Mary M. Fynn, Ph.D, RD, L.D.N

Fat soluble vitamins

Fat soluble vitamins

January 2016

There are 2 forms of vitamin A: preformed and provitamin A.

Preformed vitamin A: found in animal tissue and supplements (pills).  The preformed vitamin A compounds are called retinoids and they are the biologically active form of vitamin A.  There are 3 retinoids:

Retinol – found in animal tissue as retinyl esters

Retinal – formed from the oxidation of retinol

Retinoic acid – formed from the oxidation of retinal

Provitamin A: these are compounds called carotenoids and are found in plant foods.  Some of the carotenoids can be converted to vitamin A in the human body.  The most widely studied is beta carotene, which can be oxidatively cleaved in the intestines to produce 2 molecules of retinal.

Absorption:  the retinyl esters in food are hydrolyzed during digestion to release the retinol.  The retinol plus any retinal formed from carotenoids is re-esterified to long chain fatty acids and absorbed with the chylomicron; the vitamin A will eventually reach the liver with the chylomicron remnant.  Please note: dietary fat, which leads to chylomicron synthesis, greatly increases carotenoid absorption.

Transport:  retinol can be released from the liver and transported in the blood by plasma retinol-binding protein (RBP).  The retinol-RBP complex can attach to receptors on the surface of the target cell and permit the retinal to enter the cell.  Many tissues also have a cellular RBP which will bring the retinol to the nucleus of the cell.

Functions:

  1. visual cycle: vitamin A is required for both night and color vision.  It is part of the visual pigment of the rod and cone cells.
  2. growth
  3. reproduction
  4. maintenance of epithelial tissue and mucous secretion.

Requirement for vitamin A: the requirement of vitamin A is provided in “Retinol Activity Equivalents” (RAE), to account for vitamin A that is contributed from carotenoids.  Please note that vitamin A as the preformed vitamin is only found in animal products.

Deficiency: the vitamin A status of most Americans is thought to be adequate; however deficiencies can occur in the elderly and young children who consume diets deficient in vitamin A.  If the diet is deficient in vitamin A, including foods rich in carotenoids such as canned fruit that is dark in color (e.g., peaches) can help provide carotenoids for conversion to vitamin A.  Vitamin A deficiency is a major health problem in developing countries.  It is the leading cause of non-accidental blindness worldwide.  Symptoms of vitamin A deficiency:

  1. the eye does not recover from flashes of light.  The initial symptom is typically stumbling at dusk, as the victim is not able to adjust to the decrease in light.
  2. mucus-secreting cells don’t produce mucus, which is needed for lubrication of the cell.  This is seen primarily in the eye.  Mucus is critical to keep the eye moist and wash foreign objects from the eye.

Severe vitamin deficiency results in xerophthalmia, which is dryness of the conjunctiva and cornea and can lead to irreversible blindness.  Bitot spots (small, gray plaque on the conjunctiva) may be seen prior to xerophthalmia.

  1. Follicular hyperkeratosis – skin and hair follicle changes.  This results from changes in keratin formation.  In vitamin A deficiency there is an increase in keratin cells production, which plug the hair follicles, and give the skin a bumpy appearance.

Carotenoids:  until 15 to 20 years ago, carotenoids were discussed in nutrition only as compounds that could convert to vitamin A (provitamin A) and could help meet vitamin A requirements.  More recent work has shown that carotenoids have a specific function in the prevention of chronic diseases.  There are at least 600 different carotenoids and only a fraction of these have been adequately studied.  Some of the functions attributed to carotenoids are:

  1. antioxidants
  2. prevention of macular degeneration and cataracts.  This function seems to be specific to the carotenoids lutein and zeaxanthin, as they accumulate in the eye when consumed in the diet.  Dietary sources rich in these carotenoids are corn and leafy greens.
  3. high blood levels of various carotenoids have been shown in many studies to be related to a decrease in cancer.  The mechanisms are not completely worked out, but a number of different possibilities have been identified.

Carotenoids are found in fruits and vegetables and provide deep color as red, orange, and yellow; the deeper the color of the produce, the higher the carotenoid content in the food.  Produce grown to peak ripeness on the plant has a higher carotenoid content compared to that picked before it is completely ripened.  This is indicated by the deeper color of produce ripened on the plant.  Produce that is frozen has the same vitamin content as “retail fresh” (i.e., what is purchased in a grocery store), but typically has a higher carotenoid content (1, 2).

Note:  clinical trials with carotenoid supplements (pills) have not lead to decreases in the diseases studied.  In fact, some studies have reported an increase in diseases with carotenoid supplements (lung cancer, heart disease, death).  It is not clear why this would happen, however, possible explanation include that the mix of carotenoids present in food accounts for the protection (i.e., the one being studied may not be the sole one with benefit) and /or mega doses of the carotenoids result in toxicities also seen with general mega doses of vitamins.

Toxicity:  hypervitaminosis A can occur at intakes exceeding about 10 times the RDA for a period of months.  Vitamin A toxicity can only occur with the use of supplements and not with diet.  Symptoms include changes in the skin (dryness), muscle and joint pain, liver enlargement and cirrhosis, and severe headaches.  Chronic high intake of vitamin A, which is mainly due to supplement use (including multivitamins) and/or elevated blood level, has also been associated with an increase in hip fractures in post-menopausal women (3).  Some medications that contain high doses of vitamin A are used to treat acne and have been shown to be teratogenic when taken during pregnancy.

Dietary sources of vitamin A:  preformed vitamin A is only found in animal foods.  Good sources are liver, fish oils/ fatty fish, fortified milk, cream, butter, and eggs (found in the yolk); vitamin A is also added to margarine.

Provitamin A (carotenoids) is found in plant foods.  Deep color signifies the presence of carotenoids, so all dark fruits and vegetables are rich sources; examples include broccoli, cantaloupe, carrots, mango, spinach, sweet potatoes, winter squash, and tomato products.  As a general statement, frozen or canned produce tend to be higher in carotenoids.  Processed produce is grown to peak ripeness and then canned/ frozen.  The growing to peak ripeness on the plant increases the carotenoid content.  Additionally, frozen / canned produce is all ready to use and more can be kept in the home, relative to the fresh version.  Cooking deep colored produce in extra virgin olive oil improves the flavor and the fat increases the carotenoid absorption.

Skin cells can make vitamin D in the presence of sunlight, but as there is a vitamin D deficiency disease, it is a vitamin.  Vitamin D also has hormone-like functions, so it can be classified as a hormone.

Synthesis of vitamin D in the skin:  synthesis starts with a derivative of cholesterol that is found in the skin (dehydrocholesterol).  UV light from the sun converts 7- dehydrocholesterol to cholecalciferol (D3), an inactive form of the vitamin.  Cholecalciferol travels in the blood to the liver, where it is hydroxylated at the 25 position producing 25- OH D3.  The 25-OH D3 is inactive and can circulate in the blood for weeks.  The active from of vitamin D is formed by another hydroxylation at the 1 position to form 1, 25 (OH) 2, which is also called calcitriol.

The synthesis of 1, 25 di (OH) D3 is regulated by plasma levels of phosphate and/ or calcium.  Low plasma levels of calcium trigger the release of parathyroid hormone which stimulates the synthesis of calcitriol, while low plasma phosphate can directly stimulate the synthesis of calcitriol.  The amount of sun needed to synthesis active vitamin D depends on skin color, use of sunscreen, age, season (winter in the northern hemisphere greatly decreases synthesis), geographic location, and the time of day (highest synthesis is between 8a-4p).  If there is sufficient vitamin D in the blood, less is synthesized.

Functions:

1. regulation of plasma levels of calcium and phosphorus.  Calcium is needed for bone formation, but also has a number of other functions, such as blood clotting, triggering the release of neurotransmitters, muscle contraction and a variety of other cell functions as part of the complex calmodulin.  Thus, plasma level of calcium must be maintained to supply calcium for these functions.

How 1, 25 (OH) D3 maintains plasma calcium:

a. when blood calcium levels decrease, calcitriol increases intestinal absorption of calcium by increasing the synthesis of calcium binding protein in the intestinal cell.  Calcitriol also alters the membranes of intestinal cells which increases calcium absorption into intestinal cells.

b.1, 25 (OH) D3 with parathyroid hormone (PTH) can stimulate the release of both calcium and phosphate from the bone when there is low plasma levels of calcium and phosphate.

2. more recent function of vitamin D is in cancer prevention.  Active vitamin D has been shown to be a potent inhibitor of cell proliferation.

Deficiency:  the status of vitamin D can be assessed by measuring plasma levels of 25(OH) De [note: 1, 25 (OH) D3 levels do not indicate deficiency).  There are two forms of the deficiency, rickets in children and osteomalcia in adults.

Rickets is the deficiency disease resulting from inadequate vitamin D status in the growing infant/ child.  With adequate plasma levels of 1, 25 (OH) D3, the minerals calcium and phosphorus will deposit in the growing bone.  When there is insufficient 1, 25 (OH) D3 in the blood, these minerals are not deposited in sufficient amounts and the bones weaken and bow under pressure.  This is seen particularly in the legs, due to the weight of the person on the leg bones.  Bowed legs were common in the Industrial Revolution in England due to the number of children who worked long hours in factories, with little exposure to sunlight.  More recently, rickets has presented as an enlarged rib cage and/or rib bones that do not feel smooth to the touch, but feel like they have bumps or beads on them. The risk of rickets increases with the infant that has low sun exposure, which includes the use of sun blocks and those heavily swaddled.  Breast fed infants who do not receive vitamin D supplementation are also at risk.

Osteomalcia is the deficiency disease resulting from long term inadequate vitamin D status in the adult.  Existing bone will have a decrease in mineral content; this is manifested as bone and muscle pain that can mimic arthritis or fibromyalgia.  While osteomalcia can result from inadequate sun exposure and/ or inadequate vitamin D intake, it can also result from diseases of the kidney (as hydroxylation will be effected) or diseases of the small intestines that result in malabsorption.  Vitamin D deficiency will also lead to osteoporosis as there will be insufficient calcium absorption.  Note: vitamin D deficiency is more closely linked to osteoporosis than inadequate calcium intake.

The difference between osteomalacia and osteoporosis:

Osteoporosis is the name of the disease where there is loss of total bone content.  Inadequate bone mass is osteopenia, which precedes osteoporosis.  When the loss of bone mineral density is more than 2 standard deviations less than a normal standard, the label “osteoporosis” is used.  With osteomalacia, the amount of bone is normal, but the there is less overall mineral in the bone.

Toxicity: Vitamin D is very toxic and toxicity can occur with regular intakes of more than 100,000 IU for an extended period of time.  Toxicity does not result from sun exposure.  Toxicity of vitamin D can result in excessive calcium absorption and bone loss, resulting in hypercalcemia and calcium being deposited in the kidneys, heart, and blood vessels.  Vitamin D in pill form has been used to treat osteoporosis.  The current dietary recommendation for vitamin D is thought to be too low to maintain the blood levels of vitamin D needed to prevent osteoporosis; there is debate regarding what the requirement for vitamin D should be.  Also, the supplement form of vitamin D that is effective is cholecalciferol and not the ergosterol form.

Dietary sources of vitamin D: few foods have sufficient amounts of vitamin D.  Fatty fish are a good source (sardines, salmon, fish oil pills, as vitamin D is in the oil of the fish).  Vitamin D is fortified into milk and some cereals and nutrition bars.  Since vitamin D can be synthesized endogenously, deficiency usually occurs in people with a combination of limited dietary intake and/ or intestinal malabsorption, and limited exposure to sunlight.

 Vitamin E is a family of 8 compounds that vary in their function/ activity.  There are 4 tocopherols and 4 tocotrienols and both families have alpha, beta, gamma, delta versions.

Functions: the main function of vitamin E is as a fat soluble antioxidant.  The most active antioxidant form of vitamin E is alpha tocopherol.  Vitamin E is carried by LDL where it can help decrease oxidation of LDL, but also be brought to parts of the body that might need anti-oxidation activity.  One of the main antioxidant functions is protecting cell membranes from oxidation that results from polyunsaturated fat content in the cell membrane.  Polyunsaturated fatty acids can become part of the phospholipids in the cell membrane and readily oxidize.  Please note that no benefit has been shown from using vitamin E as a supplement to decrease oxidation.  In fact, studies have shown an increase in disease and also an increase in the risk of hemorrhagic strokes form mega doses of vitamin E.

Deficiency: a deficiency of vitamin E has only been seen in premature infants.  It presents as hemolytic anemia and results from the present of polyunsaturated fat in the red blood cell membrane, which makes the membrane susceptible to oxidation.  Preterm infants are born with inadequate levels of vitamin E and their rapid growth means an increase in requirement.  While rare in adults, vitamin E deficiency can occur in smokers as the byproducts of tobacco can destroy the vitamin E present in the lungs; vitamin E deficiency can also occur with general malabsorption.

Toxicity:  it is not clear if mega doses of vitamin E are toxic.  Some studies have indicated mega doses can result in an increase in hemorrhagic strokes.  It has been speculated that the increase in chronic diseases seen with vitamin E supplementation may be the result of an increase in oxidation due to the imbalance of vitamin E forms (i.e., positive and negative versions are balanced in nature but not in pills).

 Dietary sources of vitamin E:  Plant oils naturally contain the highest amount of vitamin E.  The vitamin E content of vegetable seed oils (corn, safflower, soybean) is used to decrease the oxidation of the oil due to the polyunsaturated fat content.  When the oil becomes rancid (indicated by the smell or taste), the oil has oxidized or exhausted the antioxidant content.  Extra virgin olive oil contains the highest amount of alpha tocopherol of any oil. As it does not oxidize, the alpha tocopherol content can be used to decrease oxidation in the body of the person consuming the extra virgin olive oil.

Vitamin E is also found in small amounts in wheat germ and whole grains (milling removes vitamin E), asparagus, peanuts, oatmeal, nuts, and seeds.  There is little to no vitamin E in animal products.  The vitamin E content of food depends on processing, handling, and storage as it is susceptible to oxygen, metals, and light.

Note: the requirement for vitamin E depends on the amount of polyunsaturated fat in the diet.  The more polyunsaturated fat one eats the more vitamin E that is required.  A diet using primarily extra virgin olive oil, which has primarily monounsaturated fat, requires less vitamin E and the alpha tocopherol in extra virgin olive oil can be used to decrease oxidation elsewhere.

There are 2 forms of vitamin K: phyloquinone which is K1 and found in plant foods and menaquinones which is K2 and found in fish oils and meats. K2 is also synthesized by bacteria in the gastrointestinal tract.

Functions: vitamin K is required for the hepatic synthesis of prothrombin and blood clotting factors II, VII, IX, and X. Vitamin K is also required for carboxylation of glutamic acid residues.  Thus, vitamin K is required for blood clotting.  Warfarin (Coumadin) interferes with this process by inhibiting the regeneration of vitamin K, which makes the blood less likely to clot.  Patients on warfarin need to regulate their intake of vitamin K.  While patients on Coumadin are typically told to avoid foods rich in vitamin K, they can also have a consistent intake of vitamin K containing foods and the dose of Coumadin can be adjusted accordingly.

Recent research has shown that vitamin K is also involved in the formation of 2 bone proteins required in bone synthesis.  Thus, vitamin K has a role in bone strength.

Deficiency:  a deficiency of vitamin K is rare as the bacteria in the large intestine synthesis vitamin K.  However, prolonged use of antibiotics and/or general malnutrition can result in vitamin K deficiency.  Infants at birth cannot synthesize vitamin K and typically received an intramuscular injection soon after birth.  Due to the role in bone strength, vitamin K deficiency has also been related to osteoporosis.

Toxicity:  vitamin K toxicity is unlikely in adults.  Mega doses in an infant can result in hemolytic anemia due to injury to the membranes of the red blood cells (RBC).

Dietary sources of vitamin K:  dietary sources are all leafy green vegetables, broccoli, peas, green beans, egg yolk, and liver.

References

  1. Rickman JC BC, Barrett DM. Nutritional comparison of fresh, frozen, and canned fruits and vegetables II. Vitamin A and carotenoids, vitamin C, minerals and fiber. Journal of the Science of Food and Agriculture 2007; 87:1185-1196.
  2. Rickman JC BD, Bruhn CM. Nutritional comparison of fresh, frozen and canned fruits and vegetables. Part 1. Vitamins C and B and phenolic compounds. Journal of the Science of Food and Agriculture 2007; 87:930-944.
  3. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women.  JAMA 2002; 287; 47-54.