The Fat-Soluble Vitamins: A, D, E, and K

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The Fat-Soluble Vitamins A, D, E, and K

• Chapter 11

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Introduction

• How fat-soluble vitamins differ from
  water-soluble 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

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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

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Conversion of ß-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
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.
Beta-carotene, a precursor
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Vitamin A and ß-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

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Vitamin A and ß-Carotene Roles in the Body

• Regulation of gene expression
• Major roles
• Vision
• Protein synthesis and cell differentiation
• Reproduction and growth

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Vitamin A and ß-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

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Conversion of Vitamin A Compounds
Retinyl esters (in animal foods)
Betacarotene (in plant foods)
IN FOODS
Retinol (supports reproduction)
Retinal (participates in vision)
Retinoic acid (regulates growth)
IN THE BODY
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Vitamin A and ß-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

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Vitamin As Role in Vision
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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
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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.
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Vitamin A and ß-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)

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Mucous Membrane Integrity
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Vitamin A maintains healthy cells in the mucous
membranes.
Without vitamin A, the normal structure and
function of the cells in the mucous membranes
are impaired.
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Vitamin A (retinol) and ß-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

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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

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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

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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

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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

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ß-Carotene Overload

• ß-carotene
• Found in many excellent fruits and vegetables
• Excess cannot evolve to Vitamin A toxicity
• Overconsumption from food harmless
• ß-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

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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 gt10,000
  IU/d before 7th week
• Vitamin A relatives prescribed for Acne
• Accutane, topical Retin-A

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Accutane Side Effects

• Ulcerative colitis
• Crohns 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

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Vitamin A and Beta-Carotene

• Recommendations
• Expressed as retinol activity equivalents (RAE)
• 1 RAE
• 1 µg. retinol
• 12 µg. ß-carotene
• 3.33 international units (IUs)
• Supplements often measured in International Units
  (IU)

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Vitamin A and ß-Carotene

• Food sources
• Animal sources for Vitamin A
• Liver (1 oz 3x RDA), dairy fat, eggs
• Plant sources for ß-Carotene
• Vitamin A precursors
• Bioavailability with fat in the same meal
• Dark green and bright orange fruits and vegetables

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ß-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

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Vitamin A / ß-carotene in Foods
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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-

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Vitamin D Synthesis and Activation
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Previtamin D3
Vitamin D3 (an inactive form)
25-hydroxy vitamin D3
1,25-dihydroxy vitamin D3 (active form)
Stepped Art
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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

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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

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Vitamin D Deficiency

• Rickets in children
• Prevalence gt50 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

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Fontanel A fontanel is an open space in the top
of a babys 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.
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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

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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.

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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.

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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.

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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.

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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

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Skin Exposure is what it takes to make Vitamin
D
?
Whats the point?
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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 gt8 reduces D synthesis
• No risk of D toxicity from too much sun
• Latitude, season, time of day,
• Overcast, smog, fog

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Vitamin D Synthesis and Latitude
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Free Radicals
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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

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Free Radicals
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Free Radicals
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Free radical
Free radical
Free radical
Polyunsaturated fatty acids
DNA and RNA
Proteins
Altered DNA and RNA
Lipid radicals
Altered proteins
Absence of specific proteins Excess of specific
proteins
Impaired cell function Inflammatory response
Cell damage Diseases Aging
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Free Radical Chain Reaction
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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

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Vitamin E as Antioxidant
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Preservatives
BHA and BHT are synthetic analogues of vitamin E
and operate by reducing oxygen radicals and
interrupting the propagation of oxidation
processes.
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Free Radicals and Disease

• Body has natural defenses and repair systems
• Vit. C, ß-carotene, Zn, Se, Mn, Cu
• Not 100 percent effective
• Less effective with age

• Oxidative stress
• Cognition
• Cancer
• Heart disease
• Arthritis and cataracts
• Diabetes
• Skin
• Lungs
• Accelerates aging

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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

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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

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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

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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

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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

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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

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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

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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

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Vitamin E in Foods
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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

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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.

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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 follow-up
  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 grainsall rich in networks of
  antioxidants and their helper moleculesprovides
  protection against many of these scourges of
  aging.

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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

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Blood-Clotting Process
Calcium and thromboplastin (a phospholipid) from
blood platelets
Fibrinogen (a soluble protein)
Vitamin K
Several precursors earlier in the series depend
on vitamin K
Prothrombin (an inactive protein)
Thrombin (an active enzyme)
Fibrin (a solid clot)
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Vitamin K Deficiency

• Primary deficiency is rare
• Secondary deficiency
• Fat absorption falters
• Antibx drugs disrupt vitamin Ks synthesis
• Anticoagulants have opposite action
• Newborn infants
• Sterile intestinal tract
• Single dose of vitamin K given at birth

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Vitamin K Toxicity

• Not common
• No adverse effects with high intakes
• No UL
• Irregular High doses can reduce effectiveness of
  anticoagulant drugs, ie. Coumadin

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"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."

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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 K-rich 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

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Vitamin K Sources

• GI tract
• Half of persons need
• Stored in liver
• Food sources
• Green vegetables
• Vegetable oils

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Vitamin K
Foods
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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