Causes of Vitamin D Deficiency and Resistance

24/9/2014
Causes of vitamin D deficiency and resistance
Official reprint from UpToDate

www.uptodate.com 2014 UpToDate
Authors
Zalman S Agus, MD
Marc K Drezner, MD
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2014. | This topic last updated: Mar 14, 2014.
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 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", 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 "Causes of hypophosphatemia"
and "Etiology of hypocalcemia in adults".)
DEFINITION 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. Clinicians variably consider the optimal serum 25(OH)D concentration to range between 20 and 40
ng/mL (50 to 100 nmol/L) or between 30 and 50 ng/mL (75 to 125 nmol/L). The range of common agreement
is 30 to 40 ng/mL (75 to 100 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 D (cholecalciferol) is normally synthesized in the skin under the
influence of sunlight in a nonenzymatic manner. In addition, vitamin D (ergocalciferol) may be ingested from
fish or plant sources. Vitamin D is then hydroxylated in the liver to 25-hydroxyvitamin D (calcidiol, 25[OH]D),
which is the major circulating form of vitamin D and the best index of vitamin D sufficiency. Calcidiol is
hydroxylated primarily in the kidney to 1,25-dihydroxyvitamin D (calcitriol), which is the most active form
(figure 1). 1,25-dihydroxyvitamin D is also formed in some other tissues but is used only within the 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 25hydroxylation 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
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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) 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:
Elderly 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 the elderly [4,5].
In addition to reduced endogenous production, vitamin D intake is often low in older subjects. It has been
estimated that approximately one-half of elderly women consume less than 137 int. units/day of vitamin D,
and nearly one-quarter consume less than 65 int. units/day (recommended intake 400 int. units/day for
people 51 to 70 years old and 600 int. units/day for people 71 years old and older) [5]. Moreover, many
clinicians believe that even in those with adequate vitamin D intake, achlorhydria, which is common in the
elderly, limits calcium absorption. The net effect of the many factors influencing vitamin D metabolism in the
elderly is the presence of relative hypocalcemia and high serum (PTH) concentrations [6,7]; this secondary
hyperparathyroidism can be attenuated by the administration of physiological doses of vitamin D [8].
However, older persons confined indoors may have low serum calcidiol (25[OH]D) concentrations even with
the current recommendations for vitamin D intake [9,10].
Children Dietary vitamin D deficiency can also occur in children, with notable differences among ethnic
groups [11]. Among 618 Asian children in the United Kingdom, 27 percent had serum 25(OH)D <10 ng/mL
(25 nmol/L) [12]. Serum 25(OH)D concentrations were correlated with ingestion of vitamin D supplements in
these children, notwithstanding that increasing skin pigmentation is associated with less cutaneous vitamin
D production. (See 'Immigrants to cold climates from warm climates' below and "Vitamin D insufficiency and
deficiency in children and adolescents".)
Vitamin D deficiency is also a concern for lactating mothers and breast-fed infants. (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 [13]. Similar seasonal
differences were seen in older groups.
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]) [14]. Inadequate
vitamin D intake, winter season, and housebound status were independent predictors of vitamin D
deficiency. 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.
Women treated for osteoporosis Unrecognized vitamin D insufficiency or deficiency is also common in
postmenopausal women seeking advice or receiving therapy for osteoporosis [10,15]. In a study of 1536
community-dwelling postmenopausal women (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 [10]. Not surprisingly, the prevalence of
vitamin D insufficiency was higher in women taking less than 400 compared with 400 int. units of vitamin D
per day. (See "Calcium and vitamin D supplementation in osteoporosis".)
Chronic renal disease Patients with chronic kidney disease (CKD) have 1,25-dihydroxyvitamin D
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(calcitriol) deficiency, but 25(OH)D deficiency may also occur [16-18]. This has been demonstrated in
patients on dialysis and in patients with CKD pre-dialysis [16,18].
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 [16].
In a study of 242 patients with CKD on dialysis, vitamin D deficiency (<15 ng/mL [37nmol/L]), was
evident in up to 28 percent of patients [18]. Women, 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 at the lumbar spine and wrist.
Despite these associations, it is unclear if improving 25(OH)D concentrations benefits these patients. (See
"Management of secondary hyperparathyroidism and mineral metabolism abnormalities in adult predialysis
patients with chronic kidney disease" and "Management of secondary hyperparathyroidism and mineral
metabolism abnormalities in dialysis patients".) The Kidney Disease Outcomes Quality Initiative (K/DOQI)
clinical practice guidelines for bone metabolism and disease in CKD, as well as other K/DOQI 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 abnormal enterohepatic circulation [19-21]. In general, malabsorption of
vitamin D occurs as a consequence of steatorrhea, which disturbs fat emulsification and chylomicronfacilitated 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 [22]. These patients often present with low bone
mineral density. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults",
section on 'Metabolic bone disease'.)
Gastric bypass In one series of 41 obese patients who had undergone long-limb gastric bypass and 202
who had undergone short-limb bypass, the following results were seen after an average of three to five
years of follow-up [23]:
At the end of the follow-up period, mean serum 25(OH)D concentrations were low in both groups, but
significantly lower in the long-limb compared with the short-limb bypass group (16.8 10.8 ng/mL
versus 22.7 11.1 ng/mL, respectively; preoperative levels were not reported). (See "Vitamin D
deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D
sufficiency'.)
Mean serum PTH concentrations were increased in both groups: 113.5 88.0 and 74.5 52.7 pg/mL in
the long-limb and short-limb bypass groups (normal PTH range 12.0 to 65 pg/mL). Some patients in the
short-limb bypass group had evidence of secondary hyperparathyroidism in spite of normal 25(OH)D
concentrations (30 ng/mL), suggestive of selective calcium malabsorption. (See "Bariatric surgery:
Postoperative nutritional management", section on 'Nutrient deficiencies'.)
In contrast, patients with cholestatic liver disease, extrahepatic biliary obstruction and diseases of the distal
portions of the small intestine, such as regional enteritis, may develop vitamin D deficiency not only
secondary to poor vitamin D absorption but disruption of enterohepatic circulation, as well [19-21].
Vitamin D deficiency may also develop in patients who have had partial or total gastrectomy for peptic ulcer
disease, bariatric surgery 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.
Metabolic bone disease associated with gastrointestinal disorders is discussed in more detail separately.
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(See "Metabolic bone disease in inflammatory bowel disease".)

Immigrants to cold climates from warm climates Vitamin D deficiency has been reported in darkskinned immigrants from warm climates to cold climates in North America and Europe. Asian Indian
immigrants to the United States may have vitamin D deficiency even with what is considered adequate sun
exposure [24].
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 subjects with persistent, nonspecific
musculoskeletal pain presenting to an inner city health clinic in Minneapolis, 93 percent were vitamin D
deficient (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)) [25]. 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 [26], and they
require more than the usual recommended dose for young adults (eg, more than 400 int. 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 [27].
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 to produce calcidiol (25[OH]D),
patients with severe parenchymal or obstructive hepatic disease may have reduced production of this
metabolite [19,21]. The majority of the liver must be dysfunctional before calcidiol synthesis is reduced.
Thus, these patients rarely manifest biochemical or histological evidence of osteomalacia unless
concomitant nutritional deficiency or interruption of the enterohepatic circulation occurs (figure 1).
Drugs Decreased circulating levels of calcidiol may also occur in patients treated with drugs such as
phenytoin, phenobarbital, carbamazepine, isoniazid, theophylline, and rifampin, due to induction of P-450
enzyme activity, which metabolizes calcidiol to inactive vitamin D metabolites [28-32]. Supplementation with
vitamin D (400 to 4000 int. units/day; 1 mcg = 40 int. units) may be necessary to prevent vitamin D
deficiency in these patients [33]. (See "Antiepileptic drugs and bone disease", section on 'Effect of AED type'
and "Antiepileptic drugs and bone disease", section on 'Calcium and vitamin D'.)
Renal 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, and may develop hypocalcemia and hypophosphatemia [34].
Calcitriol (1,25-dihydroxyvitamin D) The final step in the metabolic activation of vitamin D is 1hydroxylation of calcidiol in the proximal convoluted tubule cells of the kidney to produce calcitriol (1,25dihydroxyvitamin D) (figure 1). This reaction is stimulated by PTH, calcitonin and hypophosphatemia, and
inhibited by calcium, 1,25-dihydroxyvitamin D, and hyperphosphatemia [35]. (See "Overview of vitamin D",
section on 'Metabolism'.)
The substrate for 1-hydroxylation is incorporated into the kidney following glomerular filtration of the 25hydroxyvitamin D linked to its binding protein and megalin-directed transfer of the substrate into the renal
proximal convoluted tubule cell.
Renal failure In patients with renal failure, calcitriol (1,25 dihydroxyvitamin D) production is low due to
diminished glomerular filtration, loss of the 1-alpha-hydroxylase enzyme secondary to structural renal
compromise, and suppression of enzyme activity secondary to hyperphosphatemia. The net result is a
tendency to hypocalcemia, hyperparathyroidism, and bone disease. (See "Overview of chronic kidney
disease-mineral bone disease (CKD-MBD)".)
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Vitamin D dependent rickets type I Vitamin D-dependent rickets type I is also known as
pseudovitamin D-deficient rickets because the clinical and biochemical evidence of rickets can be corrected
with 1,25-dihydroxyvitamin D (calcitriol) treatment [36].
This form of rickets is due to an inactivating mutation in the 1-hydroxylase gene [37-39]. As a result, calcidiol
is not hydroxylated to calcitriol, and calcium is not absorbed normally. As a result of the hypocalcemia,
parathyroid hormone levels rise, resulting in an increase in urinary excretion of amino acids and phosphate.
In addition to these biochemical abnormalities, within the first year of life, patients exhibit muscle weakness
and hypotonia, motor retardation, and stunted growth. 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" 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 fewer than 50 known affected kindreds. It is
associated with endorgan resistance to calcitriol usually caused by mutations in the gene encoding the
vitamin D receptor [36,40-46].
The clinical spectrum varies widely, probably reflecting the type of mutation within the vitamin D receptor and
the amount of residual vitamin D receptor activity. Affected children usually appear normal at birth but
develop rickets within the first two years of life (image 1). A peculiar feature of the syndrome is alopecia,
which appears in approximately two-thirds of cases and is a marker of disease severity. Alopecia results
from the lack of vitamin D receptor action within keratinocytes [47-50]. Additional ectodermal anomalies may
also be seen including multiple milia, epidermal cysts, and oligodontia. (See "Etiology and treatment of
calcipenic rickets in children", section on 'Hereditary vitamin D resistant rickets'.)
The identified mutations or defects in the vitamin D receptor include the following:
Failure of 1,25(OH)2D binding to available receptors [40]
A reduction in 1,25(OH)2D receptor binding sites [41]
Abnormal binding affinity of 1,25(OH)2D to receptor [46]
Inadequate translocation of 1,25(OH)2D-receptor complex to the nucleus [51]
Diminished affinity of the 1,25(OH)2D-receptor complex for the DNA binding domain secondary to
changes in the structure of receptor zinc binding fingers [44]
The treatment of HVDRR is discussed in detail separately. (See "Etiology and treatment of calcipenic rickets
in children", section on 'Hereditary vitamin D resistant rickets'.)
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Basics topics (see "Patient information: Vitamin D deficiency (The Basics)")
Beyond the Basics topics (see "Patient information: Vitamin D deficiency (Beyond the Basics)")
SUMMARY Vitamin D deficiency can be caused by several mechanisms:
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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
Increased hepatic catabolism of 25-hydroxyvitamin 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 endorgan resistance to calcitriol due most often to mutations in the gene
encoding the vitamin D receptor. The treatment of this rare disorder is discussed separately. (See "Etiology
and treatment of calcipenic rickets in children".)
The prevalence of vitamin D deficiency is particularly high in the elderly, due to an age-associated decline in
cutaneous vitamin D production and decreased dietary vitamin D intake. Individuals with limited sun
exposure and malabsorptive gastrointestinal disease are also at risk.
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 supplementation in disease prevention", section on 'Vitamin
D'.)
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keratinocytes of vitamin D receptor null mice prevents alopecia. Endocrinology 2001; 142:5386.
49. Malloy PJ, Wang J, Srivastava T, Feldman D. Hereditary 1,25-dihydroxyvitamin D-resistant rickets with
alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D
receptor. Mol Genet Metab 2010; 99:72.
50. Forghani N, Lum C, Krishnan S, et al. Two new unrelated cases of hereditary 1,25-dihydroxyvitamin Dresistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D
receptor gene. J Pediatr Endocrinol Metab 2010; 23:843.
51. Hewison M, Rut AR, Kristjansson K, et al. Tissue resistance to 1,25-dihydroxyvitamin D without a
mutation of the vitamin D receptor gene. Clin Endocrinol (Oxf) 1993; 39:663.
Topic 2048 Version 9.0
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GRAPHICS
Pathways of vitamin D synthesis
Metabolic activation of vitamin D to calcitriol and its effects on calcium

and phosphate homeostasis. The result is an increase in the serum
calcium and phosphate concentrations.
UV: ultraviolet.
Graphic 65360 Version 4.0
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Causes of vitamin D deficiency or resistance

Deficient intake or absorption
Dietary
Inadequate sunlight exposure
Fat malabsorption
Gastrectomy
Small bowel disease
Pancreatic insufficiency
Defective 25-hydroxylation
Cirrhosis
Increased catabolism of vitamin D to inactive metabolites

Anticonvulsants
Loss of vitamin D binding protein

Nephrotic syndrome
Defective 1-alpha 25-hydroxylation

Hypoparathyroidism
Renal failure
1-alpha hydroxylase deficiency (vitamin D-dependent rickets, type 1)
Defective target organ response to calcitriol

Hereditary vitamin D-resistant rickets (vitamin D-dependent rickets, type 2)
http://www.uptodate.com.ezproxy.uniandes.edu.co:8080/contents/causes-of-vitamin-d-deficiency-and-resistance?topicKey=ENDO%2F2048&el
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Vitamin D deficiency rickets in a child
Characteristic findings of rickets in children often include radiographic

evidence of decreased mineralization around the epiphyses and bowing
of the lower extremities.
http://www.asbmr.org.
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Disclosures
Disclosures: Zalman S Agus, MD Nothing to disclose. Marc K Drezner, MD Nothing to disclose.
Clifford J Rosen, MD Nothing to disclose. Jean E Mulder, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
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Causes of Vitamin D Deficiency and Resistance

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Causes of Vitamin D Deficiency and Resistance

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24/9/2014

Causes of vitamin D deficiency and resistance

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Causes of vitamin D deficiency and resistance

Causes of vitamin D deficiency and resistance

Causes of vitamin D deficiency and resistance

(See "Metabolic bone disease in inflammatory bowel disease".)

Causes of vitamin D deficiency and resistance

Causes of vitamin D deficiency and resistance

Impaired availability of vitamin D, secondary to inadequate dietary vitamin D, malabsorptive disorders,

Causes of vitamin D deficiency and resistance

Med 1998; 338:777.

Causes of vitamin D deficiency and resistance

Causes of vitamin D deficiency and resistance

Metabolic activation of vitamin D to calcitriol and its effects on calcium

Causes of vitamin D deficiency and resistance

Causes of vitamin D deficiency or resistance

Increased catabolism of vitamin D to inactive metabolites

Loss of vitamin D binding protein

Defective 1-alpha 25-hydroxylation

Defective target organ response to calcitriol

Causes of vitamin D deficiency and resistance

Vitamin D deficiency rickets in a child

Characteristic findings of rickets in children often include radiographic

Causes of vitamin D deficiency and resistance

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