INTRODUCTION — Vitamin D has a variety of actions on calcium, phosphate, and bone metabolism. Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium and phosphorus, thereby promoting bone mineralization. At high vitamin D concentrations, under conditions of calcium and phosphate deficiency, it also stimulates bone resorption, thereby helping to maintain the supply of these ions to other tissues (figure 1). (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Calcitriol'.)
Vitamin D deficiency or resistance interferes with these processes, sometimes causing hypocalcemia and hypophosphatemia. Since hypocalcemia stimulates the release of parathyroid hormone (PTH), however, the development of hypocalcemia is often masked. The secondary hyperparathyroidism, via its actions on bone and the kidney, partially corrects the hypocalcemia but enhances urinary phosphate excretion, thereby contributing to the development of hypophosphatemia and osteomalacia. (See "Epidemiology and etiology of osteomalacia" and "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults", section on 'Laboratory findings'.)
This topic will review the major causes of vitamin D deficiency and resistance. Optimal serum vitamin D concentrations, the treatment of vitamin D deficiency, and the role of vitamin D therapy for osteoporosis are discussed in detail separately (see "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D supplementation in osteoporosis").
The major causes of hypophosphatemia and hypocalcemia are also reviewed elsewhere. (See "Hypophosphatemia: Causes of hypophosphatemia" and "Etiology of hypocalcemia in adults".)
DEFINITION — Measurement of 25-hydroxyvitamin D (25[OH]D) is the best index for determination of normal or subnormal vitamin D in the body. However, the optimal serum 25(OH)D concentration for skeletal health and extraskeletal health is controversial, and it has not been rigorously established for the population in general or for specific ethnic groups. The majority of groups define vitamin D sufficiency as a 25(OH)D concentration of at least 20 ng/mL (50 nmol/L). This topic is reviewed in detail elsewhere. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D sufficiency'.)
VITAMIN D METABOLISM — Vitamin D3 (cholecalciferol) is normally synthesized in the skin under the influence of sunlight in a nonenzymatic manner and is also available in foods of animal origin (eg, fish and egg yolks). In addition, vitamin D2 (ergocalciferol) may be ingested in limited amounts from plant sources (eg, some mushrooms and yeast). Vitamin D is then hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol or calcifediol, 25[OH]D), which is the major circulating form of vitamin D and the widely used index of vitamin D sufficiency (figure 1). 1,25-dihydroxyvitamin D is also formed in some other tissues but is used only within those tissues and not circulated. (See "Overview of vitamin D", section on 'Metabolism'.)
Vitamin D deficiency can therefore occur as a result of decreased intake or absorption, reduced sun exposure, increased hepatic catabolism, or decreased endogenous synthesis (via decreased 25-hydroxylation in the liver or 1-hydroxylation in the kidney). End-organ resistance to vitamin D causes the equivalent result as deficiency (table 1).
NUTRITIONAL DEFICIENCY AND REDUCED CUTANEOUS SYNTHESIS — In many developed countries, most vitamin D is derived from foods that are rich in the vitamin (fatty fishes) or fortified with the vitamin (milk and related products and cereals). The remainder is synthesized in the skin from 7-dehydrocholesterol under the influence of ultraviolet light, at a similar wavelength that can cause sunburn (figure 1). Vitamin D deficiency can occur in people who live without sun exposure (including those whose skin is constantly protected from the sun) and/or have enhanced skin pigmentation, or whose dietary intake is low. In some individuals, however, abundant sun exposure does not preclude vitamin D insufficiency for reasons that are poorly understood [1]. Nevertheless, vitamin D deficiency occurs most commonly in people who live in countries distant from the equator and who consume foods that are not fortified with vitamin D [2]. Vitamin D deficiency can also occur with adequate intake if there is intestinal malabsorption of vitamin D, as occurs with celiac disease.
Vitamin D deficiency due to reduced vitamin D intake, absorption, or cutaneous production should be considered especially in the following populations:
Older adults — Cutaneous vitamin D production and vitamin D stores decline with age [3]. This change is most prominent in the winter. In temperate areas such as Boston and Edmonton, as an example, cutaneous production of vitamin D virtually ceases in winter, especially in older adults [4,5].
In addition to reduced endogenous production, vitamin D intake is often low in older adults. As an example, in a study of postmenopausal women living in France, mean daily vitamin D intake from food was 144.8 international units/day, and more than one-third of women consumed <100 international units/day from food [6], levels well below the recommended intake. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Optimal intake to prevent deficiency'.)
Many clinicians believe that there is an age-dependent resistance to calcitriol that limits calcium absorption [7]. The net effect of the many factors influencing vitamin D metabolism and the effects of vitamin D in older adults is the presence of relative hypocalcemia and high serum parathyroid hormone (PTH) concentrations [8,9]; this secondary hyperparathyroidism can be attenuated by the administration of physiological doses of vitamin D [10]. However, older persons confined indoors may have low serum 25-hydroxyvitamin D (calcidiol, 25[OH]D) concentrations even with the current recommendations for vitamin D intake [11,12].
Children — Dietary vitamin D deficiency can also occur in children. The prevalence varies considerably among different countries and subpopulations because of differences in risk factors, especially skin pigmentation, sun exposure, and dietary vitamin D intake. (See "Vitamin D insufficiency and deficiency in children and adolescents".)
Vitamin D deficiency is also a concern for breastfed infants, particularly those who are exclusively breastfed [13]. (See "Vitamin D insufficiency and deficiency in children and adolescents".)
Healthy adults in the winter — Vitamin D deficiency is also common in healthy, young adults at the end of the winter. In a study of healthy adults in the Boston area who underwent 25(OH)D testing at the end of winter and summer, 36 percent of 69 subjects ages 18 to 29 had vitamin D concentrations below 20 ng/mL (50 nmol/L), but the prevalence decreased to 4 percent by the end of the summer [14]. Similar seasonal differences were seen in older groups. The impact of winter on the serum 25(OH)D is affected by several ancillary factors, most notably ancestry and skin pigmentation [15].
Hospitalized patients — In a study of 290 patients hospitalized on a general medical service, vitamin D deficiency (<15 ng/mL [37 nmol/L]) was detected in 164 patients (57 percent), of whom 65 (22 percent) were considered severely deficient (serum concentration of 25[OH]D <8 ng/mL [20 nmol/L]) [16]. Inadequate vitamin D intake, winter season, and housebound status were independent predictors of vitamin D deficiency. The prevalence of vitamin D deficiency in hospitalized patients may also be dependent, in part, upon the age of the patients on the hospital wards [17,18]. However, in a subgroup of 77 patients less than age 65 years without known risk factors, the prevalence of vitamin D deficiency was still 42 percent [16].
In a study of 135 patients admitted directly to an intensive care unit in Barcelona, Spain, the mean 25(OH)D level was 11 ng/mL [27.5 nmol/L] and the mean of the 63 non-survivors was even lower, at 8.1 ng/mL (20 nmol/L) [19]. It is unclear to what extent the very low 25(OH)D levels in these ill patients may have been the result of an acute inflammatory response as opposed to insufficient vitamin D substrate [20].
Females treated for osteoporosis — Unrecognized vitamin D insufficiency or deficiency is also common in postmenopausal females seeking advice or receiving therapy for osteoporosis [12,21]. In a study of 1536 community-dwelling postmenopausal females (evenly distributed by latitude) who were receiving osteoporosis drug therapy (bisphosphonates, raloxifene, calcitonin, or PTH), serum 25(OH)D concentrations were less than 20 and 30 ng/mL in 18 and 52 percent, respectively [12]. Not surprisingly, the prevalence of vitamin D insufficiency was higher in females taking less than 400 compared with ≥400 international units of vitamin D per day. (See "Calcium and vitamin D supplementation in osteoporosis".)
Chronic kidney disease — Patients with chronic kidney disease (CKD) have 1,25-dihydroxyvitamin D (calcitriol) deficiency, related in part to an increased production of fibroblast growth factor 23 (FGF23) with progressive kidney failure [22]. In some patients, 25(OH)D deficiency may also occur [23-25]. This has been demonstrated in patients on dialysis and in patients with stages 3 and 4 CKD predialysis [23,25].
●In a study of patients with glomerular filtration rates (GFR) <30 and 30 to 59 mL/min, serum 25(OH)D concentrations were <10 ng/mL (25 nmol/L) in 14 and 26 percent, respectively, and between 10 and 30 ng/mL (25 and 75 nmol/L) in 57 and 58 percent, respectively [23].
●In a study of 242 patients with CKD on dialysis, vitamin D deficiency (<15 ng/mL [37 nmol/L]), was evident in up to 28 percent of patients [25]. Females, patients with diabetes, and patients on peritoneal dialysis were at greater risk for vitamin D deficiency. In addition, 25(OH)D concentrations were positively associated with bone mineral density (BMD) at the lumbar spine and wrist.
Despite these associations, it is unclear if improving 25(OH)D concentrations has any benefit on metabolic bone disease in these patients (see "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis"). The Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for bone metabolism and disease in CKD, as well as other KDOQI guidelines, can be accessed through the National Kidney Foundation website.
Gastrointestinal disease — Gastrointestinal malabsorption, associated with diseases of the small intestine, hepatobiliary tree, and pancreas, may result in decreased absorption of vitamin D and/or depletion of endogenous 25(OH)D stores due to disruption of enterohepatic circulation [26-28]. In general, malabsorption of vitamin D occurs as a consequence of steatorrhea, which disturbs fat emulsification and chylomicron-facilitated absorption. While this may be associated with rickets and/or osteomalacia, many affected patients are asymptomatic or exhibit only a reduction in bone volume rather than evidence of defective bone mineralization.
Adult celiac disease is a common example of a disorder in which vitamin D malabsorption occurs and in which the suspicion for vitamin D deficiency should be high [29]. These patients often present with low BMD, most commonly without evidence of abnormal bone mineralization. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Metabolic bone disorders'.)
Metabolic bone disease associated with gastrointestinal disorders is discussed in more detail separately. (See "Metabolic bone disease in inflammatory bowel disease".)
Gastric bypass — Gastrointestinal malabsorption of vitamin D can occur after gastric surgery.
●Bariatric surgery – In a systematic review of studies evaluating vitamin D status before and after bariatric surgery, the median preoperative vitamin D level was 19 ng/mL (47 nmol/L) [30]. Median postoperative vitamin D levels, in patients treated with variable amounts of vitamin D, were higher at multiple time points tested, ranging from 24 ng/mL (60 nmol/L) at one month to 29 ng/mL (72 nmol/L) at one year and 25 ng/mL (62 nmol/L) at two years. However, vitamin D supplementation with doses of <800 international units daily in patients with vitamin D deficiency was, in general, insufficient, suggesting malabsorption and suboptimal treatment. Use of higher doses of vitamin D or use of the less hydrophobic (more absorbable) calcidiol may be necessary to sustain a normal level of serum 25(OH)D. (See "Bariatric surgery: Postoperative nutritional management", section on 'Vitamin D'.)
●Gastrectomy – Vitamin D deficiency may also develop in patients who have had partial or total gastrectomy for peptic ulcer disease, gastric cancer, or other indications. Loss of gastrointestinal acidity or malfunction of the proximal small bowel underlies the vitamin D malabsorption in such circumstances. Absence of sufficient absorbing surface or failure of intestinal mucosal cells to respond to vitamin D or its metabolites may also cause vitamin D malabsorption. Such patients may also have selective calcium malabsorption.
Patients who have musculoskeletal pain — Nonspecific musculoskeletal pain is a common symptom of vitamin D deficiency, and the prevalence of unrecognized vitamin D deficiency among patients with these symptoms is extremely high. As an example, in a study of 150 individuals with persistent, nonspecific musculoskeletal pain presenting to an urban health clinic in Minneapolis, 93 percent had vitamin D deficiency (serum 25[OH]D concentration ≤20 ng/mL [50 nmol/L]), and 28 percent of all patients had severe deficiency (concentration ≤8 ng/mL [20 nmol/L]) [31]. Thus, patients who present with nonspecific musculoskeletal pain should be screened for vitamin D deficiency.
Cystic fibrosis — Patients with advanced cystic fibrosis are usually deficient in vitamin D [32], and they require more than the usual recommended dose for young adults (eg, more than 400 international units/day). (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Musculoskeletal disorders'.)
Extensive burns — In patients with a history of extensive burn injuries, vitamin D synthesis in skin is below normal, even with sun exposure [33].
DEFICIENCY RELATED TO ABNORMAL SYNTHESIS AND CATABOLISM
Calcidiol (25-hydroxyvitamin D) — Calcidiol deficiency can result from decreased synthesis in the liver, increased catabolism, or renal loss of calcidiol bound to vitamin D-binding protein.
Decreased synthesis — Since vitamin D is hydroxylated in the liver by hepatic 25-hydroxylase (CYP2R1, 11p15.2) to produce calcidiol (25-hydroxyvitamin D [25(OH)D]), patients with severe parenchymal or obstructive hepatic disease may have reduced production of this metabolite [26,28]. The majority of the liver must be dysfunctional before calcidiol synthesis is reduced. Thus, these patients rarely manifest biochemical or histologic evidence of osteomalacia unless concomitant nutritional deficiency or interruption of the enterohepatic circulation occurs (figure 1). Obesity may suppress CYP2R1 expression and thereby reduce the synthesis of 25(OH)D [34,35], whereas weight loss may upregulate CYP2R1 expression [35].
Homozygous loss-of-function mutations of CYP2R1, the gene that encodes the enzyme principally responsible for 25-hydroxylation of vitamin D, causes vitamin D-dependent rickets type 1B (VDDR-1B) [36]. This very rare disorder significantly reduces production of 25(OH)D and could easily be mistaken for classical vitamin D deficiency. However, unlike the classical disorder, traditional treatment with vitamin D is ineffective and increases the circulating concentration of 25(OH)D only negligibly, while administration of 25(OH)D (calcidiol) therapy results in dramatic improvements in clinical symptoms, biochemical abnormalities, and bone densitometry. Patients with a heterozygous mutation of CYP2R1 may have more moderate biochemical and clinical features of vitamin D deficiency than those with a homozygous defect and, in accord, respond favorably to large doses of vitamin D, which supports a semidominant inheritance of these mutations [37]. (See "Etiology and treatment of calcipenic rickets in children", section on '25-hydroxylase deficiency'.)
Increased catabolism — Certain drugs can increase vitamin D catabolism, which may result in vitamin D deficiency. Phenytoin, phenobarbital, carbamazepine, oxcarbazepine, isoniazid, theophylline, and rifampin increase P450 enzyme activity, which metabolizes calcidiol to inactive vitamin D metabolites, decreasing circulating levels of calcidiol [38-43]. Supplementation with vitamin D (400 to 4000 international units/day; 1 mcg = 40 international units) may be necessary to prevent vitamin D deficiency in these patients [43,44]. (See "Antiseizure medications and bone disease", section on 'Effect of ASM type' and "Antiseizure medications and bone disease", section on 'Calcium and vitamin D'.)
Kidney loss — Most of the calcidiol in serum is bound to vitamin D-binding protein. Patients with the nephrotic syndrome can excrete enough vitamin D-binding protein (with calcidiol bound to it) to become vitamin D deficient, as evidenced by decreased circulating levels of 25(OH)D and bioavailable 25(OH)D, and may develop hypocalcemia and hypophosphatemia [45,46].
Calcitriol (1,25-dihydroxyvitamin D) — The final step in the metabolic activation of vitamin D is 1-hydroxylation of calcidiol in the proximal convoluted tubule cells of the kidney to produce calcitriol (1,25-dihydroxyvitamin D) (figure 1). This reaction is stimulated by parathyroid hormone (PTH), calcitonin, hypophosphatemia, and hypocalcemia and inhibited by hyperphosphatemia, hypercalcemia, 1,25-dihydroxyvitamin D, and fibroblast growth factor 23 (FGF23) [47,48]. (See "Overview of vitamin D", section on 'Metabolism'.)
The substrate for 1-hydroxylation is incorporated into the kidney following glomerular filtration of the 25(OH)D linked to its binding protein and megalin-directed transfer of the substrate into the kidney proximal convoluted tubule cell.
Kidney failure — In patients with kidney failure, calcitriol (1,25 dihydroxyvitamin D) production is low due to: (1) diminished glomerular filtration; (2) limited availability of the substrate for calcitriol production, secondary to decreased protein (megalin)-mediated reabsorption of glomerular-filtered 25(OH)D in renal proximal tubular epithelial cells; and (3) the loss of the 1-alpha-hydroxylase enzyme secondary to structural kidney compromise and suppression of enzyme activity as a consequence of hyperphosphatemia and resultant increased circulating FGF23 levels. The net result is a tendency to hypocalcemia, hyperparathyroidism, and bone disease. (See "Overview of vitamin D", section on 'Renal' and "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
Vitamin D-dependent rickets type IA (VDDR-1A) — Vitamin D-dependent rickets type IA (VDDR-1A) is also known as pseudovitamin D-deficient rickets because: (1) the biochemical evidence of rickets becomes evident, despite a normal circulating level of 25(OH)D, but generally in the presence of low levels of 1,25(OH)2D; and (2) the associated rickets and biochemical abnormalities, which are unresponsive to vitamin D/25(OH)D therapy, can be corrected with 1,25-dihydroxyvitamin D (calcitriol) treatment, maintained for life [49].
This form of rickets is an autosomal recessive disease due to an inactivating mutation in the CYP27B1 gene that encodes 25(OH)D-1-alpha-hydroxylase [50-52]. As a result, calcidiol is not hydroxylated to calcitriol, and calcium is not absorbed normally, resulting in hypocalcemia and an increase in parathyroid hormone levels, which increase urinary excretion of amino acids and phosphate. In addition to these biochemical abnormalities, within the first year of life, patients present with rickets and signs of hypocalcemia, tetany, or convulsions and exhibit muscle weakness and hypotonia, motor retardation, and stunted growth. Laboratory investigations show low serum concentrations of calcium and phosphorus and elevated alkaline phosphatase. With progression, patients develop the classic radiographic signs of vitamin D deficiency rickets and bone biopsy evidence of osteomalacia. This disorder, as well as other types of rickets, is discussed in more detail separately. (See "Etiology and treatment of calcipenic rickets in children", section on '1-alpha-hydroxylase deficiency' and "Overview of rickets in children".)
VITAMIN D RESISTANCE — What had been called type 2 vitamin D-dependent rickets is actually a form of vitamin D resistance and is now known as hereditary vitamin D-resistant rickets (HVDRR). HVDRR, an autosomal recessive disorder, is a very rare form of rickets with approximately 120 cases reported, in which inactivating homozygous or compound heterogeneous mutations in the vitamin D receptor gene have been identified, which change amino acids in either the N-terminal, DNA-binding domain (HVDRR type 2A) or the C-terminal ligand-binding domain of the vitamin D receptor protein, causing end-organ resistance to calcitriol (HVDRR type 2B) [49,53-59]. In both forms of this rachitic disease, the serum calcitriol level is markedly elevated, which could be used as a clue for diagnosis in untreated patients with rickets.
The clinical spectrum of this disorder varies widely, probably reflecting the type of mutation within the vitamin D receptor and the amount of residual vitamin D receptor activity (see "Etiology and treatment of calcipenic rickets in children", section on 'Hereditary resistance to vitamin D'):
●HVDRR type 2A – In patients where identified defects occur in the N-terminal, DNA-binding domain of the vitamin D receptor, preventing binding to DNA and causing total 1,25-dihydroxyvitamin D resistance, affected children usually appear normal at birth but develop rickets within the first two years of life (image 1). They also develop alopecia, resulting from the lack of vitamin D receptor action within keratinocytes [60-63]. Additional ectodermal anomalies may also be seen, including multiple milia, epidermal cysts, and oligodontia.
●HVDRR type 2B – In patients with mutations in the C-terminal ligand-binding domain of the vitamin D receptor, partial resistance or total resistance occurs due to disruption of 1,25-dihyroxyvitamin D binding, heterodimerization with the retinoid X receptor, or coactivator binding to the vitamin D receptor. Affected patients with this abnormality have the classical phenotype of the HVDRR 2A disease, but without alopecia or other ectodermal anomalies.
The genetic abnormalities affecting the binding domain of the vitamin D receptor protein can cause:
●A failure of 1,25-dihydroxyvitamin D binding to available receptors [53].
●A reduction in 1,25-dihydroxyvitamin D receptor binding sites [54].
●Abnormal binding affinity of 1,25-dihydroxyvitamin D to receptor [59].
●Inadequate translocation of 1,25-dihydroxyvitamin D-receptor complex to the nucleus [64].
Alternatively, genetic abnormalities affecting the ligand-binding domain of the vitamin D receptor can cause:
●Variably severe diminished affinity of the 1,25-dihydroxyvitamin D-receptor complex for the DNA-binding domain secondary to changes in the structure of receptor zinc binding fingers [57].
The treatment of HVDRR is discussed in detail separately. (See "Etiology and treatment of calcipenic rickets in children", section on 'Hereditary resistance to vitamin 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)")
●Beyond the Basics topics (see "Patient education: Vitamin D deficiency (Beyond the Basics)")
SUMMARY
●Mechanisms – Vitamin D deficiency can be caused by several mechanisms (see 'Nutritional deficiency and reduced cutaneous synthesis' above and 'Deficiency related to abnormal synthesis and catabolism' above and 'Vitamin D resistance' above):
•Impaired availability of vitamin D, secondary to inadequate dietary vitamin D, malabsorptive disorders, and/or diminished cutaneous synthesis.
•Impaired hydroxylation by the liver to produce 25-hydroxyvitamin D (25[OH]D).
•Increased hepatic catabolism of 25(OH)D.
•Impaired kidney production of 1,25-dihydroxyvitamin D.
•Renal loss of vitamin D and vitamin D-binding proteins.
•End-organ insensitivity (resistance) to vitamin D metabolites is rare. Hereditary vitamin D-resistant rickets (HVDRR) is associated with end-organ resistance to calcitriol due to variable mutations in the gene encoding the vitamin D receptor.
●Prevalence – The prevalence of vitamin D deficiency is particularly high in older adults, due to an age-associated decline in cutaneous vitamin D production, decreased dietary vitamin D intake, and age-dependent intestinal resistance to calcitriol. Individuals with limited sun exposure and malabsorptive gastrointestinal disease are also at risk. (See 'Older adults' above.)
●Clinical manifestations and treatment – Other aspects of vitamin D deficiency, including its treatment, are discussed separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D supplementation in osteoporosis" and "Vitamin intake and disease prevention", section on 'Vitamin D'.)
ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Zalman Agus, MD, and Marc K Drezner, MD, who contributed to earlier versions of this topic review.
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