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The Fat-Soluble
Vitamins: A, D, E, and K
Chapter 11
Introduction
 How fat-soluble vitamins differ from watersoluble vitamins
 Require bile for digestion and absorption
 Travel through lymphatic system
 Many require transport proteins in
bloodstream
 Excesses are stored in liver and adipose
 Risk of toxicity is greater
 RDA over time is what matters
Vitamin A and Beta-Carotene
 Vitamin A, 1st fat-soluble vitamin studied
 Precursor – beta-carotene, also a
pigment
 Absorption and conversion
 Beta-carotene
Three main active forms (retinoids)
retinol, retinal, and retinoic acid
Conversion to other active forms
Conversion of β-carotene
to Vitamin A
Retinol, the alcohol form
Retinal, the aldehyde form
Retinoic acid, the acid form
Cleavage at this point can yield two molecules
of vitamin A*
Beta-carotene, a precursor
*Sometimes cleavage occurs at other
points as well, so that one molecule of
beta-carotene may yield only one
molecule of vitamin A. Furthermore, not
all beta-carotene is converted to vitamin
A, and absorption of beta-carotene is
not as efficient as that of vitamin A. For
these reasons, 12 μg of beta-carotene
are equivalent to 1 μg of vitamin A.
Conversion of other carotenoids to
vitamin A is even less efficient.
Vitamin A and β-Carotene
 Digestion and absorption of vitamin A
 SI to lymphatic system
 Lymphatic system to liver
 Storage in liver
 Retinol-binding protein (RBP)
for transport in serum
 Cells that use vitamin A have receptors
that dictate its job in that cell
Vitamin A and β-Carotene
Roles in the Body
 Regulation of gene expression
 Major roles
 Vision
 Protein synthesis and cell
differentiation
 Reproduction and growth
Vitamin A and β-Carotene
Roles in the Body
 Retinol
 Supports reproduction
 Major transport and storage form
 Retinal
 Active in vision
 Retinoic acid
 Regulates cell differentiation, growth, and
embryonic development
Conversion of Vitamin A Compounds
Retinyl esters
IN FOODS: (in animal
foods)
Retinol
IN THE BODY: (supports
reproduction)
Beta–carotene
(in plant foods)
Retinal
(participates
in vision)
Retinoic acid
(regulates
growth)
Vitamin A and β-Carotene
Roles in the Body
 Vision
 Cornea maintenance
 Retina
Photosensitive cells
Rhodopsin (remember opsin?)
 Repeated small losses of retinal
Need for replenishment due to
oxidation from visual activity
Vitamin A’s Role in Vision
As light enters the eye,
rhodopsin within the cells
of the retina absorbs the
light.
Retina cells
(rods and
cones)
Light energy
Cornea
Eye
Nerve impulses
to the brain
The cells of the retina contain rhodopsin, a
molecule composed of opsin (a protein) and
cis-retinal (vitamin A).
cis-Retinal
trans-Retinal
As rhodopsin absorbs light, retinal changes from cis to
trans, which triggers a nerve impulse that carries visual
information to the brain.
Vitamin A and β-Carotene
Roles in the Body
 Protein synthesis & cell differentiation
 Epithelial cells on all body surfaces
Skin
Mucous membranes (Linings)
–Ex: GI lumen lining
–Ex: Respiratory tract linings
Goblet cells (secrete mucous)
Mucous Membrane Integrity
Vitamin A maintains
healthy cells in the
mucous membranes.
Mucus
Without vitamin A, the
normal structure and
function of the cells in
the mucous membranes
are impaired.
Goblet cells
Vitamin A (retinol) and β-Carotene
Roles in the Body
 Reproduction and growth
 Sperm development
 Normal fetal development
 Growth of children
 Weight and Height
 Bone remodeling
 Antioxidant, cancer protection
 Beta-carotene, not Vitamin A
Vitamin A Deficiency
 Def. symptoms can take 1-2 yrs to appear for
adult, much sooner for growing child
 Vitamin A status depends on
 Adequacy of stores, 90% in liver
 Protein status for RBP mfg.
 Consequences of deficiency
 Risk of infectious diseases
 Blindness
 Death
Vitamin A Deficiency
 Infectious diseases
 Measles, pneumonia, diarrhea
 Malaria, lung diseases/infections, HIV- AIDS
 Night blindness
 Inadequate supply of retinal to retina
 Blindness (xerophthalmia)
 Lack of vitamin A at the cornea
 Develops in stages
Vitamin A Deficiency
 Keratin- hard, insoluble hair & nail protein
 Keratinization
 Change in shape & size of epithelial cells
due to accumulation of keratin
 Skin becomes dry, rough, and scaly
 Fewer and less active goblet cells, so normal
digestion and absorption of nutrients from GI
tract falters
 Weakened defenses in epithelial cells of
respiratory tract, vagina, inner ear, and
urinary tract
Vitamin A Toxicity
 Develops when binding proteins are
swamped
 Free vitamin A damages cells
 Toxicity is a real possibility
 Preformed vitamin A from animal sources
 Fortified foods
 Supplements
 Children are most vulnerable
β-Carotene Overload
 β-carotene
 Found in many excellent fruits and vegetables
 Excess cannot evolve to Vitamin A toxicity
 Overconsumption from food harmless
 β-carotene storage in fat under skin
 Overconsumption from supplements risky
 Antioxidant becomes prooxidant, promotes cell
division, destroys Vitamin A
 Most adverse effects for those with heavy EtOH
and tobacco use
Vitamin A Toxicity
(Hypervitaminosis A)
 Bone defects
 May weaken bones
 Osteoporosis
 Overstimulation of osteoclasts
 Interferes with vitamin D and serum calcium
 Birth defects
 Cell death in the spinal cord with
>10,000 IU/d before 7th week
 Vitamin A relatives prescribed for Acne
 Accutane, topical Retin-A
Accutane Side Effects
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Ulcerative colitis
Crohn’s Disease,
Inflammatory Bowel Disease
Severe depression, suicidal thoughts
Birth defects
Liver damage, with nausea, loss of appetite,
weight loss, and jaundice
 Allergic reaction to isotretinoin, resulting in
liver disease and other health complications
Vitamin A and Beta-Carotene
 Recommendations
 Expressed as retinol activity equivalents
(RAE)
 1 RAE =
 1 µg. retinol
 12 µg. β-carotene
 3.33 international units (IU’s)
 Supplements often measured in
International Units (IU)
Vitamin A and β-Carotene
 Food sources
 Animal sources for Vitamin A
 Liver (1 oz = 3x RDA), dairy fat, eggs
 Plant sources for β-Carotene
 Vitamin A precursors
 Bioavailability with fat in the same meal
 Dark green and bright orange fruits and
vegetables
β-rich Fruits & Vegetables
 FRUITS
 Apricots, Cantaloupe, Peaches, Persimmon,
Mango, Papaya, Purple(on the inside) plums,
Watermelon
 VEGETABLES
 Beet greens, Bok Choi, Broccoli, Carrots
Collards, Dandelion Greens, Kale, Mustard
Greens, Pumpkin, Spinach, Sweet Potatoes,
Yams, Winter Squash
 Bold italics mean also C-rich
Vitamin A / β-carotene in Foods
Vitamin D- calciferol
 Not an essential nutrient
 Body synthesizes
 Sunlight
 Precursor from cholesterol
 Activation of vitamin D
 Two hydroxylation reactions
 Liver adds OH Kidneys add OH-
Vitamin D Synthesis and
Activation
In the skin:
7-dehydrocholesterol
(a precursor made in the
liver from cholesterol)
Ultraviolet
light from
the sun
Previtamin D3
Foods
(ergocalciferol from plants
and cholecalciferol from
animals)
Vitamin D3
(an inactive form)
In the liver:
Hydroxylation
25-hydroxy vitamin D3
In the
kidneys:
Hydroxylation
1,25-dihydroxy vitamin
D3 (active form)
Stepped Art
Vitamin D Roles in the Body
 Active form of vitamin D is a hormone
 Binding protein carries it to target organs
 Ca / P absorption to maintain serum levels
 Bone growth
 Ca, Mg, P, Fl absorption preferably from GI
 Bones resorbed to maintain serum levels
 Parathyroid hormone, calcitonin, calbindin
 Other roles
 Enhances or suppresses gene activity
Vitamin D Deficiency
 Overt deficiency signs are relatively rare
 Insufficiency is quite common
 Contributory factors
 Dark skin, breastfeeding without
supplementation, lack of sunlight,
not using fortified milk
 D deficiency → less calbindin transp. prot.→
low calcium absorption → calcium
deficiency→ rob the bones for calcium
Vitamin D Deficiency
 Rickets in children
 Prevalence >50% Mongolia, Tibet, Netherlands
 Bones fail to calcify normally, bend when
supporting weight
 Beaded ribs
 Osteomalacia (adult rickets)
 Poor mineralization of bones
 Bones are soft, flexible, brittle, and deformed
Fontanel
A fontanel is an
open space in the
top of a baby’s
skull before the
bones have
grown together.
In rickets, closing
of the fontanel is
delayed.
Anterior fontanel
normally closes
by the end of the
second year.
Posterior fontanel
normally closes
by the end of the
first year.
Vitamin D Deficiency
 Osteoporosis
 Loss of calcium from bones
 Reduced density results in fractures
 Elderly
 Vitamin D deficiency is especially likely
 Skin, liver, kidneys lose ability to make and
activate vitamin D
 Drink less milk
 Too much time indoors, sunscreen outdoors
 Drugs that deplete Vitamin D
Vitamin D Deficiency
Contributes to Osteoporosis
 Bone metabolism is influenced by many factors,
including vitamin D levels, hormones, genetics,
your body weight and your activity levels.
Osteoporosis, meaning "porous bones," results
from a relative lack of osteoblast activity in
comparison to osteoclast activity. Over time, this
imbalance leads to a decrease in bone density
with a concurrent rise in fracture risk. In adults,
vitamin D deficiency leads to a reduction in
osteoblast activity, thereby decreasing the rate
of bone construction.
National Academy of Science
Vitamin D Recommendations
 In response to concerns that Americans are
consuming too little vitamin D, the National Academy
of Sciences reviewed its recommendations and
offered new guidelines in November 2010. According
to the NAS, adults up to age 70 need no more than
600 IU of vitamin D daily to maintain health, and those
over 70 need no more than 800 IU. However, many
experts, including those at the University of Miami
Miller School of Medicine and the University of
Toronto, believe that even these recommendations are
too low for most age groups and that all elderly adults
should receive at least 2,000 IU of vitamin D daily.
Considerations and
Recommendations
 Many of vitamin D's functions, including its
influences on immune function and glucose and
lipid metabolism, are just beginning to come to
light. As new discoveries unfold -- including
advances in osteoporosis research – National
Academy of Science dietary guidelines for
vitamin D may change. Current guidelines reflect
an upward adjustment from those devised in
1997, but some researchers still feel these
recommendations are inadequate.
Considerations and
Recommendations
 If you are an adult under age 70
who wishes to prevent osteoporosis,
your daily vitamin D-3 intake should
be at least 600 IU, and if you are
older than 70, 800 IU. Consult your
physician about the vitamin D-3
dosage that is best for you.
Vitamin D Toxicity
 Most likely of vitamins to have toxic effects
 Toxicity raises blood calcium concentrations
 Forms stones in soft tissues, esp. kidneys
 May harden blood vessels
Skin Exposure is
what it takes
to make Vitamin D
↑
What’s the
point?
Vitamin D Sources
 Few food sources
 Oily (fishy-tasting) fish and egg yolks
 Fortified milk
 Sun exposure for 10-20 min (not 2 hrs) per day
 Dark skin or SPF >8 reduces D synthesis
 No risk of D toxicity from too much sun
 Latitude, season, time of day,
 Overcast, smog, fog
Vitamin D Synthesis and Latitude
Free Radicals
Free Radicals and Disease
 Free radical damage
 Contribute to cell damage, disease
progression, and aging
 Polyunsaturated fatty acids in lipoproteins
and membranes
 Alter DNA, RNA, and proteins
 Illicit inflammatory response
Free Radicals
Free Radicals
Free
radical
Polyunsaturated
fatty acids
Lipid radicals
Free
radical
Free
radical
DNA and RNA
Proteins
Altered DNA
and RNA
Altered proteins
Absence of specific proteins
Excess of specific proteins
Impaired cell function
Inflammatory response
Cell damage
Diseases
Aging
Free Radical Chain Reaction
Free Radicals and Disease
 Free radical
 Compound with one or more unpaired
electrons
 Look to steal electron from vulnerable
compound
 Electron-snatching chain reaction
 Free radical production
 Degrades or detours normal bodily functions
 Environmental factors
Vitamin E as Antioxidant
Preservatives
BHA and BHT are synthetic analogues of
vitamin E and operate by reducing oxygen
radicals and interrupting the propagation
of oxidation processes.
Free Radicals and Disease
 Body has natural
 Oxidative stress
defenses and repair
 Cognition
systems
 Cancer
 Vit. C, β-carotene,
Zn, Se, Mn, Cu
 Not 100 percent
effective
 Less effective with
age
 Heart disease
 Arthritis and cataracts
 Diabetes
 Skin
 Lungs
 Accelerates aging
Vitamin E
 Four different tocopherol compounds
 Alpha, beta, gamma, and delta
 Only alpha-tocopherol has vitamin E activity
in the body
 Antioxidant
 Stop chain reaction of free radicals
 Protect cells and their membranes
 Heart disease and cancer
Defending Against Free Radicals
 System of enzymes against oxidants
 Copper, selenium, manganese, and zinc
 Antioxidant vitamins
 Vitamin E
 Defends body lipids
 Beta-carotene
 Defends lipid membranes
 Vitamin C
 Protects other tissues
How Antioxidants defend the
body against cancer and CHD
 Limit free radical formation
 Neutralize(destroy) free radicals or
their precursors
 Stimulate antioxidant enzyme activity
 Repair oxidative damage
 Stimulate repair enzyme activity
 Support healthy immune system
Defending Against Heart Disease
 Oxidized LDL fills “foam cells”
 Accelerate formation of artery-clogging
plaques
 Additional changes in arterial walls
 Vitamin E protection
 Supplements
 Risk of supplement use by those who
already have heart disease
Defending Against Cancer
 Damage to cellular DNA
 Antioxidants may protect DNA from this
damage
 Inverse relationship with vegetable intake
 Positive relationship with beef and pork
intake
 Vitamin C as a prooxidant
 Destruction of cancer cells
 Vitamin E
Vitamin E Deficiency
 Primary deficiency is rare
 Secondary deficiency
 Fat malabsorption, totally fat-free diet
 Effects of deficiency
 Red blood cells break open
 Erythrocyte hemolysis
 Neuromuscular dysfunction
 Other conditions and vitamin E treatment
Vitamin E Toxicity
 Liver regulates vitamin E concentrations
despite intake
 Toxicity is rare
 UL is 65 times greater than recommended
intake for adults
 Extremely high doses of vitamin E
 May interfere with vitamin K activity
 Thin the blood, increase hemorrhage risk
Vitamin E
Recommendations & Foods
 RDA is based on alpha-tocopherol only
 U.S. intakes tend to fall short of
recommendations
 Higher requirements for smokers
 Widespread in foods
 Destroyed by heat processing and oxidation
Vitamin E in Foods
Foods, Supplements, or Both?
 Must replenish dietary antioxidants regularly
 Foods
 Antioxidants and other valuable nutrients
 Antioxidant actions of fruits and vegetables are
greater than their nutrients alone
 Supplements
 Contents, bioavailability
 Processing
 Physiological levels vs. pharmacological dose
The Bottom Line on Antioxidants
and Disease Prevention (HSPH)
Free radicals contribute to chronic diseases from
cancer to heart disease and Alzheimer's disease to
vision loss. This doesn't automatically mean that
substances with antioxidant properties will fix the
problem, especially not when they are taken out of
their natural context. The studies so far are
inconclusive, but generally don't provide strong
evidence that antioxidant supplements have a
substantial impact on disease. But keep in mind that
most of the trials conducted up to now have had
fundamental limitations due to their relatively short
duration and having been conducted in persons with
existing disease.
The Bottom Line on Antioxidants
and Disease Prevention (HSPH)
That a benefit of beta-carotene on cognitive
function was seen in the Physicians' Health
Follow-up Study only after 18 years of followup is sobering, since no other trial has
continued for so long. At the same time,
abundant evidence suggests that eating
whole fruits, vegetables, and whole grains—
all rich in networks of antioxidants and their
helper molecules—provides protection
against many of these scourges of aging.
Vitamin K
 Can be obtained from non-food source
 Bacteria in the GI tract synthesize K
 Acts primarily in blood clotting
 K is essential for activating prothrombin
 Metabolism of bone proteins
 Osteocalcin binds to bone minerals
 Low bone density w/out Vit. K and osteocalcin
 Misc. proteins needing vitamin K in the body
Blood-Clotting Process
Vitamin K
Several precursors
earlier in the series
depend on
vitamin K
Calcium and
thromboplastin (a
phospholipid) from
blood platelets
Prothrombin
(an inactive
protein)
Fibrinogen
(a soluble
protein)
Thrombin
(an active
enzyme)
Fibrin
(a solid
clot)
Vitamin K Deficiency
 Primary deficiency is rare
 Secondary deficiency
 Fat absorption falters
 Antibx drugs disrupt vitamin K’s synthesis
 Anticoagulants have opposite action
 Newborn infants
 Sterile intestinal tract
 Single dose of vitamin K given at birth
Vitamin K Toxicity
 Not common
 No adverse effects with high intakes
 No UL
 Irregular High doses can reduce
effectiveness of anticoagulant drugs, ie.
Coumadin
"Vitamin K" by Elson M. Haas M.D.
 "It is important for the production of many nutrients
that we keep our "friendly" colon bacteria active and
doing their job; to aid this process we should
minimize our use of oral antibiotics, avoid excess
sugars and processed foods, and occasionally
evaluate and treat any abnormal organisms
interfering in our colon, such as yeasts or
parasites."
 "Yogurt, kefir, and acidophilus milk may help to
increase the functioning of the intestinal bacterial
flora and therefore contribute to vitamin K
production."
How much vitamin K can I have
each day while on coumadin?
 Rather than focus on how much vitamin K
you should eat, experts say it is more
important to keep your vitamin K intake
consistent from day to day and not to have
drastic changes in amounts of vitamin Krich foods. For example, if you eat 3 cups
of a high-vitamin K food like spinach one
day and none the next, this can affect the
way your Coumadin works.
American Dietetic Association Nutrition Care Manual
Vitamin K – Sources
 GI tract
 Half of person’s need
 Stored in liver
 Food sources
 Green vegetables
 Vegetable oils
Vitamin K
Foods
The Fat-Soluble Vitamins –
In Summary
 Toxicities are possible
 Function of fat-soluble vitamins together
 Vitamins E and A
 Oxidation, absorption, and storage
 Vitamins A, D, and K
 Bone growth and remodeling
 Vitamins E and K
 Blood clotting