Vitamin D

Vitamin D is a fat-soluble vitamin that is essential for maintaining normal calcium metabolism. Vitamin D3 (cholecalciferol) can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation from sunlight, or it can be obtained from the diet. Plants synthesize vitamin D2 (ergocalciferol), which also has vitamin D activity in humans. When exposure to UVB radiation is insufficient for the synthesis of adequate amounts of vitamin D3 in the skin, adequate intake of vitamin D from the diet is essential for health.

Function

Activation of Vitamin D

Vitamin D itself is biologically inactive, and it must be metabolized to its biologically active forms. After it is consumed in the diet or synthesized in the skin, vitamin D enters the circulation and is transported to the liver. In the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. Increased exposure to sunlight or increased intake of vitamin D increases serum levels of 25(OH)D, making the serum 25(OH)D concentration a useful indicator of vitamin D nutritional status. In the kidney and other tissues, the 25(OH)D3-1-hydroxylase enzyme catalyzes a second hydroxylation of 25(OH)D, resulting in the formation of 1alpha,25-dihydroxyvitamin D [1,25(OH)2D]—the most potent form of vitamin D. Most of the physiological effects of vitamin D in the body are related to the activity of 1,25(OH)2D.

Mechanisms of Action

Many of the biological effects of 1,25(OH)2D are mediated through a nuclear transcription factor known as the vitamin D receptor (VDR). Upon entering the nucleus of a cell, 1,25(OH)2D associates with the VDR and promotes its association with the retinoic acid X receptor (RXR). In the presence of 1,25(OH)2D the VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs), and initiates a cascade of molecular interactions that modulate the transcription of specific genes. More than 50 genes in tissues throughout the body are known to be regulated by 1,25(OH)2D. Some physiological responses to 1,25(OH)2D occur too rapidly to be acting through gene transcription, suggesting that their may be also be a receptor for 1,25(OH)2D on the outer membrane of cells.

Calcium Balance

Maintenance of serum 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. Vitamin D is essential for the efficient utilization of calcium by the body. The parathyroid glands sense serum calcium levels, and secrete parathyroid hormone (PTH) if calcium levels drop too low (diagram). Elevations in PTH increase the activity of 25(OH)D3-1-hydroxylase enzyme in the kidney, resulting in increased production of 1,25(OH)2D. Increasing 1,25(OH)2D production results in changes in gene expression that normalize serum calcium by 1) increasing the intestinal absorption of dietary calcium, 2) increasing the reabsorption of calcium filtered by the kidneys and 3) mobilizing calcium from bone when there is insufficient dietary calcium to maintain normal serum calcium levels. Parathyroid hormone and 1,25(OH)2D are required for the latter two effects.

Cell Differentiation

Cells that are dividing rapidly are said to be proliferating. Differentiation results in the specialization of cells for specific functions. In general, differentiation of cells leads to a decrease in proliferation. While cellular proliferation is essential for growth and wound healing, uncontrolled proliferation of cells with certain mutations may lead to diseases like cancer. The active form of vitamin D, 1,25(OH)2D, inhibits proliferation and stimulates the differentiation of cells.

Immunity

Vitamin D in the form of 1,25(OH)2D is a potent immune system modulator. The VDR is expressed by most cells of the immune system, including T cells and antigen-presenting cells, such as dendritic cells and macrophages. Macrophages also produce the 25(OH)D3-1-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2D. There is considerable scientific evidence that 1,25(OH)2D has a variety of effects on immune system function that may enhance innate immunity and inhibit the development of autoimmunity.

Insulin Secretion

The VDR is expressed by insulin secreting cells of the pancreas, and the results of animal studies suggest that 1,25(OH)2D plays a role in insulin secretion under conditions of increased insulin demand. Limited data in humans suggests that insufficient vitamin D levels may have an adverse effect on insulin secretion and glucose tolerance in type 2 diabetes (noninsulin-dependent diabetes mellitus; NIDDM).

Blood Pressure Regulation

The renin-angiotensin system plays an important role in the regulation of blood pressure. Renin is an enzyme that catalyzes the cleavage (splitting) of a small peptide (Angiotensin I) from a larger protein (angiotensinogen) produced in the liver. Angiotensin converting enzyme (ACE) catalyzes the cleavage of angiotensin I to form angiotensin II, a peptide that can increase blood pressure by inducing the constriction of small arteries and increasing sodium and water retention. The rate of angiotensin II synthesis is dependent on renin. Recent research in mice lacking the gene encoding the VDR, indicates that 1,25(OH)2D decreases the expression of the gene encoding renin through its interaction with the VDR. Since inappropriate activation of the renin-angiotensin system is thought to play a role in some forms of human hypertension, adequate vitamin D levels may be important for decreasing the risk of high blood pressure.

Deficiency

In vitamin D deficiency, calcium absorption cannot be increased enough to satisfy the body’s calcium needs. Consequently, PTH production by the parathyroid glands is increased and calcium is mobilized from the skeleton to maintain normal serum calcium levels—a condition known as secondary hyperparathyroidism. Although it has long been known that severe vitamin D deficiency has serious consequences for bone health, recent research suggests that less obvious states of vitamin D deficiency are common and increase the risk of osteoporosis and other health problems.

Severe Vitamin D Deficiency

Rickets

In infants and children, severe vitamin D deficiency 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 fontanels (soft spots) in the skull, and the rib cage may become deformed due to the pulling action of the diaphragm. In severe cases, low serum calcium levels (hypocalcemia) may cause seizures. Although fortification of foods has led to complacency regarding vitamin D deficiency, nutritional rickets is still being reported in cities throughout the world.

Osteomalacia

Although adult bones are no longer growing, they are in a constant state of turnover. In adults with severe vitamin D deficiency, the collagenous bone matrix is preserved but bone mineral is progressively lost, resulting in bone pain and osteomalacia (soft bones).

Muscle Weakness and Pain

Vitamin D deficiency causes muscle weakness and pain in children and adults. Muscle pain and weakness was a prominent symptom of vitamin D deficiency in a study of Arab and Danish Moslem women living in Denmark. In a cross-sectional study of 150 consecutive patients referred to a clinic in Minnesota for the evaluation of persistent, nonspecific musculoskeletal pain, 93% had serum 25(OH)D levels indicative of vitamin D deficiency. A randomized controlled trial found that supplementation of elderly women with 800 IU/day of vitamin D and 1,200 mg/day of calcium for three months increased muscle strength and decreased the risk of falling by almost 50% compared to supplementation with calcium alone.

Risk Factors for Vitamin D Deficiency

Exclusively breast fed infants: Infants who are exclusively breast fed and do not receive vitamin D supplementation are at high risk of vitamin D deficiency, particularly if they have dark skin and/or receive little sun exposure. Human milk generally provides 25 IU of vitamin D per liter, which is not enough for an infant if it is the sole source of vitamin D. Older infants and toddlers exclusively fed milk substitutes and weaning foods that are not vitamin D fortified are also at risk of vitamin D deficiency. The American Academy of Pediatrics recommends that all infants that are not consuming at least 500 ml (16 ounces) of vitamin D fortified formula or milk be given a vitamin D supplement of 200 IU/day.

Dark skin: People with dark skin synthesize less vitamin D on exposure to sunlight than those with light skin. The risk of vitamin D deficiency is particularly high in dark-skinned people who live far from the equator. In the U.S., 42% of African American women between 15 and 49 years of age were vitamin D deficient compared to 4% of White women.

Aging: The elderly have reduced capacity to synthesize vitamin D in the skin when exposed to UVB radiation, and are more likely to stay indoors or use sunscreen. Institutionalized adults are at extremely high risk of vitamin D deficiency without supplementation.

Covering all exposed skin or using sunscreen whenever outside: Osteomalacia has been documented in women who cover all of their skin whenever they are outside for religious or cultural reasons. The application of sunscreen with an SPF factor of 8 reduces production of vitamin D by 95%.

Fat malabsorption syndromes: Cystic fibrosis and cholestatic liver disease impair the absorption of dietary vitamin D.

Inflammatory bowel disease: People with inflammatory bowel disease like Crohn’s disease appear to be at increased risk of vitamin D deficiency, especially those who have had small bowel resections.

Obesity: Obesity increases the risk of vitamin D deficiency. Once vitamin D is synthesized in the skin or ingested, it is deposited in body fat stores, making it less bioavailable to people with large stores of body fat.

Assessing Vitamin D Nutritional Status

Growing awareness that vitamin D insufficiency has serious health consequences beyond rickets and osteomalacia highlights the need for accurate assessment of vitamin D nutritional status. Although there is general agreement that the serum 25(OH)D level is the best indicator of vitamin D deficiency and sufficiency, the cutoff values have not been clearly defined. While laboratory reference ranges for serum 25(OH)D levels are often based on average values from populations of healthy individuals, recent research suggests that health-based cutoff values aimed at preventing secondary hyperparathyroidism and bone loss should be considerably higher. In general, serum 25(OH)D values less than 20-25 nmol/L indicate severe deficiency associated with rickets and osteomalacia. Although 50 nmol/L has been suggested as the low end of the normal range, more recent research suggests that PTH levels and calcium absorption are not optimized until serum 25(OH)D levels reach approximately 80 nmol/L . Thus, at least one vitamin D expert has argued that serum 25(OH)D values less than 80 nmol/L should be considered deficient, while another suggests that a healthy serum 25(OH)D value is between 75 nmol/L and 125 nmol/L. Data from supplementation studies indicates that vitamin D intakes of at least 800-1,000 IU/day are required by adults living in temperate latitudes to achieve serum 25(OH)D levels of at least 80 nmol/L.

Disease Prevention

Osteoporosis

Although osteoporosis is a multifactorial disease, vitamin D insufficiency can be an important contributing factor. Without sufficient vitamin D, calcium absorption cannot be maximized and the resulting elevation in PTH secretion by the parathyroid glands results in increased bone resorption, which may lead to osteoporotic fracture. A prospective cohort study that followed more than 72,000 postmenopausal women in the U.S. for 18 years found that those who consumed at least 600 IU/day of vitamin D from diet and supplements had a risk of osteoporotic hip fracture that was 37% lower than women who consumed less than 140 IU/day. The results of most clinical trials suggest that vitamin D supplementation can slow bone density losses or decrease the risk of osteoporotic fracture in men and women who are unlikely to be getting enough vitamin D.

Supplementation of postmenopausal women in the U.S. with 500 mg/day of calcium and either 100 IU/day or 700 IU/day of vitamin D for two years slowed bone density losses at the hip only in the group taking 700 IU/day. Daily supplementation of elderly men and women with 500 mg/day of calcium and 700 IU/day of vitamin D for three years reduced bone density losses at the hip and spine and reduced the frequency of nonvertebral fractures. When the calcium and vitamin D supplements were discontinued, the bone density benefits were lost within 2 years. In Denmark, supplementation of elderly women with 400 IU/day of vitamin D for two years increased bone density at the hip.

An annual injection of 150,000-300,000 IU of vitamin D2 (ergocalciferol) for four years decreased the incidence of fracture in elderly Finnish women, and oral supplementation with 800 IU/day of vitamin D and 1,200 mg/day of calcium for three years decreased the incidence of hip fracture in elderly French women. Oral supplementation of elderly adults in the UK with 100,000 IU of vitamin D once every four months (equivalent to about 800 IU/day) for five years reduced the risk of osteoporotic fracture by 33% compared to placebo. However, oral supplementation with 400 IU/day of vitamin D for more than 3 years did not affect the incidence of fracture in a study of elderly Dutch men and women. Overall, the evidence to date suggests that vitamin D supplements of about 800 IU/day may be helpful in reducing bone loss and fracture rates in the elderly. In order for vitamin D supplementation to be effective in preserving bone health, adequate calcium (1,000 to 1,200 mg/day) should also be consumed.

Cancer

Two characteristics of cancer cells are their lack of differentiation (specialization) and their rapid growth or proliferation. Many malignant tumors have been found to contain vitamin D receptors (VDR), including breast, lung, skin (melanoma), colon, and bone. Biologically active forms of vitamin D, such as 1,25(OH)2D and its analogs, have been found to induce cell differentiation and/or inhibit proliferation of a number of cancerous and noncancerous cell types maintained in cell culture.

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. However, prospective cohort studies have not generally found total vitamin D intake to be associated with significant reductions in colorectal cancer when other risk factors are taken into account. One five-year study of more than 120,000 people found that men with the highest vitamin D intakes had a risk of colorectal cancer that was 29% lower than men with the lowest vitamin D intakes. Vitamin D intake was not significantly associated with colorectal cancer risk in women. Serum 25(OH)D level, which reflects vitamin D intake and vitamin D synthesis, was inversely associated with the risk of potentially precancerous colorectal polyps and indices of colonic epithelial cell proliferation, which are considered biomarkers for colon cancer risk.

Breast Cancer

Although breast cancer mortality follows a similar geographic distribution to that of colon cancer, direct evidence of an association between vitamin D nutritional status and breast cancer risk is limited. A prospective study of women who participated in 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 20 years later. More recently, a 16-year study of more than 88,000 women found that higher intakes of vitamin D were associated with significantly lower breast cancer risk in premenopausal women but not postmenopausal women.

Prostate Cancer

Epidemiological 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 D. 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 D synthesis. Geographically, mortality from prostate cancer is inversely associated with the availability of sunlight. Recent findings that prostate cells in culture can synthesize the 25(OH)D3-1-hydroxylase enzyme and that, unlike the renal enzyme, its synthesis is not influenced by PTH or calcium levels also provide support for the idea that increasing 25(OH)D levels may be useful in preventing prostate cancer. In contrast, prospective studies have not generally found significant relationships between serum 25(OH)D levels and subsequent risk of developing prostate cancer. Although a prospective study of Finnish men found that low serum 25(OH)D levels were associated with earlier and more aggressive prostate cancer development, another prospective study of men from Finland, Norway and Sweden found a U-shaped relationship between serum 25(OH)D levels and prostate cancer risk. In that study serum 25(OH)D concentrations of 19 nmol/L or lower and 80 nmol/L or higher were associated with higher prostate cancer risk. Further research is needed to determine the nature of the relationship between vitamin D nutritional status and prostate cancer risk.

Autoimmune Diseases

Insulin-dependent diabetes mellitus (IDDM), multiple sclerosis (MS), and rheumatoid arthritis (RA) are each examples of autoimmune disease. Autoimmune diseases occur when the body mounts an immune response to its own tissue, rather than a foreign pathogen. In IDDM, insulin producing beta-cells of the pancreas are the target of the inappropriate immune response. In MS, the targets are the myelin producing cells of the central nervous system, and in RA, the targets are the collagen producing cells of the joints. Autoimmune responses are mediated by immune cells called T cells. The biologically active form of vitamin D, 1,25(OH)2D, has been found to modulate T cell responses, such that the autoimmune responses are diminished. Treatment with 1,25(OH)2D has beneficial effects in animal models of IDDM , MS, and RA. epidemiological studies have found that the prevalence of IDDM, MS, and RA increases as latitude increases, suggesting that lower exposure to UVB radiation and associated decreases in vitamin D synthesis may play a role in the pathology of these diseases. The results of several prospective cohort studies also suggest that adequate vitamin D intake may decrease the risk of autoimmune diseases. A prospective cohort study of children born in Finland during the year 1966 and followed for thirty years found that those who received vitamin D supplementation in the first year of life had a significantly lower risk of developing IDDM, while children suspected of developing rickets (severe vitamin D deficiency) during the first year of life had a significantly higher risk of developing IDDM. Vitamin D supplement use was associated with a significant reduction in the risk of developing MS in two large cohorts of women followed for at least ten years. Similarly, postmenopausal women with the highest total vitamin D intakes were at significantly lower risk of developing RA after eleven years of follow up than those with the lowest intakes. Evidence from animal models and epidemiological studies suggests that maintaining sufficient vitamin D levels may help decrease the risk of several autoimmune diseases.

Hypertension (High Blood Pressure)

The results of epidemiological and clinical studies suggest an inverse relationship between serum 1,25(OH)2D levels and blood pressure, which may be explained by recent findings that 1,25(OH)2D decreases the expression of the gene encoding renin (see Function). Data from epidemiological studies suggest that conditions that decrease vitamin D synthesis in the skin, such as having dark skin and living in temperate latitudes, are associated with increased prevalence of hypertension. A controlled clinical trial in 18 hypertensive men and women living in the Netherlands found that exposure to UVB radiation three times weekly for six weeks during the winter increased serum 25(OH)D levels and significantly decreased 24-hour ambulatory systolic and diastolic blood pressure measurements by an average of 6 mm Hg. In randomized controlled trials of vitamin D supplementation, a combination of 1,600 IU/day of vitamin D and 800 mg/day of calcium for eight weeks significantly decreased systolic blood pressure in elderly women by 9% compared to calcium alone, but supplementation with 400 IU/day or a single dose of 100,000 IU of vitamin D did not significantly lower blood pressure in elderly men and women over the next two months. At present, data from controlled clinical trials are too limited to determine whether vitamin D supplementation will be effective in lowering blood pressure or preventing hypertension.

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. The elderly 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 radiation 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. According to Dr. Michael Holick, as little as 5-10 minutes of sun exposure on arms and legs or face and arms three times weekly between 11:00 am and 2:00 pm during the spring, summer, and fall at 42 degrees latitude should provide a light-skinned individual with adequate vitamin D and allow for storage of any excess for use during the winter with minimal risk of skin damage.

Safety

Toxicity

Vitamin D toxicity (hypervitaminosis D) induces abnormally high serum calcium levels (hypercalcemia), which could result in bone loss, kidney stones, and calcification of organs like the heart and kidneys if untreated over a long period of time. When the Food and Nutrition Board of the Institute of Medicine established the tolerable upper intake level (UL) for vitamin D, published studies that adequately documented the lowest intake levels of vitamin D that induced hypercalcemia were very limited. Because the consequences of hypercalcemia are severe, the Food and Nutrition Board established a very conservative UL of 2,000 IU/day (50 mcg/day) for children and adults. Research published since 1997 suggests that the UL for adults is likely overly conservative and that vitamin D toxicity is very unlikely in healthy people at intake levels lower than 10,000 IU/day. Vitamin D toxicity has not been observed to result from sun exposure. Certain medical conditions can increase the risk of hypercalcemia in response to vitamin D, including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma. People with these conditions may develop hypercalcemia in response to any increase in vitamin D nutrition and should consult a qualified health care provider regarding any increase in vitamin D intake.

Drug interactions

The following medications increase the metabolism of vitamin D and may decrease serum 25(OH)D levels: phenytoin (Dilantin), fosphenytoin (Cerebyx), phenobarbital (Luminal), carbamazepine (Tegretol), and rifampin (Rimactane). The following medications should not be taken at the same time as vitamin D because they can decrease the intestinal absorption of vitamin D: cholestyramine (Questran), colestipol (Colestid), orlistat (Xenical), mineral oil, and the fat substitute Olestra. The oral anti-fungal medication, ketoconazole, inhibits the 25(OH)D3-1-hydroxylase enzyme and has been found to reduce serum levels of 1,25(OH)D in healthy men . The induction of hypercalcemia by toxic levels of vitamin D may precipitate cardiac arrhythmia in patients on digitalis (Digoxin).

Linus Pauling Institute Recommendation

The Linus Pauling Institute recommends that generally healthy adults take a multivitamin supplement that supplies 400 IU (10 mcg) of vitamin D daily. Additionally, at least 10-15 minutes of sun exposure on the arms and legs or face and arms at least three times weekly between 11:00 am and 2:00 pm 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.

Older adults (65 years and older) and people with minimal sun exposure

In addition to the 400 IU (10 mcg) of vitamin D provided by a multivitamin supplement, people over the age of 65 and people who get minimal sun exposure throughout the year should take an additional vitamin D supplement of 400 IU/day (10 mcg/day) to provide a total of 800 IU/day (20 mcg/day).

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/