ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Overview of vitamin D

Overview of vitamin D
Authors:
Sassan Pazirandeh, MD
David L Burns, MD
Section Editor:
Kathleen J Motil, MD, PhD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Sep 23, 2021.

INTRODUCTION — Vitamin D is a fat-soluble vitamin. Very few foods naturally contain vitamin D (fatty fish livers are the exception), so dermal synthesis is the major natural source of the vitamin. Vitamin D from the diet or dermal synthesis is biologically inactive and requires enzymatic conversion to active metabolites (figure 1). Vitamin D is converted enzymatically in the liver to 25-hydroxyvitamin D (25[OH]D), the major circulating form of vitamin D, and then in the kidney to 1,25-dihydroxyvitamin D, the active form of vitamin D.

Vitamin D and its metabolites have a significant clinical role because of their interrelationship with calcium homeostasis and bone metabolism. Rickets (children) and osteomalacia (children and adults) due to severe vitamin D deficiency are now uncommon except in populations with unusually low sun exposure, lack of vitamin D in fortified foods, and malabsorptive syndromes. Subclinical vitamin D deficiency, as measured by low serum 25(OH)D, is very common. In the National Health and Nutrition Examination Survey (NHANES) 2005 to 2006, 41.6 percent of adult participants (≥20 years) had 25(OH)D levels below 20 ng/mL (50 nmol/L) [1]. This degree of vitamin D deficiency may contribute to the development of osteoporosis and an increased risk of fractures and falls in older adults. Vitamin D may also regulate many other cellular functions.

This topic review provides an overview of vitamin D. Other reviews discuss specific issues related to vitamin D:

(See "Causes of vitamin D deficiency and resistance".)

(See "Overview of rickets in children" and "Etiology and treatment of calcipenic rickets in children".)

(See "Epidemiology and etiology of osteomalacia" and "Clinical manifestations, diagnosis, and treatment of osteomalacia".)

(See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Vitamin D insufficiency and deficiency in children and adolescents".)

(See "Vitamin D and extraskeletal health".)

(See "Calcium and vitamin D supplementation in osteoporosis".)

CHEMISTRY — Vitamin D, or calciferol, is a generic term and refers to a group of lipid soluble compounds with a four-ringed cholesterol backbone. 25-hydroxyvitamin D (25[OH]D) is the major circulating form of vitamin D. It has a half-life of two to three weeks, compared with 24 hours for parent vitamin D [2]. It has activity at bone and intestine but is less than 1 percent as potent as 1,25-dihydroxyvitamin D, the most active form of vitamin D. The half-life of 1,25-dihydroxyvitamin D is approximately four to six hours. 1,25-dihydroxyvitamin D binds to intracellular receptors in target tissues and regulates gene transcription [3]. It appears to function through a single vitamin D receptor (VDR), which is nearly universally expressed in nucleated cells. The receptor is a member of the class II steroid hormone receptor and is closely related to the retinoic acid and thyroid hormone receptors [4]. Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium. Other effects include a lesser stimulation of intestinal phosphate absorption, direct suppression of parathyroid hormone (PTH) release from the parathyroid gland, regulation of osteoblast function, and permissively allowing PTH-induced osteoclast activation and bone resorption (figure 1).

SOURCES — Very few foods naturally contain vitamin D (fatty fish livers are the exception); dermal synthesis is the major natural source of the vitamin. Previtamin D3 is synthesized nonenzymatically in skin from 7-dehydrocholesterol during exposure to the ultraviolet (UV) rays in sunlight. Previtamin D3 undergoes a temperature-dependent rearrangement to form vitamin D3 (cholecalciferol) (figure 1). This system is exceedingly efficient, and it is estimated that brief casual exposure of the arms and face is equivalent to ingestion of 200 international units per day [5]. However, the length of daily exposure required to obtain the sunlight equivalent of oral vitamin D supplementation is difficult to predict on an individual basis and varies with the skin type, latitude, season, and time of day [6,7]. Prolonged exposure of the skin to sunlight does not produce toxic amounts of vitamin D3 because of photoconversion of previtamin D3 and vitamin D3 to inactive metabolites (lumisterol; tachysterol; 5,6-transvitamin D; and suprasterol 1 and 2) [8,9]. In addition, sunlight induces production of melanin, which reduces production of vitamin D3 in the skin.

Infants, disabled persons, and older adults may have inadequate sun exposure, while the skin of those older than 70 years of age also does not convert vitamin D effectively. In addition, at northern latitudes, there is not enough radiation to convert vitamin D, particularly during the winter. For these reasons, in the United States, milk, infant formula, breakfast cereals, and some other foods are fortified with synthetic vitamin D2 (ergocalciferol), which is derived from radiation of ergosterol found in plants, the mold ergot, and plankton, or with vitamin D3. In other parts of the world, cereals and bread products are often fortified with vitamin D.

ABSORPTION — Dietary vitamin D is incorporated into micelles, absorbed by enterocytes, and then packaged into chylomicrons. Disorders associated with fat malabsorption, such as celiac disease, Crohn disease, pancreatic insufficiency, cystic fibrosis, short gut syndrome, and cholestatic liver disease, are associated with low serum 25-hydroxyvitamin D (25[OH]D) levels. (See "Causes of vitamin D deficiency and resistance", section on 'Gastrointestinal disease'.)

METABOLISM — Vitamin D from the diet or dermal synthesis is biologically inactive and requires enzymatic conversion in the liver and kidney to active metabolites.

Hepatic — Dietary vitamin D travels to the liver, bound to vitamin D-binding protein and in continued association with chylomicrons and lipoproteins, where it and endogenously synthesized vitamin D3 are metabolized [10,11]. The hepatic enzyme 25–hydroxylase places a hydroxyl group in the 25 position of the vitamin D molecule, resulting in the formation of 25-hydroxyvitamin D (25[OH]D, calcidiol) (figure 1). 25-hydroxyvitamin D2 has a lower affinity than 25-hydroxyvitamin D3 for vitamin D-binding protein. Thus, 25-hydroxyvitamin D2 has a shorter half-life than 25-hydroxyvitamin D3, and treatment with vitamin D2 may not increase serum total 25(OH)D levels as efficiently as vitamin D3. The treatment of vitamin D deficiency is discussed in detail elsewhere. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Preparations'.)

Renal — 25-hydroxyvitamin D2 and D3 produced by the liver enter the circulation and travel to the kidney, again bound to vitamin D-binding protein. This protein has a single binding site, which binds vitamin D and all of its metabolites. Only 3 to 5 percent of the total circulating binding sites are normally occupied; as a result, this protein is not rate-limiting in vitamin D metabolism unless large amounts are lost in the urine, as in the nephrotic syndrome [12]. In the renal tubule, entry of the filtered 25(OH)D-vitamin D-binding protein complex into the cells is facilitated by receptor-mediated endocytosis [13]. At least two proteins working in tandem are involved in this process: cubilin and megalin [13,14]. Cubilin and megalin, expressed in the renal proximal tubule, are multiligand receptors that facilitate uptake of extracellular ligands. Deficiency of either of these proteins results in increased 25(OH)D excretion in the urine and, at least in experimental models, 1,25-dihydroxyvitamin D deficiency and bone disease [13-15].

Within the tubular cell, 25(OH)D is released from the binding protein. The renal tubular cells contain two enzymes, 1-alpha-hydroxylase (CYP27B1) and 24-alpha-hydroxylase (CYP24), that can further hydroxylate 25(OH)D, producing 1,25-dihydroxyvitamin D, the most active form of vitamin D, or 24,25-dihydroxyvitamin D, an inactive metabolite (figure 1) [16-18]. Both enzymes are members of the P450 system [19]. Studies in vitamin D-deficient animals suggest that the proximal tubule is the important site of synthesis. In contrast, studies in the normal human kidney indicate that the distal nephron is the predominant site of 1-alpha-hydroxylase expression under conditions of vitamin D sufficiency [18].

The 1-alpha-hydroxylase enzyme is also expressed in extrarenal sites, including the gastrointestinal tract, skin, vasculature, mammary epithelial cells, osteoblasts, and osteoclasts [20,21]. The most widely recognized manifestation of extrarenal synthesis of 1,25-dihydroxyvitamin D is hypercalcemia and hypercalciuria in patients with granulomatous diseases, such as sarcoid. In this setting, parathyroid hormone (PTH)-independent extrarenal production of 1,25-dihydroxyvitamin D from 25(OH)D by activated macrophages occurs in the lung and lymph nodes. (See "Hypercalcemia in granulomatous diseases", section on 'Sarcoidosis'.)

The plasma 1,25-dihydroxyvitamin D concentration is a function both of the availability of 25(OH)D and of the activities of the renal enzymes 1-alpha-hydroxylase and 24-alpha-hydroxylase. The renal 1-alpha-hydroxylase enzyme is primarily regulated by the following factors [11,19]:

PTH

Serum calcium and phosphate concentrations

Fibroblast growth factor 23 (FGF23)

Increased PTH secretion (most often due to a fall in the plasma calcium concentration) and hypophosphatemia stimulate the enzyme and enhance 1,25 dihydroxyvitamin D production [22]. 1,25-dihydroxyvitamin D, in turn, inhibits the synthesis and secretion of PTH, providing negative feedback regulation of 1,25-diydroxyvitamin D production. 1,25-dihydroxyvitamin D synthesis may also be modulated by vitamin D receptors (VDRs) on the cell surface; downregulation of these receptors may play an important role in regulating vitamin D activation [23].

FGF23 inhibits renal production of 1,25-dihydroxyvitamin D by limiting 1-alpha-hydroxylase activity in the renal proximal tubule and by simultaneously increasing expression of 24-alpha-hydroxylase and production of 24,25-dihydroxyvitamin D (an inactive metabolite) [24]. 1,25-dihydroxyvitamin D stimulates FGF23, a phosphaturic hormone, creating a feedback loop. Experimental data suggest that FGF23 decreases renal reabsorption of phosphate, and thereby counteracts the increased gastrointestinal phosphate reabsorption induced by 1,25-dihydroxyvitamin D, maintaining phosphate homeostasis [25].

Both 1,25-dihydroxyvitamin D and 25(OH)D are degraded in part by hydroxylation by a 24-hydroxylase [11,17]. The activity of the 24-hydroxylase gene is increased by 1,25-dihydroxyvitamin D, which therefore promotes its own inactivation, and decreased by PTH, thereby allowing more active hormone to be formed [17].

REQUIREMENTS

Recommended intake — In 2010, the Institute of Medicine (IOM, now called the National Academy of Medicine [NAM]) released a report on dietary intake requirements for calcium and vitamin D (table 1) [26]. Its Recommended Dietary Allowance (RDA) of vitamin D for children 1 to 18 years and adults through age 70 years is 600 international units (15 mcg) daily. Its RDA is 800 international units (20 mcg) daily after age 71 years [26]. For pregnant and lactating mothers, it recommends 600 international units (15 mcg) per day. The intake can be provided in the diet or as a vitamin D supplement. Vitamin D intake is often low in older adults, who also do not have regular effective sun exposure. Thus, for older adults, we suggest supplementation with 600 to 800 international units of vitamin D daily. Older persons confined indoors and other high risk groups may have low serum 25-hydroxyvitamin D (25[OH]D) concentrations at this intake level and may require higher intakes.

The estimated adequate intake for infants up to 12 months is 400 international units (10 mcg) daily. Vitamin D supplementation should be given to infants who are exclusively breastfed, because the vitamin D content of human milk is low. The Pediatric Endocrine Society also recommends supplementation with 400 international units daily of vitamin D beginning within days of birth for infants who are exclusively breastfed [27]. Most infant formulas contain at least 400 international units/L of vitamin D, so formula-fed infants will also require supplementation to meet this goal, unless they consume at least 1000 mL daily of formula. For children one year and older, consumption of at least one liter of vitamin D-fortified milk daily is usually sufficient to meet at least two-thirds of the recommended daily intake. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Prevention'.)

The recommendations for dietary vitamin D intake were based upon the beneficial effects of calcium and vitamin D on skeletal health (see "Calcium and vitamin D supplementation in osteoporosis", section on 'Efficacy'). The evidence supporting a benefit of vitamin D on extraskeletal outcomes was inconsistent, inconclusive as to causality, and insufficient and therefore was not used as a basis for dietary reference intake development [28]. (See "Vitamin D and extraskeletal health".)

Estimates of vitamin D requirements vary and depend in part upon sun exposure and the standards used to define a deficient state. The IOM committee assumed minimal sun exposure when establishing the dietary reference intakes for vitamin D. Casual exposure to sunlight provides amounts of vitamin D that are adequate to prevent rickets in many people but is influenced by geographic location, season, use of sun block lotion, and skin pigmentation [29]. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Skin pigmentation and low sun exposure'.)

Vitamin D requirements also may depend on disease states and concomitant medications. As an example, patients undergoing long-term treatment with glucocorticoids may benefit from higher levels of supplementation of vitamin D and calcium. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)

Optimal serum 25-hydroxyvitamin D — The best laboratory indicator of vitamin D adequacy is the serum 25(OH)D concentration [30]. The lower limit of normal for 25(OH)D levels varies depending on the geographic location and sunlight exposure of the reference population (range 8 to 15 ng/mL). However, there is no consensus on the optimal 25(OH)D concentration for skeletal or extraskeletal health. The IOM concluded that a serum 25(OH)D concentration of 20 ng/mL (50 nmol/L) is sufficient for most individuals [2], but other experts (Endocrine Society, National Osteoporosis Foundation [NOF], International Osteoporosis Foundation [IOF], American Geriatrics Society [AGS]) suggest that a minimum level of 30 ng/mL (75 nmol/L) is necessary in older adults to minimize the risk of falls and fracture [31-35]. The serum parathyroid hormone (PTH) level typically is inversely related to 25(OH)D levels in adults and may be a useful secondary indicator of vitamin D insufficiency. In general, this relationship is weak for children. Controversies surrounding the optimal serum 25(OH)D concentration are reviewed separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D sufficiency'.)

DEFICIENCY AND RESISTANCE — Vitamin D deficiency or resistance is caused by one of four mechanisms (see "Causes of vitamin D deficiency and resistance"):

Impaired availability of vitamin D, secondary to inadequate dietary vitamin D, fat malabsorptive disorders, and/or lack of sunlight (photoisomerization)

Impaired hydroxylation by the liver to produce 25-hydroxyvitamin D (25[OH]D)

Impaired hydroxylation by the kidneys to produce 1,25-dihydroxyvitamin D (vitamin D-dependent rickets type 1, chronic renal insufficiency)

End-organ insensitivity to vitamin D metabolites (hereditary vitamin D-resistant rickets [HVDRR, vitamin D-dependent rickets type 2])

Several studies have shown suboptimal serum levels of 25(OH)D and vitamin D intake in the United States and other countries [27,36-40]. (See 'Requirements' above and "Vitamin D insufficiency and deficiency in children and adolescents" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Lack of vitamin D activity leads to reduced intestinal absorption of calcium and phosphorus. Early in vitamin D deficiency, hypophosphatemia is more marked than hypocalcemia. With persistent vitamin D deficiency, hypocalcemia occurs and causes secondary hyperparathyroidism, which leads to phosphaturia, demineralization of bones, and, when prolonged and severe, to osteomalacia in adults and rickets and osteomalacia in children. (See "Epidemiology and etiology of osteomalacia" and "Etiology and treatment of calcipenic rickets in children", section on 'Nutritional rickets'.)

Overt vitamin D deficiency resulting in rickets and osteomalacia in children and osteomalacia in adults is now uncommon in most developed countries. However, subclinical vitamin D deficiency occurs even in developed countries and is associated with osteoporosis, increased risk of falls, and possibly fractures. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Clinical manifestations'.)

Glucocorticoids, when used chronically in high doses, inhibit intestinal vitamin D-dependent calcium absorption, which is one of the mechanisms whereby chronic glucocorticoid excess leads to osteoporosis and fractures. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

Vitamin D stores decline with age, especially in the winter. Controlled trials have demonstrated that vitamin D and calcium supplementation can reduce the risk of falls and fractures in older adults. (See "Calcium and vitamin D supplementation in osteoporosis" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Benefits of vitamin D supplementation'.)

EXCESS — The intake at which the dose of vitamin D becomes toxic is not clear. The Institute of Medicine (IOM, now called the National Academy of Medicine [NAM]) has defined the "tolerable upper intake level" (UL) for vitamin D as 100 micrograms (4000 international units) daily for healthy adults and children 9 to 18 years [26]. This is also the UL for pregnant and lactating women. The UL for infants and children up to nine years old is lower (table 1). For patients with malabsorption (eg, celiac disease, gastrectomy, inflammatory bowel disease), oral dosing of vitamin D depends upon the absorptive capacity of the individual patient. High doses of vitamin D of 10,000 to 50,000 units daily may be necessary to replete vitamin D in some patients. Such patients require careful monitoring to avoid toxicity. Indications for high-dose vitamin D supplementation and the UL for vitamin D supplementation are discussed in more detail separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)

Vitamin D intoxication generally occurs after inappropriate use of vitamin D preparations. It may occur in fad dieters who consume "megadoses" of supplements or in patients who take vitamin D replacement therapy for malabsorption, renal osteodystrophy, osteoporosis, or psoriasis. Vitamin D intoxication has been documented in adults taking more than 60,000 international units per day [41]. Case reports have described hypervitaminosis D due to errors in manufacturing, formulation or prescription, including milk that was inadvertently excessively fortified with vitamin D [42,43]. Prolonged exposure of the skin to sunlight does not produce toxic amounts of vitamin D3 (cholecalciferol), due to photoconversion of previtamin D3 and vitamin D3 to inactive metabolites [8,9]. Multiple studies reveal that prolonged exposure of the skin to sunlight results in a maximum serum 25-hydroxyvitamin D (25[OH]D) level of <80 ng/mL (200 nmol/L) [7,44,45].

Symptoms of acute intoxication are due to hypercalcemia and include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness. Chronic intoxication may cause nephrocalcinosis, bone demineralization, and pain. The diagnosis and treatment of vitamin D toxicity are reviewed separately. (See "Diagnostic approach to hypercalcemia" and "Treatment of hypercalcemia".)

There is some feedback regulation of the hepatic 25-hydroxylase, and the liver has the capacity to metabolize 25(OH)D to inactive metabolites. This is accomplished by the P450 system and is enhanced by alcohol, barbiturates, and phenytoin. However, it is insufficient to prevent vitamin D intoxication following the ingestion of large amounts of vitamin D. The liver is the usual storage system for vitamin D. When large amounts of vitamin D are ingested, much of the excess vitamin D is stored in adipose tissue [46]. As these sites become saturated, the vitamin D remains in serum and is converted to toxic levels of 25(OH)D [4]. (See "Etiology of hypercalcemia", section on 'Hypervitaminosis D'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vitamin D deficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Vitamin D deficiency (The Basics)" and "Patient education: Calcium and vitamin D for bone health (The Basics)" and "Patient education: Vitamin D for babies and children (The Basics)")

Beyond the Basics topics (see "Patient education: Vitamin D deficiency (Beyond the Basics)" and "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Very few foods naturally contain vitamin D; fatty fish and eggs are the exceptions. Dermal synthesis and foods fortified with vitamin D are the major sources of the vitamin. (See 'Sources' above.)

Vitamin D3 (cholecalciferol) is synthesized nonenzymatically in skin from 7-dehydrocholesterol during exposure to the ultraviolet (UV) rays in sunlight. Vitamin D3 from the skin or diet must be 25-hydroxylated in the liver, then 1-hydroxylated in the kidneys to the active form, 1,25-dihydroxycholecalciferol (calcitriol) (figure 1). (See 'Metabolism' above.)

The Recommended Dietary Allowance (RDA) for vitamin D is 600 international units (units) daily for adults through age 70 years and for children 1 to 18 years of age (table 1). For adults 71 years and older, 800 international units (20 micrograms) daily is recommended for the prevention and treatment of osteoporosis. Vitamin D intake and effective sun exposure are often inadequate in older adults. In older adults, particularly those at increased risk of falls and fracture, we suggest supplementation with vitamin D (Grade 2B). We administer 600 to 800 international units daily. (See 'Requirements' above and "Calcium and vitamin D supplementation in osteoporosis".)

Vitamin D deficiency can be caused by unusually low sun exposure combined with lack of vitamin D-fortified foods or malabsorption. Alternatively, impaired hydroxylation of vitamin D in liver or kidney can prevent metabolism into the physiologically active form. Rarely, genetic defects may cause the end organs to be unresponsive to vitamin D, as in hereditary vitamin D-resistant rickets (HVDRR). (See 'Deficiency and resistance' above and "Causes of vitamin D deficiency and resistance".)

Vitamin D intoxication generally occurs after inappropriate use of vitamin D preparations. Prolonged exposure of the skin to sunlight does not produce toxic amounts of vitamin D3, due to photoconversion of previtamin D3 and vitamin D3 to inactive metabolites. Symptoms of acute intoxication are due to hypercalcemia and include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness. Long-term intoxication can cause bone demineralization and pain. In children, the hypercalcemia can cause brain injury. (See 'Excess' above and "Diagnostic approach to hypercalcemia" and "Treatment of hypercalcemia".)

The Institute of Medicine (IOM, now called the National Academy of Medicine [NAM]) has defined the "tolerable upper intake level" (UL) for vitamin D as 100 micrograms (4000 international units) daily for healthy adults and children 9 to 18 years (table 1). The UL for infants and children up to nine years old is lower. (See 'Excess' above.)

  1. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res 2011; 31:48.
  2. http://books.nap.edu/openbook.php?record_id=13050 (Accessed on December 08, 2010).
  3. Lowe KE, Maiyar AC, Norman AW. Vitamin D-mediated gene expression. Crit Rev Eukaryot Gene Expr 1992; 2:65.
  4. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 2004; 80:1689S.
  5. Haddad JG. Vitamin D--solar rays, the Milky Way, or both? N Engl J Med 1992; 326:1213.
  6. Terushkin V, Bender A, Psaty EL, et al. Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes. J Am Acad Dermatol 2010; 62:929.e1.
  7. Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 2007; 92:2130.
  8. Holick MF. Vitamin D: A millenium perspective. J Cell Biochem 2003; 88:296.
  9. Holick MF, MacLaughlin JA, Doppelt SH. Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science 1981; 211:590.
  10. Brown AJ. Regulation of vitamin D action. Nephrol Dial Transplant 1999; 14:11.
  11. Christakos S, Ajibade DV, Dhawan P, et al. Vitamin D: metabolism. Endocrinol Metab Clin North Am 2010; 39:243.
  12. Vaziri ND. Endocrinological consequences of the nephrotic syndrome. Am J Nephrol 1993; 13:360.
  13. Nykjaer A, Dragun D, Walther D, et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 1999; 96:507.
  14. Nykjaer A, Fyfe JC, Kozyraki R, et al. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci U S A 2001; 98:13895.
  15. Negri AL. Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein/25-(OH)D3 complex. Nephrology (Carlton) 2006; 11:510.
  16. Kawashima H, Torikai S, Kurokawa K. Localization of 25-hydroxyvitamin D3 1 alpha-hydroxylase and 24-hydroxylase along the rat nephron. Proc Natl Acad Sci U S A 1981; 78:1199.
  17. Zierold C, Darwish HM, DeLuca HF. Identification of a vitamin D-response element in the rat calcidiol (25-hydroxyvitamin D3) 24-hydroxylase gene. Proc Natl Acad Sci U S A 1994; 91:900.
  18. Zehnder D, Bland R, Walker EA, et al. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in the human kidney. J Am Soc Nephrol 1999; 10:2465.
  19. Takeyama K, Kitanaka S, Sato T, et al. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science 1997; 277:1827.
  20. van Driel M, Koedam M, Buurman CJ, et al. Evidence that both 1alpha,25-dihydroxyvitamin D3 and 24-hydroxylated D3 enhance human osteoblast differentiation and mineralization. J Cell Biochem 2006; 99:922.
  21. Hewison M, Burke F, Evans KN, et al. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 2007; 103:316.
  22. Portale AA, Halloran BP, Morris RC Jr. Physiologic regulation of the serum concentration of 1,25-dihydroxyvitamin D by phosphorus in normal men. J Clin Invest 1989; 83:1494.
  23. Iida K, Shinki T, Yamaguchi A, et al. A possible role of vitamin D receptors in regulating vitamin D activation in the kidney. Proc Natl Acad Sci U S A 1995; 92:6112.
  24. Prié D, Friedlander G. Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. Clin J Am Soc Nephrol 2010; 5:1717.
  25. Liu S, Tang W, Zhou J, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 2006; 17:1305.
  26. Institute of Medicine. Report at a Glance, Report Brief: Dietary reference intakes for calcium and vitamin D, released 11/30/2010. http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx (Accessed on December 01, 2010).
  27. Misra M, Pacaud D, Petryk A, et al. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 2008; 122:398.
  28. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011; 96:53.
  29. Holick MF. McCollum Award Lecture, 1994: vitamin D--new horizons for the 21st century. Am J Clin Nutr 1994; 60:619.
  30. Food and Nutrition Board of the Institute of Medicine. Vitamin D. In: Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, fluoride, National Academies Press, Washington, DC 1997. p.250.
  31. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96:1911.
  32. Vieth R. What is the optimal vitamin D status for health? Prog Biophys Mol Biol 2006; 92:26.
  33. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int 2010; 21:1151.
  34. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc 2014; 62:147.
  35. 2013 Clinician's guide to prevention and treatment of osteoporosis http://nof.org/files/nof/public/content/resource/913/files/580.pdf (Accessed on January 23, 2014).
  36. Gordon CM, DePeter KC, Feldman HA, et al. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004; 158:531.
  37. Cole CR, Grant FK, Tangpricha V, et al. 25-hydroxyvitamin D status of healthy, low-income, minority children in Atlanta, Georgia. Pediatrics 2010; 125:633.
  38. Razzaghy-Azar M, Shakiba M. Assessment of vitamin D status in healthy children and adolescents living in Tehran and its relation to iPTH, gender, weight and height. Ann Hum Biol 2010; 37:692.
  39. Mansbach JM, Ginde AA, Camargo CA Jr. Serum 25-hydroxyvitamin D levels among US children aged 1 to 11 years: do children need more vitamin D? Pediatrics 2009; 124:1404.
  40. Rovner AJ, O'Brien KO. Hypovitaminosis D among healthy children in the United States: a review of the current evidence. Arch Pediatr Adolesc Med 2008; 162:513.
  41. Morgan SL, Weinsier RL. Fundamentals of clinical nutrition, Mosby, St. Louis 1998. p.3.
  42. Jacobus CH, Holick MF, Shao Q, et al. Hypervitaminosis D associated with drinking milk. N Engl J Med 1992; 326:1173.
  43. Vogiatzi MG, Jacobson-Dickman E, DeBoer MD, Drugs, and Therapeutics Committee of The Pediatric Endocrine Society. Vitamin D supplementation and risk of toxicity in pediatrics: a review of current literature. J Clin Endocrinol Metab 2014; 99:1132.
  44. Nair-Shalliker V, Clements M, Fenech M, Armstrong BK. Personal sun exposure and serum 25-hydroxy vitamin D concentrations. Photochem Photobiol 2013; 89:208.
  45. Barger-Lux MJ, Heaney RP. Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption. J Clin Endocrinol Metab 2002; 87:4952.
  46. Wortsman J, Matsuoka LY, Chen TC, et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 2000; 72:690.
Topic 2033 Version 26.0

References