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Vitamin D  is a group of fat-soluble prohormones (meaning that it has no hormone activity itself, but is converted to the active hormone 1,25-D through a tightly regulated synthesis mechanism.). The two major forms are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol). The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation.

 

Role of Vitamin D

Vitamin D plays an important role in the maintenance of organ systems.
  • Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys.
  • It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts . Without sufficient vitamin D, bones can become thin, brittle, or misshapen.However, at very high levels it will promote the resorption of bone.
  • It inhibits parathyroid hormone secretion from the parathyroid gland.
  • Vitamin D affects the immune system by promoting phagocytosis, anti-tumor activity, and immunomodulatory functions.
  • Vitamin D has other roles in human health, including modulation of neuromuscular and immune function and reduction of inflammation. Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D.

Forms of Vitamin D

Several forms (vitamers) of vitamin D have been discovered. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol.

  • Vitamin D1: molecular compound of ergocalciferol with lumisterol, 1:1
  • Vitamin D2: ergocalciferol or calciferol (made from ergosterol)
  • Vitamin D3: cholecalciferol (made from 7-dehydrocholesterol in the skin).
  • Vitamin D4: 22-dihydroergocalciferol
  • Vitamin D5: sitocalciferol (made from 7-dehydrositosterol)

Vitamin D Reference Intakes

Intake reference values for vitamin D and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies (formerly National Academy of Sciences). DRI is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and gender], include:

  • Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97-98%) healthy people.
  • Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
  • Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects].

The FNB established an AI for vitamin D that represents a daily intake that is sufficient to maintain bone health and normal calcium metabolism in healthy people. AIs for vitamin D are listed in both micrograms (mcg) and International Units (IUs); the biological activity of 1 mcg is equal to 40 IU (Table 2). The AIs for vitamin D are based on the assumption that the vitamin is not synthesized by exposure to sunlight.

Adequate Intakes (AIs) for Vitamin D

AgeChildrenMenWomenPregnancyLactation
Birth to 13 years 5 mcg
(200 IU)
       
14-18 years   5 mcg
(200 IU)
5 mcg
(200 IU)
5 mcg
(200 IU)
5 mcg
(200 IU)
19-50 years   5 mcg
(200 IU)
5 mcg
(200 IU)
5 mcg
(200 IU)
5 mcg
(200 IU)
51-70 years   10 mcg
(400 IU)
10 mcg
(400 IU)
   
71+ years   15 mcg
(600 IU)
15 mcg
(600 IU)
   

Vitamin D Sources

Food

Few foods are naturally rich in vitamin D. The flesh of fish (such as salmon, tuna, and mackerel) and fish liver oils are among the best sources. Small amounts of vitamin D are found in beef liver, cheese, and egg yolks. Vitamin D in these foods is primarily in the form of vitamin D3 (cholecalciferol) and its metabolite 25(OH)D3. Some mushrooms provide vitamin D2 (ergocalciferol) in variable amounts.

Most vitamin D intake is in the form of fortified products including milk, soy milk and cereal grains or supplementsFor example, almost all of the U.S. milk supply is fortified with 100 IU/cup of vitamin D (25% of the Daily Value or 50% of the AI level for ages 14-50 years). In the 1930s, a milk fortification program was implemented in the United States to combat rickets, then a major public health problem. This program virtually eliminated the disorder at that time]. Other dairy products made from milk, such as cheese and ice cream, are generally not fortified. Ready-to-eat breakfast cereals often contain added vitamin D, as do some brands of orange juice, yogurt, and margarine. In the United States, foods allowed to be fortified with vitamin D include cereal flours and related products, milk and products made from milk, and calcium-fortified fruit juices and drinks. Maximum levels of added vitamin D are specified by law.

Selected Food Sources of Vitamin D
FoodIUs per serving*Percent DV**
Cod liver oil, 1 tablespoon 1,360 340
Salmon, cooked, 3.5 ounces 360 90
Mackerel, cooked, 3.5 ounces 345 90
Tuna fish, canned in oil, 3 ounces 200 50
Sardines, canned in oil, drained, 1.75 ounces 250 70
Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup 98 25
Margarine, fortified, 1 tablespoon 60 15
Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 0.75-1 cup (more heavily fortified cereals might provide more of the DV) 40 10
Egg, 1 whole (vitamin D is found in yolk) 20 6
Liver, beef, cooked, 3.5 ounces 15 4
Cheese, Swiss, 1 ounce 12 4

*IUs = International Units.
**DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin D is 400 IU for adults and children age 5 and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.


The U.S. Department of Agriculture's Nutrient Database Web site, http://www.nal.usda.gov/fnic/foodcomp/search/, lists the nutrient content of many foods; relatively few have been analyzed for vitamin D content.

Sun exposure
Most people meet their vitamin D needs through exposure to sunlight]. Ultraviolet (UV) B radiation with a wavelength of 290-315 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3 . Season, geographic latitude, time of day, cloud cover, smog, skin melanin content, and sunscreen are among the factors that affect UV radiation exposure and vitamin D synthesis. The UV energy above 42 degrees north latitude (a line approximately between the northern border of California and Boston) is insufficient for cutaneous vitamin D synthesis from November through February [6]; in far northern latitudes, this reduced intensity lasts for up to 6 months. Latitudes below 34 degrees north (a line between Los Angeles and Columbia, South Carolina) allow for cutaneous production of vitamin D throughout the year [14]

Complete cloud cover reduces UV energy by 50%; shade (including that produced by severe pollution) reduces it by 60%. UVB radiation does not penetrate glass, so exposure to sunshine indoors through a window does not produce vitamin D. Sunscreens with a sun protection factor of 8 or more appear to block vitamin D-producing UV rays, although in practice people generally do not apply sufficient amounts, cover all sun-exposed skin, or reapply sunscreen regularly. Skin likely synthesizes some vitamin D even when it is protected by sunscreen as typically applied.

The factors that affect UV radiation exposure and research to date on the amount of sun exposure needed to maintain adequate vitamin D levels make it difficult to provide general guidelines. It has been suggested, for example, that approximately 5-30 minutes of sun exposure between 10 AM and 3 PM at least twice a week to the face, arms, legs, or back without sunscreen usually lead to sufficient vitamin D synthesis and that the moderate use of commercial tanning beds that emit 2-6% UVB radiation is also effective. Individuals with limited sun exposure need to include good sources of vitamin D in their diet or take a supplement.

Despite the importance of the sun to vitamin D synthesis, it is prudent to limit exposure of skin to sunlight. UV radiation is a carcinogen responsible for most of the estimated 1.5 million skin cancers and the 8,000 deaths due to metastatic melanoma that occur annually in the United States. Lifetime cumulative UV damage to skin is also largely responsible for some age-associated dryness and other cosmetic changes. It is not known whether a desirable level of regular sun exposure exists that imposes no (or minimal) risk of skin cancer over time.

Dietary supplements
In supplements and fortified foods, vitamin D is available in two forms, D2 (ergocalciferol) and D3
(cholecalciferol). Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol. The two forms have traditionally been regarded as equivalent based on their ability to cure rickets, but evidence has been offered that they are metabolized differently. Vitamin D3 could be more than three times as effective as vitamin D2 in raising serum 25(OH)D concentrations and maintaining those levels for a longer time, and its metabolites have superior affinity for vitamin D-binding proteins in plasma. Because metabolite receptor affinity is not a functional assessment, as the earlier results for the healing of rickets were, further research is needed on the comparative physiological effects of both forms. Many supplements are being reformulated to contain vitamin D3 instead of vitamin D2. Both forms (as well as vitamin D in foods and from cutaneous synthesis) effectively raise serum 25(OH)D levels.


Vitamin D Deficiencies

Nutrient deficiencies are usually the result of dietary inadequacy, impaired absorption and use, increased requirement, or increased excretion. A vitamin D deficiency can occur when usual intake is lower than recommended levels over time, exposure to sunlight is limited, the kidneys cannot convert vitamin D to its active form, or absorption of vitamin D from the digestive tract is inadequate. Vitamin D-deficient diets are associated with milk allergy, lactose intolerance, and strict vegetarianism.

Obtaining sufficient vitamin D from natural food sources alone can be difficult. For many people, consuming vitamin D-fortified foods and being exposed to sunlight are essential for maintaining a healthy vitamin D status. In some groups, dietary supplements might be required to meet the daily need for vitamin D.

Rickets and osteomalacia are the classical vitamin D deficiency diseases. In children, vitamin D deficiency causes rickets, a disease characterized by a failure of bone tissue to properly mineralize, resulting in soft bones and skeletal deformities. In adults, vitamin D deficiency can lead to osteomalacia, resulting in weak muscles and bones. Symptoms of bone pain and muscle weakness can indicate inadequate vitamin D levels, but such symptoms can be subtle and go undetected in the initial stages.

Older adults
Americans aged 50 and older are at increased risk of developing vitamin D insufficiency. As people age, skin cannot synthesize vitamin D as efficiently and the kidney is less able to convert vitamin D to its active hormone form. As many as half of older adults in the United States with hip fractures could have serum 25(OH)D levels <12 ng/mL (<30 nmol/L).

People with limited sun exposure
Homebound individuals, people living in northern latitudes (such as New England and Alaska), women who wear long robes and head coverings for religious reasons, and people with occupations that prevent sun exposure are unlikely to obtain adequate vitamin D from sunlight.

People with dark skin
Greater amounts of the pigment melanin result in darker skin and reduce the skin's ability to produce vitamin D from exposure to sunlight. Some studies suggest that older adults, especially women, with darker skin are at high risk of developing vitamin D insufficiency. However, one group with dark skin, African Americans, generally has lower levels of 25(OH)D yet develops fewer osteoporotic fractures than Caucasians (see section below on osteoporosis).

People with fat malabsorption
As a fat-soluble vitamin, vitamin D requires some dietary fat in the gut for absorption. Individuals who have a reduced ability to absorb dietary fat might require vitamin D supplements. Fat malabsorption is associated with a variety of medical conditions including pancreatic enzyme deficiency, Crohn's disease, cystic fibrosis, celiac disease, surgical removal of part of the stomach or intestines, and some forms of liver disease.

People who are obese
Individuals with a body mass index (BMI) ≥30 typically have a low plasma concentration of 25(OH)D]; this level decreases as obesity and body fat increase. Obesity does not affect skin's capacity to synthesize vitamin D, but greater amounts of subcutaneous fat sequester more of the vitamin and alter its release into the circulation. Even with orally administered vitamin D, BMI is inversely correlated with peak serum concentrations, probably because some vitamin D is sequestered in the larger pools of body fat.

Osteoporosis
More than 25 million adults in the United States have or are at risk of developing osteoporosis, a disease characterized by fragile bones that significantly increases the risk of bone fractures
. Osteoporosis is most often associated with inadequate calcium intakes (generally <1,000-1,200 mg/day), but insufficient vitamin D contributes to osteoporosis by reducing calcium absorption. Although rickets and osteomalacia are extreme examples of the effects of vitamin D deficiency, osteoporosis is an example of a long-term effect of calcium and vitamin D insufficiency. Adequate storage levels of vitamin D maintain bone strength and might help prevent osteoporosis in older adults, nonambulatory individuals who have difficulty exercising, postmenopausal women, and individuals on chronic steroid therapy.

Normal bone is constantly being remodeled. During menopause, the balance between these processes changes, resulting in more bone being resorbed than rebuilt. Hormone therapy with estrogen and progesterone might be able to delay the onset of osteoporosis. However, some medical groups and professional societies recommend that postmenopausal women consider using other agents to slow or stop bone resorption because of the potential adverse health effects of hormone therapy.

ost supplementation trials of the effects of vitamin D on bone health also include calcium, so it is not possible to isolate the effects of each nutrient. The authors of a recent evidence-based review of research concluded that supplements of both vitamin D3 (at 700-800 IU/day) and calcium (500-1,200 mg/day) decreased the risk of falls, fractures, and bone loss in elderly individuals aged 62-85 years. The decreased risk of fractures occurred primarily in elderly women aged 85 years, on average, and living in a nursing home. Women should consult their healthcare providers about their needs for vitamin D (and calcium) as part of an overall plan to prevent or treat osteoporosis.

African Americans have lower levels of 25(OH)D than Caucasians, yet they develop fewer osteoporotic fractures. This suggests that factors other than vitamin D provide protection. African Americans have an advantage in bone density from early childhood, a function of their more efficient calcium economy, and have a lower risk of fracture even when they have the same bone density as Caucasians. They also have a higher prevalence of obesity, and the resulting higher estrogen levels in obese women might protect them from bone loss]. Further reducing the risk of osteoporosis in African Americans are their lower levels of bone-turnover markers, shorter hip-axis length, and superior renal calcium conservation. However, despite this advantage in bone density, osteoporosis is a significant health problem among African Americans as they age. 

Chronic disease

Low blood levels of vitamin D have long been associated with disease, and the assumption has been that vitamin D supplements may protect against disease. However, new research demonstrates that ingested vitamin D is immunosuppressive and that low blood levels of vitamin D may be actually a result of the disease process. Supplementation may make the disease worse. In a new report Trevor Marshall, Ph.D., professor at Australia’s Murdoch University School of Biological Medicine and Biotechnology, explains how increased vitamin D intake affects much more than just nutrition or bone health. The paper explains how the Vitamin D Nuclear Receptor (VDR) acts in the repression or transcription of hundreds of genes, including genes associated with diseases ranging from cancers to multiple sclerosis. Marshall's research has demonstrated how ingested vitamin D can actually block VDR activation, the opposite effect to that of Sunshine. Instead of a positive effect on gene expression, Marshall reported that his own work, as well as the work of others, shows that quite nominal doses of ingested vitamin D can suppress the proper operation of the immune system.  Marshall and his researchers also found that vitamin D supplementation, even at levels many consider desirable, interferes with recoveryof people with such chronic diseases.

Journal reference: Marshall TG. Vitamin D discovery outpaces FDA decision making. Bioessays. 2008 Jan 15;30(2):173-182 [Epub ahead of print] Online ISSN: 1521-1878 Print ISSN: 0265-9247 PMID: 18200565

Coronary disease prevention

Research indicates that vitamin D may play a role in preventing or reversing coronary disease. As with cancer incidence, a qualitative inverse correlations was found between coronary disease incidence and serum vitamin D levels of 32.0 versus 35.5 ng/mL. Cholesterol levels were found to be reduced in gardeners in the UK during the summer months. Heart attacks peak in winter and decline in summer in temperate but not tropical latitudes. The issue of vitamin D in heart health has not yet been settled. Exercise may account for some of the benefit attributed to vitamin D, since vitamin D levels are higher in physically active persons. Moreover, there may be an upper limit after which cardiac benefits decline. One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL. These sun-living groups results do not generalize to sun-deprived urban dwellers. Among a group with heavy sun exposure, taking supplemental vitamin D may result in blood levels over the ideal range, while urban dwellers not taking supplemental vitamin D may fall under the levels recognized as ideal, and being above or below the preferable levels may cause adverse affects on the health of each group.

Researchers at the Harvard Medical School in Boston reported in Circulation, the Journal of the American Heart Association, January 2008 that vitamin D deficiency is associated with an increase in high blood pressure and cardiovascular risk. Researchers monitored the vitamin D levels, blood pressure and other cardiovascular risk factors of 1739 people, of an average age of 59 years for 5 years. They found that those people with low levels of vitamin D had a 62% higher risk of a cardiovascular event than those with normal vitamin D levels.

Cancer
Laboratory and animal evidence as well as epidemiologic data suggest that vitamin D status could affect cancer risk. Strong biological and mechanistic bases indicate that vitamin D plays a role in the prevention of colon, prostate, and breast cancers. Emerging epidemiologic data suggest that vitamin D has a protective effect against colon cancer, but the data are not as strong for a protective effect against prostate and breast cancer, and are variable for cancers at other sites. Studies do not consistently show a protective effect or no effect, however. One study of Finnish smokers, for example, found that subjects in the highest quintile of baseline vitamin D status have a three-fold higher risk of developing pancreatic cancer.

Vitamin D emerged as a protective factor in a prospective, cross-sectional study of 3,121 adults aged ≥50 years (96% men) who underwent a colonoscopy. The study found that 10% had at least one advanced cancerous lesion. Those with the highest vitamin D intakes (>645 IU/day) had a significantly lower risk of these lesions. However, the Women's Health Initiative, in which 36,282 postmenopausal women of various races and ethnicities were randomly assigned to receive 400 IU vitamin D plus 1,000 mg calcium daily or a placebo, found no significant differences between the groups in the incidence of colorectal cancers over 7 years. More recently, a clinical trial focused on bone health in 1,179 postmenopausal women residing in rural Nebraska found that subjects supplemented daily with calcium (1,400-1,500 mg) and vitamin D3 (1,100 IU) had a significantly lower incidence of cancer over 4 years compared to women taking a placebo. The small number of cancers reported (50) precludes generalizing about a protective effect from either or both nutrients or for cancers at different sites. This caution is supported by an analysis of 16,618 participants in NHANES III, where total cancer mortality was found to be unrelated to baseline vitamin D status. However, colorectal cancer mortality was inversely related to serum 25(OH)D concentrations; levels >80 nmol/L were associated with a 72% risk reduction than those <50 nmol/L.

Further research is needed to determine whether vitamin D inadequacy in particular increases cancer risk, whether greater exposure to the nutrient is protective, and whether some individuals could be at increased risk of cancer because of vitamin D exposure.

Other conditions
A growing body of research suggests that vitamin D might play some role in the prevention and treatment of type 1 and type 2 diabetes, hypertension, glucose intolerance, multiple sclerosis, and other medical conditions. However, most evidence for these roles comes from in vitro, animal, and epidemiological studies, not the randomized clinical trials considered to be more definitive. Until such trials are conducted, the implications of the available evidence for public health and patient care will be debated.


Vitamin D toxicity

Vitamin D toxicity can cause nonspecific symptoms such as nausea, vomiting, poor appetite, constipation, weakness, and weight loss. More seriously, it can also raise blood levels of calcium, causing mental status changes such as confusion and heart rhythm abnormalities. The use of supplements of both calcium (1,000 mg/day) and vitamin D (400 IU/day) by postmenopausal women was associated with a 17% increase in the risk of kidney stones over 7 years in the Women's Health Initiative. Deposition of calcium and phosphate in the kidneys and other soft tissues can also be caused by excessive vitamin D levels. A serum 25(OH)D concentration consistently >200 ng/mL (>500 nmol/L) is considered to be potentially toxic. In an animal model, concentrations ≤400 ng/mL (≤1,000 nmol/L) were not associated with harm.

Excessive sun exposure does not result in vitamin D toxicity because the sustained heat on the skin is thought to photodegrade previtamin D 3 and vitamin D3 as it is formed. High intakes of dietary vitamin D are very unlikely to result in toxicity unless large amounts of cod liver oil are consumed; toxicity is more likely to occur from high intakes of supplements.

Long-term intakes above the UL increase the risk of adverse health effects. Substantially larger doses administered for a short time or periodically (e.g., 50,000 IU/week for 8 weeks) do not cause toxicity. Rather, the excess is stored and used as needed to maintain normal serum 25(OH)D concentrations when vitamin D intakes or sun exposure are limited.

Tolerable Upper Intake Levels (ULs) for Vitamin D
AgeChildrenMenWomenPregnancyLactation
Birth to 12 months 25 mcg
(1,000 IU)
       
1-13 years 50 mcg
(2,000 IU)
       
14+ years   50 mcg
(2,000 IU)
50 mcg
(2,000 IU)
50 mcg
(2,000 IU)
50 mcg
(2,000 IU)


Several nutrition scientists recently challenged these ULs, first published in 1997. They pointed to newer clinical trials conducted in healthy adults that found no evidence of vitamin D toxicity at doses ≥10,000 IU/day. Although vitamin D supplements above recommended levels given in clinical trials have not shown harm, most trials were not adequately designed to assess harm. Evidence is not sufficient to determine the potential risks of excess vitamin D in infants, children, and women of reproductive age.

 

Vitamin D Interactions with Medicines

Vitamin D supplements have the potential to interact with several types of medications. A few examples are provided below. Individuals taking these medications on a regular basis should discuss vitamin D intakes with their healthcare providers.

Steroids
Corticosteroid medications such as prednisone, often prescribed to reduce inflammation, can reduce calcium absorption] and impair vitamin D metabolism. These effects can further contribute to the loss of bone and the development of osteoporosis associated with their long-term use.

Other medications
Both the weight-loss drug orlistat (brand names Xenical® and alli™) and the cholesterol-lowering drug cholestyramine (brand names Questran®, LoCholest®, and Prevalite®) can reduce the absorption of vitamin D and other fat-soluble vitamins. Both phenobarbital and phenytoin (brand name Dilantin®), used to prevent and control epileptic seizures, increase the hepatic metabolism of vitamin D to inactive compounds and reduce calcium absorption.

Vitamin D Deficiency Prevention

According to the 2005 Dietary Guidelines for Americans, "nutrient needs should be met primarily through consuming foods. Foods provide an array of nutrients and other compounds that may have beneficial effects on health. In certain cases, fortified foods and dietary supplements may be useful sources of one or more nutrients that otherwise might be consumed in less than recommended amounts. However, dietary supplements, while recommended in some cases, cannot replace a healthful diet."The Dietary Guidelines for Americans describes a healthy diet as one that

  • Emphasizes a variety of fruits, vegetables, whole grains, and fat-free or low-fat milk and milk products.
    Milk is fortified with vitamin D, as are many ready-to-eat cereals and a few brands of yogurt and orange juice. Cheese naturally contains small amounts of vitamin D.
  • Includes lean meats, poultry, fish, beans, eggs, and nuts.
    Fish such as salmon, tuna, and mackerel are very good sources of vitamin D. Small amounts of vitamin D are also found in beef liver and egg yolks.
  • Is low in saturated fats, trans fats, cholesterol, salt (sodium), and added sugars.
  • Stays within your daily calorie needs.
For more information about building a healthful diet, refer to the Dietary Guidelines for Americans (http://www.health.gov/dietaryguidelines/dga2005/document/default.htm) and the U.S. Department of Agriculture's food guidance system, My Pyramid (http://www.mypyramid.gov).
 
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