Vitamin D is a fat-soluble vitamin that exists in many forms. The form utilized primarily by humans is vitamin D3 (cholecalciferol).

VITAMIN D

Vitamin D is a fat-soluble vitamin that exists in many forms. The form utilized primarily by humans is vitamin D3 (cholecalciferol). Animals (including humans) can convert cholesterol to 7-dehydrocholesterol, which is a precursor of vitamin D3. Exposure to the ultraviolet light in sunlight (UVB radiation) converts 7-dehydrocholesterol in the skin to vitamin D3. In fact, adequate exposure to sunlight can eliminate the requirement for vitamin D in the diet (see Sources), making it only “conditionally essential”. Vitamin D3 is not itself biologically active, but must be modified by the body to have any physiologic effects (1).

FUNCTION

Calcium metabolism: Maintenance of blood calcium levels within a narrow range is vital for normal functioning of the nervous system, as well as for bone growth, and maintenance of bone density. This tight regulation is accomplished through a complex system, sometimes called the vitamin D endocrine system, because the active form of vitamin D3 has a mechanism of action similar to some hormones, for example, thyroid hormone (2).

Vitamin D endocrine system (Diagram): Once vitamin D3 enters the circulation from either the diet or the skin, it is bound to the vitamin D-binding protein and transported to the liver. In the liver, vitamin D3 ishydroxylated on carbon molecule #25 to form 25-hydroxyvitamin D3(25-OH-D3), also known as calcidiol. Though the synthesis of calcidiol is controlled in the liver, increased exposure to sunlight or increased intake of vitamin D3 results in increased blood levels of calcidiol, making it a useful indicator of vitamin D nutritional status. Although calcidiol is the major circulating form of vitamin D, it is not biologically active. To exert physiologic effects, 25-OH-D3 must be hydroxylated on carbon #1 to form 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], also called calcitriol. This hydroxylation reaction is catalyzed by an enzyme in the kidneys(2).

The parathyroid glands sense the blood calcium level, and secrete parathyroid hormone (PTH) if  it becomes too low, for example, when dietary calcium intake is inadequate. PTH stimulates the activity of the 1-hydroxylase enzyme in the kidney, resulting in increased production of calcitriol, the biologically active form of vitamin D3. Increased blood levels of calcitriol restore normal blood calcium levels in three different ways: 1) by activating the vitamin D-dependent transport system in thesmall intestine, increasing the absorption of dietary calcium, 2) by increasing the mobilization of calcium from bone into the circulation, and 3) increasing the reabsorption of calcium by the kidneys.  PTH is also required to increase bone calcium mobilization and calcium reabsorption by the kidneys. However, PTH is not required for the effect of calcitriol on the intestinal absorption of calcium (1).

Vitamin D receptor (VDR): The physiologic effects of calcitriol require proteins known as receptors.  Calcitriol enters the cell and interacts with with a vitamin D receptor (VDR) in the nucleus to form a complex. The calcitriol/VDR complex combines with another receptor, the retinoic acid X receptor (RXR), to form a heterodimer, which can then interact with small portions of DNA known as vitamin D responsive elements (VDRE). The interaction of a VDR/RXR heterodimer with a VDRE results in a change in the rate of transcription of a nearby gene (2). In this manner, the the activity of vitamin D-dependent calcium transporters in the small intestine, osteoblasts in bone, and the 1-hydroxylase enzyme in the kidneys may be increased.

Cell differentiation: Cells that are dividing rapidly are said to be proliferating.  Cell proliferation can be observed during growth and wound healing (regeneration). Differentiation results in the specialization of cells for specific functions, such as those of a nerve cell. In general, differentiation of cells leads to a decrease in proliferation.  Psoriasis is a disease characterized by the proliferation of skin cells called keratinocytes.  The identification of VDR in keratinocytes led to the use of creams containing analogs of calcitriol in the treatment of severe cases of psoriasis (3).

Immunity: Vitamin D receptors (VDR) have been identified in cells that play a critical role in the immune system. Specialized white blood cells, known as T-lymphocytes or T-cells, are involved in the recognition of foreign pathogensknown as antigens, and coordinating the immune response. Some diseases are associated with immune responses to inappropriate antigens.  For example,autoimmune diseases occur when an immune response is mounted to an antigen belonging to oneself rather than a foreign antigen, and allergies occur when the antigen is an innocuous foreign substance (4). Immune responses that are mediated by T-cells can be inhibited by large doses of calcitriol. However, a deficiency of vitamin D also interferes with T-cell mediated immunity (3). The presence of VDR in T-cells suggests that vitamin D plays a role in the function and/or the development of T-cells (5). Pharmacologic doses of calcitriol have had beneficial effects in animal models of several autoimmune diseases, mediated by T-cells (see Disease Prevention).

DEFICIENCY

Bone is considered a mineralized connective tissue.  The matrix of bone consists mainly of connective elements known as collagen, while bone mineral consists largely of hydroxyapatite crystals, which contain large amounts of calcium and phosphorus (1). The manifestations of severe vitamin D deficiency are seen mainly in bone.

Rickets:  In infants and children, prolonged vitamin D deficiency results in a condition known as rickets. Rickets results in the failure of bone to mineralize. Rapidly growing bones are most severely affected by rickets. The growth plates of bones continue to enlarge, but in the absence of adequate mineralization, weight-bearing limbs (arms and legs) become bowed. In infants, rickets may result in delayed closure of the fontanelles (soft spots) in the skull, and the rib cage may become deformed due to the pulling action of the diaphragm. The treatment of rickets includes vitamin D or calcitriol supplementation, a diet that provides adequate calcium and phosphorus, and a plan for the prevention of future vitamin D deficiency. Although fortification of foods has led to complacency regarding vitamin D deficiency, nutritional rickets is still being reported in a number of U.S. cities (6).

Osteomalacia: Although adult bones are no longer growing, they are in a constant state of turnover. Bone is a dynamic tissue that is continually remodeling in response to stress. The remodeling process involves the demineralization and remineralization of bone through the action of bone cells called osteoclasts and osteoblasts, respectively. In adults with prolonged vitamin D deficiency, the collagenous bone matrix is preserved but bone mineral is progressively lost as a result of normal bone turnover, resulting in bone pain and osteomalacia (soft bones). Although they both result in fragile bones, osteomalacia differs from osteoporosis in several ways. Osteomalacia is relatively rare and characterized by a decreased bone mineral content in the presence of a relative increase in the collagenous bone matrix. In contrast, osteoporosis is characterized by a decrease in total bone mass, with no change in the ratio of bone mineral to collagenous bone matrix (1).  Moreover, osteoporosis is a much more common condition whose cause appears to be multifactorial (see Disease Prevention).

Risk factors for vitamin D deficiency (1):

Infancy:

      Infants who have little or no sun exposure, and do not consume vitamin D-fortified formula are at increased risk, especially those born just before winter in northern or southern latitudes.

Elderly individuals with minimal sun exposure:

      The elderly have reduced capacity to synthesize vitamin D in response to sunlight exposure, and are more likely to stay indoors or use sunscreen for the prevention of skin cancer.

Dark skin:

      Individuals with darkly pigmented skin, e.g., those of African or Indian descent living in northern or southern latitudes synthesize less vitamin D on exposure to sunlight than those with light skin.

Covering all exposed skin when outside:

      Osteomalacia has been documented in Arab women who cover all of their skin at all times when going outside, for religious or cultural reasons.

Fat malabsorption syndromes:Cystic fibrosis

      and

cholestatic liver disease

      impair the absorption of dietary vitamin D.

Kidney failure:

      Severe kidney disease can impair the conversion of calcidiol to the biologically active form of vitamin D, calcitriol.

Genetic disease:

      A rare genetic disease affects the activity of the 1-hydroxylase enzyme in the kidneys that converts calcidiol to its active form, calcitriol.

Seizure disorders (epilepsy):

      Long-term treatment with

anticonvulsant

      medications, such as phenytoin, can stimulate liver enzymes that break down and inactivate calcitriol (see

Drug Interactions

    ).

The Adequate Intake Level (AI): In 1997, the Food and Nutrition Board (FNB) of the Institute of Medicine felt that the issue of sunlight exposure confounded the existing data on vitamin D requirements, making it impossible to calculate an RDA.  Instead, the FNB set an adequate intake level (AI) that assumes that no vitamin D is synthesized in the skin through exposure to sunlight (7). The recommendation was based on the maintenance of a healthy skeleton.

AI for men and women 19 through 50 years of age: 5 micrograms (mcg)/day or 200 international units (IU)/day
AI for men and women 51 through 70 years of age: 10 mcg/day or 400 IU/day
AI for men and women over 70 years of age: 15 mcg/day or 600 IU/day

DISEASE PREVENTION

Osteoporosis: Deficiency or altered metabolism of vitamin D appears to play a role in osteoporosis. Insufficient vitamin D intake results in reduced calcium absorption, increased parathyroid hormone (PTH) secretion, and increasedresorption of bone. Increased blood levels of PTH and decreased blood levels of calcidiol, both indicators of inadequate vitamin D nutritional status, have been associated with decreased bone mineral density in older adults (8). In temperate latitudes, for example Boston (42 degrees north), synthesis of vitamin D by the skin does not occur from November to March (see Sources). A study of postmenopausal women in Boston found that supplementation with 400 IU of vitamin D resulted in reduced bone loss from the lumbar spine in winter (9). In a similar population of postmenopausal women, a two-year trial of 500 mg of calcium (bringing total calcium intake to an average of 1,000 mg/day) and either 100 IU or 700 IU/day of vitamin D (bringing total vitamin D intake to 200 IU or 800 IU/day, respectively) resulted in a decreased loss of bone density at thefemoral neck (hip) in the group taking 700 IU of vitamin D, although there was no difference in bone loss from the spine between the two groups (10).  More recently, daily supplementation with 500 mg of calcium and 700 IU of vitamin D reduced bone loss in the femoral neck, spine, and total body in men and women over 65 years of age, and reduced the frequency of nonvertebral fractures over a three-year period (11). When the calcium and vitamin D supplementation were discontinued, the improvements in bone density at the femoral neck and spine in both men and women were lost within 2 years. Men, but not women, retained a small improvement in total body bone density at the end of two years (12). Thus, it appears that calcium and vitamin D supplementation must be maintained to provide any lasting benefit with respect to bone density.

Although the prevention of fracture is the primary goal in the prevention and treatment of osteoporosis, fewer studies have measured fracture incidence as an endpoint, because the larger sample sizes and longer duration required make such studies more difficult and costly. Two large trials have examined the effect of vitamin D supplementation on the incidence of osteoporotic fractures. A French study of 3,270 elderly women found a significant decrease in hip fractures after 1.5 and 3 years of supplementation with 800 IU/day of vitamin D and 1,200 mg/day of calcium compared to placebo (13).  However, a Dutch study of 1,916 women and 662 men found no difference in fracture incidence after 3.5 years of supplementation with 400 IU of vitamin D or placebo (14).  Overall, the evidence to date suggests that vitamin D supplements of 400 IU to 800 IU may be helpful in reducing bone loss and fracture rates in the elderly, especially in women living in temperate latitudes.  In order for vitamin D supplementation to be effective in preserving bone health, adequate calcium (1,000 to 1,500 mg/day) must also be consumed. Vitamin D supplementation may also be a useful adjunct to medical therapies aimed at preventing and treating osteoporosis, such as hormone replacement therapy (HRT) or bisphosphonate therapy (e.g., etidronate or alendronate) (8).

Cancer: Two characteristics of cancerous cells are their lack of differentiation(specialization) and their rapid growth or proliferation. Many malignant (cancerous) tumors have been found to contain vitamin D receptors (VDR), including breast, lung, skin (melanoma), colon, and bone.  Biologically active forms of vitamin D3, such as calcitriol and its analogs, have been found to induce differentiation and/or inhibit proliferation of a number of cancerous and non-cancerous cell types (15).

Prostate cancer: Epidemiologic studies show correlations between risk factors for prostate cancer and conditions that can result in decreased vitamin D levels. Increased age is associated with an increased risk of prostate cancer, as well as with decreased sun exposure and decreased capacity to synthesize vitamin D3. The incidence of prostate cancer is higher in African American men than in white American men, and the high melanin content of dark skin is known to reduce the efficiency of vitamin D3 synthesis. Geographically, mortality from prostate cancer is inversely associated with the availability of sunlight, as it is high in the U.S. and northwest Europe, but low in Africa, Central America, and South America. The active metabolite of vitamin D, calcitriol, inhibits the growth of human prostate cancer cells in culture, but the mechanism for this effect is not clear (15). Two small non-randomized trials have examined the effects of calcitriol on humans. Blood tests for prostate-specific antigen (PSA) measure a protein produced by prostate cells and are useful for monitoring the response of prostate cancer to treatment. In a small trial, only 2 out of 13 men with prostate cancer that was unresponsive to hormone treatment showed decreased PSA levels during a course of treatment with calcitriol (16). In another small study, six out of seven prostate cancer patients  had significantly decreased PSA levels after a course of treatment with calcitriol (17). Unlike takingphysiologic doses of vitamin D, which must be metabolized to form calcitriol, taking pharmacologic doses of calcitriol carries with it the risk for serious side effects (see Safety).  Although the use of calcitriol or newly developed analogs as preventive or therapeutic agents for prostate cancer appears promising, there is presently insufficient human data to evaluate their efficacy or safety.

Colorectal cancer: The geographic distribution of colon cancer is similar to the historic geographic distribution of rickets, providing circumstantial evidence that  decreased sunlight exposure and diminished vitamin D nutritional status may be related to an increased risk of colon cancer. A number of observational studies have found an association between colon cancer risk and dietary intake of vitamin D. The majority of those studies indicated that an intake of 160 IU of vitamin D/day or more was associated with a reduced risk of colon cancer (18). However, two large prospective studies of women, the Nurses’ Health Study (19)and the Iowa Women’s Health Study (20) did not find significant associations between vitamin D intake and the risk of colorectal cancer after statistical adjustment for other risk factors.

Breast cancer: In cell culture, the growth of some human breast cancer cell lines is inhibited by the active form of vitamin D, calcitriol. Breast cancer mortality follows a similar geographic distribution to that of colon cancer (18). An examination of the data from the first National Health and Nutrition Examination Survey (NHANES I) found that several measures of sunlight exposure and dietary vitamin D intake were associated with a reduced risk of breast cancer (21). A case-control study of more than 300 women found blood levels of calcitriol at the time of diagnosis of breast cancer to be significantly lower in white women, but not African American women, than in comparable women without breast cancer (22). Blood levels of calcidiol, the form of vitamin D generally used to assess vitamin D nutritional status, did not differ between women with and without breast cancer. In contrast, a case-control study of 96 white women who were subsequently diagnosed with breast cancer, found that pre-diagnostic blood levels of calcitriol did not differ from those of a comparable group of women who did not develop breast cancer over the same period of time. The average length of follow up was 15 years (23).  Presently, the relationship between vitamin D nutritional status and breast cancer risk in humans requires further clarification.

High-dose vitamin D and calcitriol therapy carry risks of serious side effects (seeSafety). At present, the evidence relating vitamin D to the prevention or treatment of cancer in humans is limited and mostly circumstantial. Future research and the development of safer vitamin D analogs are needed before vitamin D can be recommended as a therapy for cancer.

Autoimmune disease: Insulin-dependent diabetes mellitus (IDDM), multiple sclerosis (MS), and rheumatoid arthritis (RA) are each examples of autoimmune disease. In IDDM, insulin producing beta (b)-cells of the pancreas are the target of the inappropriate immune response. In MS and RA, the targets are the myelin producing cells of the central nervous system and the collagen producing cells of the joints, respectively. The autoimmune responses are mediated by T-lymphocytes (T-cells). The biologically active form of vitamin D, calcitriol, has been found to modulate T-cell responses, such that the autoimmune responses are diminished. Treatment with calcitriol has had beneficial effects in animal models of IDDM, MS, and RA. In humans, increased incidence of IDDM, MS, and RA are found in geographic regions with low supplies of vitamin D (low sunlight exposure and low dietary intake). Presently, vitamin D and calcium supplementation are advocated for individuals at risk of osteoporosis from corticosteroid regimens prescribed to treat autoimmune diseases (5, 24). Although the use of vitamin D and vitamin D analogs in the therapy of certain autoimmune diseases holds promise, further research is required before their safety and efficacy can be determined.

SOURCES

Sunlight: Sunlight exposure provides most people with their entire vitamin D requirement. Children and young adults who spend a short time outside two or three times a week will generally synthesize all the vitamin D they need.  Elderly individuals have diminished capacity to synthesize vitamin D from sunlight exposure, and frequently use sunscreen or protective clothing in order to prevent skin cancer and sun damage. The application of sunscreen with an SPF factor of 8 reduces production of vitamin D by 95%. In latitudes around 40 degrees north or 40 degrees south (Boston is 42 degrees north), there is insufficient UVB light available for vitamin D synthesis from November to early March. Ten degrees farther north or south (Edmonton, Canada) this “vitamin D winter” extends from mid October to mid March. A survey of elderly people who took a multivitamin supplement or drank 3 glasses of milk daily found that about 80% of them were vitamin D deficient by the end of winter. These findings have led some experts to recommend small amounts of regular sun exposure to elderly individuals (2). About 15 minutes of exposure on the hands, face, and forearms three times a week in the morning or late afternoon during the spring, summer, and fall should provide adequate vitamin D and allow for storage of any excess in fat for use during the winter with minimal risk of skin damage.  A sunscreen may be applied after the 15 minutes, if additional sun exposure is planned.

Foods: Vitamin D is found naturally in very few foods. Foods containing vitamin D include some fatty fish (herring, salmon, sardines), fish liver oils,  and eggs from hens that have been fed vitamin D. In the U.S., milk and infant formula are fortified with vitamin D to contain 10 mcg (400 IU)/quart. However, other dairy products such as cheese and yogurt are not usually fortified with vitamin D. Some cereals and breads are also fortified with vitamin D. Accurate estimates of average dietary intakes of vitamin D are difficult because of the high variability of the vitamin D content of fortified foods (7,25).  The vitamin D contents of some vitamin D-rich foods are listed in the table below in both international units (IU) and micrograms (mcg).  For more information on the nutrient content of foods you eat frequently, search the USDA food composition database.

Food Serving Vitamin D (IU) Vitamin D (mcg)
Cod liver oil 1 tablespoon 1360 34
Salmon 3 ounces 425 10.6
Herring 3 ounces 765 19.1
Shrimp, canned 3 ounces 90 2.3
Sardines, canned 3 ounces 255 6.4
Cereal, fortified 1 serving (usually 1 cup) 40 to 50 1 to 1.3
Egg yolk 1 25 0.63
Cow’s milk, fortified 8 ounces 100 2.5

SAFETY

Toxicity: Vitamin D toxicity is also called, hypervitaminosis D. Vitamin D toxicity has not been observed to result from sun exposure. Hypervitaminosis D appears to result primarily from vitamin D supplementation over many years at pharmacologic doses of 10, 000 to 50,000 IU/day (250 to 1250 mcg/day) (7). The adverse effects of hypervitaminosis D appear to be due mainly to the elevated blood calcium levels it induces. Symptoms include loss of appetite, nausea, vomiting, excessive thirst, excessive urination, severe itching,  muscular weakness, joint pain, and ultimately disorientation, coma, and death. Blood and urinary calcium levels are elevated. If the condition persists, demineralization of bones and calcification of organs, such as the heart and kidneys, may also occur. The potential for vitamin D toxicity is higher if an individual is taking one of the drug formulations of calcitriol [1,25(OH)2D3] because it bypasses physiological control mechanisms that limit its production in the kidneys (see Function). Because the consequences of vitamin D toxicity are severe, the Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper level of intake (UL) for vitamin D at 2,000 IU/day (50 mcg/day) for adults, five times lower than the dose generally observed to cause hypervitaminosis D in healthy individuals (7)

Drug interactions: Anticonvulsants (phenytoin and phenobarbitol) increase the metabolism of calcitriol in the liver, thereby increasing the requirement of individuals on long-term anticonvulsant therapy for vitamin D. Cholestyramine, a bile acid binding resin used to treat elevated cholesterol levels, and mineral oil can decrease the intestinal absorption of vitamin D. The induction of hypercalcemia (elevated blood calcium levels) by toxic levels of vitamin D may precipitate cardiac arrhythmia in patients on digitalis (digoxin) or verapamil, a calcium channel blocker, used to treat high blood pressure (26).

THE LINUS PAULING RECOMMENDATION

The Linus Pauling Institute recommends that generally healthy adults take a multivitamin/multimineral supplement that supplies 400 IU (10 mcg) of vitamin D daily. If there is no reason to avoid all sun exposure, getting at least 15 minutes of sun exposure on the arms, face, and hands three times a week in the morning or late afternoon during the spring, summer, and fall may help residents of temperate latitudes (much of the U.S.) avoid vitamin D deficiency at the end of winter (see Sources).

Older adults (65 years and older): In addition to the 400 IU (10 mcg) of vitamin D usually provided by a multivitamin/multimineral supplement, individuals over the age of 65 should consider taking an additional 400 IU (10 mcg) of vitamin D to provide a total of 800 IU (20mcg)/day.

REFERENCES

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