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3
Overview of Vitamin D
INTRODUCTION
Vitamin D, first identified as a vitamin early in the 20th century, is now recognized as a prohormone. A unique aspect of vitamin D as a nutrient is that it can be synthesized by the human body through the action of sunlight. These dual sources of vitamin D make it challenging to develop dietary reference intake values.
Vitamin D, also known as calciferol, comprises a group of fat-soluble seco-sterols. The two major forms are vitamin D2 and vitamin D3. Vitamin D2 (ergocalciferol) is largely human-made and added to foods, whereas vitamin D3 (cholecalciferol) is synthesized in the skin of humans from 7-dehydrocholesterol and is also consumed in the diet via the intake of animal-based foods. Both vitamin D3 and vitamin D2 are synthesized commercially and found in dietary supplements or fortified foods. The D2 and D3 forms differ only in their side chain structure. The differences do not affect metabolism (i.e., activation), and both forms function as prohormones. When activated, the D2 and D3 forms have been reported to exhibit identical responses in the body, and the potency related to the ability to cure vitamin D–deficiency rickets is the same (Fieser and Fieser, 1959; Jones et al., 1998; Jurutka et al., 2001). Experimental animal studies have indicated that vitamin D2 is less toxic than vitamin D3, but this has not been demonstrated in humans.
The activation steps involved in converting vitamin D from the diet and cutaneous synthesis are illustrated in Figure 3-1. Vitamin D, in either the D2 or D3 form, is considered biologically inactive until it undergoes two
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FIGURE 3-1 Overview of vitamin D synthesis, intake, and activation.
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enzymatic hydroxylation reactions. The first takes place in the liver, mediated by the 25-hydroxylase (most likely cytochrome P450 2R1 [CYP2R1]) which forms 25-hydroxyvitamin D (hereafter referred to as 25OHD). The second reaction takes place in the kidney, mediated by 1α-hydroxylase (CYP27B1), which converts 25OHD to the biologically active hormone, calcitriol (1,25-dihydroxyvitamin D). The 1α-hydroxylase gene is also expressed in several extra-renal tissues, but its contribution to calcitriol formation in these tissues is unknown. 25OHD, the precursor of calcitriol, is the major circulating form of vitamin D; it circulates bound to a specific plasma carrier protein, vitamin D binding protein (DBP). DBP also transports vitamin D and calcitriol.
The renal synthesis of calcitriol is tightly regulated by two counter-acting hormones, with up-regulation via parathyroid hormone (PTH) and down-regulation via fibroblast-like growth factor-23 (FGF23) (Galitzer et al., 2008; Bergwitz and Juppner, 2010). Low serum phosphorus levels stimulate calcitriol synthesis, whereas high serum phosphorus levels inhibit it. Following its synthesis in the kidney, calcitriol binds to DBP to be transported to target organs. The biological actions of calcitriol, involve regulation of gene expression at the transcriptional level, and are mediated through binding to a vitamin D receptor (VDR), located primarily in the nuclei of target cells (Jones et al., 1998; Jurutka et al., 2001). Additional hydroxylation reactions, such as that mediated by CYP24A1, as shown in Figure 3-1, result in more polar metabolites with greatly reduced or no apparent biological activity.
The classical actions of vitamin D—which by itself is inactive—are due to the functions of the active metabolite, calcitriol. These actions take the form of the regulation of serum calcium and phosphate homeostasis and, in turn, the development and maintenance of bone health (DeLuca, 1988; Reichel et al., 1989; Jones et al., 1998). Non-classical functions are less well elucidated. VDRs are found fairly ubiquitously throughout the body in tissues not involved with calcium and phosphate homeostasis, and the presence of VDRs in these tissues implies that calcitriol may play a more general role or that ligands other than calcitriol can activate the VDR. Furthermore, the specific vitamin D–responsive elements (VDREs), considered the hallmark of vitamin D action, are present in a large number of human genes involved in a wide range of classical and non-classical roles, such as the regulation of cell proliferation, cell differentiation, and apoptosis. It has been suggested that calcitriol exerts immunomodulatory and anti-proliferative effects through autocrine and paracrine pathways (Adams and Hewison, 2008). These wide-ranging actions of calcitriol have further been hypothesized to play a potential role in preventive or therapeutic action in cancer (Masuda and Jones, 2006) and chronic conditions such
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as auto-immune conditions (including type 1 diabetes), cardiovascular disease, and infections (Holick et al., 2007).
Outside of the biological forms of vitamin D, a number of analogues based on the vitamin D structure have been synthesized for use as potential pharmacological agents. These are not, however, dietary or biosynthesized compounds; rather, they are designed for specific applications in research or clinical treatment. Examples of synthetic analogues that have gained importance in clinical medicine are briefly mentioned below.
The term vitamin D is generally used in this report to refer to both the D2 and D3 forms as well as their metabolites, although the two forms are distinguished when necessary for clarification (see Box 3-1 for definitions). Vitamin D levels in the diet—from foods and supplements—are expressed in International Units (IU), but may be expressed elsewhere in micrograms (μg). The biological activity of 1 μg of vitamin D is equivalent to 40 IU. Owing to the frequency with which serum 25OHD levels are included in this report text, the levels are expressed only as nanomoles per liter (nmol/L). As shown in Box 3-1, the nanomoles per liter measure can be converted to nanograms per milliliter (ng/mL) by dividing by a factor of 2.5.
BOX 3-1
Terms and Conversions Used in Reference to Vitamin D
Terms:
Vitamin D—also referred to as calciferol
Vitamin D2—also referred to as ergocalciferol
Vitamin D3—also referred to as cholecalciferol
25OHD—25-hydroxyvitamin D also referred to as calcidiol or calcifediol; indicates no distinction between D2 and D3 forms. When relevant, forms are distinguished as 25OHD2 and 25OHD3
Calcitriol—1,25-dihydroxyvitamin D3 (Note: Ercalcitriol—refers to 1,25-dihydroxyvitamin D2, but in this report, the term “calcitriol” will be used for both)
24,25(OH)2D—24,25-dihydroxyvitamin D
IU = International Unit is a measurement based on biological activity or effect; 1 IU of vitamin D is defined as the activity of 0.025 μg of cholecalciferol in bioassays with rats and chicks.
Conversions for Vitamin D3:
[sources] 40 IU = 1 μg
[serum] 2.5 nmol/L = 1 ng/mL
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SOURCES OF VITAMIN D
Diet
The dietary sources of vitamin D include food and dietary supplements; therefore, “total vitamin D intake” reflects the combined dietary contribution from foods and supplements. There are a few naturally occurring food sources of vitamin D. These include fatty fish, fish liver oil, and egg yolk. Some foods are, however, fortified with vitamin D. After vitamin D was recognized as important for the prevention of rickets in the 1920s (Steenbock and Black, 1924), vitamin D fortification of some foods was initiated on a voluntary basis.
In the United States, fluid milk is voluntarily fortified with 400 IU per quart (or 385 IU/L) of vitamin D (U.S. regulations do not specify the form) (FDA, 2009). In Canada, under the Food and Drug Regulation,1 fortification of fluid milk and margarine with vitamin D is mandatory. Fluid milk must contain 35–45 IU vitamin D per 100 mL and margarine, 530 IU per 100 g. In addition, fortified plant-based beverages must contain vitamin D in an amount equivalent to fluid milk. In analyses conducted in the 1980s and early 1990s, a significant portion of milk samples in the United States were found to contain less than the specified amount of vitamin D (Tanner et al., 1988). Holick et al. (1992) found that 62 percent of milk sampled from five eastern states contained less than 80 percent and 10 percent contained more than 120 percent of the amount of vitamin D stated on the label. Chen et al. (1993) reported similar findings. A more recent report on vitamin D–fortified milk sampled in New York State over a period of 4 years showed that an average of only 47.7 percent of samples fell within the range of acceptable levels of vitamin D fortification (Murphy et al., 2001). However, recent surveys from the U.S. Department of Agriculture (USDA) indicate that these problems have been corrected. In a presentation to this committee, Byrdwell (2009) reported that a USDA survey of milk samples taken in 2007 from 24 locations across the United States showed that most samples had vitamin D levels within the range of 400 to 600 IU/quart.
In Canada, Faulkner et al. (2000) surveyed milk samples and found that 20 percent of skim milk, 40 percent of 2 percent fat milk, and 20 percent of whole milk, contained the recommended level of vitamin D. Samples collected by the Canadian Food Inspection Agency from 1999 through 2009 and analyzed for vitamin D indicated that during the last 4 years of sample collection, 47 to 69 percent were within the range specified by regulation (personal communication, S. Brooks, Health Canada, April
1
Available online at http://laws.justice.gc.ca/PDF/Regulation/C/C.R.C.,_c._870.pdf (accessed July 23, 2010).
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30, 2010). In addition, over the past 5 years, the average vitamin D content of analyzed milk samples fell within this range. Over time, manufacturers in the United States have added vitamin D to other foods, and the food industry is increasingly marketing foods fortified with vitamin D (Yetley, 2008). Based on data from a U.S. Food and Drug Administration (FDA) survey that provides information on the labels of processed, packaged food products in the United States, Yetley (2008) reported that almost all fluid milks, approximately 75 percent of ready-to-eat breakfast cereals, slightly more than half of all milk substitutes, approximately one-quarter of yogurts, and approximately 8 to 14 percent of cheeses, juices, and spreads are fortified with vitamin D in the U.S. market. Many product labels included in the survey indicated that the form of added vitamin D was vitamin D3. However, some milk substitutes are fortified with vitamin D2. Cereal labels did not specify the form of added vitamin D. Levels of vitamin D ranged from 40 IU per regulatory serving for cereals and cheeses to 60 IU per regulatory serving for spreads and 100 IU per regulatory serving for fluid milk. Several food categories had within-category ranges of 40 to 100 IU of vitamin D per regulatory serving. Serum vitamin D and 25OHD have low penetrance into breast milk, together comprising 40 to 50 IU of antirachitic activity per liter, most of which is contributed by 25OHD (Leerbeck and Sondergaard, 1980; Hollis et al., 1981; Reeve et al., 1982; Specker et al., 1985). Data from the USDA report the vitamin D content of human milk to be 4.3 IU/100 kcal.2 However, the vitamin D biological activity may be higher than the analyzed values, because human milk contains small amounts of 25OHD in addition to vitamin D3 (Reeve et al., 1982); further, the biological activity of 25OHD is approximately 50 percent higher than that of vitamin D (Blunt et al., 1968).
The FDA has established that infant formula must contain 40 to 100 IU of vitamin D per 100 kcal.3 Commercial infant formulas contain approximately 60 IU of vitamin D per 100 kcal, as estimated by the USDA food composition database,4 and Yetley (2008) reported that commercial milk-based infant formulas collected between 2003 and 2006 contained 87
2
USDA National Nutrient Database for Standard Reference Release 23. NBD No. 01107. Milk, human, mature, fluid. Available online at http://www.ars.usda.gov/Services/docs.htm?docid=8964 (accessed August 3, 2010).
3
USDA National Nutrient Database for Standard Reference Release 23. NBD No. 03946. Infant formula, ROSS, SIMILAC LACTOSE FREE ADVANCE, ready-to-feed, with ARA and DHA; and NDB no. 03815. Infant formula, MEAD JOHNSON, ENFAMIL LIPIL, with iron, ready-to-feed, with ARA and DHA. Available online at http://www.ars.usda.gov/main/site_main.htm?modecode=12-35-45-00 (accessed April 28, 2010).
4
Available online at http://www.nal.usda.gov/fnic/foodcomp/search/ (accessed March 16, 2010).
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to 184 percent of label declarations. In Canada, infant formula is required by regulation to contain between 40 and 80 IU of vitamin D per 100 kcal.
In recent years, dietary supplements containing vitamin D have become more common and have been more frequently consumed. The form of vitamin D used in supplement products can be either vitamin D2 or vitamin D3. It would appear from informal observations of the market place that manufacturers are increasingly switching from vitamin D2 to vitamin D3, and some are increasing the vitamin D content of their products. Traditionally, many marketed dietary supplements have contained 400 IU per daily dose, but levels in supplements have been increasing. In the United States, vitamin D can now be found in multi-vitamin/multi-mineral formulations as well as a single supplement in a range of dosage levels, including 1,000 to 5,000 IU of vitamin D3 per dose and even up to 50,000 IU of vitamin D2 per dose. In Canada, dosage levels of vitamin D above 1,000 IU are obtainable only with a prescription.
Information about current national survey estimates of the intake of vitamin D from foods and supplements can be found in Chapter 7.
Synthesis in the Skin
Vitamin D3 is synthesized in human skin from 7-dehydrocholesterol following exposure to ultraviolet B (UVB) radiation with wavelength 290 to 320 nm.5 The process of UVB-mediated conversion of 7-dehydrocholesterol to the previtamin D3 form and subsequent thermal isomerization to vitamin D3 occurring in the epidermis is illustrated in Figure 3-2.
The production of vitamin D3 in skin is a function of the amount of UVB radiation reaching the dermis as well as the availability of 7-dehydrocholesterol (Holick, 1995). As such, the level of synthesis is influenced by a number of factors, as described below in the section entitled “Measures Associated with Vitamin D: Serum 25OHD,” including season of the year, skin pigmentation, latitude, use of sunscreen, clothing, and amount of skin exposed. Age is also a factor, in that synthesis of vitamin D declines with increasing age, due in part to a fall in 7-dehydrocholesterol levels and due in part to alterations in skin morphology (MacLaughlin and Holick, 1985).
Toxic levels of vitamin D do not occur from prolonged sun exposure. Thermal activation of previtamin D3 in the skin gives rise to multiple non–vitamin D forms, such as lumisterol, tachysterol and others (Holick et al., 1981; Webb et al., 1989), as illustrated in Figure 3-2; this limits the
5
The chemical processes that lead to the formation of vitamin D3 from its precursor are non-enzymatic and can take place ex vivo and in organic solvents, as well as in vivo. Therefore, vitamin D3 can also be synthesized commercially.
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FIGURE 3-2 Photochemical events that lead to the production and regulation of vitamin D3 (cholecalciferol) in the skin.
NOTE: DBP = vitamin D binding protein.
SOURCE: Holick (1994). Reprinted with permission from the American Journal of Clinical Nutrition (1994, volume 60, pages 619-630), American Society for Nutrition.
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formation of vitamin D3 itself. Vitamin D3 can also be converted to nonactive forms.
The absolute percentage of circulating 25OHD that arises from cutaneous synthesis versus oral intake of vitamin D in the free-living North American population cannot be clearly specified. Individuals living at Earth’s poles during winter months and submariner crew members with very limited or no measurable UVB exposure have detectable levels of 25OHD in blood, arising from dietary sources and likely from previously synthesized and stored vitamin D. This topic is further explored in the section below that focuses on serum 25OHD.
METABOLISM OF VITAMIN D
Absorption
Owing to its fat-soluble nature, dietary vitamin D (either D2 or D3) is absorbed with other dietary fats in the small intestine (Haddad et al., 1993; Holick, 1995). The efficient absorption of vitamin D is dependent upon the presence of fat in the lumen, which triggers the release of bile acids and pancreatic lipase (Weber, 1981, 1983). In turn, bile acids initiate the emulsification of lipids, pancreatic lipase hydrolyzes the triglycerides into monoglycerides and free fatty acids, and bile acids support the formation of lipid-containing micelles, which diffuse into enterocytes. Early studies demonstrated that radiolabeled vitamin D3 appeared almost exclusively in the lymphatics and in the chylomicron fraction of plasma; as well, subjects with impaired bile acid release or pancreatic insufficiency both demonstrated significantly reduced absorption of vitamin D (Thompson et al., 1966; Blomstrand and Forsgren, 1967; Compston et al., 1981). Subsequently, other clinical and experimental animal studies confirmed that vitamin D is most efficiently absorbed when consumed with foods containing fat (Weber, 1981; Johnson et al., 2005; Mulligan and Licata, 2010) and, conversely, that a weight-loss agent that blocks fat absorption also impairs the absorption of vitamin D (James et al., 1997; McDuffie et al., 2002). The optimal amount of fat required for maximal absorption of vitamin D has not been determined.
Within the intestinal wall, vitamin D, cholesterol, triglycerides, lipoproteins, and other lipids are packaged together into chylomicrons. Importantly, while a fraction of newly absorbed intestinal vitamin D is also transported along with amino acids and carbohydrates into the portal system to reach the liver directly, the main pathway of vitamin D uptake is incorporation into chylomicrons that reach the systemic circulation via the lymphatics. Chylomicron lipids are metabolized in peripheral tissues that express lipoprotein lipase, but particularly in adipose tissue and
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skeletal muscle, which are rich in this enzyme. During hydrolysis of the chylomicron triglycerides, a fraction of the vitamin D contained in the chylomicron can be taken up by these tissues. Uptake into adipose tissue and skeletal muscle accounts for the rapid postprandial disappearance of vitamin D from plasma and probably also explains why increased adiposity causes sequestering of vitamin D and is associated with lower 25OHD levels (Jones, 2008). What remains of the original chylomicron after lipolysis is a chylomicron remnant, a cholesterol-enriched, triglyceride-depleted particle that still contains a fraction of its vitamin D content.
Metabolism to the Active Hormonal Form
Vitamin D, regardless of origin, is an inactive prohormone and must first be metabolized to its hormonal form before it can function. Once vitamin D enters the circulation from the skin or from the lymph, it is cleared by the liver or storage tissues within a few hours. The processes that follow are illustrated in Figure 3-3. Vitamin D is converted in the liver to 25OHD, a process carried out by a CYP enzyme that has yet to be fully defined but is likely CYP2R1 (Cheng et al., 2003). The crystal structure of CYP2R1 has been determined with vitamin D in the active site, and the enzyme has been shown to metabolize both vitamin D2 and vitamin D3 equally efficiently (Strushkevich et al., 2008). There is little, if any, feedback regulation of this enzyme. A large genome-wide association study of factors that might be determinants of the circulating 25OHD levels identified the human chromosomal 11p15 locus of CYP2R1 as a significant determinant, whereas the loci of the other enzymes purported to have 25-hydroxylase activity (e.g., CYP27A1 and CYP3A4) were not identified (Wang et al., 2010). The other determinants of serum 25OHD besides CYP2R1 have been reported to be DBP (also known as Gc protein), which has six common phenotypes (Laing and Cooke, 2005) as well as 7-dehydrocholesterol reductase and CYP24A1. Increasing intake of vitamin D results in higher blood levels of 25OHD, although perhaps not in a linear manner (Stamp et al., 1977; Clements et al., 1987).
At this point, 25OHD bound to DBP circulates in the blood stream and, when calcitriol is required due to a lack of calcium (or lack of phosphate), 25OHD is 1α-hydroxylated in the kidney to form calcitriol, the active form, by the 1α-hydroxylase enzyme (also known as CYP27B1) (Tanaka and DeLuca, 1983). This metabolic step is very tightly regulated by blood calcium and phosphate levels through PTH and the phosphaturic hormone, FGF23, and constitutes the basis of the vitamin D endocrine system that is central to maintaining calcium and phosphate homeostasis (see discussion below on functions and physiological actions). FGF23 acts by reducing the expression of renal sodium–phosphate transporters and reducing serum calcitriol levels.
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FIGURE 3-3 The metabolism of vitamin D3 from synthesis/intake to formation of metabolites. The process is the same for vitamin D2 once it enters the circulation.
NOTE: CYP = cytochrome P450 (a large and diverse group of enzymes).
SOURCE: Reprinted with permission from Hector DeLuca.
Production of the CYP27B1 enzyme is stimulated by PTH, which is secreted in response to a lack of calcium. It is also stimulated by the hypophosphatemic action of FGF23 on renal phosphate excretion, but to a lesser extent. When PTH is suppressed, or FGF23, produced by osteocytes, is stimulated, 1α-hydroxylation is markedly reduced (Liu et al., 2007; Quarles, 2008). Furthermore, calcitriol can act as a suppressor of CYP27B1, although the mechanism is not fully understood.
Calcitriol has its strongest metabolic activity in inducing its own destruction by stimulating the 24-hydroxylase enzyme (now known as CYP24A1;
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