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Research Newsletter-Spring/Summer 2008


Victoria J. Drake, Ph.D.
LPI Research Associate

Vitamin D is a fat-soluble vitamin that functions as a hormone in the body to regulate calcium metabolism. Together with parathyroid hormone (PTH), vitamin D tightly controls blood concentrations of calcium. For example, when serum calcium levels are low, such as when dietary calcium intake is inadequate, PTH is secreted from the parathyroid glands. PTH stimulates the activation of vitamin D from its prohormone form; active vitamin D in turn promotes intestinal absorption of calcium, mobilizes calcium from bone, and increases retention of calcium by the kidneys. These actions effectively increase serum levels of calcium. Maintaining calcium homeostasis is vital for normal functioning of the nervous system, as well as for bone growth and maintenance of bone density. Thus, vitamin D is necessary for skeletal integrity and the prevention of rickets, osteomalacia (loss of bone mineralization), and osteoporosis.

In addition to its well-known involvement in calcium balance and bone metabolism, vitamin D has a number of other physiological roles, including maintaining muscle strength, modulating immune function, and regulating blood pressure. Moreover, vitamin D functions to help regulate cellular differentiation, the biological process by which cells become specialized for a specific function. Due to these physiological functions, vitamin D has been implicated in protection against muscle pain and weakness, certain autoimmune diseases, hypertension, and even some forms of cancer.

Vitamin D metabolism and biochemical action

Vitamin D is essentially a prohormone that is biologically inactive and therefore must be metabolized to its active form by the liver and kidneys. In the liver, provitamin D is converted to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. In the kidneys, this metabolite is further converted to the active, most potent form of vitamin D: 1,25-dihydroxyvitamin D [1,25(OH)2D]. Most of the physiological effects of vitamin D in the body are related to the hormone activity of 1,25(OH)2D. Biological effects of 1,25(OH)2D are primarily mediated through a transcription factor called the vitamin D receptor (VDR). Transcription factors are proteins that function to initiate, enhance, or inhibit the expression of certain genes. Once inside a cell's nucleus, 1,25(OH)2D binds to the VDR and, along with other cofactors, initiates a cell-signaling cascade that ultimately modulates gene expression. More than 50 genes in tissues throughout the body are regulated by 1,25(OH)2D.

What are sources of vitamin D?

Vitamin D is a unique nutrient because its requirements can be met not only by dietary intake, but also from exposure to sunlight. Humans can synthesize vitamin D3 (cholecalciferol) in skin cells following exposure to ultraviolet-B radiation. In fact, sunlight exposure can provide most people with their entire vitamin D requirement, although people living in Northern latitudes cannot produce sufficient vitamin D during the winter months. Additionally, individuals with dark-colored skin synthesize markedly less vitamin D on exposure to sunlight than those with light-colored skin. The elderly also have diminished capacity to synthesize vitamin D from sunlight exposure. Further, using sunscreen blocks endogenous production of vitamin D.

When sun exposure is insufficient for the synthesis of adequate amounts of vitamin D in the skin, obtaining vitamin D from foods or supplements is essential for health. However, very few foods naturally contain vitamin D. The richest sources of vitamin D include oily fish, such as mackerel, salmon, or 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 so that they contain 400 IU (10 mcg) per quart. However, other dairy products, such as cheese and yogurt, are not always fortified with vitamin D. Certain cereals, breads, soy and rice milks, as well as orange juice, may be fortified with vitamin D. Today, products sold in the U.S. are typically fortified with vitamin D3 instead of vitamin D2 (ergocalciferol), a form synthesized by fungi and plants. A few studies indicate that vitamin D2 may be less active in humans than vitamin D3.

Measurement of vitamin D status

Increased exposure to sunlight or increased dietary intake of vitamin D increases serum levels of 25(OH)D, making the serum 25(OH)D concentration a useful clinical indicator of vitamin D status. There is general agreement that serum 25(OH)D level is the best indicator of vitamin D status; however, the cutoff values have not been clearly defined. Some experts believe that current laboratory reference ranges, with 20-25 nmol/L (8-10 ng/mL) as the cutoff for severe deficiency, may be too low. Research suggests that PTH levels and calcium absorption may not be optimized until serum 25(OH)D levels reach approximately 80 nmol/L (32 ng/mL). It has been estimated that vitamin D intakes of at least 800 to 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.

Vitamin D deficiency

Inadequate vitamin D from sun exposure or dietary intake leads to deficiency states. Severe vitamin D deficiency has serious consequences for bone health, manifesting as rickets in children and osteomalacia in adults. Vitamin D deficiency during infancy or childhood results in failure of bone to mineralize, thereby leading to weak, softened bones and the skeletal disorder called rickets. Malformed bones, such as bowed legs, are a hallmark of rickets. In infants, rickets may result in delayed closure of the fontanels (soft spots) in the skull, rib cage deformities, and seizures induced by low levels of serum calcium. Although fortification of foods has led to complacency regarding vitamin D deficiency, nutritional rickets is still being reported throughout the world. Severe vitamin D deficiency in adults leads to a condition known as osteomalacia, which is characterized by weak muscles and bones as well as bone pain. These symptoms result from progressive loss of bone mineralization.

Today, less obvious states of vitamin D deficiency are actually quite common in both children and adults. Such milder vitamin D deficiencies increase the risk of osteoporosis and possibly other health problems, including multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular disease, and certain types of cancer.

Risk factors for vitamin D deficiency

There are several factors that place individuals at risk for vitamin D deficiency. Infants who are exclusively breast-fed are at high risk of vitamin D deficiency because human milk generally does not provide sufficient 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. On the advice of the medical community, parents often use sunscreen on their children. Sunscreen effectively blocks skin synthesis of vitamin D. For instance, applying sunscreen with a sun protection factor (SPF) of 8 reduces vitamin D production by about 95%. Likewise, individuals who cover all exposed skin whenever outside (e.g., for religious or cultural reasons) are at risk for vitamin D deficiency. People with dark-colored skin have a reduced ability to synthesize vitamin D upon exposure to sunlight than those with light-colored skin. Elderly individuals also have a lower capacity to synthesize vitamin D on exposure to ultraviolet-B radiation and often stay indoors. Institutionalized adults who are not supplemented with vitamin D are at extremely high risk of vitamin D deficiency. Additionally, individuals with inflammatory bowel disease or fat malabsorption syndromes are at a heightened risk for vitamin D deficiency. Further, obesity increases the risk of vitamin D deficiency because obese individuals cannot easily access the vitamin D stored in body fat.

Vitamin D toxicity

Vitamin D toxicity, called hypervitaminosis D, causes abnormally high serum levels of calcium (hypercalcemia). If untreated for long periods of time, this can result in bone loss, kidney stones, and calcification of organs. Hypercalcemia has been observed following daily doses of greater than 50,000 IU of vitamin D. However, the Food and Nutrition Board of the Institute of Medicine conservatively established the tolerable upper intake level (UL) for vitamin D at 2,000 IU/day (50 micrograms/day). Many experts believe that vitamin D toxicity is very unlikely in healthy people at intake levels below 10,000 IU/day.

Yet, certain medical conditions can increase the risk of hypercalcemia in response to an increase in vitamin D nutrition. Such conditions include primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma. Patients with these medical conditions should consult a qualified health care provider regarding any increase in vitamin D intake.

Sun exposure controversy

Sun exposure can provide most people with their entire vitamin D requirement, but the same radiation that stimulates vitamin D synthesis in skin can also cause skin damage. Ultraviolet light has been linked to melanoma and nonmelanoma forms of skin cancer, but the causes of skin cancer appear to be multifactorial. Due to concerns of skin damage and cancer, many people use sunscreen or protective clothing whenever outdoors; others avoid the sun altogether.

However, several recent studies have reported that vitamin D may protect against various internal cancers. Results of some, but not all, studies suggest that higher 25(OH)D blood levels may be beneficial against development of colorectal, breast, and prostate cancers. Vitamin D is known to be important in preventing osteoporosis and may also have a role in preventing hypertension and autoimmune diseases.

Given the fact that vitamin D deficiency is so widespread and that vitamin D may protect against certain diseases, moderate exposure to sunlight may indeed be sensible. Application of sunscreen after 10 to 15 minutes in the sun would block any deleterious effects of ultraviolet light.

Dietary intake recommendations

In 1997, the Food and Nutrition Board of the Institute of Medicine set adequate intake (AI) levels that assume no skin synthesis of vitamin D. The AI values (see Table below) reflect vitamin D intakes likely to maintain serum 25(OH)D levels of at least 37.5 nmol/L (15 ng/mL). While the AI level may help individuals avoid overt deficiency, many experts feel these dietary intake recommendations are inadequate. The LPI recommends that healthy adults take a multivitamin supplement daily that supplies 400 IU of vitamin D. For people over the age of 50, an additional 400 IU/day is recommended.

Adequate Intake (AI) for Vitamin D

Last updated June 2008

For more updated information on vitamin D, including the current LPI recommendation, see the article in the Micronutrient Information Center.