Gave Baby Too Much Vitamin D
Gave Baby Too Much Vitamin D
Vitamin D Supplementation and Risk of Toxicity in Pediatrics: A Review of Current Literature
Maria G. Vogiatzi, 1Weill Cornell Medical College (M.G.V.), New York, New York 10065; *Address all correspondence and requests for reprints to: Maria Vogiatzi, MD, Weill Cornell Medical College, Pediatric Endocrinology, Box 103, 525 East 68th Street, New York, NY 10065. Search for other works by this author on: 2SUNY Downstate Medical Center (E.J.-D.), Brooklyn, New York 11203; Search for other works by this author on: 3University of Virginia Health System (M.D.D.), Charlottesville, Virginia 22908 Search for other works by this author on: for the Drugs, and Therapeutics Committee of The Pediatric Endocrine Society Search for other works by this author on:
Received:
30 September 2013
Accepted:
13 January 2014
Context:
Although vitamin D toxicity is rare in children, increased use of vitamin D formulations, re-examination of optimal vitamin D levels, and use of higher doses lend potential for an increased incidence of vitamin D toxicity.
Evidence Acquisition:
A PubMed search was conducted through May 2013 for cases of vitamin D intoxication and vitamin D trials in pediatrics. Safety data were collected and reviewed.
Evidence Synthesis:
A small number of pediatric studies tested vitamin D doses at or above the currently recommended upper tolerable intake. In children and adolescents, vitamin D excess was rare and usually asymptomatic. Recent cases of intoxication relate to errors in manufacturing, formulation, or prescription; involve high total intake in the range of 240 000 to 4 500 000 IU; and present with severe hypercalcemia, hypercalciuria, or nephrocalcinosis. However, mild hypercalcemia and hypervitaminosis using currently recommended doses have been reported in infants with rickets.
Conclusions:
Although rare, cases of vitamin D intoxication that present with dramatic life-threatening symptoms still occur in children. Moreover, recent studies in infants raise a potential need for monitoring vitamin D levels when doses at or above the currently recommended upper range are used. Further studies are needed to clarify these findings. The Drugs and Therapeutics Committee of the Pediatric Endocrine Society suggests obtaining serum 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level intake that is currently recommended.
Over the past decade, there has been increased focus on the benefits of vitamin D on bone health and, potentially, other disease states (1–3). Re-examination of optimal serum levels and multiple reports regarding high rates of vitamin D insufficiency and deficiency resulted in revised recommendations for minimum vitamin D intake and new guidelines for treatment with high vitamin D doses (4–13). In light of a growing body of research, recent reports of vitamin D intoxication (14–36) and increased use of vitamin D supplementation, the Drugs and Therapeutics committee of the Pediatric Endocrine Society (PES) undertook a systematic review of the safety of currently recommended high vitamin D doses as well as reported cases of intoxications in pediatrics. Herein, we present these outcomes and describe changes in vitamin D metabolism during intoxication, causes and symptoms of toxicity, and current management. Finally, we propose recommendations for the monitoring of children who receive vitamin D supplementation and those with evidence or suspicion of intoxication.
Search Strategy
We performed a PubMed search through May 2013 of publications in English. We searched for vitamin D trials in pediatrics. Publications that involved administration of high vitamin D doses were reviewed, and information on vitamin D excess and toxicity (ie, hypercalcemia, hypercalciuria) was gathered. A similar PubMed search was performed for cases of vitamin D intoxication in both adults and pediatrics. All reported cases were reviewed, and data on the causes, symptoms, biochemical abnormalities, and treatment were summarized for this report. The following terms were used for the search: "vitamin D excess," "vitamin D intoxication," "hypervitaminosis," "vitamin D trial and child," "vitamin D and hypercalcemia," "vitamin D and hypercalciuria," "calcitriol and intoxication," and "calcitriol and hypercalcemia."
Vitamin D Metabolism and Pathophysiology During Vitamin D Intoxication
Vitamin D is available in two forms: ergocalciferol or vitamin D2 and cholecalciferol or vitamin D3. Vitamin D2 and D3 are found as dietary supplements (Table 1) and in various food items naturally or after fortification. Vitamin D3 is also generated from endogenous 7-dehydrocholesterol via sun exposure (1, 3) (Figure 1).
Figure 1.
Diagram showing the main steps of vitamin D synthesis and metabolism. Cholecalciferol or vitamin D3 is produced from 7-dehydrocholesterol in the skin by exposure to sunlight. Vitamin D3 formed in this fashion as well as vitamin D3 and D2 taken from dietary sources or commercially available supplements circulate in the bloodstream bound to the DBP. They are converted to 25OHD in the liver in a constitutive process, which is largely dependent on substrate availability. 25OHD is further hydroxylated in the kidney to the active form 1,25(OH)2D in a tightly regulated process. The primary regulatory pathways that control the production of 1,25(OH)2D and activity of CYP27B1, which catalyzes the conversion of 25OHD to 1,25(OH)2D, are depicted here (dotted arrows). Specifically, hypercalcemia inhibits 1,25(OH)2D synthesis, whereas hypocalcemia stimulates its production primarily due to an increase in PTH secretion. Hypophosphatemia and PTH up-regulate CYP27B1 and increase renal production of 1,25(OH)2D, whereas FGF-23 does the opposite. 1,25(OH)2D regulates its own synthesis by down-regulating CYP27B1 activity and suppressing PTH secretion. 1,25(OH)2D, the active vitamin D form, binds to the VDR to increase intestinal calcium absorption and exert the other vitamin D-related actions. Finally, 1,25(OH)2D increases CYP24A1 activity to catabolize 25OHD and 1,25(OH)2D to water-soluble products that are excreted in the bile. The enzymes involved in each step, all cytochrome P450s (CYP), are shown in red.
Figure 1.
Diagram showing the main steps of vitamin D synthesis and metabolism. Cholecalciferol or vitamin D3 is produced from 7-dehydrocholesterol in the skin by exposure to sunlight. Vitamin D3 formed in this fashion as well as vitamin D3 and D2 taken from dietary sources or commercially available supplements circulate in the bloodstream bound to the DBP. They are converted to 25OHD in the liver in a constitutive process, which is largely dependent on substrate availability. 25OHD is further hydroxylated in the kidney to the active form 1,25(OH)2D in a tightly regulated process. The primary regulatory pathways that control the production of 1,25(OH)2D and activity of CYP27B1, which catalyzes the conversion of 25OHD to 1,25(OH)2D, are depicted here (dotted arrows). Specifically, hypercalcemia inhibits 1,25(OH)2D synthesis, whereas hypocalcemia stimulates its production primarily due to an increase in PTH secretion. Hypophosphatemia and PTH up-regulate CYP27B1 and increase renal production of 1,25(OH)2D, whereas FGF-23 does the opposite. 1,25(OH)2D regulates its own synthesis by down-regulating CYP27B1 activity and suppressing PTH secretion. 1,25(OH)2D, the active vitamin D form, binds to the VDR to increase intestinal calcium absorption and exert the other vitamin D-related actions. Finally, 1,25(OH)2D increases CYP24A1 activity to catabolize 25OHD and 1,25(OH)2D to water-soluble products that are excreted in the bile. The enzymes involved in each step, all cytochrome P450s (CYP), are shown in red.
Table 1.
Vitamin D Preparations Available in the United States, Showing Various Formulations Among Vitamin D Products
| Ergocalciferol (vitamin D2) | |
|---|---|
| Solution, 8000 IU/mL | Requires prescription |
| Gel-cap, 50 000 IU | Requires prescription |
| Tablets and capsules, eg, 200–5000 IU | Over the counter |
| Cholecalciferol (vitamin D3) | |
| Solution, eg, 400 and 5000 IU/mL | Over the counter |
| Drops, eg, 400–2000 IU/drop | Over the counter |
| Tablets and capsules, eg, 200, 400, 1000, 5000, 10 000, and 50 000 IU | Over the counter |
| Calcitriol (1,25-dihydroxycholecalciferol) | |
| Capsules, 0.25 and 0.5 μg | Requires prescription |
| Injectable solution, 1 or 2 μg/mL | Requires prescription |
| Ergocalciferol (vitamin D2) | |
|---|---|
| Solution, 8000 IU/mL | Requires prescription |
| Gel-cap, 50 000 IU | Requires prescription |
| Tablets and capsules, eg, 200–5000 IU | Over the counter |
| Cholecalciferol (vitamin D3) | |
| Solution, eg, 400 and 5000 IU/mL | Over the counter |
| Drops, eg, 400–2000 IU/drop | Over the counter |
| Tablets and capsules, eg, 200, 400, 1000, 5000, 10 000, and 50 000 IU | Over the counter |
| Calcitriol (1,25-dihydroxycholecalciferol) | |
| Capsules, 0.25 and 0.5 μg | Requires prescription |
| Injectable solution, 1 or 2 μg/mL | Requires prescription |
Table 1.
Vitamin D Preparations Available in the United States, Showing Various Formulations Among Vitamin D Products
| Ergocalciferol (vitamin D2) | |
|---|---|
| Solution, 8000 IU/mL | Requires prescription |
| Gel-cap, 50 000 IU | Requires prescription |
| Tablets and capsules, eg, 200–5000 IU | Over the counter |
| Cholecalciferol (vitamin D3) | |
| Solution, eg, 400 and 5000 IU/mL | Over the counter |
| Drops, eg, 400–2000 IU/drop | Over the counter |
| Tablets and capsules, eg, 200, 400, 1000, 5000, 10 000, and 50 000 IU | Over the counter |
| Calcitriol (1,25-dihydroxycholecalciferol) | |
| Capsules, 0.25 and 0.5 μg | Requires prescription |
| Injectable solution, 1 or 2 μg/mL | Requires prescription |
| Ergocalciferol (vitamin D2) | |
|---|---|
| Solution, 8000 IU/mL | Requires prescription |
| Gel-cap, 50 000 IU | Requires prescription |
| Tablets and capsules, eg, 200–5000 IU | Over the counter |
| Cholecalciferol (vitamin D3) | |
| Solution, eg, 400 and 5000 IU/mL | Over the counter |
| Drops, eg, 400–2000 IU/drop | Over the counter |
| Tablets and capsules, eg, 200, 400, 1000, 5000, 10 000, and 50 000 IU | Over the counter |
| Calcitriol (1,25-dihydroxycholecalciferol) | |
| Capsules, 0.25 and 0.5 μg | Requires prescription |
| Injectable solution, 1 or 2 μg/mL | Requires prescription |
The most important steps in vitamin D metabolism are shown in Figure 1. Vitamin D hydroxylation to 25-hydroxyvitamin D (25OHD) in the liver depends on substrate availability, and therefore, 25OHD concentrations rise in circulation during excess or intoxication (37). In contrast, the subsequent 1α-hydroxylation to 1,25-dihydroxyvitamin D [1,25(OH)2D] in the kidney is tightly regulated by PTH and under negative feedback by calcium, phosphorus, fibroblast growth factor 23 (FGF-23), and 1,25(OH)2D itself (37). Consequently, in vitamin D intoxication, serum 1,25(OH)2D concentrations are usually normal and do not correlate with serum calcium concentrations.
The body kinetics of vitamin D2 and D3 and 25OHD have significant implications on symptomatology and management during intoxication. Both vitamin D2 and D3 are lipophilic and rapidly removed from the circulation by various tissues such as adipose and muscle where they may remain stored for almost 2 months (1–3, 37, 38). Their metabolite, 25OHD, has high affinity for its transport protein, vitamin D binding protein (DBP), which results in a long half-life of 2–3 weeks. 25OHD is also lipophilic and can be stored in adipose tissue, remaining there for months, depending on the extent of vitamin D stores (1–3, 37, 38). Hence, vitamin D intoxication may take weeks to resolve and require a prolonged course of treatment. Although both vitamin D2 and D3 undergo the same hydroxylation steps and are equipotent in treating rickets, vitamin D2 has been found less toxic in animal studies and less efficacious in raising serum 25OHD concentration than vitamin D3, when administered in the form of boluses (39). However, according to a recent meta-analysis, this difference between D2 and D3 is lost with daily administration, implying differences in the catabolism of these two vitamin D forms (40). Pediatric data comparing the efficacy of D2 and D3 are sparse, and hence, further studies are needed to confirm similar events in children.
Animal studies and a limited number of observations from human cases offer insight into alterations in vitamin D metabolism during states of intoxication (37, 38, 41, 42). Under physiological conditions, 1,25(OH)2D has high affinity for the vitamin D receptor (VDR), making it the active vitamin D metabolite. The precise vitamin D metabolite responsible for the hypercalcemia during vitamin D intoxication is still a matter of debate, although evidence points to 25OHD as the main culprit (36–38). During intoxication, 25OHD concentrations rise in the circulation and, at sufficiently high levels, can bind to VDR and stimulate transcription (Figure 1). In addition, the elevated 25OHD concentrations can compete and displace 1,25(OH)2D from its transport protein DBP, thus increasing the "free" and biological active component of 1,25(OH)2D. Indeed, increased free 1,25(OH)2D concentrations with normal total 1,25(OH)2D levels were reported in adults with vitamin D intoxication (43).
During intoxication, high concentrations of either 25OHD or free 1,25(OH)2D lead to hypercalcemia by increasing intestinal calcium absorption and bone resorption (44, 45). In turn, hypercalcemia increases the calcium load that is filtered through the kidney, resulting in hypercalciuria via a mechanism that involves increased calcium excretion in the distal tubule (46–48). Persistently elevated serum calcium concentrations may also cause polyuria and dehydration because of an inability of the kidneys to appropriately concentrate urine. The mechanisms behind this renal concentration defect are incompletely understood and may involve tubular interstitial injury because of calcium deposition in the medulla, down-regulation of aquaporin-2 water channel, or activation of the calcium-sensing receptors (49–51).
In addition to various vitamin D2 and D3 preparations, 1,25(OH)2D or calcitriol is also available for the treatment for the hypocalcemia and secondary hyperparathyroidism of renal failure (52) or rare conditions such as hypoparathyroidism, pseudohypoparathyroidism, or hypophosphatemic rickets. Reports of intoxication caused by excessive calcitriol intake in these patients are extremely rare (53–55). Hypercalcemia due to ingestion of calcitriol usually lasts only 1 to 2 days because of the relatively short biological half-life of calcitriol. Thus, stopping the calcitriol and hydration with iv saline may be the only therapy that is needed. Because calcitriol is not used as a supplement or prescribed for the treatment of vitamin D deficiency or insufficiency in children, we restrict our discussion only to safety and toxicity related to vitamin D2 or D3.
Current Recommendations on Daily Vitamin D Intake and Treatment of Insufficiency or Deficiency
The most recent pediatric recommendations for daily requirements, upper level intake, and vitamin D doses for the treatment of vitamin D insufficiency and deficiency are presented in Table 2 (5, 7, 10–13). The table indicates considerable lack of consensus. The difference in recommendations reflects an ongoing debate about what constitutes optimal or adequate vitamin D levels for skeletal health (5–13). The Endocrine Society with its published guidelines advocates for 25OHD concentrations above 30 ng/mL (75 nmol/L) as ideal for bone health and defines deficiency as levels less than 20 ng/mL (50 nmol/L). The Institute of Medicine (IOM) accepts levels above 20 ng/mL as sufficient. The debate is based primarily on data from the adult literature. Only a limited number of studies have evaluated the effect of vitamin D on bone mass at doses that raise serum 25OHD concentrations above 30 ng/mL in pediatrics (56–59). The results are so far inconsistent. Therefore, the higher vitamin D cutoffs of 30 ng/mL have not been the official recommendation of the American Academy of Pediatrics, PES, or their European counterparts (10–13). However, the discussion has generated confusion among treating physicians and the public about appropriate vitamin D levels and supplementation.
Table 2.
Recent Pediatric Recommendations of Vitamin D Intake
| Age | Maintenance Vitamin D Doses | ||||||
|---|---|---|---|---|---|---|---|
| AAP and PES | IOM | Endocrine Society for Patients at Risk for Vitamin D Deficiency b | EFSA and ESPGHAN d | ||||
| Daily Requirement, IU a | Recommended Dietary Allowance, IU | Upper Level Intake, IU | Daily Requirement, IU | Upper Level Intake, IU | Recommended Daily Supplementation, IU | Upper Level Intake, IU | |
| 0–6 mo | 400 | c | 1000 | 400–1000 | 2000 | 400 | 1000 |
| 6–12 mo | 400 | c | 1500 | 400–1000 | 2000 | 400 | 1000 |
| 1–3 y | 400 | 600 | 2500 | 600–1000 | 4000 | None | 2000 |
| 4–8 y | 400 | 600 | 3000 | 600–1000 | 4000 | None | 2000 |
| 9–10 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 2000 |
| 11–18 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 4000 |
| Age | Maintenance Vitamin D Doses | ||||||
|---|---|---|---|---|---|---|---|
| AAP and PES | IOM | Endocrine Society for Patients at Risk for Vitamin D Deficiency b | EFSA and ESPGHAN d | ||||
| Daily Requirement, IU a | Recommended Dietary Allowance, IU | Upper Level Intake, IU | Daily Requirement, IU | Upper Level Intake, IU | Recommended Daily Supplementation, IU | Upper Level Intake, IU | |
| 0–6 mo | 400 | c | 1000 | 400–1000 | 2000 | 400 | 1000 |
| 6–12 mo | 400 | c | 1500 | 400–1000 | 2000 | 400 | 1000 |
| 1–3 y | 400 | 600 | 2500 | 600–1000 | 4000 | None | 2000 |
| 4–8 y | 400 | 600 | 3000 | 600–1000 | 4000 | None | 2000 |
| 9–10 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 2000 |
| 11–18 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 4000 |
| Age | Treatment of vitamin D deficiency or insufficiency | |
|---|---|---|
| PES | Endocrine Society b | |
| 0–1 mo | 1000 IU/d for 2–4 wk | 2000 IU/d or 50 000 IU/wk for 6 wk |
| 1–12 mo | 1000–5000 IU/d for 2–4 wk | |
| >12 mo | >5000 IU/d for 2–4 wk | |
| Age | Treatment of vitamin D deficiency or insufficiency | |
|---|---|---|
| PES | Endocrine Society b | |
| 0–1 mo | 1000 IU/d for 2–4 wk | 2000 IU/d or 50 000 IU/wk for 6 wk |
| 1–12 mo | 1000–5000 IU/d for 2–4 wk | |
| >12 mo | >5000 IU/d for 2–4 wk | |
Abbreviations: AAP, American Academy of Pediatrics; PES, Pediatric Endocrine Society; IOM, Institute of Medicine; EFSA, European Food Safety Authority; ESPGHAN, European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
a PES recommendations for premature infants, dark-skinned infants and children, and for those residing at higher latitudes (above 40°): 800 IU/d.
b Obesity. Malabsorption, use of medications such as anticonvulsants or ketoconazole: increase recommended doses by two or three times.
c Adequate intake is 400 IU/d.
d Recommendations do not cover children with chronic diseases or preterm infants.
Table 2.
Recent Pediatric Recommendations of Vitamin D Intake
| Age | Maintenance Vitamin D Doses | ||||||
|---|---|---|---|---|---|---|---|
| AAP and PES | IOM | Endocrine Society for Patients at Risk for Vitamin D Deficiency b | EFSA and ESPGHAN d | ||||
| Daily Requirement, IU a | Recommended Dietary Allowance, IU | Upper Level Intake, IU | Daily Requirement, IU | Upper Level Intake, IU | Recommended Daily Supplementation, IU | Upper Level Intake, IU | |
| 0–6 mo | 400 | c | 1000 | 400–1000 | 2000 | 400 | 1000 |
| 6–12 mo | 400 | c | 1500 | 400–1000 | 2000 | 400 | 1000 |
| 1–3 y | 400 | 600 | 2500 | 600–1000 | 4000 | None | 2000 |
| 4–8 y | 400 | 600 | 3000 | 600–1000 | 4000 | None | 2000 |
| 9–10 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 2000 |
| 11–18 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 4000 |
| Age | Maintenance Vitamin D Doses | ||||||
|---|---|---|---|---|---|---|---|
| AAP and PES | IOM | Endocrine Society for Patients at Risk for Vitamin D Deficiency b | EFSA and ESPGHAN d | ||||
| Daily Requirement, IU a | Recommended Dietary Allowance, IU | Upper Level Intake, IU | Daily Requirement, IU | Upper Level Intake, IU | Recommended Daily Supplementation, IU | Upper Level Intake, IU | |
| 0–6 mo | 400 | c | 1000 | 400–1000 | 2000 | 400 | 1000 |
| 6–12 mo | 400 | c | 1500 | 400–1000 | 2000 | 400 | 1000 |
| 1–3 y | 400 | 600 | 2500 | 600–1000 | 4000 | None | 2000 |
| 4–8 y | 400 | 600 | 3000 | 600–1000 | 4000 | None | 2000 |
| 9–10 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 2000 |
| 11–18 y | 400 | 600 | 4000 | 600–1000 | 4000 | None | 4000 |
| Age | Treatment of vitamin D deficiency or insufficiency | |
|---|---|---|
| PES | Endocrine Society b | |
| 0–1 mo | 1000 IU/d for 2–4 wk | 2000 IU/d or 50 000 IU/wk for 6 wk |
| 1–12 mo | 1000–5000 IU/d for 2–4 wk | |
| >12 mo | >5000 IU/d for 2–4 wk | |
| Age | Treatment of vitamin D deficiency or insufficiency | |
|---|---|---|
| PES | Endocrine Society b | |
| 0–1 mo | 1000 IU/d for 2–4 wk | 2000 IU/d or 50 000 IU/wk for 6 wk |
| 1–12 mo | 1000–5000 IU/d for 2–4 wk | |
| >12 mo | >5000 IU/d for 2–4 wk | |
Abbreviations: AAP, American Academy of Pediatrics; PES, Pediatric Endocrine Society; IOM, Institute of Medicine; EFSA, European Food Safety Authority; ESPGHAN, European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
a PES recommendations for premature infants, dark-skinned infants and children, and for those residing at higher latitudes (above 40°): 800 IU/d.
b Obesity. Malabsorption, use of medications such as anticonvulsants or ketoconazole: increase recommended doses by two or three times.
c Adequate intake is 400 IU/d.
d Recommendations do not cover children with chronic diseases or preterm infants.
Safety Data of High Vitamin D Doses in Pediatrics
Although vitamin D deficiency is detrimental for bone health, the consequent approach that higher doses are protective and confer a reduced risk for disease has been challenged by recent data in adults that indicate that high doses of vitamin D raise the incidence of falls and fractures (60, 61). These events were linked to the mode of vitamin D administration as stoss therapy, ie, as a single large bolus compared to smaller intermittent doses (62). Beyond skeletal health, similar curvilinear or U-shaped response has been described for other vitamin D outcomes, including all-cause mortality, cardiovascular disease, and selected cancers, so that the IOM cautions against maintaining serum 25OHD concentrations above 50 ng/mL (125 nmol/L) (6). Experts call for more studies, and this statement cannot be more compelling than in pediatrics where data on the safety and long-term use of high vitamin D doses are limited.
In the late 1930s, treatment of infants with high vitamin D doses was reported to impair growth (63). The pediatric experience with stoss therapy indicates that single doses of 600 000 IU in infants with rickets were associated with high rates of hypercalcemia, whereas doses in the range of 100 000 to 200 000 IU had no ill effects (64–67). Hypercalcemia was also observed in a few infants who received single doses of 300 000 IU (65). More recently, a number of trials in healthy children tested vitamin D doses at the upper levels set by the IOM and with the goal of increasing serum concentrations above 30 ng/mL. Specifically, Gordon et al (68) randomized 40 infants and toddlers with 25OHD levels <20 ng/mL to either 2000 IU vitamin D2 or D3 daily or 50 000 IU D2 weekly for 6 weeks. Only a few children attained serum 25OHD levels above 100 ng/mL, although without a significant rise in serum calcium (68). In a birth cohort study that examined the effect of vitamin D on the risk for type I diabetes, infants treated with 2000 IU daily for 1 year suffered no undesired effects (69). However, serum 25OHD and calcium concentrations were not monitored. Two randomized dose-escalating trials used vitamin D3 doses up to 1600 IU/d in full-term healthy infants and documented a dose-dependent rise in 25OHD concentrations with increasing vitamin D supplementation (56, 59). The first one, a short-term study of 3 months that involved 113 newborns, showed no case of vitamin D excess and associated hypercalcemia or hypercalciuria (56). The second included 132 1-month-old term infants randomized to receive vitamin D3 at 400, 800, 1200, and 1600 IU/d for 11 months. Again, no harm was documented (59). High doses at 1600 IU/d did not result in improved skeletal outcomes despite mean 25OHD concentrations of 72 ng/mL (measured by liquid chromatography tandem mass spectrometry). Of interest, 25OHD concentrations were also measured for safety purposes during the course of the trial by an immunoassay, which provided readings frequently above 100 ng/mL resulting in premature discontinuation of this arm (59). These events underscore the variability among vitamin D assays. The authors concluded that the dose of 1600 IU/d "exceeded the healthy population target range of 50 ng/mL" without extra benefits.
Safety data of high vitamin D doses in older children and adolescents are quite limited. Vitamin D3 supplementation at 1000 IU daily for 8 weeks as part of a calcium absorption study in preteen children raised the average 25OHD value above 30 ng/mL but did not result in excess (70). The daily dose of 2000 IU D3 for 16 weeks caused no toxicity or adverse effects in adolescent boys and girls (71). Similarly, preteen and teen children who received the equivalent of 2000 IU daily for 1 year experienced no adverse effects. Vitamin D excess, ie, 25OHD concentrations >100 ng/mL, were reported in 1.5% of the subjects without associated hypercalcemia (57, 58). No recent study has addressed the safety of vitamin D supplementation with doses as high as 4000 IU daily in children. The current recommendations of 4000 IU/d as the upper tolerable vitamin D intake in children (Table 1) were based on a "variety of observations dated back to 1940" (5–7).
There are important lessons to be gleaned from vitamin D studies in children with various disorders that make them particularly vulnerable to vitamin D deficiency. In children and adolescents with inflammatory bowel disease and serum 25OHD levels <20 ng/mL, oral doses of 2000 IU vitamin D2 or D3 daily or 50 000 IU D2 weekly for 6 weeks raised levels above 20 ng/mL in 75–95% of subjects without toxicity (72). Similar findings were observed in another randomized trial of calcium and vitamin D supplementation in children with inflammatory bowel disease that used 50 000 IU of vitamin D2 monthly for 6 months (73). In cystic fibrosis, a few studies examined the effect of high vitamin D doses including 50 000 IU given daily or three times weekly (74–76). In these studies, daily intake of 50 000 IU vitamin D2 for 28 days was required to raise 25OHD concentrations above 30 ng/mL (76). Although no toxicity was reported, serum calcium concentrations were not monitored, and occasional subjects achieved 25OHD levels in the 250–310 ng/mL range (76). The immune effects of high vitamin D doses were tested in a few trials in children and adolescents infected with HIV. Vitamin D3 doses of 100 000 IU once every 2 months or 50 000 IU monthly did not result in excess or other toxicity (77–79). Similar findings were observed in preteen children treated with doses equivalent to 1600 IU daily (80).
Based on the present literature, vitamin D intake that approaches the upper ranges that are currently recommended caused no significant ill effects in children, although vitamin D excess was observed in some studies. However, the data are limited, and most of the studies are short term. Clearly, more extensive longitudinal data are required in both healthy and high-risk children to reinforce long-term use of high-dose vitamin D therapy. Furthermore, special attention should be paid to those with high calcium intake or an underlying condition that predisposes to hypercalcemia (such as Williams syndrome) because high vitamin D doses may provoke or exacerbate hypercalcemia in such cases.
Vitamin D Excess and Intoxication in Children: Definitions and Associations With Hypercalcemia
Serum concentrations exceeding 150 ng/mL (375 nmol/L) have been proposed by The Endocrine Society to define intoxication, whereas levels up to 100 ng/mL (250 nmol/L) are cited as safe for both children and adults (7). These cutoffs, which are based on a few older studies, are accepted by the PES (10). The specific vitamin D intake that results in excess or intoxication and the severity of corresponding hypercalcemia have not been clearly established in pediatrics. Hence, we looked into the current cases of intoxication to determine associations between serum 25OHD concentrations and hypercalcemia.
Reports on vitamin D intoxication in infants and young children (24–35) typically describe cases that received extremely large doses, in the range of 240 000 to 4 500 000 IU, or approximately 40 000 to 560 000 IU/kg. This intake resulted in serum 25OHD levels in the range of 250–670 ng/mL leading to severe hypercalcemia (24–35). Serum calcium concentrations in the range of 14–18 mg/dL (3.5–4.5 mmol/L) were reported, with occasional values as high as 20 mg/dL (Figure 2). Among these cases, there is significant variability in the amount of vitamin D administered and the resulting serum 25OHD concentrations. Furthermore, even with comparable serum 25OHD levels, the severity of hypercalcemia and symptomatology is unpredictable. Some of this variability may be explained by differences in vitamin D assay (81, 82) or length of time between ingestion and laboratory evaluation.
Figure 2.
Serum calcium concentrations plotted against 25OHD concentrations (left) and vitamin D intake (right) in infants and children with vitamin D intoxication. Data are derived from reported cases of intoxication (24–35). Depicted values are those on clinical presentation and before any therapeutic intervention. As patients came to medical attention at various time points after ingestion, the peak 25OHD concentrations may have been missed in some of these reports.
Figure 2.
Serum calcium concentrations plotted against 25OHD concentrations (left) and vitamin D intake (right) in infants and children with vitamin D intoxication. Data are derived from reported cases of intoxication (24–35). Depicted values are those on clinical presentation and before any therapeutic intervention. As patients came to medical attention at various time points after ingestion, the peak 25OHD concentrations may have been missed in some of these reports.
Beyond these cases, mild asymptomatic hypercalcemia associated with 25OHD concentrations above 75 ng/mL was recently reported in three young children with rickets who received therapy according to currently accepted guidelines and believed to be safe (36). These cases raise the concern that even recommended treatment doses have the potential for toxicity.
The variability in both serum 25OHD concentrations and resulting hypercalcemia for a given amount of vitamin D needs also to be interpreted in light of recent developments in genetics. Polymorphisms in genes that regulate the synthesis and hydroxylation of vitamin D as well as the synthesis of DBP have been shown to influence circulating 25OHD levels (83–85). Furthermore, defects in 24-hydroxylation caused by CYP24A1 loss-of-function mutations lead to decreased degradation of 1,25(OH)2D and the syndrome of idiopathic infantile hypercalcemia (IIH) (86–89). Affected individuals manifest increased sensitivity to vitamin D and may develop severe hypercalcemia and hypercalciuria, even with small vitamin D doses. Although this syndrome is rare, it exemplifies the role of genotype on vitamin D metabolism and response to supplementation. It also raises the question whether genetics should be taken into account when prescribing vitamin D, a subject that warrants further studies (90). Although we hope to have these answers in the future, at the moment the data support special consideration and evaluation of individual cases who respond to vitamin D supplementation in an unorthodox way.
Causes of Vitamin D Intoxication
Vitamin D intoxication is a rare event. However, the exact incidence is unclear because there are no systematic studies that have addressed this question.
Vitamin D intoxication from dietary sources has been reported over the last 20 years. Examples include accidental use of veterinary vitamin D concentrate that was mistaken as cooking oil (43) or excessive milk fortification (70 to 600 times above the state limit) by a home delivery dairy in the state of Massachusetts (91, 92). In adults, recent reports describe cases of accidental or intentional intake of excessive vitamin D caused by a variety of circumstances such as misinterpretation of prescription instruction or inappropriate prescription of excessive vitamin D doses for vague musculoskeletal complaints without monitoring 25OHD concentrations (14–23, 93, 94). In both the United States and Europe, intoxication has been reported after manufacturing errors of over-the-counter vitamin D formulations that contained substantially higher concentrations than claimed on the label (14, 17, 18). Because the production of such supplements is not overseen by the Food and Drug Administration, their content can be quite variable. In a recent study, just over one-half of over-the-counter preparations and only one-third of the compounded pills met the US Pharmacopeial Convention standards containing 90–110% of the active ingredient, whereas the rest had either higher or lower concentrations than expected (95).
Pediatric reports include an outbreak of hypercalciuria in the United Kingdom during the 1950s attributed to overfortification of infant formula (96). However, some of these cases are now attributed to other disorders, such as Williams syndrome or IIH caused by CYP24A1 mutations (86–89). Over the last decade, a number of infants with suspected rickets who were prescribed high vitamin D doses without prior measurement of 25OHD concentrations presented with severe life-threatening hypercalcemia (24, 29–32). Intoxication also occurred after intentional ingestion of products bought through the internet for "good health" (28) or dosing errors because of parent misinterpretation of the prescribed doses (25, 30). One case involved an infant who received a 30-fold overdose of vitamin D when the mother switched over-the-counter formulations from one that contained 400 IU/mL to another that contained 400 IU per drop. Unaware of the change in concentration, the mother continued to administer 1 mL, resulting in a daily vitamin D intake of 12 000 IU (33).
Symptoms and Diagnosis of Vitamin D Intoxication
Children with vitamin D intoxication present with symptoms of hypercalcemia, such as poor appetite, weight loss, abdominal pain, vomiting, constipation, polyuria, and polydipsia, and in severe cases, life-threatening dehydration (24–32). Because the complaints of hypercalcemia are nonspecific, symptoms can be present for prolonged periods before a child worsens and comes to medical attention. In some cases, the concentration of calcium in the glomerular filtrate may exceed its solubility, resulting in calcium precipitation in the renal tubules and nephrocalcinosis. This complication occurs in approximately 25% of patients with vitamin D intoxication, whereas in some pediatric series, vitamin D intoxication accounts for about 10% of all cases of nephrocalcinosis (97). Dehydration, decreased glomerular filtration rate, and nephrocalcinosis may all compromise renal function resulting in renal tubular acidosis and insufficiency. Metastatic vascular calcifications have also been reported (24–32).
The diagnosis of vitamin D intoxication is based on elevated serum 25OHD concentrations, which are associated with hypercalcemia or hypercalciuria, whereas serum 1,25(OH)2D levels are normal and PTH is suppressed. In contrast, hypercalcemia and hypercalciuria in the presence of normal serum 25OHD concentrations, increased 1,25(OH)2D levels, and suppressed PTH raise the suspicion of IIH. In such cases, 24,25-dihydroxyvitamin D concentrations are low or undetectable (86–89).
Treatment of Vitamin D Intoxication
Treatment efforts target children and adolescents with symptomatic hypercalcemia. As a first step, the source of vitamin D is removed, and the levels are allowed to decrease with time, an event that typically occurs over several weeks. Because vitamin D has a long half-life, serum 25OHD concentrations may occasionally continue to climb after discontinuation of vitamin D administration. Therefore, it is prudent to monitor symptoms and serum calcium concentrations for those asymptomatic patients with excessively high 25OHD levels.
The first line of therapy of hypercalcemia is iv hydration with normal saline at 1.5–2.5 maintenance to increase the glomerular filtration rate and calcium excretion. Intravenous hydration can be combined with specific diuretics that increase calcium excretion, such as loop diuretics. Furosemide at 1–2 mg/kg/d, as divided doses every 4–6 hours, is usually given. Thiazides, on the other hand, should be avoided because they increase calcium reabsorption at the distal tubule and, therefore, can further exacerbate hypercalcemia.
Glucocorticoids and calcitonin can be added if symptomatic hypercalcemia persists despite hydration and diuretics. Glucocorticoids prevent renal calcium reabsorption and inhibit the production and activity of 1,25(OH)2D, thus decreasing intestinal calcium absorption (98). Prednisone at 1–2 mg/kg/d (or 20–40 mg/m2/d), given as divided doses every 4 hours up to 2 weeks, has been used in children with vitamin D intoxication (34); onset of action is expected within 24–72 hours. Steroids can be combined with sc calcitonin, given at doses of 2–4 IU/kg every 6 to 12 hours, because of its a rapid effect on serum calcium. However, its therapeutic value is limited because of tachyphylaxis. Anaphylactic shock has also been reported (99).
Bone resorption is increased in vitamin D intoxication (100, 101), and therefore, antiresorptive therapy with bisphosphonates, such as pamidronate and alendronate, can successfully lower serum calcium levels in intoxicated children and adults (29–32, 100, 101). Doses of 5 or 10 mg alendronate or 0.5–1 mg/kg/dose of pamidronate have been used in pediatrics. In a recent series of six infants with vitamin D intoxication, oral alendronate achieved normocalcemia four times faster than steroids (34). Repeated courses over a period of weeks may be required in cases of persistent 25OHD elevations.
As a last resort, hemodialysis can lower serum calcium rapidly and can be used in life-threatening cases that do not respond to treatment with other means, such as acute or chronic renal failure or hypercalcemic crisis.
Conclusion and Recommendations
Awareness of the benefits of vitamin D has increased both in the medical community and the general population. As such, over-the-counter and prescribed vitamin D intake has followed suit. Unregulated supplements and formulations of vitamin D are readily available in pharmacies and health food stores alike. Because both underdosing and overtreatment with vitamin D can have considerable consequences, the need to regulate the available formulations must be recognized. Furthermore, vitamin D intoxication has been reported after misunderstanding of physician instructions, emphasizing the need for improved communication regarding dosing. Based on this most recent review of the literature, we suggest the following guidelines for the prevention and management of vitamin D excess and intoxication in pediatrics:
- 1.
Health care providers should be aware of the various vitamin D preparations and counsel patients on both desirable doses and variability among formulations.
- 2.
Empirical therapy of vitamin D deficiency with high vitamin D doses, such as stoss therapy, is discouraged without previous documentation of 25OHD concentrations and monitoring of 25OHD and serum calcium levels.
- 3.
Health care providers should consider monitoring vitamin D levels in infants and children receiving treatment doses at the upper ranges currently recommended (5, 7). Although there is insufficient evidence to guide the frequency of such testing, we suggest 25OHD measurements no more than every 6 months.
- 4.
Vitamin D excess or intoxication should be included in the differential of children who present with hypercalcemia or hypercalciuria.
- 5.
Serum calcium concentrations should be monitored in children with serum 25OHD concentrations above 150 ng/mL (375 nmol/L) measured by a reliable assay such as liquid chromatography tandem mass spectrometry.
- 6.
For asymptomatic patients with vitamin D intoxication, we suggest monitoring of clinical symptoms and serum 25OHD and calcium levels until serum 25OHD values start declining.
Acknowledgments
We thank the following members of the Pediatric Endocrine Society Drug and Therapeutics Committee for careful review of the manuscript and constructive comments: Patricia Fechner, Chirag Kapadia, Bradley Miller, Susan Myers, Todd Nebesio, Sripriya Raman, J. B. Quintos, David Weinstein, and Steven M. Willi.
No external funding was secured for this study.
Disclosure Summary: The authors have no conflicts to disclose.
Abbreviations
-
DBP
vitamin D binding protein
-
FGF-23
fibroblast growth factor 23
-
IIH
idiopathic infantile hypercalcemia
-
1,25(OH)2D
-
25OHD
-
VDR
References
1.
Kimball
S
, Fuleihan Gel-H Vieth R
Vitamin D: a growing perspective
.
Crit Rev Clin Lab Sci
.
2008
;
45
:
339
–
414
.
2.
Holick
MF
, Chen TC Lu Z Sauter E
Vitamin D and skin physiology: a D-lightful story
.
J Bone Miner Res
.
2007
;
22
:
V28
–
V33
.
3.
Holick
MF
.
The D-lightful vitamin D for child health
.
JPEN J Parenter Enteral Nutr
.
2012
;
36
(
1 suppl
):
9S
–
19S
.
4.
Saintonge
S
, Bang H Gerber LM
Implications of a new definition of vitamin D deficiency in a multiracial US adolescent population: the National Health and Nutrition Examination Survey III
.
Pediatrics
.
2009
;
123
(
3
):
797
–
803
.
5.
Institute of Medicine
.
Dietary reference intakes for calcium and vitamin D
.
Washington, DC
:
The National Academies Press
;
2011
.
6.
Ross
AC
, Manson JE Abrams SA
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
–
58
.
7.
Holick
MF
, Binkley NC Bischoff-Ferrari HA
Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline
.
J Clin Endocrinol Metab
.
2011
;
96
:
1911
–
1930
.
8.
Holick
MF
, Binkley NC Bischoff-Ferrari HA
Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited
.
J Clin Endocrinol Metab
.
2012
;
97
:
1153
–
1158
.
9.
Rosen
CJ
, Abrams SA Aloia JF
IOM committee members respond to Endocrine Society vitamin D guideline
.
J Clin Endocrinol Metab
.
2012
;
97
:
1146
–
1152
.
10.
Misra
M
, Pacaud D Petryk A Collett-Solberg PF Kappy M
Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society
.
Vitamin D deficiency in children and its management: review of current knowledge and recommendations
.
Pediatrics
.
2008
;
122
:
398
–
417
.
11.
Wagner
CL
, Greer FR
Prevention of rickets and vitamin D deficiency in infants, children, and adolescents
.
Pediatrics
.
2008
;
122
:
1142
–
1152
.
12.
EFSA Panel on Dietetic Products, Nutrition and Allergies
.
Scientific opinion on the tolerable upper intake level of vitamin D
.
EFSA J
.
2012
;
10
:
2813
.
13.
Braegger
C
, Campoy C Colomb V
Vitamin D in the healthy European paediatric population
.
J Pediatr Gastroenterol Nutr
.
2013
;
56
:
692
–
701
.
14.
Araki
T
, Holick MF Alfonso BD
Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States
.
J Clin Endocrinol Metab
.
2011
;
96
:
3603
–
3608
.
15.
Ashizawa
N
, Arakawa S Koide Y Toda G Seto S Yano K
Hypercalcemia due to vitamin D intoxication with clinical features mimicking acute myocardial infarction
.
Intern Med
.
2003
;
42
:
340
–
344
.
16.
Granado-Lorencio
F
, Rubio E Blanco-Navarro I Pérez-Sacristán B RodrÃguez-Pena R GarcÃa López FJ
Hypercalcemia, hypervitaminosis A and 3-epi-25-OH-D3 levels after consumption of an "over the counter" vitamin D remedy. A case report
.
Food Chem Toxicol
.
2012
;
50
:
2106
–
2108
.
17.
Kaptein
S
, Risselada AJ Boerma EC Egbers PH Nieboer P
Life-threatening complications of vitamin D intoxication due to over-the-counter supplements
.
Clin Toxicol (Phila)
.
2010
;
48
:
460
–
462
.
18.
Klontz
KC
, Acheson DW
Dietary supplement-induced vitamin D intoxication
.
N Engl J Med
.
2007
;
357
:
308
–
309
.
19.
Koutkia
P
, Chen TC Holick MF
Vitamin D intoxication associated with an over-the-counter supplement
.
N Engl J Med
.
2001
;
345
:
66
–
67
.
20.
Naik
MA
, Banday KA Najar MS Reshi AR Bhat MA
Vitamin D intoxication presenting as acute renal failure
.
Indian J Nephrol
.
2008
;
18
:
125
–
126
.
21.
Nordt
SP
, Williams SR Clark RF
Pharmacologic misadventure resulting in hypercalcemia from vitamin D intoxication
.
J Emerg Med
.
2002
;
22
:
302
–
303
.
22.
Pandita
KK
, Pandita S Hassan T
"Toxic" beef bone soup
.
Clin Cases Miner Bone Metab
.
2011
;
8
:
43
–
44
.
23.
Taskapan
H
, Vieth R Oreopoulos DG
Unusually prolonged vitamin D intoxication after discontinuation of vitamin D: possible role of primary hyperparathyroidism
.
Int Urol Nephrol
.
2008
;
40
:
801
–
805
.
24.
Atabek
ME
, Pirgon O Sert A
Oral alendronate therapy for severe vitamin D intoxication of the infant with nephrocalcinosis
.
J Pediatr Endocrinol Metab
.
2006
;
19
:
169
–
172
.
25.
Barrueto
F
Jr, Wang-Flores HH Howland MA Hoffman RS Nelson LS
Acute vitamin D intoxication in a child
.
Pediatrics
.
2005
;
116
:
e453
–
e456
.
26.
Bereket
A
, Erdogan T
Oral bisphosphonate therapy for vitamin D intoxication of the infant
.
Pediatrics
.
2003
;
111
:
899
–
901
.
27.
Chambellan-Tison
C
, Horen B Plat-Wilson G Moulin P Claudet I
Severe hypercalcemia due to vitamin D intoxication [in French]
.
Arch Pediatr
.
2007
;
14
:
1328
–
1332
.
28.
Chatterjee
M
, Speiser PW
Pamidronate treatment of hypercalcemia caused by vitamin D toxicity
.
J Pediatr Endocrinol Metab
.
2007
;
20
:
1241
–
1248
.
29.
Doneray
H
, Ozkan B Caner I Ozkan A Karakelleoglu C
Intragastric alendronate therapy in two infants with vitamin D intoxication: a new method
.
Clin Toxicol (Phila)
.
2008
;
46
:
300
–
302
.
30.
Ezgu
FS
, Buyan N Gündüz M Tümer L Okur I Hasanoglu A
Vitamin D intoxication and hypercalcaemia in an infant treated with pamidronate infusions
.
Eur J Pediatr
.
2004
;
163
:
163
–
165
.
31.
Hatun
S
, Cizmecioglu F
Use of alendronate in the treatment of vitamin D intoxication in infants
.
Turk J Pediatr
.
2005
;
47
:
373
–
375
.
32.
Orbak
Z
, Doneray H Keskin F Turgut A Alp H Karakelleoglu C
Vitamin D intoxication and therapy with alendronate (case report and review of literature)
.
Eur J Pediatr
.
2006
;
165
:
583
–
584
.
33.
Rajakumar
K
, Reis EC Holick MF
Dosing error with over-the-counter vitamin D supplement: a risk for vitamin D toxicity in infants
.
Clin Pediatr (Phila)
.
2013
;
52
:
82
–
85
.
34.
Sezer
RG
, Guran T Paketçi C Seren LP Bozaykut A Bereket A
Comparison of oral alendronate versus prednisolone in treatment of infants with vitamin D intoxication
.
Acta Paediatrica
.
2012
;
101
:
e122
–
e125
.
35.
Joshi
R
.
Hypercalcemia due to hypervitaminosis D: report of seven patients
.
J Trop Pediatr
.
2009
;
55
:
396
–
398
.
36.
Vanstone
MB
, Oberfield SE Shader L Ardeshirpour L Carpenter TO
Hypercalcemia in children receiving pharmacologic doses of vitamin D
.
Pediatrics
.
2012
;
129
:
e1060
–
e1063
.
37.
de Paula
FJ
, Rosen CJ
Vitamin D safety and requirements
.
Arch Biochem Biophys
.
2012
;
523
:
64
–
72
.
38.
Shroff
R
, Knott C Rees L
The virtues of vitamin D–but how much is too much?
Pediatr Nephrol
.
2010
;
25
:
1607
–
1620
.
39.
Jones
G
.
Extrarenal vitamin D activation and interactions between vitamin D2, vitamin D3, and vitamin D analogs
.
Annu Rev Nutr
.
2013
;
33
:
23
–
44
.
40.
Tripkovic
L
, Lambert H Hart K
Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis
.
Am J Clin Nutr
.
2012
;
95
:
1357
–
1364
.
41.
Deluca
HF
, Prahl JM Plum LA
1,25-Dihydroxyvitamin D is not responsible for toxicity caused by vitamin D or 25-hydroxyvitamin D
.
Arch Biochem Biophys
.
2011
;
505
:
226
–
230
.
42.
Jones
G
.
Pharmacokinetics of vitamin D toxicity
.
Am J Clin Nutr
.
2008
;
88
:
582S
–
586S
.
43.
Pettifor
JM
, Bikle DD Cavaleros M Zachen D Kamdar MC Ross FP
Serum levels of free 1,25-dihydroxyvitamin D in vitamin D toxicity
.
Ann Intern Med
.
1995
;
122
:
511
–
513
.
44.
Bouillon
R
, Van Cromphaut S Carmeliet G
Intestinal calcium absorption: molecular vitamin D mediated mechanisms
.
J Cell Biochem
.
2003
;
88
:
332
–
339
.
45.
Bell
TD
, Demay MB Burnett-Bowie SA
The biology and pathology of vitamin D control in bone
.
J Cell Biochem
.
2010
;
111
:
7
–
13
.
46.
Friedman
PA
, Gesek FA
Calcium transport in renal epithelial cells
.
Am J Physiol
.
1993
;
264
:
F181
–
F198
.
47.
Hoenderop
JG
, Nilius B Bindels RJ
Molecular mechanism of active Ca2+ reabsorption in the distal nephron
.
Annu Rev Physiol
.
2002
;
64
:
529
–
549
.
48.
Gesek
FA
, Friedman PA
On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells
.
J Clin Invest
.
1992
;
90
:
749
–
758
.
49.
Hebert
SC
.
Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney
.
Kidney Int
.
1996
;
50
:
2129
–
2139
.
50.
Wang
WH
, Lu M Hebert SC
Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL
.
Am J Physiol
.
1996
;
271
:
C103
–
C111
.
51.
Sands
JM
, Naruse M Baum M
Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct
.
J Clin Invest
.
1997
;
99
:
1399
–
1405
.
52.
Salusky
IB
.
Bone and mineral metabolism in childhood end-stage renal disease
.
Pediatr Clin North Am
.
1995
;
42
:
1531
–
1550
.
53.
Koch
M
, Kohnle M
Successful off-label use of cinacalcet HCl after standard therapy failure in a young man with pseudohypoparathyroidism Type 1b and vitamin D intoxication sequelae
.
Clin Nephrol
.
2008
;
70
:
439
–
444
.
54.
Schroth
M
, Dötsch J Dörr HG
Hypercalcemia and idiopathic hypoparathyroidism
.
J Clin Pharm Ther
.
2001
;
26
:
453
–
455
.
55.
Stickler
GB
, Morgenstern BZ
Hypophosphataemic rickets: final height and clinical symptoms in adults
.
Lancet
.
1989
;
2
:
902
–
905
.
56.
Holmlund-Suila
E
, Viljakainen H Hytinantti T Lamberg-Allardt C Andersson S Mäkitie O
High-dose vitamin d intervention in infants–effects on vitamin d status, calcium homeostasis, and bone strength
.
J Clin Endocrinol Metab
.
2012
;
97
:
4139
–
4147
.
57.
El-Hajj Fuleihan
G
, Nabulsi M Tamim H
Effect of vitamin D replacement on musculoskeletal parameters in school children: A randomized controlled trial
.
J Clin Endocrinol Metab
.
2006
;
91
:
405
–
412
.
58.
Maalouf
J
, Nabulsi M Vieth R
Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children
.
J Clin Endocrinol Metab
.
2008
;
93
:
2693
–
2701
.
59.
Gallo
S
, Comeau K Vanstone C
Effect of different dosages of oral vitamin D supplementation on vitamin D status in healthy, breastfed infants: a randomized trial
.
JAMA
.
2013
;
309
:
1785
–
1792
.
60.
Sanders
KM
, Stuart AL Williamson EJ
Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial [published correction appears in JAMA. 2010;303:2357]
.
JAMA
.
2010
;
303
:
1815
–
1822
.
61.
Smith
H
, Anderson F Raphael H Maslin P Crozier S Cooper C
Effect of annual intramuscular vitamin D on fracture risk in elderly men and women–a population-based, randomized, double-blind, placebo-controlled trial
.
Rheumatology
.
2007
;
46
:
1852
–
1857
.
62.
Sanders
KM
, Nicholson GC Ebeling PR
Is high dose vitamin D harmful?
Calcif Tissue Int
.
2013
;
92
:
191
–
206
.
63.
Jeans
PC
, Stearns G
The effect of vitamin D on linear growth in infancy: II. The effect of intakes above 1,800 U.S.P. units daily
.
J Pediatr
.
1938
;
13
:
730
–
740
.
64.
Markestad
T
, Hesse V Siebenhuner M
Intermittent high-dose vitamin D prophylaxis during infancy: effect on vitamin D metabolites, calcium, and phosphorus
.
Am J Clin Nutr
.
1987
;
46
:
652
–
658
.
65.
Cesur
Y
, Caksen H Gündem A Kirimi E Odabas D
Comparison of low and high dose of vitamin D treatment in nutritional vitamin D deficiency rickets
.
J Pediatr Endocrinol Metab
.
2003
;
16
:
1105
–
1109
.
66.
Shah
BR
, Finberg L
Single-day therapy for nutritional vitamin D-deficiency rickets: a preferred method
.
J Pediatr
.
1994
;
125
:
487
–
490
.
67.
Zeghoud
F
, Ben-Mekhbi H Djeghri N Garabédian M
Vitamin D prophylaxis during infancy: comparison of the long-term effects of three intermittent doses (15, 5, or 2.5 mg) on 25-hydroxyvitamin D concentrations
.
Am J Clin Nutr
.
1994
;
60
:
393
–
396
.
68.
Gordon
CM
, Williams AL Feldman HA
Treatment of hypovitaminosis D in infants and toddlers
.
J Clin Endocrinol Metab
.
2008
;
93
:
2716
–
2721
.
69.
Hyppönen
E
, Läärä E Reunanen A Järvelin MR Virtanen SM
Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study
.
Lancet
.
2001
;
358
:
1500
–
1503
.
70.
Abrams
SA
, Hawthorne KM Chen Z
Supplementation with 1000 IU vitamin D/d leads to parathyroid hormone suppression, but not increased fractional calcium absorption, in 4–8-y-old children: a double-blind randomized controlled trial
.
Am J Clin Nutr
.
2013
;
97
:
217
–
223
.
71.
Dong
Y
, Stallmann-Jorgensen IS Pollock NK
A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness
.
J Clin Endocrinol Metab
.
2010
;
95
:
4584
–
4591
.
72.
Pappa
HM
, Mitchell PD Jiang H
Treatment of vitamin D insufficiency in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing three regimens
.
J Clin Endocrinol Metab
.
2012
;
97
:
2134
–
2142
.
73.
Benchimol
EI
, Ward LM Gallagher JC
Effect of calcium and vitamin D supplementation on bone mineral density in children with inflammatory bowel disease
.
J Pediatr Gastroenterol Nutr
.
2007
;
45
:
538
–
545
.
74.
Boas
SR
, Hageman JR Ho LT Liveris M
Very high-dose ergocalciferol is effective for correcting vitamin D deficiency in children and young adults with cystic fibrosis
.
J Cyst Fibros
.
2009
;
8
:
270
–
272
.
75.
Green
D
, Carson K Leonard A
Current treatment recommendations for correcting vitamin D deficiency in pediatric patients with cystic fibrosis are inadequate
.
J Pediatr
.
2008
;
153
:
554
–
559
.
76.
Green
DM
, Leonard AR Paranjape SM Rosenstein BJ Zeitlin PL Mogayzel PJ
Transient effectiveness of vitamin D2 therapy in pediatric cystic fibrosis patients
.
J Cyst Fibros
.
2010
;
9
:
143
–
149
.
77.
Havens
PL
, Mulligan K Hazra R
Serum 25-hydroxyvitamin D response to vitamin D3 supplementation 50,000 IU monthly in youth with HIV-1 infection
.
J Clin Endocrinol Metab
.
2012
;
97
:
4004
–
4013
.
78.
Arpadi
SM
, McMahon D Abrams EJ
Effect of bimonthly supplementation with oral cholecalciferol on serum 25-hydroxyvitamin D concentrations in HIV-infected children and adolescents [published correction appears in Pediatrics. 2009;123:1437]
.
Pediatrics
.
2009
;
123
:
e121
–
e126
.
79.
Havens
PL
, Stephensen CB Hazra R
Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial
.
Clin Infect Dis
.
2012
;
54
:
1013
–
1025
.
80.
Kakalia
S
, Sochett EB Stephens D Assor E Read SE Bitnun A
Vitamin D supplementation and CD4 count in children infected with human immunodeficiency virus
.
J Pediatr
.
2011
;
159
:
951
–
957
.
81.
Fraser
WD
, Milan AM
Vitamin D assays: past and present debates, difficulties, and developments
.
Calcif Tissue Int
.
2013
;
92
:
118
–
127
.
82.
Singh
RJ
.
Quantitation of 25-OH-vitamin D (25OHD) using liquid tandem mass spectrometry (LC-MS-MS)
.
Methods Mol Biol
.
2010
;
603
:
509
–
517
.
83.
Wang
TJ
, Zhang F Richards JB
Common genetic determinants of vitamin D insufficiency: a genome-wide association study
.
Lancet
.
2010
;
376
:
180
–
188
.
84.
Sinotte
M
, Diorio C Bérubé S Pollak M Brisson J
Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women
.
Am J Clin Nutr
.
2009
;
89
:
634
–
640
.
85.
Hunter
D
, De Lange M Snieder H
Genetic contribution to bone metabolism, calcium excretion, and vitamin D and parathyroid hormone regulation
.
J Bone Miner Res
.
2001
;
16
:
371
–
378
.
86.
Schlingmann
KP
, Kaufmann M Weber S
Mutations in CYP24A1 and idiopathic infantile hypercalcemia
.
N Engl J Med
.
2011
;
365
:
410
–
421
.
87.
Dauber
A
, Nguyen TT Sochett E
Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia
.
J Clin Endocrinol Metab
.
2012
;
97
:
E268
–
E274
.
88.
Nguyen
M
, Boutignon H Mallet E
Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment
.
J Pediatr
.
2010
;
157
:
296
–
302
.
89.
Tebben
PJ
, Milliner DS Horst RL
Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy
.
J Clin Endocrinol Metab
.
2012
;
97
:
E423
–
E427
.
90.
Bouillon
R
.
Genetic and environmental determinants of vitamin D status
.
The Lancet
.
2010
;
376
:
148
–
149
.
91.
Blank
S
, Scanlon KS Sinks TH Lett S Falk H
An outbreak of hypervitaminosis D associated with the overfortification of milk from a home-delivery dairy
.
Am J Public Health
.
1995
;
85
:
656
–
659
.
92.
Jacobus
CH
, Holick MF Shao Q Chen TC Holm IA Kolodny JM Fuleihan GE Seely EW
Hypervitaminosis D associated with drinking milk
.
N Engl J Med
.
1992
;
326
:
1173
–
1177
.
93.
Koul
PA
, Ahmad SH Ahmad F Jan RA Shah SU Khan UH
Vitamin D toxicity in adults: a case series from an area with endemic hypovitaminosis D
.
Oman Med J
.
2011
;
26
:
201
–
204
.
94.
Lowe
H
, Cusano NE Binkley N Blaner WS Bilezikian JP
Vitamin D toxicity due to a commonly available "over the counter" remedy from the Dominican Republic
.
J Clin Endocrinol Metab
.
2011
;
96
:
291
–
295
.
95.
LeBlanc
ES
, Perrin N Johnson JD Ballatore A Hillier T
Over-the-counter and compounded vitamin D: is potency what we expect?
JAMA Intern Med
.
2013
;
173
:
585
–
586
.
96.
Samuel
HS
.
Vitamin D as a public health problem
.
Br Med J
.
1964
;
1
:
1654
–
1655
.
97.
Ammenti
A
, Pelizzoni A Cecconi M Molinari PP Montini G
Nephrocalcinosis in children: a retrospective multi-centre study
.
Acta Paediatrica
.
2009
;
98
:
1628
–
1631
.
98.
Sjöden
G
, Lindgren U
The effect of prednisolone on kidney calcification in vitamin D-treated rats
.
Calcif Tissue Int
.
1985
;
37
:
613
–
616
.
99.
Porcel
SL
, Cumplido JA de la Hoz B Cuevas M Losada E
Anaphylaxis to calcitonin
.
Allergol Immunopathol (Madr)
.
2000
;
28
:
243
–
245
.
100.
Gurkan
F
, Davutoglu M Bosnak M Ece A Dikici B Bilici M Haspolat K
Pamidronate treatment in acute vitamin D intoxication
.
J Endocrinol Invest
.
2004
;
27
:
680
–
682
.
101.
Selby
PL
, Davies M Marks JS Mawer EB
Vitamin D intoxication causes hypercalcaemia by increased bone resorption which responds to pamidronate
.
Clin Endocrinol (Oxf)
.
1995
;
43
:
531
–
536
.
Copyright © 2014 by The Endocrine Society
Source: https://academic.oup.com/jcem/article/99/4/1132/2537181
Leave a Comment