1. The Fat-Soluble Vitamins: A, D, E, and K
Chapter 11

3. 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

4. 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

5. 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*
*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.
Figure 11.1: Forms of Vitamin A.
In this diagram, corners represent carbon atoms, as in all previous diagrams in this book. A further simplification here is that methyl groups (CH3) are understood to be at the ends of the lines extending from corners. (See Appendix C for complete structures.)
Beta-carotene, a precursor

6. 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

7. Vitamin A and β-Carotene Roles in the Body
Regulation of gene expression
Major roles
Vision
Protein synthesis and cell differentiation
Reproduction and growth

8. 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

9. Conversion of Vitamin A Compounds
Retinyl esters (in animal foods)
Beta–carotene (in plant foods)
IN FOODS:
Retinol (supports reproduction)
Retinal (participates in vision)
Retinoic acid (regulates growth)
IN THE BODY:
Figure 11.2: Conversion of Vitamin A Compounds.
Notice that the conversion from retinol to retinal is reversible, whereas the pathway from retinal to retinoic acid is not.

10. 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

11. Vitamin A’s Role in Vision

12. As light enters the eye, rhodopsin within the cells
of the retina absorbs the
light.
Retina cells (rods and cones)
Light energy
Figure 11.3: Vitamin A’s Role in Vision.
The retina receives the image formed by the lens and converts light energy into chemical energy and nerve signals that reach the brain via the optic nerve.
Cornea
Eye
Nerve impulses to the brain

13. The cells of the retina contain rhodopsin, a molecule composed of opsin (a protein) and cis-retinal (vitamin A).
cis-Retinal
trans-Retinal
Figure 11.3: Vitamin A’s Role in Vision.
The retina receives the image formed by the lens and converts light energy into chemical energy and nerve signals that reach the brain via the optic nerve.
As rhodopsin absorbs light, retinal changes from cis to trans, which triggers a nerve impulse that carries visual information to the brain.

14. 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)

15. Mucous Membrane Integrity

16. 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.
Goblet cells
Figure 11.4: Mucous Membrane Integrity.
Mucus

17. 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

18. Vitamin A Deficiency Vitamin A status depends on
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

19. Vitamin A Deficiency Infectious diseases Night blindness
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

20. Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness.
These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

21. Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness.
These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

22. Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness.
These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

23. Figure 11.5: Vitamin A–Deficiency Symptom—Night Blindness.
These photographs illustrate the eyes’ slow recovery in response to a flash of bright light at night. In animal research studies, the response rate is measured with electrodes.

24. Vitamin A Deficiency Keratinization
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

25. Figure 11.6: Vitamin A–Deficiency Symptom—The Rough Skin of Keratinization.

26. 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

27. 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

28. Figure 11.7: Symptom of Beta-Carotene Excess—Discoloration of the Skin.

29. 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

30. Accutane Side Effects 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

31. 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)

32. 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

33. β-rich Fruits & Vegetables
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

34. The carotenoids in foods bring colors to meals; the retinoids in our eyes allow us to see them.p

35. Vitamin A / β-carotene in Foods

36. 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-

37. Vitamin D Synthesis and Activation

38. (a precursor made in the liver from cholesterol)
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)
Hydroxylation
In the liver:
Figure 11.9: Animated! Vitamin D Synthesis and Activation.
The precursor of vitamin D is made in the liver from cholesterol (see Figure 5-11 on p. 147 and Appendix C). The activation of vitamin D is a closely regulated process. The final product, active vitamin D, is also known as 1,25-dihydroxycholecalciferol (or calcitriol).
25-hydroxy vitamin D3
Hydroxylation
In the kidneys:
1,25-dihydroxy vitamin D3 (active form)
Stepped Art

39. 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

40. 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

41. Vitamin D Deficiency Rickets in children Osteomalacia (adult rickets)
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

42. Figure 11.10: Vitamin D–Deficiency Symptoms—Bowed Legs and Beaded Ribs of Rickets.

43. 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.

44. Vitamin D Deficiency Osteoporosis Elderly 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

45. 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.

46. 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 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.

47. 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.

48. 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.

49. 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

50. Skin Exposure is what it takes to make Vitamin D↑
What’s the point?

51. Vitamin D Sources Few food sources
Oily (fishy-tasting) fish and egg yolks
Fortified milk
Sun exposure for 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

52. Vitamin D Synthesis and Latitude

53. Free Radicals

54. 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

55. Free Radicals

56. Free Radicals

57. Polyunsaturated fatty acids DNA and RNA Proteins
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
Figure H11.1: Free-Radical Damage.
Free radicals are highly reactive. They might attack the polyunsaturated fatty acids in a cell membrane, which generates lipid radicals that damage cells and accelerate disease progression. Free radicals might also attack and damage DNA, RNA, and proteins, which interferes with the body’s ability to maintain normal cell function, causing disease and premature aging.
Cell damage Diseases
Aging

58. Free Radical Chain Reaction

59. Free Radicals and Disease
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

60. Vitamin E as Antioxidant

61. of oxidation processes.
Preservatives
BHA and BHT are synthetic analogues of vitamin E and operate by reducing oxygen radicals and interrupting the propagation
of oxidation processes.

62. Free Radicals and Disease
Body has natural defenses and repair systems
Vit. C, β-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

63. Vitamin E Four different tocopherol compounds Antioxidant
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

64. 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

65. 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

66. 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

67. 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

68. 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

69. 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

70. 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

71. Vitamin E in Foods

72. 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

73. 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.

74. 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 grains—all rich in networks of antioxidants and their helper molecules—provides protection against many of these scourges of aging.

75. 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

76. 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)
Figure 11.12: Blood-Clotting Process.
When blood is exposed to air, foreign substances, or secretions from injured tissues, platelets (small, cell-like structures in the blood) release a phospholipid known as thromboplastin. Thromboplastin catalyzes the conversion of the inactive protein prothrombin to the active enzyme thrombin. Thrombin then catalyzes the conversion of the precursor protein fibrinogen to the active protein fibrin that forms the clot.

77. 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

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

79. "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."

80. 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

81. Vitamin K – Sources GI tract Food sources Half of person’s need
Stored in liver
Food sources
Green vegetables
Vegetable oils

82. Vitamin K
Foods
Notable food sources of vitamin K include green vegetables such as collards, spinach, bib lettuce, brussels sprouts, and cabbage and vegetable oils such as soybean oil and canola oil.

83. 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