The term vitamin D refers to the secosterols ergocalciferol or vitamin D2 and cholecalciferol or vitamin D3 as well as to the metabolites and analogues of these substances. All forms of vitamin D possess antirachitic activity. Vitamin D is different from all of the other vitamins in human nutrition because it is the only vitamin that is a conditional one. Vitamin D3 is synthesized in the skin from 7-dehydrocholesterol via photochemical reactions using ultraviolet B (UV-B) radiation from sunlight. However, there are conditions where the synthesis of vitamin D3 in the skin is not sufficient to meet physiological requirements. Humans who are not exposed to sufficient sunlight due to reason of geography, shelter or clothing, require dietary intake of vitamin D. Under these conditions, vitamin D is an essential nutrient. Vitamin D without a subscript refers to either vitamin D2 or vitamin D3.
Vitamin D is the principal regulator of calcium homeostasis in the body. It is particularly important in skeletal development and bone mineralization. Vitamin D is a prohormone. That is, it has no hormone activity itself, but is converted to a molecule which does.
The active form of vitamin D is 1alpha, 25-dihydroxyvitamin D or 1,25(OH2)D (again, when D is used without a subscript it refers to either D2 or D3). The vitamin D hormone 1,25 (OH2)D mediates its actions via binding to vitamin D receptors (VDRs) which are principally located in the nuclei of target cells. 1,25(OH2)D enhances the efficiency of calcium absorption, and, to a much lesser extent, phosphorus absorption, from the small intestine. Vitamin D deficiency is characterized by inadequate mineralization or demineralization of the skeleton. Inadequate mineralization of the skeleton is the cause of rickets in children (vitamin D is also known as the antirachitic factor), while demineralization of the skeleton results in osteomalacia in adults. Further, vitamin D deficiency in adults can lead to osteoporosis. This results from a compensatory increase in the production of parathyroid hormone resulting in resorption of bone.
Very few foods are natural sources of vitamin D. Foods that do contain vitamin D include fatty fish, fish liver oils (e.g., cod liver oil) and eggs from hens that have been fed vitamin D. Nearly all the vitamin D intake from foods comes from fortified milk products and other foods, such as breakfast cereals, which have been fortified with vitamin D. Vitamin D is a fat-soluble vitamin and therefore its absorption is adversely affected in those with malabsorption disorders. Those with chronic liver disease, cystic fibrosis, Crohn's disease, Whipple's disease and sprue are prone to vitamin D deficiency. Others at risk for vitamin D deficiency, include those that do not drink milk and who do not receive much sunlight, those who live in regions where they receive little natural light, and alcoholics. The elderly are at risk for vitamin D deficiency for several reasons, including inadequate exposure to sunlight, consumption of low amounts of vitamin D-containing foods and the use of certain drugs, which interfere with the absorption and/or metabolism of vitamin D (see Interactions). In addition, older adults need higher amounts of vitamin D than younger adults because of decreased absorption of the vitamin. The use of sunscreens is another factor that can negatively affect vitamin D status. However, those who spend time in the sun without using a sunscreen put themselves at risk for skin cancers.
Over the last several years, studies have indicated that vitamin D may play beneficial roles in a wide range of diseases and disorders, including osteoporosis, cancer, multiple sclerosis, heart disease, psoriasis and Alzheimer's disease. We are also gaining greater insight into the mechanism of the various actions of the vitamin/prohormone. As mentioned above, it appears the active form of vitamin D, 1,25 (OH2)D3, mediates its actions via binding to the vitamin D receptor (VDR). The VDR is a high-affinity receptor, which acts as a ligand-activated transcription factor. Ligand binding results in obligate VDR heterodimerization with the retinoid X receptor (RXR). This receptor is a common partner for nuclear receptors. The activated heterodimer binds with strong affinity to vitamin D response elements (VDREs) in the promotion of target genes, close to the basic transcriptional machinery. The process is associated with the recruitment and assembly of several nuclear proteins serving as positive or negative coregulators, ultimately altering the rate of gene transcription. VDR, like other nuclear receptors, recruits in the nucleus co-regulators with either histone acetyltransferase or histone deacetylase activities. Histone acetylation results in a more relaxed chromatin structure associated with greater levels of gene transcription. On the other hand, histone deacetylation results in a less relaxed chromatin structure associated with lesser levels of gene transcription. Thus, VDR function is directly linked to epigenetic events. Importantly, the global tissue distribution of VDR underscores the ability of 1,25 (OH2)D3 to regulate cellular processes not directly related to mineral and skeletal homeostasis.
The two forms of vitamin D used for nutritional supplementation are the secosterols ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Secosterols or secosteroids are derived from the cyclopentanoperhydrophenanthrene ring structure, the basic structure of all steroids. The cyclopentanoperhydrophenanthrene structure is comprised of four rings (A, B, C and D). Secosterols or secosteroids are steroids in which one of the rings has been broken. In the case of vitamin D, the bond between carbons 9 and 10 of ring B is broken, and this is indicated by the inclusion of ""9, 10-seco'' in the chemical name of the molecule. Seco is from the Greek word for split.
Vitamin D2 is derived from fungal and plant sources. It is usually produced by the ultraviolet irradiation of the fungal sterol ergosterol. Vitamin D2 is also known as ergocalciferol. Its chemical names are 9, 10-seco (5Z, 7E)-5, 7, 10(19), 22-ergostatetraene-3beta-ol and (3 beta, 5Z, 7E, 22E)-9, 10-secoergosta-5, 7, 10(19), 22-tetraen-3-ol. Its molecular formula is C28H44O and its molecular weight is 396.66 daltons. The configuration of the double bonds are notated E for entgegen (from the German, meaning to stand opposite to) or trans, and Z for zusammen (from the German, meaning together) or cis. Vitamin D2 is represented by the following structural formula:
Vitamin D3 is derived from animal sources. Vitamin D3 is also known as cholecalciferol and calciol. Its chemical names are 9, 10-seco (5Z, 7E)-5, 7, 10(19) cholestatriene-3beta-ol and (3beta, 5Z, 7E)-9, 10-secocholesta-5, 7, 10(19)-trien-3-ol. Its molecular formula is C27H44O, and its molecular weight is 384.65 daltons. The only structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of vitamin D2 contains a double bond between carbons 22 and 23 and a methyl group on carbon 24. The structural formula of vitamin D3 can be represented as follows:
Pharmaceutical forms of vitamin D include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene. Calcitriol and doxercalciferol are used to treat certain metabolic disorders; calcipotriene is used topically for the treatment of psoriasis.
Vitamin D analogues called deltanoids are being developed as chemopreventive agents. These analogues separate desirable antiproliferative and pro-differentiation activities from the undesirable hypercalcemic activity of vitamin D. High doses of vitamin D can result in hypercalcemia.
Actions & Pharmacology
Vitamin D may have anti-osteoporotic, antituberculosis, anti-inflammatory (immunomodulatory), anticarcinogenic, antipsoriatic, antioxidant and mood-modulatory activities.
Mechanism of Action
Antiosteoporotic activity: Osteoporosis results from an imbalance between bone resorption and bone formation. Decreased vitamin D levels result in decreased production of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2 D). 1,25 (OH)2 D enhances the efficiency of calcium absorption. Chronic vitamin D deficiency results in decreased calcium absorption and secondary hyperparathyroidism. Increased bone resorption may be a consequence of vitamin D deficiency, resulting from secondary hyperparathyroidism. Therefore, vitamin D supplementation might be expected to protect against osteoporosis and fractures in those with occult vitamin D deficiency. Vitamin D may also be effective in the treatment of corticosteroid-induced osteoporosis by virtue of its stimulation of calcium absorption from the small intestine and its inhibition of the secretion and production of parathyroid hormone.
Antituberculosis activity: In the prechemotherapy era, tuberculosis (TB) was treated with good nutrition, vitamin D-containing cod-liver oil, rest, sunlight (especially sunlight) and fresh air. This regimen was the basis of the sanatorium movement for the treatment of tuberculosis. Those who are familiar with Thomas Mann's The Magic Mountain know that the setting of the novel is a tuberculosis sanatorium in Davos in the Swiss Alps. The first sanatorium in the United States was established in Saranac Lake, New York, in the heart of the Adirondack Mountains. Well over a century ago, it was thought that sunlight could treat tuberculosis.
In 1903, the Danish physician Niels Ryberg Finsen was awarded the Nobel Prize in Physiology or Medicine ""in recognition of his contribution to the treatment of diseases, especially lupus vulgaris (tuberculosis of the skin), with concentrated light radiation, whereby he has opened a new avenue for medical science.'' Unfortunately, he could not attend the award ceremony, since he was very ill from a progressive hereditary disorder, Niemann-Pick disease. The philosopher Jacob Bronowski held that the greatest discoveries in science are made when the scientist tries to answer a very personal question. For Finsen, that question was how to treat his serious and disabling disease. In his 20s, he began to believe that, since he lived in a house facing the north, he would feel better if he received more sun. He began to collect observations about animals seeking the sun and he became more and more convinced that the sun had useful and important effects on the organism. In simple experiments, he found that the most refractive rays from the sun or from an electric arc had a stimulating effect on tissue. He eventually exposed patients with lupus vulgaris to high-intensity light produced from an electric arc lamp. The exposure of a small area of affected skin to the intense light, comprised of both ultraviolet and infrared rays, produced a moderate sunburn, leading to the peeling away of the superficial skin layers and leaving normal, healthy skin. He discovered that this phototherapeutic treatment cured or substantially improved tuberculosis of the skin in approximately 95% of those affected with this disorder. By the 1920s, sun exposure for the treatment of pulmonary tuberculosis had become routine. It also became clearer why sanatoria located in the Swiss Alps, the Adirondacks, or other places where the absorption of the sun's rays by the atmosphere was small had a good success rate with their tuberculosis patients. Sadly, the concentrated chemical light ray therapy did not stop the progression of Finsen's Niemann-Pick disease, and he died at the age of 43.
It is only recently that the mechanism of the antituberculosis effect of sunlight has become clearer. It appears that sunlight, by stimulating the synthesis of vitamin D, upregulates the expression of a microbe-fighting peptide known as LL-37 (cathelicidin). Sunlight, especially its UVB rays, induces the synthesis within the skin of vitamin D3 (cholecalciferol) from 7-dehydrocholesterol (7-DHC). Vitamin D3 is converted successively to 25-hydroxyvitamin D3 and then to 1,25-dihydroxyvitamin D3 within the skin keratinocytes. Sunlight also induces the expression of the vitamin D receptor (VDR). Together, 1,25-dihydroxyvitamin D3 and the VDR induce the expression of the gene encoding the human antimicrobial peptide LL-37. Human LL-37 is a 37 aminoacid peptide that belongs to the cathelicidin family of antimicrobial peptides. (LL-37 is also referred to as cathelicidin, its family name.) The above pathway for the production of the antimicrobial peptide LL-37 is located in the skin. There is yet another pathway for the production of LL-37 that is located in the circulating monocytes-macrophages. That pathway begins with vitamin D3 entering the systemic circulation where it is transported to the liver to be converted to 25-hydroxyvitamin D3. Circulating monocytes are activated by toll-like receptor2/1 (TLR2/1) agonists present on specific microbes. The genes encoding VDR and CYP27B1 are induced. CYP27B1 converts 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3, which joins with the VDR and activates the gene encoding LL-37, leading to an increase in cellular LL-37 and enhanced microbicidal activity of the phagocytes.
Immunomodulatory/anti-inflammatory activities: Vitamin D has been found to modulate nuclear factor-kappa B (NF-kappaB) activation and to modulate the canonical Wnt signaling pathway. Increased NF-kappaB activity was noted in fibroblasts derived from VDR-/-mice, probably due to a loss of both VDR-mediated stabilization of IkappaBalpha, a potent NF-kappaB inhibitor, by 1,25 (OH)2 D3, and physical interaction between VDR and the p65 subunit of NF-kappaB. Vitamin D was found to upregulate IkappaBalpha levels in murine macrophage cells by increasing mRNA stability and decreasing IkappaBalpha phosphorylation, all molecular events that led to blunting of NF-kappaB activity. The vitamin D-VDR mediated effects on the NF-kappaB signaling pathway, a major proinflammatory pathway, provide a strong mechanistic rationale for the well-documented anti-inflammatory/immunomodulatory role of vitamin D.
Vitamin D deficiency has long been suspected to increase the susceptibility to tuberculosis. The active form of vitamin D, 1,25 (OH)2 D, has been found to enhance the ability of mononuclear phagocytes to suppress the intracellular growth of Mycobacterium tuberculosis. 1,25(OH)2D has demonstrated beneficial effects in animal models of such autoimmune diseases as rheumatoid arthritis. It has also been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin (IL)-1 and IL-2, as well as to suppress immunoglobulin secretion by B lymphocytes. These effects are thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25(OH)2D has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.
Anticarcinogenic activity: 1,25-dihydroxyvitamin D has been found to induce differentiation, to inhibit cell proliferation and to induce apoptosis in a number of malignant cell lines, including human prostate cancer cells. 1,25-dihydroxyvitamin D suppresses the in vivo growth of human cancer (colon cancer, malignant melanoma) solid tumor xenografts. It has been demonstrated in various cancer cell lines that 1,25-dihydroxyvitamin D causes a dose-dependent inhibition of cell proliferation and switches cellular activity from proliferation to differentiation. 1,25-dihydroxyvitamin D has also been demonstrated to inhibit the growth of renal cell carcinoma cells in culture, to inhibit the growth of retinoblastoma in mice and to be antiproliferative and pro-differentiating for leukemia cells. The anticarcinogenic activity of the active form of vitamin D appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25-dihydroxyvitamin D and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. For example, the binding of 1,25-dihydroxyvitamin D to the VDR in intestinal cells activates the transcription of the calcium-binding protein which enhances the absorption of calcium. It is thought that the anticarcinogenic effect of vitamin D is mediated via VDRs in cancer cells.
The mechanism of action of the anticarcinogenic activity of vitamin D, however, is not fully understood. A recurring observation is that one of the key antiproliferative actions of vitamin D is upregulation of members of the Cip/Kip family of inhibitors of cell cycle progression, such as p21waf1/cip1, a regulatory action on the cell cycle that vitamin D shares with the tumor suppressor protein p53. It has been shown that the tumor p21 gene has at least three vitamin D-responsive promoter regions, in two of which p53 also colocalizes. 1,25-dihydroxyvitamin D has been found to induce apoptosis of cancer cells in vitro and in vivo. It downregulates the antiapoptotic bcl-2 protein and upregulates p53 expression, resulting in active cell death. It also upregulates clusterin and cathepsin B. 1,25-dihydroxyvitamin D has also been shown to have antiangiogenesis activity. In vitro, it was found to inhibit vascular endothelial growth factor (VEGF)-induced endothelial sprouting and elongation and to have a significant inhibitory effect on VEGF-induced endothelial cell proliferation. In vivo, it was found to produce tumors that were less vascularized than tumors formed in mice treated with vehicle alone.
Antipsoriatic activity: 1,25-dihydroxyvitamin D and its analogues have been found to be effective in the treatment of psoriasis when applied topically. Psoriasis is a cutaneous disorder involving abnormal cellular proliferation and differentiation. The mechanism of action of 1,25-dihydroxyvitamin D and its analogues in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation.
Antioxidant activity: Vitamin D3 has been found to inhibit lipid peroxidation in rat hepatocytes in vivo, to inhibit iron-dependent lipid peroxidation in liposomes and to modulate cellular antioxidant defense in lymphoma-bearing mice. The mechanism of the antioxidant effect of vitamin D is unknown.
Mood modulating activity: Vitamin D3, in two human studies, was found to significantly enhance positive affect and possibly reduce negative affect. The mechanism of this possible mood-modulating effect is unclear. It is speculated that vitamin D may affect brain serotonin levels.
Vitamin D is principally absorbed in the small intestine. It is absorbed from the lumen of the small intestine into the enterocytes by passive diffusion. Vitamin D is delivered to the enterocytes in micelles formed from bile acids and other substances. The efficiency of absorption of vitamin D is high. Approximately 50% to 80% of ingested vitamin D is absorbed. Vitamin D is secreted by the enterocytes into the lymphatics in the form of chylomicrons. It enters the circulation via the thoracic duct. Vitamin D is transported in the blood bound to an alpha-globulin vitamin D binding protein. This protein is also known as the vitamin D-binding protein (DBP) and the group-specific component (Gc) protein. A large faction of circulating vitamin D is extracted by the hepatocytes. It is metabolized to 25-hydroxyvitamin D (25(OH)D) or calcidiol in the hepatocytes, via the enzyme vitamin D 25-hydroxylase. 25(OH)D is the major circulating form of vitamin D. This metabolite of vitamin D, however, is not biologically active under physiological conditions. The biologically active hormone form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2 D) or calcitriol, is produced in the kidney via the enzyme 25-hydroxyvitamin D1-alpha-hydroxylase. This enzyme is a cytochrome P450 mixed function oxygenase also known as CYP27B1. 25(OH)D and 1,25(OH)2 D may undergo hydroxylation catalyzed by the enzyme cytochrome P450C24 (CYP24), also a cytochrome P450 mixed function oxygenase, to form 24, 25-dihydroxyvitamin D (24, 25(OH)2 D) and 1,24,25-trihydroxyvitamin D (1,24,25(OH)3 D), respectively. Deactivation of 1,25(OH)2 D and 25 (OH) D occurs via hydroxylation at C-24 catalyzed by CYP24. Other metabolites of 1,25 (OH)2 D include calcitroic acid and the lactone 1alpha, 25R (OH)2-26,23S-lactone cholecalciferol. Vitamin D and its metabolites are excreted primarily via the biliary route. The final degradation product of 1, 25 (OH)2 D3 is calcitroic acid, which is excreted by the kidney.
Indications & Usage
In recent years, it can be argued, no major nutrient has garnered as much research attention as vitamin D, nor produced as many significant positive results. Once a dowdy backbencher in the supplement marketplace, vitamin D now appears to be reaching for superstar supplement status, partly due to the findings that most of us do not get adequate amounts of this crucial vitamin, either from diet or sun exposure, and that this deficit can result in serious negative health consequences. Since the first edition of this PDR appeared, evidence of vitamin D's benefit in bone health has expanded and solidified considerably. It appears to reduce bone loss in aging men and in postmenopausal women, and to significantly reduce the risk of falls among the aging. Some have calculated that in this context alone increased vitamin D intake could save the economy billions of dollars a year in avoidable medical costs. It also helps ensure normal bone development in infants and toddlers. Evidence is mounting that demonstrates significant anticancer and cardioprotective effects of vitamin D. Some researchers have concluded that half of all colorectal cancers in the United States might be prevented through increased vitamin D intake. Some 28,000 deaths from this cancer alone might thus be prevented, say these researchers. Other research suggests that vitamin D is useful in breast, prostate and ovarian cancers, among others.
Research is intensifying with respect to vitamin D's role in heart health as a result, in part, of recent findings that vitamin D levels are associated with all-cause and cardiovascular mortality. Indeed, some recent research observations suggest that vitamin D supplementation might have an antimortality effect generally. Vitamin D has immunomodulating activity and may be helpful in some autoimmune disorders, including multiple sclerosis. It has antimicrobial properties and may be useful, for example, in tuberculosis. It shows some promise in both type 1 and type 2 diabetes. It may be neuroprotective and shows very preliminary promise of impeding cognitive decline in those with Alzheimer's disease. It may have some positive impact in some forms of mental depression and may be radioprotective. Additionally, it may be of benefit in seizure, bilateral cochlear deafness, sick sinus syndrome and some forms of infertility. Its hoped-for usefulness in chronic kidney disease remains unproven.
Hypercalcemia can result either from excess intakes of prescribed forms of vitamin D or from consumption of high amounts of vitamin D2 or vitamin D3. The hypercalcemia associated with hypervitaminosis D may cause multiple debilitating effects. Anorexia, nausea and vomiting have been observed in hypercalcemic individuals treated with 1,250 to 5,000 micrograms (50,000 to 200,000 IU)/day of vitamin D. Hypercalcemia can result in a loss of the urinary concentrating mechanism of the kidney tubule, resulting in polyuria and polydipsia. The prolonged ingestion of excessive amounts of vitamin D and the accompanying hypercalcemia can result in metastatic calcification of soft tissues, including the kidney, blood vessels, heart and lungs. Typically, chronic ingestion of 50,000 to 100,000 IU/day of vitamin D is required to produce hypercalcemia. Since vitamin D stores in fat may be substantial, vitamin D intoxication may persist for weeks after vitamin D ingestion is terminated. The elimination half-life of vitamin D is about 20 to 29 days.
Supplemental vitamin D is available as vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol). Typical dosage is 200 to 400 IU (5 to 10 micrograms) daily. Pre- and postnatal multi-vitamin, multi-mineral supplements typically deliver a dose of 400 IU daily. Vitamin D2, which comes from the UV irradiation of ergosterol obtained from yeast, has been used for the prevention and treatment of vitamin D deficiency in children and adults for over 80 years and has been considered to be equally as effective as vitamin D3 for bone health. However, a couple of reports suggest that vitamin D2 is less effective than vitamin D3 in maintaining vitamin D status. A recent study, though, found that a 1,000 IU dose of vitamin D2 daily was as effective as 1,000 IU of vitamin D3 in maintaining serum 25-hydroxyvitamin D levels.
Although it is not commonly done, it would be a wise to have one's serum vitamin D level checked by a physician. In fact, recognizing that adequate vitamin D levels might save millions of dollars for the healthcare industry, it would be a good idea to have vitamin D levels as part of a regular blood panel. Serum 25-hydroxyvitamin D3 is the major circulating form of vitamin D. It has been suggested by some of the leading vitamin D researchers that a beneficial level of serum 25-hydroxyvitamin D3 should be at least 30 nanograms per milliliter (30 ng/ml), but not more than 150 ng/ml. For some, this may require 2,000 to 3,000 IU a day, or higher, to reach that goal. Consult your physician before exceeding 2,000 IU daily.
Pharmaceutical preparations containing 50,000 IU (1,250 micrograms) of vitamin D2 are used in the treatment of vitamin D deficiency in the elderly and in those with malabsorption syndromes, nephrotic syndrome and hepatic failure. Dosage used is 50,000 IU once weekly for eight weeks. This must be done under medical supervision.
The Food and Nutrition Board of the Institute of Medicine of the U.S. National Academy of Sciences has recommended the following adequate intakes (AI) for vitamin D (the biological activity of one microgram of vitamin D2 or vitamin D3 is 40 IU [international units]):
|0 through 12 months||5.0 micrograms (200 IU)/day|
|1 through 8 years||5.0 micrograms (200 IU)/day|
|9 through 18 years||5.0 micrograms (200 IU)/day|
|9 through 18||5.0 micrograms (200 IU)/day|
|19 through 50 years||5.0 micrograms (200 IU)/day|
|51 through 70 years||10.0 micrograms (400 IU)/day|
|Older than 70 years||15.0 micrograms (600 IU)/day|
|19 through 50 years||5.0 micrograms (200 IU)/day|
|51 through 70 years||10.0 micrograms (400 IU)/day|
|Older than 70 years||15.0 micrograms (600 IU)/day|
|14 through 50 years||5.0 micrograms (200 IU)/day|
|14 through 50 years||5.0 micrograms (200 IU)/day|
The LOAEL (lowest-observed-adverse-effect level) for vitamin D is set at 95 micrograms (3,800 IU)/day. The adverse effect referenced is hypercalcemia which is defined as a serum calcium level above 2.75 mmoles per liter or 11 milligrams per deciliter. The NOAEL (no observed-adverse-effect level) for vitamin D is set at 60 micrograms (2,400 IU) /day.
The Food and Nutrition Board of the Institute of Medicine has recommended the following tolerable upper limit intake levels (UL) for vitamin D:
|0 through 12 months||25 micrograms (1,000 IU)/day|
|1 through 18 years||50 micrograms (2,000 IU)/day|
|Older than 18 years||50 micrograms (2,000 IU)/day|
|14 through 50 years||50 micrograms (2,000 IU)/day|
|14 through 50 years||50 micrograms (2,000 IU)/day|
The DV (Daily Value) for vitamin D, which is used for determining the percentage of nutrient daily values on nutritional supplement and food labels, is 400 IU. This is based on the U.S. RDA for vitamin D.
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Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA. 1999;281:1505-1511.Li M, Hener P, Zhang Z, et al. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci USA. 2006;103(31):11736-11741.Lipkin M, Lamprecht SA. Mechanisms of action of vitamin D: recent findings and new questions. J Med Food. 2006;9(2):135-137.Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med. 1996;124:400-406.Liu PT, Stenger S, Li H, et al.Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770-1773.Lowe KE, Norman AW. Vitamin D and psoriasis. Nutr Rev 1992;50:138-142.Maalouf J, Nabulsi M, Vieth R, et al. Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children. 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Nutr Rev. 1998;56(5 Pt 1):148-150.Oudshoorn C, Mattace-Raso FU, van der Velde N, et al. Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 2008;25(6):539-543.Palmer SC, McGregor DO, Macaskill P, et al. Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med. 2007;147(12):840-853.Prabhala A, Garg R, Dandona P. Severe myopathy associated with vitamin D deficiency in Western New York. Arch Intern Med. 2000;160:1199-1203.Raghuwanshi A, Joshi SS, Christakos S. Vitamin D and multiple sclerosis. J Cell Biochem. 2008;105(2):338-343.Ralph AP, Kelly PM, Anstey NM. L-arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis. Trends Microbiol. 2008;16(7):336-344.Richards JB, Valdes AM, Gardner JP, et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr. 2007;86(5):1420-1425.Sardar S, Chakraborty A, Chatterjee M. Comparative effectiveness of vitamin D3 and dietary vitamin E on peroxidation of lipids and enzymes of the hepatic antioxidant system in Sprague-Dawley rats. Int J Vitam Nutr Res. 1996;66:39-45.Sato Y, Asoh T, Oizumi K. High prevalence of vitamin D deficiency and reduced bone mass in elderly women with Alzheimer's disease. Bone. 1998;23:555-557.Shah N, Bernardini J, Piraino B. Prevalence and correction of 25(OH) vitamin D deficiency in peritoneal dialysis patients. Perit Dial Int. 2005;25(4):362-366.Takasu H, Sugita A, Uchiyama Y, et al. c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs. J Clin Invest. 2006;116(2):528-535.Tonelli M. Vitamin D in patients with chronic kidney disease: nothing new under the sun. Ann Intern Med. 2007;147(12):880-881.Tsoukas CD, Watry D, Escobar SS, et al. Inhibition of interleukin-1 production by 1,25-dihydroxyvitamin D3. 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Research & Summary
Vitamin D is an important prohormone derived from diet, from supplements and from our skin's ability to synthesize it with the help of sunlight. Since it is naturally available in very few foods (principally in fatty fish), a number of foods, especially milk and some cereals, have been fortified with it in an effort to provide greater intake. Though principally known for its important role in calcium metabolism and skeletal mineralization, it is widely present in many organs/tissues of the body where it plays varied and complex roles, which are only gradually beginning to be more fully understood. Various recent studies indicate that most of us get inadequate vitamin D either in our diets or via exposure to sunlight. How significant is this inadequacy? One study suggested that a majority of us are getting less than half of the currently recommended amount of this vitamin.
Other studies indicate that at least 40% of elderly men and women are frankly vitamin D deficient. Why is this? In our distant history, it has been pointed out, we were largely unclothed and exposed to much more sunlight and to sunlight, moreover, that was not attenuated by the prevalent air pollution we experience globally today. Given the much shorter life spans of that early human history, the development of skin cancers later in life was not the issue that it is today. Prevalent use of sunscreens and concern about skin cancer and aging have today further reduced our exposure to sunlight and thus to endogenous vitamin D production via skin synthesis. Increasingly, researchers are thus recommending supplementation with vitamin D ""to at least 800 IU of vitamin D, per day'' (New England Journal of Medicine). The National Academy of Sciences has set 2,000 IU daily as the safe upper intake level. Obtaining even 800 IU through diet is almost impossible unless one eats large amounts of oily fish or spends inordinate amounts of time, unprotected, in sunlight—not advised. Considerably higher doses of Vitamin D pose toxicity issues and should be avoided. (See Dosage and Administration for more-detailed recommendations.)
It has long been known that vitamin D deficiencies can lead to rickets and other bone problems in the young. Now the importance of this vitamin in the bone health of the elderly is becoming clearer. Most of the case control studies that have addressed this issue have found an inverse relationship between vitamin D levels and fracture in elderly men and postmenopausal women. There are, however, some inconsistencies in the data and the association is strongest for white, postmenopausal women. Functional bone health outcomes, such as the effect of falls, are the best-investigated aspect of this emerging picture. In a meta-analysis of vitamin D's effect on falls, a reduction of 22% in the risks attending these falls was reported among ambulatory or institutionalized older individuals with stable health. Only double-blind, randomized trials were included in the analysis—and the positive effect reported was said to be independent of calcium supplementation and several other important variables. The favorable result seen here was attributed in large part to the binding of a vitamin D metabolite to a highly specific nuclear receptor in muscle tissue (an action reported in several other research inquiries), resulting in enhanced muscle function which, in turn, it was hypothesized, helped prevent falls. This effect helps reduce the so-called ""body sway'' often observed in the aging. In some of the studies, doses in the 400 IU daily range were said to be insufficient to exert a significant effect, whereas 800 IU daily did exert significant effect. Given the high morbidity, mortality and economic cost of falls among the elderly, the authors of this meta-analysis stated that the case for supplementation in this population is ""compelling.'' Other data established a clear relationship between low serum levels of vitamin D and incidence of osteoarthritis and bone fracture. The progression of osteoarthritis of the knee was associated with low dietary intake of vitamin D in the Framingham study.
A high incidence of occult vitamin D deficiency was found in a group of postmenopausal women who had suffered hip fractures. The researchers suggested that ""repletion of vitamin D and suppression of parathyroid hormone at the time of fracture may reduce future fracture risk and facilitate hip fracture repair.'' They added that ""supplements of about 800 IU of vitamin D per day and calcium may be necessary to attenuate bone loss in the winter and to reduce fractures.''
Some have doubted that supplemental vitamin D would have much direct impact on osteoporosis and bone fracture. Vitamin D deficiency has not been shown to be a direct cause of osteoporosis. It produces osteomalacia, a defect in bone mineralization, rather than the reduction in bone mass that characterizes osteoporosis. Nonetheless, osteomalacia itself may predispose to bone fracture. Others have observed that vitamin D deficiency, now known to be considerably more prevalent in elderly populations than previously suspected, can also result in muscle weakness, another possible contributor to falls and fractures. And recently at least one function of vitamin D in osteoblasts associated with the development of clinical osteoporosis has been found.
Some studies have, in fact, failed to find any benefit from supplemental vitamin D in the prevention and treatment of osteoporosis. The majority of studies, however, have reported significant benefits, evidenced by a review of 23 studies. Positive outcomes, measured primarily by increase in bone density, were associated, in this review, with higher doses, longer duration of use and more sensitive methods of measuring bone mass.
Some of the best results have been obtained in studies using considerably higher than the typical 400 IU doses daily and administering calcium simultaneously. Response also appears sensitive to the subject population. More geriatric and infirm populations that are indoors more tend to have lower vitamin D levels and greater suppression of serum parathyroid hormone levels, and these populations seem to show greater response to vitamin D therapy.
In a three-year study, supplemental vitamin D was given at a dose of 800 IUs daily in combination with a calcium supplement. The population group included nursing home residents who were indoors most of the time. The vitamin D-calcium combination was found to significantly protect against hip fracture in this randomized, double-blind, placebo-controlled study.
In another recent three-year double-blind, placebo-controlled study, a combination of vitamin D (700 IUs daily) and calcium (500 milligrams daily) was tested for its effects on nonvertebral fracture incidence and bone mass maintenance in 389 men and women older than 65. The researchers concluded that this combination ""led to a positive change in biochemical markers related to bone turnover, slowed the rate of bone loss and significantly decreased fracture incidence.''
There is evidence from in vitro, animal and clinical research that supplemental vitamin D, administered during pregnancy in appropriate circumstances and under a physician's supervision, can be of benefit to the neonate, helping to ensure healthy osteogenesis and to prevent low-birth weight. There is also evidence that supplemental vitamin D enhances lactational performance in some. Again, supplemental vitamin D in greater than U.S. RDA amounts should be used during pregnancy and breast feeding only with the recommendation and monitoring of a physician.
There is an abundance of epidemiological data establishing an inverse relationship between vitamin D levels and cancer incidence, particularly with respect to colorectal, breast, prostate and ovarian cancers. It should be noted that black populations have lower levels of vitamin D than do white populations. These levels, in fact, are about half the levels seen in white populations. Some studies have shown that some black populations have higher incidences of some cancers, and researchers, in some instances, have associated these higher incidences to lower vitamin D levels. It has been noted for some time that age-adjusted death rates for colon cancer are higher in areas with low levels of winter sunlight and lower in areas with high levels of winter sunlight. Lower circulating levels of vitamin D are similarly—and highly—correlated with higher incidences of colon cancer. There is a markedly greater risk of colon cancer in the Northeast and lower risks in the South, West and Southwest. One research group recently concluded that intake of 1,000 IU of vitamin D daily is associated with a 50% reduction in risk of colorectal cancer. This was the research group that also concluded that half of the 145,000 new cases of colorectal cancer per year in the U.S. could be prevented with intakes of vitamin D in the 1,000 IU daily range. Another suggests 2,000 IU daily in order to achieve, they estimate, a 50% reduction in colorectal cancer incidence in the U.S. Still another research group, noting a relationship between low levels of vitamin D and digestive-system cancers, has recommended 1,500 IU daily of vitamin D as a preventive for that subset of cancers.
Breast cancer rates are also higher in low-sunlight areas, and observational studies again establish that women with the lowest levels of vitamin D may be at as much as five times the risk of getting breast cancer as those with the highest levels. Supplementing animals with vitamin D, sometimes in combination with calcium, has significantly decreased mammary malignancy in those animal models. Incidence of prostate cancer is three to six times higher, as measured in various studies, in men with low levels of vitamin D, compared to those with high levels. Similar findings apply to ovarian cancer. One group of reviewers has recently stated that it will require doses of 3,500 IU of vitamin D daily to achieve a 50% reduction in breast cancer incidence in the U.S. That dose should be taken only if a medical doctor recommends it and provides monitoring. Worldwide, this group estimates that 250,000 cases of colorectal cancer and 350,000 cases of breast cancer could be prevented with adequate vitamin D intake.
Recently, the results of a four-year population-based, double-blind, placebo-controlled trial revealed a substantially reduced all-cancer risk in postmenopausal women attributable, the researchers concluded, to enhanced calcium and vitamin D nutrition. The amount of vitamin D used in this study was 1,100 IU daily.
Some other recent studies have suggested that higher levels of vitamin D are associated with lower mortality in general, not only with respect to cancer. A meta-analysis of 18 independent, randomized, controlled trials involving 57,311 participants discerned a significant anti-mortality effect associated with vitamin D supplementation. Another group has similarly reported recently that, among 13,331 subjects included in the Third National Health and Nutrition Examination Survey (NHANES III), those with the lowest levels of vitamin D had the highest incidence of all-cause mortality. The subject population was considered representative of the general U.S. population.
The mechanisms by which vitamin D may inhibit mortality overall remain to be clarified; some of the mechanisms by which it inhibits cancer have been partially delineated. There is evidence that it inhibits tumor angiogenesis and exerts antiproliferative effects through enhancement of intercellular communication. It has been shown to inhibit mitosis of breast epithelial cells and to induce apoptosis in various cancer cell lines. It exerts antimetastatic and antiproliferative effects on prostate cells. There is some evidence that vitamin D may be useful in preventing prostate cancer but that vitamin D analogs may be required to effectively treat it once established.
Vitamin D is found in vascular smooth muscle, endothelium and cardiomyocytes. Its favorable role in heart health is suggested by the repeated observation that low serum vitamin D levels are associated with greater prevalence of peripheral arterial disease in the general U.S. population, as well as in many other populations around the world. In in vitro experiments, vitamin D exhibits anticoagulant activity and exhibits other properties that might be favorable to cardiovascular health. In animal studies it inhibits the renin-angiotensin system as well as myocardial cell hypertrophy. The results of a nested case-control study in 18,225 men aged 40 to 75 in the Health Professionals Follow-up Study indicated that low levels of vitamin D are associated with higher risk of heart attack, even after controlling for factors known to be contributive to coronary artery disease. And recently the authors of a prospective cohort study of 3,258 consecutive male and female patients scheduled for coronary angiography at a single center concluded that vitamin D levels are independently associated with all-cause and cardiovascular mortality. The intervention trials needed to establish a definite causal relationship have yet to be conducted, but are needed and warranted.
Preliminary evidence that vitamin D might be able to improve glucose tolerance in some diabetics began to emerge several years ago. Recently, the author of a case report stated that regular doses of vitamin D, up to 2,000 IU daily, showed some efficacy in reducing the risk of developing type 1 diabetes and that vitamin D intervention had improved glycemic control and insulin sensitivity in both type 1 and type 2 diabetics, as well as in normal individuals. This author cited earlier reports that low vitamin D levels have been associated with insulin resistance and obesity. In the case studies cited by this author, reversal of vitamin D deficiency resulted in changes favorable in those with diabetes. Insulin sensitivity has reportedly been improved more by vitamin D administration than by either metformin or troglitazone in one study. Follow-up was too brief in this study, however, to allow for meaningful conclusions. In another study, supplementation with 500 mg of calcium and 700 IU of vitamin D prevented a rise in fasting glucose and slowed the progression of insulin resistance over a three-year period, compared with placebo, in patients with impaired fasting glucose. Three Asian patients exhibited reduced glycemic control after receiving vitamin D2. Unknown metabolites in vitamin D2, it was suggested, might be responsible for the adverse effect seen in that study. Different vitamin D receptor genotypes in various ethnic groups have also been seen to be variable determinants of insulin secretory capacity. Given the overall suggestion of benefit in these preliminary studies, and the fact that prior research has found that vitamin D can help prevent islet cell death and can help improve the survival of islet cell grafts, further study is clearly warranted.
Vitamin D exhibits a number of immunomodulating abilities that may be involved in observed positive effects in some autoimmune disorders, in some infections and, as previously noted, in some cancers. Research conducted some years ago suggested that it increases the potency of cytokines and enhances phagocyte activity and antibody-dependent cytotoxicity of macrophages, and that it boosts natural killer cell activity and helps regulate T cells, among other things. Vitamin D-deficient subjects given supplemental vitamin D have reportedly had significantly fewer infections. One researcher has observed that vitamin D is a ""flexible'' bi-directional immunomodulator that, in some circumstances, can also dampen immune activity in favorable ways. It has been reported, for example, to improve joint symptoms caused by autoimmune psoriatic arthritis. Animal experiments suggest efficacy in some other disorders with autoimmune components, such as multiple sclerosis and rheumatoid arthritis. It has also shown some preliminary ability to control graft rejection and thus may prove helpful in transplantation. Some have suggested that vitamin D and its analogs may be superior to cyclosporine in suppressing transplant rejection and without the serious side effects of that drug. A vitamin D analog's antiproliferative and immunomodulating activities may account for some of its early reported success in treating some with psoriasis. Vitamin D itself has not exhibited this ability in that condition.
Much attention has been given to Vitamin D as a possible adjunctive immunotherapy in tuberculosis, a major public health hazard. In the 1800s and early 1900s, sunlight and vitamin D-rich cod-liver oil were the treatments of choice for tuberculosis. With the advent of antimycobacterial drugs, those once effective treatments were set aside and largely forgotten. Then in vitro tests reminded researchers that vitamin D can inhibit the growth of Mycobacterium tuberculosis. It has been demonstrated that human macrophages require activated vitamin D to kill TB bacilli. It has also recently been shown that vitamin D upregulates the expression of a microbe-fighting peptide. With tuberculosis resurgent again and often very difficult to treat with available drugs, vitamin D is being re-examined anew in this context, particularly as a possible preventive among at-risk populations. A recent review of this issue suggested that vitamin D might have the potential to shorten treatment, reduce infectivity and improve response in drug-resistant TB to other interventives. These reviewers have called for clinical trials to further assess the safety and efficacy of vitamin D in the treatment and prevention of tuberculosis, particularly in conjunction with other substances.
There is emerging evidence that vitamin D has some neuroprotective properties and that it may help inhibit neurocognitive decline and dysfunction, including, possibly, Alzheimer's disease. A recent review of the research literature concluded that vitamin D has neuroprotective effects attributable to its antioxidative, immunomodulating, nerve conducting and detoxifying properties. The vitamin D receptor and catalytic enzymes, these researchers report, have been localized in brain areas related to complex planning and processing and to new memory formation. They concede that the extent to which vitamin D and cognitive function are related remains indefinite but conclude that ""the biological plausibility of this relationship is well supported.'' Quoting studies that show that elderly populations worldwide are 40-100% vitamin D deficient, and that age-related dementia is an enormous and growing public health problem, they conclude that ""the need for well designed longitudinal investigations of vitamin D and cognitive function are critical.'' Some have estimated the national direct and indirect costs of dementia to be in the neighborhood of $100 billion annually. And the U.S. Census Bureau has estimated that nearly 19 million Americans will be age 85 by 2050 and that more than half of these will have some form of dementia.
In a recent cross-sectional study, researchers examined serum levels and Mini-Mental State Examination (MMSE) test scores of 225 older outpatients diagnosed with probable Alzheimer's disease. The vitamin D-sufficient patients were found to have significantly higher MMSE scores compared with vitamin D-insufficient patients. Vitamins B1, B6 and B12 were also examined in this study, but no correlation was observed between levels of these nutrients and MMSE performance. More-definitive studies will be needed—and are warranted—to determine a definite causal relationship between the vitamin and enhanced cognition in Alzheimer's patients.
A relationship between season and frequency of multiple sclerosis (MS) lesions has been observed. Investigators have postulated that vitamin D levels, whether enhanced by diet, supplementation or sunlight, contribute to diminished MS lesion activity. They concluded: ""The impressive correlation also supports the need for proper clinical trials to test whether vitamin D nutrition can reduce formation of CNS lesions and slow the progression of MS.''
Recently, a large population-based study revealed a strong relationship between low serum vitamin D levels/increased parathyroid hormone levels and depression (and severity of depression) in older adults. The finding persisted after adjusting for age, sex, smoking status, BMI, health status, level of urbanization and level of physical activity. Low levels of vitamin D cause an increase in serum parathyroid hormone levels, and primary hyperparathyroidism has been associated with minor depressive disorders. Improvement in mood is commonly seen with successful treatment of hyperparathyroidism. Some previous studies yielded conflicting results with regard to vitamin D's possible role in major depressive disorders; there was some indication in one study it might be helpful in seasonal-related depression. Vitamin D receptor distribution has been reported particularly dense in the human hypothalamus, in areas implicated in the pathogenesis of depression. More pathophysiologic research is needed to further explore this finding. It has been suggested that some future large-scale vitamin D intervention studies on, for example, osteoporosis, might usefully include mood as one of the outcome measures.
Additionally, vitamin D has shown some positive effects on spermatogenesis and benefit in some cases of bilateral cochlear deafness; there is a case study in which it seemed to obliterate the symptoms of sick sinus syndrome, a disorder of sinus node function that is generally treated with antiarrhythmia drugs. In one recent in vitro study, a vitamin D derivative (calcitriol) protected keratinocytes from deleterious effects of ionizing radiation. A recent meta-analysis found that vitamin D compounds do not consistently benefit those with chronic kidney disease.Get the sunshine vitamin at the Pure Matters Shop.
Contraindications, Precautions & Adverse Reactions
Vitamin D is contraindicated in those with hypercalcemia and in those with evidence of vitamin D toxicity. Vitamin D is contraindicated in those with hypersensitivity to any component of a vitamin D-containing product.
Pregnant women and nursing mothers should avoid vitamin D supplemental intakes greater than U.S. RDA amounts of the vitamin unless higher amounts are prescribed by their physicians. The U.S. RDA for vitamin D is 400 IU or 10 micrograms daily.
Pharmaceutical use of vitamin D must only be undertaken under medical supervision.
Supplemental vitamin D should be used cautiously in those on digoxin or any cardiac glycoside. Hypercalcemia in those on digoxin may precipitate cardiac arrhythmias. Supplemental doses of vitamin D greater that upper limit intake levels (UL) should only be used if medically prescribed and should be avoided by those on digoxin or other cardiac glycoside. The UL for adults is 2,000 IU or 50 micrograms daily.
Concomitant use of thiazides and pharmacologic doses of vitamin D may cause hypercalcemia in some.
Dosage of vitamin D up to 60 micrograms (2,400 IU)/day in healthy individuals rarely causes adverse reactions. Chronic dosage of 95 micrograms (3,800 IU)/day or greater in healthy individuals may cause hypercalcemia. Early symptoms of hypercalcemia, include nausea and vomiting, weakness, headache, somnolence, dry mouth, constipation, metallic taste, muscle pain and bone pain. Late symptoms and signs of hypercalcemia, include polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis, pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated ALT (SGPT) and AST (SGOT), ectopic calcification, nephrocalcinosis, hypertension and cardiac arrhythmias.Get the sunshine vitamin at the Pure Matters Shop.
Cholestyramine: Concomitant intake of cholestyramine and vitamin D may reduce the absorption of vitamin D.
Colestipol: Concomitant intake of colestipol and vitamin D may reduce the absorption of vitamin D.
HIV protease inhibitors: The HIV protease inhibitors ritonavir, indinavir and nelfinavir may impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. This is based on in vitro studies conducted in human hepatocyte and monocyte cell lines. Ritonavir had the most potent inhibitory effect.
Ketoconazole: Ketoconazole may inhibit the biosynthesis and catabolism of 1,25-dihydroxyvitamin D. Reductions in serum 1,25-dihydroxyvitamin D concentrations have been observed following the administration of 300 to 1,200 milligrams daily of ketoconazole to healthy men for seven days.
Mineral Oil: Concomitant use of mineral oil and vitamin D may reduce the absorption of vitamin D.
Orlistat: Orlistat may decrease the absorption of vitamin D.
Phenobarbital and Phenytoin: Phenobarbital and phenytoin may reduce plasma levels of 25-hydroxyvitamin D by inhibiting vitamin D 25-hydroxylase activity in the liver.
Calcium: Concomitant intake of calcium and vitamin D may be more effective than no therapy or calcium alone in corticosteroid-induced osteoporosis.
Olestra: The fat substitute olestra inhibits the absorption of vitamin D as well as the other fat-soluble vitamins A, E and K. Vitamins A, D, E (alpha-tocopherol) and K are added to olestra to compensate for this. Olestra contains 12 IU (0.3 micrograms) of vitamin D per gram.