Chapter 12: The Fat-Soluble Vitamins

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Vitamins

Defining a vitamin

Essential organic substances Body cannot synthesize enough to maintain health Absence from the diet will produce deficiency signs and symptoms Yield no energy, but facilitate energy-yielding chemical reactions May be fat- or water-soluble

Differences in natural versus synthetic but natural is not always better All vitamins have probably been discovered Evidence is that TPN can support life
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Storage of Vitamins in the Body

Fat-soluble are generally well stored

except vitamin K
except vitamin B12 and B6

Water-soluble are generally excreted daily

Vitamin deficiency occurs when that vitamin is lacking in the diet and body stores are exhausted

Vitamin Toxicity
Toxicity of vitamin A is most likely Unlikely to develop toxicity of any vitamin unless individual vitamin supplements are used Balanced multivitamin and mineral supplement should supply < 2 x DRI

Malabsorption of Vitamins
Fat malabsorption leads to deficiencies of fat-soluble vitamins Alcohol abuse affects absorption of some B vitamins Intestinal diseases can affect absorption of some vitamins and minerals

Daily Reference Intakes (DRI)

Nutrient recommendations to promote health and prevent disease National Academy of Sciences

Food and Nutrition Board

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Estimated Average Requirements (EAR)

Nutrient intake estimated to meet the needs of 50% of the individuals in a certain age and gender group Uses a measurable functional marker

i.e., hemoglobin level for iron Vitamin C content in neutrophils (White Blood Cells
-WBCs)

Adjusted for amount absorbed

Recommended Dietary Allowances (RDA)

Nutrient intake that is sufficient to meet the needs of 97 98% of individuals in an age and gender group EAR x 1.2-1.4 (2 Standard Deviations) Can only be set if EAR is established

Adequate Intakes (AI)

In the absence of adequate information to establish an RDA, AI is assigned Based on estimates of intakes that appear to maintain nutrition status in certain population Set for some vitamins, choline, some minerals, essential fatty acids, fiber Set for children under the age of 1

The Dietary Supplement Health and Education Act (DSHEA) 94

Classifies vitamins, minerals, amino acids, herbal remedies as foods. Dietary supplements can be sold without Food and Drug Administration (FDA) approval. Product label can claim a functional benefit but not a disease benefit unless it meets very specific FDA criteria. Printed information can be displayed separately in the store. FDA must prove this food is unsafe before it can be prevented from being sold whereas if it were classified as a drug the drug company must prove safety and efficacy before it is put on the market.

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Fat Soluble Vitamins

A, D, E, K

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Digestion and Absorption of Fat-Soluble Vitamins

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Absorption of Fat-Soluble Vitamins

Adequate absorption depends on absorption of fat 40 90% of ingested fat-soluble vitamins absorbed

Transport of Fat-Soluble Vitamins

Transported by chylomicrons and lipoproteins Carried to liver as remnants, then stored in liver or redistributed

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Vitamin A
Deficiency of vitamin A is the most common cause of non-accidental blindness, worldwide Preformed

Retinoids

retinal, retinol, retinoic acid

Found in animal products Carotenoids Must be converted to retinoid form Found in plant products

Provitamin A

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Interconversion of Retinoids

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Conversion of Carotenoids to Retinoids

Enzymatic conversion of carotenoids occurs in liver or intestinal cells, forming retinal and retinoic acid Provitamin A carotenoids

Beta-carotene Alpha carotene Beta-cryptoxanthin

Other carotenoids

Lutein Lycopene Zeaxanthin

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Absorption of Vitamin A

Retinoids

Retinyl esters broken down to free retinol in small intestine - requires bile, digestive enzymes, integration into micelles Once absorbed, retinyl esters reformed in intestinal cells 90% of retinoids can be absorbed Absorbed intact, absorption rate much lower Intestinal cells can convert carotenoids to retinoids if necessary
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Carotenoids

Transport and Storage of Vitamin A

Liver stores 90% of vitamin A in the body Reserve is adequate for several months Transported via chylomicrons from intestinal cells to the liver Retinol is released from the liver into the general circulation bound to retinol-binding protein (RBP), in the bloodstream attaches to transthyretin/prealbumin and then delivered to target tissue Carotenoids are released from the liver on VLDLs (Very Low Density Lipoprotein)
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Excretion of Vitamin A
Not readily excreted though some lost in urine Kidney disease and aging increase risk of toxicity because excretion is impaired

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Functions of Vitamin A

Gene Expression (Retinoic Acid)

The activation of a specific site on DNA, which results in either the activation or the inhibition of genes controlling for

Cell Differentiation Cell Growth

The process of transforming an unspecialized cell into a specialized cell Involving the production, maintenance of structure and function of epithelial and mucus forming cells Lungs, GI tract, skin, eyes

Immunity

Vision (Retinal)

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Function of Vitamin A: Vision

Retinal participates in turning visual light into nerve signals in retina of eye The nerve signals travel to visual centers in the brain to decipher the shape, color and movement of objects

Cones in the retina

Responsible for vision under bright lights Detect shape and color Responsible for vision in dim lights Detect shape and movement
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Rods in the retina

Visual Pathway

Thalamus Visual Cortex Retina

Rods and Cones (aqua)

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Rods and Cones

Rod

Cone
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The Visual Cycle within a Rod or Cone*

*Cones use photopsin

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Rhodopsin in the Rod Membrane

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Function of Vitamin A:Gene Expression

Target cells contain cellular retinoid binding proteins

Direct retinoids to functional sites within cells Protect retinoids from degradation

RAR, RXR receptors on the nucleus

Retinoid-receptor complex binds to DNA Directs gene expression

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Functions of Vitamin A: Growth and Differentiation of Cells

Retinoic acid is necessary for cellular differentiation

During embryo development In adult stem cells

Ex. , bone marrow differentiates into RBCs, WBCs, platelets

Retinoic acid influences production, structure, and function of epithelial cells that line the outside (skin) and external passages (mucus forming cells) within the body
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Functions of Vitamin A: Immunity

Necessary for antiviral and anti-tumor activity by increasing the production of interleukin 1 and other cytokines, which serve as important stimulators of T and B lymphocyte production Deficiency leads to decreased resistance to infections

Since 1920s have known risk of death form measles and diarrhea is greater in children if they are vitamin A deficient Supplementation with Vitamin A may decrease severity of infections in a deficient person

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Vitamin A Analogs for Acne

Topical treatment (Retin-A)

Causes irritation, followed by peeling of skin Antibacterial effects Regulates development of skin cells Caution regarding birth defects

Oral treatment

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Possible Carotenoid Functions

Prevention of cardiovascular disease

Cancer prevention

Antioxidant capabilities 5 servings/day of fruits and vegetables Antioxidant capabilities Lung, oral, and prostate cancers Studies indicate that vitamin A-containing foods are more protective than supplements

Age-related macular degeneration Cataracts In general, foods rich in vitamin A and other phytochemicals are advised rather than supplements

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RDA for Vitamin A for Adults

900 RAE for men 700 RAE for women Average intake meets RDA Most stored in the liver Vitamin A supplements are unnecessary No separate RDA for carotenoids

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Measuring Vitamin A

International unit (IU)-crude method of measurement Retinol activity equivalent (RAE) -current, more precise method of measurement

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Vitamin A in Foods

Preformed Liver, fish oils, eggs, fortified milk*, other fortified foods*

Stable palmitate form used

Contributes ~70% of vitamin A intake for Americans Provitamin A carotenoids Dark leafy green, yellow-orange vegetables/fruits

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Food Sources of Vitamin A

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Deficiency of Vitamin A

Most susceptible populations:

Inadequate fruit, veg and milk intake Liver disease (limits storage) Fat malabsorption

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Deficiency of Vitamin A: Signs and Symptoms

Night blindness Decreased mucus production Decreased immunity Xerophthalmia

Bacterial invasion of the eye Conjunctival xerosis dryness from decreased mucus production Bitots spots dry eye with hardened epithelial cell Irreversible blindness

Follicular hyperkeratosis Macular Degeneration

Permanent softening and scarring of the cornea

lack of carotenoids; lutein & zeaxanthin

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Night Blindness (center of picture)

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Bitots Spot (dry eye with hardened epithelial cell)

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Irreversible Blindness (softening and scarring of the cornea)

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Follicular Hyperkeratosis

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Macular Degeneration

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Vitamin A Toxicity
Acute short term (100x RDA) Acute fatal dose (12 g) Chronic

Hypervitaminosis A results from long-term supplement use

UL = 3000 g retinol for adults and pregnant women

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Toxicity of Vitamin A

Acute short-term megadose (100 x RDA); symptoms disappear when intake stops
GI

effects Headaches Blurred vision Poor muscle coordination

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Toxicity of Vitamin A

Chronic long-term megadose; possible permanent damage

Reduced Bone Mineral Density

Bone and muscle pain

Liver Damage
Increased liver size Loss of appetite

Teratogenic Miscellaneous
Skin disorders Headache Dry skin Hair loss Vomiting
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Toxicity During Pregnancy

Upper Limit

Pregnancy

<18 2800 ug 19-50 3000 ug

Spontaneous abortion Teratogenic; birth defects or malformations of the developing fetus during pregnancy

Craniofacial malformations

Ears, limbs, heart, eyes

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Teratogenic Vitamin A Toxicity

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Health Effects of Vitamin A

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Toxicity of Carotenoids

Not likely, as rate of conversion of carotenoids to retinoic acid by liver is slow and efficiency of absorption of carotenoids decreases as intake increases Hypercarotenemia

High amounts of carotenoids in the bloodstream Excessive consumption of carrots/squash/betacarotene supplements Skin turns a yellow-orange color

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Content Review
What are the functions of vitamin A? What are the two forms of vitamin A and in what foods can they be found? How does vitamin A help with night vision? What are the effects of a diet that is deficient in vitamin A? What are the effects of a diet that is toxic in vitamin A?

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Vitamin D: Overview
Prohormone; precursor of a hormone Derived from cholesterol Synthesis from sun exposure Insufficient sun exposure makes this a vitamin Activated by enzymes in liver and kidneys Deficiency diseases

Rickets Osteomalacia
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Vitamin D Metabolism

Ergocalciferol D2 Cholecalciferol D3

Calcitriol

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active vit D hormone

Forms of Vitamin D

Ergocalciferol D2

Cholecalciferol D3

Source: foods and supplements Stored in adipose Source: skin and supplements Greater vit D levels (25-OH D) seen with D3 supplements Stored in adipose Made in liver Made in kidneys Active hormone form Production activated by parathyroid hormone (PTH) when calcium levels are low Lasts 1 day
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25-OH D

Calcitriol

Forms of Vitamin D

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Absorption of Vitamin D2
~80% of vitamin D consumed is incorporated into micelles Absorbed in the small intestine Fat malabsorption impairs vitamin D absorption; celiac disease, pancreatic disease

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Transport, Storage, Metabolism, and Excretion of Vitamin D

Transport

Small intestine to liver in form of chylomicrons in lymphatic system and bloodstream to target tissue acting as a hormone In fat tissue
Involves the skin, liver and kidneys Vitamin D is active when calcium is inadequate Mainly via bile

Storage

Metabolism

Excretion

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Functions of Vitamin D

Regulate blood calcium

When calcium levels are low With parathyroid hormone vitamin D,

& vit D

Increased intestinal absorption of calcium from food *When calcium levels are high

releases calcium from bone decreases excretion of calcium from the kidneys Can be prolonged if inadequate vitamin D and calcium are ingested

thyroid gland releases calcitonin hormone promoting calcium deposition into the bone * does not require vit D

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Functions of Vitamin E

Cell differentiation

Linked to reduction of breast, ovarian, colon, and prostate cancer development Cell differentiation induces normal cells to form preventing poorly differentiated abnormal tumor cells to grow

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Vitamin D Needs

Due to variation in sunlight exposure, no RDA set, but AI established as:

Adequate sun exposure to meet the AI for Vitamin D

5 g/d (200 IU/d) for adults under age 51 10 ug/d (400 IU/d) for adults 51-70 15 g/d (600 IU/d) for adults > 70

Only from March to October in latitude above Atlanta, Georgia Exposure of face, arms and hands, 2 x a week, Light skinned

Dark skinned

~ 10 minutes, > 30 minutes

Infants are born with vitamin D, but American Academy of Pediatrics recommends supplementing breastfed infants with 5 g (200 IU)/d until weaned to fortified infant formula or age 1 when cows milk can be given

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Food Sources of Vitamin D

Fatty fish (salmon, herring) Fortified milk Some fortified cereal

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Food Sources of Vitamin D

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Vitamin D Deficiency

Rickets poor bone mineralization, weakening the bone in children

Enlarged head, joints and rib cage Deformed pelvis and bowed legs

Osteomalacia poor bone mineralization of newly synthesized bone in adults

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Upper Level for Vitamin D

UL = 50 g/d (2000 IU/d) Regular intake of 5-10x the AI can be toxic

Over-absorption of calcium (hypercalcemia; high calcium levels in the blood) Calcium deposits in kidneys, heart, and blood vessels, narrowing of pulmonary arteries and aorta, Teratogenic toxicity; facial changes, mental retardation

Results from consuming megadoses, not excess sun exposure

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Content Review
Why is vitamin D considered a prohormone? How is vitamin D metabolized? What are the functions of vitamin D? What are good sources (food and nonfood) of vitamin D?

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Miracle Vitamin D

Vitamin D Sources

Sun exposure

SPF 8 reduces synthesis by 97.5% Though test of fortified milk show a high variability of vitamin D content

Foods

Vitamin D Deficiency

>50% of older adults are deficient

EXPERT OPINION

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Vitamin E

Tocopherols and tocotrienols

4 forms of each; alpha, beta, gamma, delta Most active form is the d (or RRR) isomer of alpha tocopherol

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Absorption, Transport, Storage, and Excretion of Vitamin E

Absorption

Dependent on the absorption of dietary fat Dependent on bile and pancreatic enzyme for absorption Incorporated into chylomicrons to the liver, then incorporated into lipoproteins; VLDL and HDL
In adipose tissue, liver, and muscle Found in cell membranes, especially the lungs Via bile and urine
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Transport

Storage

Excreted

Functions of Vitamin E

Antioxidant

Vitamin E is able to donate electron to oxidizing agent Protects the cell from attack by free radicals Oxidative Stress; damage to lipids, proteins and DNA produced by excessive production of free radicals Protects PUFAs within the cell membrane and plasma lipoproteins Prevents the alteration of cells DNA and risk for cancer development
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Free Radical Formation

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Vitamin E, An Antioxidant

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Free Radicals
Production of free radicals are a normal result of cell metabolism and immune function Smoking, excess sun exposure and pollution can cause significant oxidative damage Destructive to cells; set off a chain reaction

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Complex of Antioxidant Protection

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Enzymatic Protection From Oxidative Damage

Glutathione peroxidase

A selenium containing enzyme Helps breakdown peroxidized fatty acids (that tends to form free radical)
A copper and zinc containing enzyme Reacts with peroxide and single oxygen (free radicals)

Superoxide dismutase and catalase

Catalase An iron containing enzyme Helps break down hydrogen peroxide to water
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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 Supplement of vitamin E for Cardiovascular Disease (CVD) is questionable

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Vitamin E in Foods
Plant oils Wheat germ Asparagus Peanuts Margarine Nuts and seeds Actual amount is dependent on harvesting, processing, storage and cooking

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Food Sources of Vitamin E

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Vitamin E Needs

RDA =

15 mg/d of d isomer of alpha tocopherol for women and men 22 IU of natural source 33 IU of synthetic form (RDI uses 30 IU)

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

22 x .67 =~15 mg

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

33 x .45 =~15 mg

Natural vitamin E is more potent than the synthetic form because more is in the d isomer of alpha tocopherol

Average intake of Americans is only ~ 2/3 RDA

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Vitamin E Deficiency
Rare Consequences of deficiency

Hemolytic anemia

Susceptible populations

Premature infants People with fat malabsorption People on very low-fat diets Smokers (destruction of vitamin E in lungs)

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Hemolytic Anemia

Breakdown of RBC membrane causes cell content to leak into plasma of the blood
This film displays an increase in polychromatophilic macrocytes (reticulocytes), small dense poikilocytes, including keratocytes (bitten cells) characteristic of oxidative red cell damage.

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Upper Level for Vitamin E

Supplements up to 800 IU is probably harmless Upper Level is 1,000 mg/d of any form of supplemental alpha-tocopherol Upper Level is 1500 IU (natural sources) or 1100 IU (synthetic forms) Inhibit vitamin K metabolism and anticoagulants Possible impact on prostate health

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Content Review
What are the functions of vitamin E? What is an antioxidant? What are some of the signs of vitamin E deficiency? Can vitamin E be toxic? Why/not? What is glutathione peroxidase and what is its role with vitamin E?

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Vitamin K (Koagulation)
Phylloquinone (K1) from plant sources Menaquinones (K2) from fish oils, meats, and intestinal bacteria

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Absorption, Transport, Storage & Excretion of Vitamin K

Absorption

Requires bile and pancreatic enzymes Up to 80% of dietary vitamin K is absorbed in small intestine ~10% of menaquinones synthesized by intestinal bacteria is absorbed in colon
Incorporated into chylomicrons and delivered to liver via lymphatic system

Transport

Storage

In the liver and incorporated into lipoproteins

Primarily via bile
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Excretion

Functions of Vitamin K: Coagulation

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Functions of Vitamin K

Formation of osteocalcin

a protein produced in bone that is thought to bind calcium synthesis of osteocalcin is aided by vitamin K Low intake is associated with increased risk for hip fractures

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Dietary Sources of Vitamin K

Liver Green leafy vegetables Broccoli Peas Green beans Resistant to cooking losses Limited vitamin K stored in the body

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Food Sources of Vitamin K

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Vitamin K Needs

AI =

90 g/d for women, 120 g/d for men

Daily Value = 80 g/d AI achieved by most people

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Vitamin K Deficiency

Antibiotics

Destroy intestinal bacteria Inhibit vitamin K synthesis and absorption Potential for excessive bleeding

Excess vitamins A and E interferes with vitamin K Newborns are injected with vitamin K (breast milk is a poor source)

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Content Review
What are the functions of vitamin K? What are some good food sources of vitamin K?

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Nutrient Supplements

Product intended to supplement the diet that contains one of the following:

Vitamin Mineral Herb or other botanical Amino acid Dietary substance to supplement the diet

$17 billion/year industry in United States Little regulation by FDA

NUTRITION FOCUS

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Nutrient Supplements
Structure or function claims Reasons claimed for use

Reduce susceptibility to health problems Prevent heart attacks Prevent cancer Reduce stress Increase energy

Little evidence supports benefit of daily multivitamin and mineral supplement

NUTRITION FOCUS
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Nutrient Supplements

Rationale to recommend supplement use

North Americans unwilling to change food habits Risk for birth defects with folate deficiency Older adults at risk for vitamin B12 deficiency
Phytochemicals Fiber Bulkiness of calcium Low absorption of magnesium, zinc, and copper Megadoses present risk for toxicity Drug-nutrient interactions

Rationale for obtaining nutrients from food

NUTRITION FOCUS

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Nutrient Supplements

People most likely to need supplements

Women of childbearing age folic acid Women with excessive menstrual bleeding iron People with low energy intakes MVI Strict vegans iron, calcium, zinc, vitamin B12 Newborns vitamin K Older infants fluoride Limited milk intake and restricted sun exposure vitamin D People with lactose maldigestion or intolerance calcium Older adults vitamin B12 People with diets low in plant oils vitamin E People with fat malabsorption fat-soluble vitamins Drug-nutrient interactions Picky eaters Smokers and alcohol abusers

NUTRITION FOCUS

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Nutrient Supplements

Choosing a supplement

Nationally-recognized brand ~100% Daily Values for nutrients

Take with or just after meals Exercise caution to prevent overdose Avoid unnecessary ingredients

NUTRITION FOCUS

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