

Chronic-Hypervitaminosis A

• Long-term supplement use (3-10x RDA)

• Bone/muscle pain, loss of appetite, skin

disorders, headache, dry skin, hair loss,

increased liver size, vomiting

• Discontinue supplement is recommended

• Possible permanent damage

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Toxicity of Vitamin A

Acute

• Ingestion of LARGE dose(s) of vitamin A

(within a short period)

• Result in intestinal upset, headache,

blurred vision, muscular incoordination

• Symptoms disappear when supplements

are stopped

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Toxicity of Vitamin A

Teratogenic

• Physical defect on developing fetus as a

result of excess vitamin A intake

• Spontaneous abortion, birth defects

• May occur with as little as 3 x RDA of

preformed vitamin A

Upper Level for Vitamin A

• 3000ug for adults

• 12 g of vitamin A can be fatal

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Effects of Vitamin A

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

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Toxicity of Carotenoids

Hypercarotenemia

• High amounts of carotenoids in the

bloodstream

• Excessive consumption of carrots/squash/

beta-carotene supplements

• Skin turns a yellow-orange color

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Sunlight and Health • 2500 years ago, Hippocrates (BC 460~377)

– In the northern hemisphere, the southern

side of the hill, receiving the most

sunlight, was “the healthiest place to

live”

• 1822, Polish physician Sniadecki

– “exposure to outdoors and sunlight for

the prevention and cure of rickets”.

• 1890, Dr. Theodore Palm

– “A map of rickets incidence was also

a map of sunlight deficiency”

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Vitamin D • 1922, EV McCollum

– Oxidized cod liver oil cannot prevent

xerophthalmia but cure rickets. The factor that

cures rickets is a new vitamin, which they

called vitamin D.

• 1928, Windaus, Rosenheim and Hess

– the Nobel Prize for Chemistry, in

understanding “Constitution of sterols and their

connection with other substances occurring in

nature”, namely vitamin D, sunlight exposure

and cholesterol

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Vitamin D • Been discovered in early 20th

century and have DRI

• Prohormone

• Derived from cholesterol

• Synthesis from sun exposure

• Insufficient sun exposure makes this a vitamin

• Activated by enzymes in liver and kidneys

• Deficiency can cause diseases

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Absorption of Vitamin D

• ~80% of vitamin D consumed is

incorporated into micelles

• Absorbed in the small intestine and

transported via chylomicrons

• Transported through the lymphatic

system

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Metabolism and Storage of Vitamin D

• Activation by the liver and the kidneys

• Stored in fat tissue

• Activate vitamin D when calcium is

inadequate

• Excretion of vitamin D mainly via bile

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Calcitriol improves Ca/P absorption from the intestine and helps with bone formation

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Vitamin D and Cell Differentiation

• Regulates blood calcium

• Aids calcium absorption

• Influence differentiation and function of

the some cells

• Linked to reduction of breast, colon, and

prostate cancer development

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Role in Bone Formation

• Calcitriol creates a supersaturated Ca +

Phos solution

• Causes Ca + Phos to deposit in the bones

• Strengthen bones

• Rickets is the result of low vitamin D

• Osteomalacia (soft bone) is rickets in the

adult

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Food Sources of Vitamin D

• Fatty fish (salmon, herring)

• Fortified milk

• Some fortified cereal

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The Adequate Intake (AI) for Vitamin D

• Light skinned individuals can produce

enough vitamin D to meet the AI from

casual sun exposure

• For those who has minimal sunlight

exposure

– 10 μg/day (400 IU) for people 50 yrs

– 15 μg/day (600 IU) for adults > 50 yrs

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Deficiency of Vitamin D

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Before tx 2 years after treatment

Nigeria Rickets

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Who is at Risk for Deficiency? • Elderly (staying indoors)

• People living in the northern climate

• People with fat malabsorption need sun

exposure

• Vitamin D resistance

– Resistance to the action of vitamin D

– May be due to lack of calcitriol synthesis

or inability to bind to nuclear receptor

– Requires large doses of calcitriol

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Toxicity Warning

• Vitamin D can be very toxic

• Regular intake of 5-10x the AI can be toxic

• Result from excess supplementation (not

from sun exposure or milk consumption)

• Sign and symptoms: over absorption of

calcium (hypercalcemia), increase calcium

excretion

• Calcium deposits in soft tissues-heart

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Vitamin E • Tocols=tocopherols+tocotrienols

• Amount absorbed is dependent on fat intake

– Incorporated into micelles

– Requires bile and fat digesting enzymes

• Transported via chylomicrons to the liver

• Transported by VLDL, LDL, HDL from liver

• Concentrated in areas where fat is found

• Excreted via bile and urine (much in feces

due to limited absorption)

Naturally Occurring Tocopherols

-tocopherol

-tocopherol

-tocopherol

-tocopherol

CH3

CH3

CH3

H CH3 CH3 CH3 CH3 H

HO

H3C O

CH3

phytyl tail

CH3 CH3

CH3

HO

O

phytyl tail

CH3

HO

H3C O

phytyl tail

CH3 CH3

HO

O

phytyl tail

2R 4’R 8’R

Naturally Occurring Tocotrienols

-tocotrienol

-tocotrienol

-tocotrienol

-tocotrienol

CH3

CH3

CH3

HO

H3C O

CH3

CH3 CH3

CH3

HO

O

tail

CH3

HO

H3C O

tail

CH3 CH3

HO

O

tail

CH3

unsaturated tail

CH3

CH3 CH3

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Vitamin E Functions

• Specific role in a required metabolic

function has not been found

• Major function appears to be as a fat-

soluble, “chain-breaking” antioxidant

– Peroxyl radical scavenger

– Protects PUFA within membranes and

lipoproteins

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Free Radicals • Production is normal result of cell

metabolism and immune function

• Destructive to cells; set off a chain rx

• Lipid peroxidation

• More vitamin E is found in the lungs

• Smoking causes significant oxidative

damage

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Redox Agent

• Vitamin E is able to donate electron to

oxidizing agent

• Protect the cell from attack by free

radicals

• Protects PUFAs within the cell membrane

and plasma lipoproteins

• Prevents the alteration of cell’s DNA and

risk for cancer development

Lipid

Peroxidation

H H

=

R-OO-H

R-H ROO

Peroxyl Radical

Initiation

Propagation

O2

Carbon-centered

Free Radical

Initiating

Event

R

Chain

Reaction

Lipid Hydroperoxide

Polyunsaturated fat

Vitamin E Chain Breaking Antioxidant

H H

=

R-OO-H

R-H ROO

Peroxyl Radical

Initiation

Propagation

Termination

via

Antioxidant

O2

Carbon-centered

Free Radical

Initiating

Event

R

TO

TOH

Chain

Reaction

R-OO-H

Lipid Hydroperoxide

Lipid Hydroperoxide

Polyunsaturated fat

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DRIs (AI)

RRR-α-Tocopherol (mg/day)

1 IU dl--tocopherol = 0.45 mg (synthetic source)

1 IU d--tocopherol = 0.67 mg (natural sources)

Life Stage AI

19+ yrs, M

19+ yrs, F

Pregnancy

Lactation

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12

14 15

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The More The Better?

• Vitamin E is only one of many

antioxidants

• It is likely that the combination of

antioxidants is more effective

• Diversify your antioxidant intake with a

balanced and varied diet

• Megadose of one antioxidant may

interfere with the action of another

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Food Sources of Vitamin E

• Plant oils

• Wheat germ

• Asparagus

• Peanuts

• Margarine

• Nuts and seeds

• Dependent on harvesting,

processing, storage and

cooking

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Deficiency of Vitamin E

• Hemolytic anemia

• Peripheral neuropathy

• Maldigestion of fat

• Insufficient bile production

• Rare

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Who is at Risk for Deficiency?

• Premature infants

• People with fat malabsorption

– Cystic fibrosis (囊胞性纖維症), celiac

disease (乳糜瀉), liver disease

• Low selenium intake

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Celiac disease (CD)

• an autoimmune disorder that affects

genetically susceptible individuals and is

induced by dietary gluten (麩質, 麵筋).

• Tx consists of a lifelong gluten-free diet.

• CD is common and affects about 1% of

the general population.

• The classic symptoms include diarrhea

and malabsorption, but many patients

have only mild symptoms.

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Toxicity of Vitamin E

• Extremely safe

• Extremely high levels can slow

absorption of carotenoids

• Inhibits vitamin K metabolism and

coagulation

• CHD-platelets and LDL oxidation

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Toxicity of Vitamin E

• Supplements up to 800 IU is probably

harmless

• Upper Level is 1,000 mg/day of any

form of supplementary alpha-tocopherol

• Upper Level is 1500 IU (natural sources)

or 1100 IU (synthetic forms)

• Inhibit vitamin K metabolism and

anticoagulants

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Vitamin K (“Koagulation”)

• Phylloquinone (K1) and menaquinones (K2)

• 40%-80% of dietary vitamin K is absorbed

• Absorption requires bile & pancreatic enzymes

• Menaquinones are synthesized by the bacteria

in the colon and are absorbed

• Role in the coagulation process

• Calcium-binding potential

• Formation of osteocalcin (骨鈣素)

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Vitamin K and compounds with vitamin K activity

O

O

1

4 3

2

3

O

O

6

O

O

Menadione (Vit K3) Menaquinone-7 (Vit K2)

Phylloquinone (Vit K1)

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Drugs and Vitamin K

• Anticoagulant

– Lessens vitamin K reactivation

– Lessens blood clotting process

– Monitor vitamin K intake

• Antibiotics

– Destroy intestinal bacteria

– Inhibits vitamin K synthesis & absorption

– Potential for excessive bleeding

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Vitamin K antagonists

O

OH

O

OH

O O

O

OH

O

O

O

O 3

Vitamin K1 Warfarin

Cl

O

O 3

Chloro-K Dicumarol

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Vitamin K cycle

Immature clotting Carboxylated clotting protein protein

Epoxide reductase

(blocked by warfarin and dicoumarol)

Vitamin KH2 Vitamin K epoxide

Carboxylase

O2 CO2

WARF: The Wisconsin Alumni Research Foundation

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Food Sources of Vitamin K

• Liver

• Green leafy vegetables

• Broccoli

• Peas

• Green beans

• Resistant to cooking losses

• Limited vitamin K stored in the body

83 Prothrombin Time (PT/INR)

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• Warfarin 的作用就是減少維他命K在肝臟被製

造成凝血的蛋白因子。所以這就像一個翹翹版，

一邊是warfarin ，一邊是維他命K的攝取量(假

定大腸製造的維他命K量是固定的)。翹翹板太

傾向右邊就會出血，太向左邊則易栓塞。

• 維生素K會影響warfarin的藥效，含多量維生素

K食物(例如綠茶、醃燻豬肉、肝臟、綠色葉菜

及花椰菜等)的食用量應固定，不要自行增減。

• 只要病人臨床無症狀，就warfarin劑量不變，

完全靠類似下圖一樣的問卷來計算維他命K食

物攝取以調控PT/INR值。

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AI for Vitamin K

• 90 ug/day for women

• 120 ug/day for men

• RDA met by most

• Excess vitamins A and E interferes

with vitamin K

• Newborns are injected with vitamin K

1 mg (breast milk is a poor source)

• Toxicity unlikely; readily excreted

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Dietary Reference Intakes

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國人膳食營養素參考攝取量

Dietary Reference Intakes (DRIs)

= RDA, AI, EAR & UL

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建議攝取量

Recommended Dietary Allowance

~可滿足97-98﹪的健康人群每天 所需要的營養素量

RDA = EAR + 2SD

(RDA)

90

intake to meet requirement

pro

po

rtio

n o

f p

op

ula

tio

n

Estimated Average Requirement

mean ± 2 sd = 95% range

RDA threshold

intake

RDA

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足夠攝取量

Adequate Intakes (AI)

~當數據不足無法定出RDA值時，以

健康者實際攝取量的數據衍算出來

之營養素量

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平均需要量

Estimated Average Requirement

~為滿足健康人群中半數的人所需 要的營養素量

(EAR)

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上限攝取量

Tolerable Upper Intake Levels

~對於絕大多數人不會引發危害風 險的營養素攝取最高限量

UL = NOAEL or LOAEL / uncertainty factor

(UL)

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DRIs

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Approaches for setting DRIs

~ based on scientific data from observational and experimental studies

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Approaches for setting DRIs

• Nutrient functions and the

indicators of adequacy

• Reduction of developmental

abnormalities and chronic

degenerative diseases

• Clinical effects of inadequate intake

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