Dietary Reference Intakes for Calcium and Vitamin D (2011) / Chapter Skim
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3 Overview of Vitamin D
3 Overview of Vitamin D
Pages 75-124
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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 75
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76 DIETARY REFERENCE INTAKES FOR CALCIUM AND VITAMIN D FIGURE 3-1 Overview of vitamin D synthesis, intake, and activation. fig 3-1.eps bitmap
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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)
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. The biological activity of 1 µg of vitamin D is equivalent to 40 IU.
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. In Canada, under the Food and Drug Regulation,1 fortification of fluid milk and margarine with vitamin D is mandatory.
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reported that commercial milk-based infant formulas collected between 2003 and 2006 contained 87 2USDA National Nutrient Database for Standard Reference Release 23.
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. 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.
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. Reprintedbitmap with permission from the American Journal of Clinical Nutrition (1994, volume 60, pages 619-630)
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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
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From page 84... ...
. 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)
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OVERVIEW OF VITAMIN D 85 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.
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. The active forms of vitamin D2 are also catabolized by CYP24A1 into a series of biliary metabolites, somewhat analogous to those of vitamin D3.
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(1988) suggested that there was enhanced uptake and clearance of vitamin D by adipose tissue in obese subjects compared with those of normal weights.
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From page 88... ...
The implication of these studies is that vitamin D deposited in fat tissue is not readily available, and obese individuals may require larger than usual doses of vitamin D supplements to achieve a serum 25OHD level comparable to that of their normal weight counterparts. In support of the hypothesis that vitamin D is stored in adipose tissues, weight reduction studies show that serum 25OHD levels rise when obese individuals lose body fat (Riedt et al., 2005; Zitterman et al., 2009; Tzotzas et al., 2010)
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From page 89... ...
Calcitriol -- functioning as part of the endocrine system for maintaining serum calcium levels as outlined in Chapter 2 -- elevates plasma ionized calcium levels to the normal range by three different mechanisms (see Figure 2-1 in Chapter 2)
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Calcitriol, through its receptor, the VDR, suppresses parathyroid gene expression and parathyroid cell proliferation, providing important feedback loops that reinforce the direct action of increased serum calcium levels (Slatopolsky et al., 1984; Silver et al., 1986)
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From page 91... ...
. The active hormone, calcitriol, was shown to consistently inhibit the growth of cancer cells and promote differentiation in vitro by regulating multiple pathways (Deeb et al., 2007; Kovalenko et al., 2010)
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Vascular endothelial growth factor (VEGF) expression by cancer cells is suppressed and endothelial cell responses to VEGF are inhibited by vitamin D, an observation supported by in vivo xenograft studies (Mantell et al., 2000; Bao et al., 2006)
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. Differences in toxicity for humans, as judged by the dose to cause hypervitaminosis D, are unclear, but there is evidence from experimental animal data to suggest that D2 is less toxic than D3.
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Vitamin D–dependent rickets type I (VDDR I) is an autosomal recessive trait that results in abnormally low calcitriol levels but normal serum 25OHD levels.
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Although a recent set of systematic reviews (Cranney et al., 2007; Chung et al., 2009) , to be discussed in Chapter 4, did not report specifically on bone mass for this age group in relation to vitamin D nutriture, the reviews suggested the possibility of a relationship between serum levels of 25OHD and bone mineral density (BMD)
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From page 96... ...
MEASURES ASSOCIATED WITH VITAMIN D: SERUM 25OHD Serum 25OHD level is widely considered as a marker of vitamin D nutriture, and consideration of serum 25OHD measures for the purposes of nutrient reference value development has generated notable interest. There is agreement that circulating serum 25OHD levels are currently the best available indicator of the net incoming contributions from cutaneous synthesis and total intake (foods and supplements)
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From page 97... ...
, its formation is not directly regulated by vitamin D intake, its levels are regulated by other factors (such as serum PTH) , and, even in the presence of severe vitamin D deficiency the calcitriol level may be normal or even elevated as a result of up-regulation of the 1a-hydroxylase enzyme.
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From page 98... ...
Another study of serum 25OHD response to total intake under conditions of minimal sun exposure used two populations based in Cork, Ireland (51°N) , and Coleraine, Northern Ireland (55°N)
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. Reprinted with permission from the American Journal of Clinical Nutrition (2008, 88, 1535-42)
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However, many variables can affect the cutaneous synthesis of vitamin D, making it difficult to estimate an average amount of vitamin D and, in turn, serum 25OHD levels that are produced by sun exposure in North America. There is, however, agreement that sun exposure is a significant source of the circulating serum 25OHD in summer for many North Americans, and is notably reduced as a contributor in the winter months.
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. Although these data suggest that average cutaneous synthesis during the summer in northern latitudes equates to 2,000 IU/day, this may be a questionable conclusion given the many variables that come into play, ranging from feedback mechanisms to skin pigmentation to baseline levels of 25OHD.
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From page 102... ...
(2007) studied the incremental change in serum 25OHD levels in individuals with average 25OHD baseline levels of 52 nmol/L and with different skin pigmentation who were exposed to different daily doses of 20 to 80 mJ/cm2 of UVB light three times per week for 4 weeks on 90 percent of their skin surface area.
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; x is UVB dose (in mJ/cm2 per session) ; y is skin lightness (expressed as the L*
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. Nevertheless, Holick and colleagues used a serum vitamin D3 assay to augment in vitro methodology and suggested that, at latitudes above 43°N, cutaneous synthesis contributes little serum 25OHD to the system in the winter months between October and March in North America (Webb et al., 1988; Matsuoka et al., 1989)
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. Likewise, ethnic practices, such as extensive skin coverage with clothing, urban environments that reduce or block sunlight, air pollution, and cloud cover that reduces solar penetration can variously reduce sun exposure.
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. It is interesting that in severely obese individuals after malabsorptive gastric bypass surgery, vitamin D supplementation resulted in a marked rise in serum 25OHD level of approximately 3 nmol/100 IU intake when the dose was 800 to 2,000 IU/day, but only a 1 nmol/L rise when intake was increased to 5,000 IU/day (Goldner et al., 2009)
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. The two most common types of assays are • Antibody-based methods, which use a kit or an automated clinical chemistry platform; and • Liquid chromatography (LC)
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Recently, LC-based assays have also undergone a radical transformation with the replacement of the UV detection step by a "universal detector" in the form of a tandem mass spectrometer (LC-MS/MS) (Jones and Makin, 2000)
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, similar to those used in other areas of clinical chemistry. Since its inception in the early 1990s, DEQAS has grown steadily, such that it now serves as a quarterly monitor of performance of analysts and 25OHD analytical methods for approximately 700 laboratories worldwide (Carter et al., 2010)
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over time. A standard reference material (SRM 972, Vitamin D in Human Serum)
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American Journal of Clinical Nutrition 87(6)
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Proceedings of a conference held September 2007 in Bethesda, Maryland, USA. American Journal of Clinical Nutrition 88(2)
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American Journal of Clinical Nutrition 88(6)
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Paper prepared for the Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Washington, DC.
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2003. Short-chain fatty acids and colon cancer cells: the vitamin D receptor -- butyrate connection.
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American Journal of Clinical Nutrition 60(4)
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1996. Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells.
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1988. Regulation of epidermal growth factor receptor levels by 1,25-dihydroxyvitamin D3 in human breast cancer cells.
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American Journal of Clinical Nutrition 88(6)
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American Journal of Clinical Nutrition 36(1)
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American Journal of Clinical Nutrition 89(4)
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American Journal of Clinical Nutrition 68(4)
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American Journal of Physiology 271(1 Pt 2)
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American Journal of Clinical Nutrition 89(3)
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