Overview of vitamin DAuthorsSassan Pazirandeh, MDDavid L Burns, MDSection EditorsKathleen J Motil, MD, PhDMarc K Drezner, MDDeputy EditorJean E Mulder, MDAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through:Aug 2015.|This topic last updated:May 08, 2014.INTRODUCTIONVitamin 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 20ng/mL(50nmol/L)[1]. This degree of vitamin D deficiency may contribute to the development of osteoporosis and an increased risk of fractures and falls in the elderly. 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".)CHEMISTRYVitamin 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).SOURCESVery 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.ABSORPTIONDietary 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'.)METABOLISMVitamin D from the diet or dermal synthesis is biologically inactive and requires enzymatic conversion in the liver and kidney to active metabolites.HepaticDietary vitamin D travels to the liver, bound to vitamin Dbinding protein and in continued association with chylomicrons and lipoproteins, where it and endogenously-synthesized vitamin D3 are metabolized [10,11]. The hepatic enzyme 25hydroxylase 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'.)Renal25-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 P-450 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]:PTHSerum calcium and phosphate concentrationsFibroblast 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].REQUIREMENTSAdequate intakeIn 2010, the Institute of Medicine (IOM) 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 (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Groups at high risk for suboptimal intake'.)The estimated adequate intake for infants up to 12 months is 400 international units (10 mcg) daily (table 2). Vitamin D supplementation should be given to infants who are exclusively breast fed, because the vitamin D content of human milk is low. The Lawson Wilkins Pediatric Endocrine Society also recommends supplementation with 400 international units daily of vitamin D beginning within days of birth for infants who are exclusively breast-fed [27]. Most infant formulas contain at least 400units/Lof vitamin D, so formula-fed infants will also require supplementation to meet this goal, unless they consume at least 1000 mL daily of formula. Vitamin D intake of at least 400units/dayis also recommended for children who do not consume at least one liter of vitamin D-fortified milk daily [27]. (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 'Decreased synthesis'.)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 DThe 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 15ng/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 20ng/mL(50nmol/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 30ng/mL(75nmol/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 RESISTANCEVitamin 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/orlack 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 "Pathogenesis, 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 the elderly. (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 repletion'.)EXCESSThe intake at which the dose of vitamin D becomes toxic is not clear. The Institute of Medicine (IOM) 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 2). 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) because of 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