Introduction

Vitamin D (also referred to as “calciferol”) is a fat-soluble vitamin that is naturally present in a few foods, added to others, and available as a dietary supplement. It is also produced endogenously when ultraviolet (UV) rays from sunlight strike the skin and trigger vitamin D synthesis.

Vitamin D obtained from sun exposure, foods, and supplements is biologically inert and must undergo two hydroxylations in the body for activation. The first hydroxylation, which occurs in the liver, converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as “calcidiol.” The second hydroxylation occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as “calcitriol”.^[1]

Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal bone mineralization and to prevent hypocalcemic tetany (involuntary contraction of muscles, leading to cramps and spasms). It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts.^[1-3] Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Vitamin D sufficiency prevents rickets in children and osteomalacia in adults. Together with calcium, vitamin D also helps protect older adults from osteoporosis.

Vitamin D has other roles in the body, including reduction of inflammation as well as modulation of such processes as cell growth, neuromuscular and immune function, and glucose metabolism.^[1-3] Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D. Many tissues have vitamin D receptors, and some convert 25(OH)D to 1,25(OH)2D.

In foods and dietary supplements, vitamin D has two main forms, D2 (ergocalciferol) and D3 (cholecalciferol), that differ chemically only in their side-chain structures. Both forms are well absorbed in the small intestine. Absorption occurs by simple passive diffusion and by a mechanism that involves intestinal membrane carrier proteins .^[4] The concurrent presence of fat in the gut enhances vitamin D absorption, but some vitamin D is absorbed even without dietary fat. Neither aging nor obesity alters vitamin D absorption from the gut.^[4]

Serum concentration of 25(OH)D is currently the main indicator of vitamin D status. It reflects vitamin D produced endogenously and that obtained from foods and supplements [1]. In serum, 25(OH)D has a fairly long circulating half-life of 15 days^[1]. Serum concentrations of 25(OH)D are reported in both nanomoles per liter (nmol/L) and nanograms per milliliter (ng/mL). One nmol/L is equal to 0.4 ng/mL, and 1 ng/mL is equal to 2.5 nmol/L.
Assessing vitamin D status by measuring serum 25(OH)D concentrations is complicated by the considerable variability of the available assays (the two most common ones involve antibodies or chromatography) used by laboratories that conduct the analyses .^[5,6] As a result, a finding can be falsely low or falsely high, depending on the assay used and the laboratory. The international Vitamin D Standardization Program has developed procedures for standardizing the laboratory measurement of 25(OH)D to improve clinical and public health practice .^[5,7-10]

In contrast to 25(OH)D, circulating 1,25(OH)2D is generally not a good indicator of vitamin D status because it has a short half-life measured in hours, and serum levels are tightly regulated by parathyroid hormone, calcium, and phosphate^[1]. Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe .^[2]
Although 25(OH)D functions as a biomarker of exposure, the extent to which 25(OH)D levels also serve as a biomarker of effect on the body (i.e., relating to health status or outcomes) is not clear.^[1,3]

Table 1: Serum 25-Hydroxyvitamin D [25(OH)D] Concentrations and Health [1]
nmol/L*	ng/mL*	Health status
<30	<12	Associated with vitamin D deficiency, which can lead to rickets in infants and children and osteomalacia in adults
30 to <50	12 to <20	Generally considered inadequate for bone and overall health in healthy individuals
≥50	≥20	Generally considered adequate for bone and overall health in healthy individuals
>125	>50	Linked to potential adverse effects, particularly at >150 nmol/L (>60 ng/mL)

*Serum concentrations of 25(OH)D are reported in both nanomoles per liter (nmol/L) and nanograms per milliliter (ng/mL). One nmol/L = 0.4 ng/mL, and 1 ng/mL = 2.5 nmol/L.

Optimal serum concentrations of 25(OH)D for bone and general health have not been established because they are likely to vary by stage of life, by race and ethnicity, and with each physiological measure used ^[1,13,14]. In addition, although 25(OH)D levels rise in response to increased vitamin D intake, the relationship is nonlinear ^[1]. The amount of increase varies, for example, by baseline serum levels and duration of supplementation.

Recommended Intakes

Intake recommendations for vitamin D and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by expert committees of NASEM ^[1]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and sex, include:

· Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.

· Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.

· Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.

· Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.
An FNB committee established RDAs for vitamin D to indicate daily intakes sufficient to maintain bone health and normal calcium metabolism in healthy people. RDAs for vitamin D are listed in both micrograms (mcg) and international units (IU); 1 mcg vitamin D is equal to 40 IU (Table 2). Even though sunlight is a major source of vitamin D for some people, the FNB based the vitamin D RDAs on the assumption that people receive minimal sun exposure^[1]. For infants, the FNB committee developed AIs based on the amount of vitamin D that maintains serum 25(OH)D levels above 20 ng/mL (50 nmol/L) and supports bone development.

Table 2: Recommended Dietary Allowances (RDAs) for Vitamin D [1]
Age	Male	Female	Pregnancy	Lactation
0-12 months*	10 mcg (400 IU)	10 mcg (400 IU)
1–13 years	15 mcg (600 IU)	15 mcg (600 IU)
14–18 years	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)
19–50 years	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)	15 mcg (600 IU)
51–70 years	15 mcg (600 IU)	15 mcg (600 IU)
>70 years	20 mcg (800 IU)	20 mcg (800 IU)

*Adequate Intake (AI)

Many other countries around the world and some professional societies have somewhat different guidelines for vitamin D intakes^[15]. These differences are a result of an incomplete understanding of the biology and clinical implications of vitamin D, different purposes for the guidelines (e.g., for public health in a healthy population or for clinical practice), and/or the use in some guidelines of observational studies in addition to randomized clinical trials to establish recommendations^[9,15]. The Endocrine Society states, for example, that to maintain serum 25(OH)D levels above 75 nmol/L (30 ng/mL), adults might need at least 37.5 to 50 mcg (1,500–2,000 IU)/day of supplemental vitamin D, and children and adolescents might need at least 25 mcg (1,000 IU)/day ^[11]. In contrast, the United Kingdom government recommends intakes of 10 mcg (400 IU)/day for its citizens aged 4 years and older^[16].

Sources of Vitamin D

Food

Few foods naturally contain vitamin D. The flesh of fatty fish (such as trout, salmon, tuna, and mackerel) and fish liver oils are among the best sources^[17,1]. An animal’s diet affects the amount of vitamin D in its tissues. Beef liver, cheese, and egg yolks have small amounts of vitamin D, primarily in the form of vitamin D3 and its metabolite 25(OH)D3. Mushrooms provide variable amounts of vitamin D2^[17]. Some mushrooms available on the market have been treated with UV light to increase their levels of vitamin D2. In addition, the Food and Drug Administration (FDA) has approved UV-treated mushroom powder as a food additive for use as a source of vitamin D2 in food products [18]. Very limited evidence suggests no substantial differences in the bioavailability of vitamin D from various foods^[19].

Animal-based foods typically provide some vitamin D in the form of 25(OH)D in addition to vitamin D3. The impact of this form on vitamin D status is an emerging area of research. Studies show that 25(OH)D appears to be approximately five times more potent than the parent vitamin for raising serum 25(OH)D concentrations^[17,20,21]. One study found that when the 25(OH)D content of beef, pork, chicken, turkey, and eggs is taken into account, the total amount of vitamin D in the food is 2 to 18 times higher than the amount in the parent vitamin alone, depending on the food ^[20].

Fortified foods provide most of the vitamin D in American diets ^[1,22]. For example, almost all of the U.S. milk supply is voluntarily fortified with about 3 mcg/cup (120 IU), usually in the form of vitamin D3^[23]. In Canada, milk must be fortified with 0.88–1.0 mcg/100 mL (35–40 IU), and the required amount for margarine is at least 13.25 mcg/100 g (530 IU). Other dairy products made from milk, such as cheese and ice cream, are not usually fortified in the United States or Canada. Plant milk alternatives (such as beverages made from soy, almond, or oats) are often fortified with similar amounts of vitamin D to those in fortified cow’s milk (about 3 mcg [120 IU]/cup); the Nutrition Facts label lists the actual amount ^[24]. Ready-to-eat breakfast cereals often contain added vitamin D, as do some brands of orange juice, yogurt, margarine, and other food products.

The United States mandates the fortification of infant formula with 1–2.5 mcg/100 kcal (40–100 IU) vitamin D; 1–2 mcg/100 kcal (40–80 IU) is the required amount in Canada^[1].

A variety of foods and their vitamin D levels per serving are listed in Table 3.

Table 3: Vitamin D Content of Selected Foods[25]
Food*	Micrograms (mcg) per serving	International Units (IU) per serving	Percent DV*
Cod liver oil, 1 tablespoon	34.0	1,360	170
Trout (rainbow), farmed, cooked, 3 ounces	16.2	645	81
Salmon (sockeye), cooked, 3 ounces	14.2	570	71
Mushrooms, white, raw, sliced, exposed to UV light, ½ cup	9.2	366	46
Milk, 2% milkfat, vitamin D fortified, 1 cup	2.9	120	15
Soy, almond, and oat milks, vitamin D fortified, various brands, 1 cup	2.5-3.6	100-144	13-18
Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 1 serving	2.0	80	10
Sardines (Atlantic), canned in oil, drained, 2 sardines	1.2	46	6
Egg, 1 large, scrambled**	1.1	44	6
Liver, beef, braised, 3 ounces	1.0	42	5
Tuna fish (light), canned in water, drained, 3 ounces	1.0	40	5
Cheese, cheddar, 1 ounce	0.3	12	2
Mushrooms, portabella, raw, diced, ½ cup	0.1	4	1
Chicken breast, roasted, 3 ounces	0.1	4	1
Beef, ground, 90% lean, broiled, 3 ounces	0	1.7	0
Broccoli, raw, chopped, ½ cup	0	0	0
Carrots, raw, chopped, ½ cup	0	0	0
Almonds, dry roasted, 1 ounce	0	0	0
Apple, large	0	0	0
Banana, large	0	0	0
Rice, brown, long-grain, cooked, 1 cup	0	0	0
Whole wheat bread, 1 slice	0	0	0
Lentils, boiled, ½ cup	0	0	0
Sunflower seeds, roasted, ½ cup	0	0	0
Edamame, shelled, cooked, ½ cup	0	0	0

* DV = Daily Value. The FDA developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin D on the new Nutrition Facts and Supplement Facts labels and used for the values in Table 3 is 20 mcg (800 IU) for adults and children aged 4 years and older^[26]. The new labels must list vitamin D content in mcg per serving and have the option of also listing the amount in IUs in parentheses. FDA required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list a vitamin D DV of 400 IU until January 2021 [28,29]. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.
** Vitamin D is in the yolk.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin D arranged by nutrient content and by food name. However, FoodData Central does not include the amounts of 25(OH)D in foods.

Sun exposure

Most people in the world meet at least some of their vitamin D needs through exposure to sunlight^[1]. Type B UV (UVB) radiation with a wavelength of approximately 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3. Season, time of day, length of day, cloud cover, smog, skin melanin content, and sunscreen are among the factors that affect UV radiation exposure and vitamin D synthesis. Older people and people with dark skin are less able to produce vitamin D from sunlight ^[1]. UVB radiation does not penetrate glass, so exposure to sunshine indoors through a window does not produce vitamin D^[29].

The factors that affect UV radiation exposure, individual responsiveness, and uncertainties about the amount of sun exposure needed to maintain adequate vitamin D levels make it difficult to provide guidelines on how much sun exposure is required for sufficient vitamin D synthesis ^[15,30]. Some expert bodies and vitamin D researchers suggest, for example, that approximately 5–30 minutes of sun exposure, particularly between 10 a.m. and 4 p.m., either daily or at least twice a week to the face, arms, hands, and legs without sunscreen usually leads to sufficient vitamin D synthesis ^[13,15,30]. Moderate use of commercial tanning beds that emit 2% to 6% UVB radiation is also effective ^[13,31].

But despite the importance of the sun for vitamin D synthesis, limiting skin exposure to sunlight and UV radiation from tanning beds is prudent ^[30]. UV radiation is a carcinogen, and UV exposure is the most preventable cause of skin cancer. Federal agencies and national organizations advise taking photoprotective measures to reduce the risk of skin cancer, including using sunscreen with a sun protection factor (SPF) of 15 or higher, whenever people are exposed to the sun ^[30,32]. Sunscreens with an SPF of 8 or more appear to block vitamin D-producing UV rays. In practice, however, people usually do not apply sufficient amounts of sunscreen, cover all sun-exposed skin, or reapply sunscreen regularly. Their skin probably synthesizes some vitamin D, even with typically applied sunscreen amounts ^[1,30].

Dietary supplements

Dietary supplements can contain vitamins D2 or D3. Vitamin D2 is manufactured using UV irradiation of ergosterol in yeast, and vitamin D3 is produced with irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol ^[13]. Both forms raise serum 25(OH)D levels, and they seem to have equivalent ability to cure rickets^[4]. In addition, most steps in the metabolism and actions of vitamins D2 and D3 are identical. However, most evidence indicates that vitamin D3 increases serum 25(OH)D levels to a greater extent and maintains these higher levels longer than vitamin D2, even though both forms are well absorbed in the gut ^[33-36].

Some studies have used dietary supplements containing the 25(OH)D3 form of vitamin D. Per equivalent microgram dose, 25(OH)D3 is three to five times as potent as vitamin D3 ^[37,38]. However, no 25(OH)D3 dietary supplements appear to be available to consumers on the U.S. market at this time ^[39].

Vitamin D Intakes and Status

Most people in the United States consume less than recommended amounts of vitamin D. An analysis of data from the 2015–2016 National Health and Nutrition Examination Survey (NHANES) found that average daily vitamin D intakes from foods and beverages were 5.1 mcg (204 IU) in men, 4.2 mcg (168 IU) in women, and 4.9 mcg (196 IU) in children aged 2–19 years ^[40]. In fact, 2013–2016 NHANES data showed that 92% of men, more than 97% of women, and 94% of people aged 1 year and older ingested less than the EAR of 10 mcg (400 IU) of vitamin D from food and beverages ^[41].

The analysis of 2015–2016 data also showed that 28% of all individuals aged 2 years and older in the United States took a dietary supplement containing vitamin D^[40]. In addition, 26% of participants aged 2–5 years and 14% of those aged 6–11 years took supplements; rates increased with age from 10% of those aged 12–19 years to 49% of men and 59% of women aged 60 and older. Total vitamin D intakes were three times higher with supplement use than with diet alone; the mean intake from foods and beverages alone for individuals aged 2 and older was 4.8 mcg (192 IU) but increased to 19.9 mcg (796 IU) when dietary supplements were included.

Some people take very high doses of vitamin D supplements. In 2013–2014, an estimated 3.2% of the U.S. adult population took supplements containing 100 mcg (4,000 IU) or more vitamin D^[42].

One might expect a large proportion of the U.S. population to have vitamin D inadequacy on the basis of vitamin D intakes from foods, beverages, and even dietary supplements. However, comparing vitamin D intakes to serum 25(OH)D levels is problematic. One reason is that sun exposure affects vitamin D status, so serum 25(OH)D levels are usually higher than would be predicted on the basis of vitamin D dietary intakes alone^[1]. Another reason is that animal foods contain some 25(OH)D. This form of vitamin D is not included in intake surveys and is

considerably more potent than vitamins D2 or D3 at raising serum 25(OH)D levels^[43].
An analysis of NHANES 2011–2014 data on serum 25(OH)D levels found that most people in the United States aged 1 year and older had sufficient vitamin D intakes according to the FNB thresholds ^[44]. However, 18% were at risk of inadequacy (levels of 30–49 nmol/L [12–19.6 ng/mL]), and 5% were at risk of deficiency (levels below 30 nmol/L [12 ng/mL]). Four percent had levels higher than 125 nmol/L (50 ng/mL). Proportions at risk of deficiency were lowest among children aged 1–5 years (0.5%), peaked at 7.6% in adults aged 20–39 years, and fell to 2.9% among adults aged 60 years and older; patterns were similar for risks of inadequacy. Rates of deficiency varied by race and ethnicity: 17.5% of non-Hispanic Blacks were at risk of vitamin D deficiency, as were 7.6% of non-Hispanic Asians, 5.9% of Hispanics, and 2.1% of non-Hispanic White people. Again, the pattern was similar for the risk of inadequacy. Vitamin D status in the United States remained stable in the decade between 2003–2004 and 2013–2014.

Vitamin D Deficiency

People can develop vitamin D deficiency when usual intakes are lower over time than recommended levels, exposure to sunlight is limited, the kidneys cannot convert 25(OH)D to its active form, or absorption of vitamin D from the digestive tract is inadequate. Diets low in vitamin D are more common in people who have milk allergy or lactose intolerance and those who consume an ovo-vegetarian or vegan diet ^[1].

In children, vitamin D deficiency is manifested as rickets, a disease characterized by a failure of bone tissue to become properly mineralized, resulting in soft bones and skeletal deformities ^[45]. In addition to bone deformities and pain, severe rickets can cause failure to thrive, developmental delay, hypocalcemic seizures, tetanic spasms, cardiomyopathy, and dental abnormalities ^[46,47].
Prolonged exclusive breastfeeding without vitamin D supplementation can cause rickets in infants, and, in the United States, rickets is most common among breastfed Black infants and children ^[48]. In one Minnesota county, the incidence rate of rickets in children younger than 3 years in the decade beginning in 2000 was 24.1 per 100,000^[49]. Rickets occurred mainly in Black children who were breastfed longer, were born with low birthweight, weighed less, and were shorter than other children. The incidence rate of rickets in the infants and children (younger than 7) seen by 2,325 pediatricians throughout Canada was 2.9 per 100,000 in 2002–2004, and almost all patients with rickets had been breastfed ^[50].

The fortification of milk (a good source of calcium) and other staples, such as breakfast cereals and margarine, with vitamin D beginning in the 1930s along with the use of cod liver oil made rickets rare in the United States^[31,51]. However, the incidence of rickets is increasing globally, even in the United States and Europe, especially among immigrants from African, Middle-Eastern, and Asian countries ^[52]. Possible explanations for this increase include genetic differences in vitamin D metabolism, dietary preferences, and behaviors that lead to less sun exposure^[46,47].

In adults and adolescents, vitamin D deficiency can lead to osteomalacia, in which existing bone is incompletely or defectively mineralized during the remodeling process, resulting in weak bones^[47]. Signs and symptoms of osteomalacia are similar to those of rickets and include bone deformities and pain, hypocalcemic seizures, tetanic spasms, and dental abnormalities^[46].
Screening for vitamin D status is becoming a more common part of the routine laboratory bloodwork ordered by primary-care physicians, irrespective of any indications for this practice^[6,53-55]. No studies have examined whether such screening for vitamin D deficiency results in improved health outcomes^[56]. The U.S. Preventive Services Task Force (USPSTF) found insufficient evidence to assess the benefits and harms of screening for vitamin D deficiency in asymptomatic adults^[6]. It added that no national professional organization recommends population screening for vitamin D deficiency.

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