S P E C I A L F E A T U R E

C l i n i c a l R e v i e w

Vitamin D Supplementation and Risk of Toxicity in

Pediatrics: A Review of Current Literature

Maria G. Vogiatzi, Elka Jacobson-Dickman, Mark D. DeBoer, for the Drugs,

and Therapeutics Committee of The Pediatric Endocrine Society
Weill Cornell Medical College (M.G.V.), New York, New York 10065; SUNY Downstate Medical Center
(E.J.-D.), Brooklyn, New York 11203; and University of Virginia Health System (M.D.D.), Charlottesville,
Virginia 22908

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 hypervi-
taminosis using currently recommended doses have been reported in infants with rickets.

Conclusions: Although rare, cases of vitamin D intoxication that present with dramatic life-threat-
ening 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 Com-
mittee 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. (J Clin Endocrinol Metab 99: 11321141, 2014)

ver the past decade, there has been increased focus on recommended high vitamin D doses as well as reported
O the benefits of vitamin D on bone health and, po- cases of intoxications in pediatrics. Herein, we present
these outcomes and describe changes in vitamin D metab-
tentially, other disease states (13). Re-examination of op-
timal serum levels and multiple reports regarding high olism during intoxication, causes and symptoms of tox-
icity, and current management. Finally, we propose rec-
rates of vitamin D insufficiency and deficiency resulted in
ommendations for the monitoring of children who receive
revised recommendations for minimum vitamin D intake
vitamin D supplementation and those with evidence or
and new guidelines for treatment with high vitamin D suspicion of intoxication.
doses (4 13). In light of a growing body of research, recent
reports of vitamin D intoxication (14 36) and increased
Search Strategy
use of vitamin D supplementation, the Drugs and Thera-
peutics committee of the Pediatric Endocrine Society (PES) We performed a PubMed search through May 2013 of
undertook a systematic review of the safety of currently publications in English. We searched for vitamin D trials

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: DBP, vitamin D binding protein; FGF-23, fibroblast growth factor 23; IIH,
Printed in U.S.A. idiopathic infantile hypercalcemia; 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25OHD, 25-
Copyright 2014 by the Endocrine Society hydroxyvitamin D; VDR, vitamin D receptor.
Received September 30, 2013. Accepted January 13, 2014.
First Published Online January 23, 2014

1132 jcem.endojournals.org J Clin Endocrinol Metab, April 2014, 99(4):11321141 doi: 10.1210/jc.2013-3655

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doi: 10.1210/jc.2013-3655 jcem.endojournals.org 1133

Table 1. Vitamin D Preparations Available in the 7-dehydrocholesterol

United States, Showing Various Formulations Among Skin-sun exposure

Vitamin D Products Ergocalciferol or vit D2 Cholecalciferol or vit D3

(plants; supplements) (sh; supplements)
Ergocalciferol (vitamin D2)
Solution, 8000 IU/mL Requires prescription CYP2R1 & CYP27A1
Gel-cap, 50 000 IU Requires prescription Circulates bound to DBP No nega control re n
Tablets and capsules, eg, 200 5000 Over the counter Rapid uptake by adipose Conversion depends on
e substrate availability
IU
Cholecalciferol (vitamin D3) 24,25(OH)2D
CYP24A1
25OHD
Solution, eg, 400 and 5000 IU/mL Over the counter (circulates bound to DBP)
Drops, eg, 400 2000 IU/drop Over the counter
Tablets and capsules, eg, 200, 400, Over the counter
Calcium, phosphate
1000, 5000, 10 000, and 50 000 IU CYP27B1
Calcitriol (1,25-dihydroxycholecalciferol) FGF-23
Capsules, 0.25 and 0.5 g Requires prescription
Injectable solution, 1 or 2 g/mL Requires prescription PTH

C24 ox CYP24A1
pathway 1,25(OH)2D
in pediatrics. Publications that involved administration of
high vitamin D doses were reviewed, and information on VDR
vitamin D excess and toxicity (ie, hypercalcemia, hyper- (expressed in in nal epithelium
)
calciuria) was gathered. A similar PubMed search was per-
formed for cases of vitamin D intoxication in both adults
incr of calcium & phosphate
and pediatrics. All reported cases were reviewed, and data increased bone re n
on the causes, symptoms, biochemical abnormalities, and decr
metabolic, immune & other extra-skeletal eects
treatment were summarized for this report. The following
Figure 1. Diagram showing the main steps of vitamin D synthesis and
terms were used for the search: vitamin D excess, vi- metabolism. Cholecalciferol or vitamin D3 is produced from 7-
tamin D intoxication, hypervitaminosis, vitamin D dehydrocholesterol in the skin by exposure to sunlight. Vitamin D3
trial and child, vitamin D and hypercalcemia, vita- formed in this fashion as well as vitamin D3 and D2 taken from dietary
sources or commercially available supplements circulate in the
min D and hypercalciuria, calcitriol and intoxication, bloodstream bound to the DBP. They are converted to 25OHD in the
and calcitriol and hypercalcemia. 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
Vitamin D Metabolism and CYP27B1, which catalyzes the conversion of 25OHD to 1,25(OH)2D,
Pathophysiology During Vitamin D are depicted here (dotted arrows). Specifically, hypercalcemia inhibits
1,25(OH)2D synthesis, whereas hypocalcemia stimulates its production
Intoxication primarily due to an increase in PTH secretion. Hypophosphatemia and
PTH up-regulate CYP27B1 and increase renal production of
Vitamin D is available in two forms: ergocalciferol or vi- 1,25(OH)2D, whereas FGF-23 does the opposite. 1,25(OH)2D regulates
tamin D2 and cholecalciferol or vitamin D3. Vitamin D2 its own synthesis by down-regulating CYP27B1 activity and
suppressing PTH secretion. 1,25(OH)2D, the active vitamin D form,
and D3 are found as dietary supplements (Table 1) and in binds to the VDR to increase intestinal calcium absorption and exert
various food items naturally or after fortification. Vitamin the other vitamin D-related actions. Finally, 1,25(OH)2D increases
D3 is also generated from endogenous 7-dehydrocholes- CYP24A1 activity to catabolize 25OHD and 1,25(OH)2D to water-
soluble products that are excreted in the bile. The enzymes involved in
terol via sun exposure (1, 3) (Figure 1). each step, all cytochrome P450s (CYP), are shown in red.
The most important steps in vitamin D metabolism are
shown in Figure 1. Vitamin D hydroxylation to 25-hy- normal and do not correlate with serum calcium
droxyvitamin D (25OHD) in the liver depends on sub- concentrations.
strate availability, and therefore, 25OHD concentrations The body kinetics of vitamin D2 and D3 and 25OHD
rise in circulation during excess or intoxication (37). In have significant implications on symptomatology and
contrast, the subsequent 1-hydroxylation to 1,25-dihy- management during intoxication. Both vitamin D2 and D3
droxyvitamin D [1,25(OH)2D] in the kidney is tightly reg- are lipophilic and rapidly removed from the circulation by
ulated by PTH and under negative feedback by calcium, various tissues such as adipose and muscle where they may
phosphorus, fibroblast growth factor 23 (FGF-23), and remain stored for almost 2 months (13, 37, 38). Their
1,25(OH)2D itself (37). Consequently, in vitamin D in- metabolite, 25OHD, has high affinity for its transport
toxication, serum 1,25(OH)2D concentrations are usually protein, vitamin D binding protein (DBP), which results in

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1134 Vogiatzi et al Risk of Vitamin D Toxicity in Pediatrics J Clin Endocrinol Metab, April 2014, 99(4):11321141

a long half-life of 23 weeks. 25OHD is also lipophilic and of renal failure (52) or rare conditions such as hypopara-
can be stored in adipose tissue, remaining there for thyroidism, pseudohypoparathyroidism, or hypophos-
months, depending on the extent of vitamin D stores (13, phatemic rickets. Reports of intoxication caused by ex-
37, 38). Hence, vitamin D intoxication may take weeks to cessive calcitriol intake in these patients are extremely rare
resolve and require a prolonged course of treatment. Al- (5355). Hypercalcemia due to ingestion of calcitriol usu-
though both vitamin D2 and D3 undergo the same hy- ally lasts only 1 to 2 days because of the relatively short
droxylation steps and are equipotent in treating rickets, biological half-life of calcitriol. Thus, stopping the cal-
vitamin D2 has been found less toxic in animal studies and citriol and hydration with iv saline may be the only therapy
less efficacious in raising serum 25OHD concentration that is needed. Because calcitriol is not used as a supple-
than vitamin D3, when administered in the form of boluses ment or prescribed for the treatment of vitamin D defi-
(39). However, according to a recent meta-analysis, this ciency or insufficiency in children, we restrict our discus-
difference between D2 and D3 is lost with daily adminis- sion only to safety and toxicity related to vitamin D2 or D3.
tration, implying differences in the catabolism of these two
vitamin D forms (40). Pediatric data comparing the effi-
cacy of D2 and D3 are sparse, and hence, further studies are Current Recommendations on Daily
needed to confirm similar events in children. Vitamin D Intake and Treatment of
Animal studies and a limited number of observations Insufficiency or Deficiency
from human cases offer insight into alterations in vitamin
The most recent pediatric recommendations for daily re-
D metabolism during states of intoxication (37, 38, 41,
quirements, upper level intake, and vitamin D doses for the
42). Under physiological conditions, 1,25(OH)2D has
treatment of vitamin D insufficiency and deficiency are
high affinity for the vitamin D receptor (VDR), making it
presented in Table 2 (5, 7, 10 13). The table indicates
the active vitamin D metabolite. The precise vitamin D
considerable lack of consensus. The difference in recom-
metabolite responsible for the hypercalcemia during vita-
mendations reflects an ongoing debate about what con-
min D intoxication is still a matter of debate, although
stitutes optimal or adequate vitamin D levels for skeletal
evidence points to 25OHD as the main culprit (36 38).
health (513). The Endocrine Society with its published
During intoxication, 25OHD concentrations rise in the
guidelines advocates for 25OHD concentrations above 30
circulation and, at sufficiently high levels, can bind to
ng/mL (75 nmol/L) as ideal for bone health and defines
VDR and stimulate transcription (Figure 1). In addition,
deficiency as levels less than 20 ng/mL (50 nmol/L). The
the elevated 25OHD concentrations can compete and dis-
Institute of Medicine (IOM) accepts levels above 20 ng/mL
place 1,25(OH)2D from its transport protein DBP, thus
as sufficient. The debate is based primarily on data from
increasing the free and biological active component of
the adult literature. Only a limited number of studies have
1,25(OH)2D. Indeed, increased free 1,25(OH)2D concen-
evaluated the effect of vitamin D on bone mass at doses
trations with normal total 1,25(OH)2D levels were re-
that raise serum 25OHD concentrations above 30 ng/mL
ported in adults with vitamin D intoxication (43).
in pediatrics (56 59). The results are so far inconsistent.
During intoxication, high concentrations of either
Therefore, the higher vitamin D cutoffs of 30 ng/mL have
25OHD or free 1,25(OH)2D lead to hypercalcemia by
not been the official recommendation of the American
increasing intestinal calcium absorption and bone resorp-
Academy of Pediatrics, PES, or their European counter-
tion (44, 45). In turn, hypercalcemia increases the calcium parts (10 13). However, the discussion has generated
load that is filtered through the kidney, resulting in hy- confusion among treating physicians and the public about
percalciuria via a mechanism that involves increased cal- appropriate vitamin D levels and supplementation.
cium excretion in the distal tubule (46 48). Persistently
elevated serum calcium concentrations may also cause
polyuria and dehydration because of an inability of the
Safety Data of High Vitamin D Doses in
kidneys to appropriately concentrate urine. The mecha-
Pediatrics
nisms behind this renal concentration defect are incom-
pletely understood and may involve tubular interstitial Although vitamin D deficiency is detrimental for bone
injury because of calcium deposition in the medulla, health, the consequent approach that higher doses are pro-
down-regulation of aquaporin-2 water channel, or acti- tective and confer a reduced risk for disease has been chal-
vation of the calcium-sensing receptors (49 51). lenged by recent data in adults that indicate that high doses
In addition to various vitamin D2 and D3 preparations, of vitamin D raise the incidence of falls and fractures (60,
1,25(OH)2D or calcitriol is also available for the treatment 61). These events were linked to the mode of vitamin D
for the hypocalcemia and secondary hyperparathyroidism administration as stoss therapy, ie, as a single large bolus

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doi: 10.1210/jc.2013-3655 jcem.endojournals.org 1135

Table 2. Recent Pediatric Recommendations of Vitamin D Intake

Maintenance Vitamin D Doses

Endocrine Society for

Patients at Risk for
AAP and PES IOM Vitamin D Deficiencyb EFSA and ESPGHANd
Recommended Upper Upper Recommended Upper
Daily Dietary Level Daily Level Daily Level
Requirement, Allowance, Intake, Requirement, Intake, Supplementation, Intake,
Age IUa IU IU IU IU IU IU
c
0 6 mo 400 1000 400 1000 2000 400 1000
c
6 12 mo 400 1500 400 1000 2000 400 1000
13 y 400 600 2500 600 1000 4000 None 2000
48 y 400 600 3000 600 1000 4000 None 2000
9 10 y 400 600 4000 600 1000 4000 None 2000
1118 y 400 600 4000 600 1000 4000 None 4000
Treatment of vitamin D deficiency or insufficiency

Age PES Endocrine Societyb

0 1 mo 1000 IU/d for 2 4 wk 2000 IU/d or 50 000 IU/wk for 6 wk
112 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.

compared to smaller intermittent doses (62). Beyond skel- In a birth cohort study that examined the effect of vitamin
etal health, similar curvilinear or U-shaped response has D on the risk for type I diabetes, infants treated with 2000
been described for other vitamin D outcomes, including IU daily for 1 year suffered no undesired effects (69). How-
all-cause mortality, cardiovascular disease, and selected ever, serum 25OHD and calcium concentrations were not
cancers, so that the IOM cautions against maintaining monitored. Two randomized dose-escalating trials used
serum 25OHD concentrations above 50 ng/mL (125 vitamin D3 doses up to 1600 IU/d in full-term healthy
nmol/L) (6). Experts call for more studies, and this state- infants and documented a dose-dependent rise in 25OHD
ment cannot be more compelling than in pediatrics where concentrations with increasing vitamin D supplementa-
data on the safety and long-term use of high vitamin D tion (56, 59). The first one, a short-term study of 3 months
doses are limited. that involved 113 newborns, showed no case of vitamin D
In the late 1930s, treatment of infants with high vitamin excess and associated hypercalcemia or hypercalciuria
D doses was reported to impair growth (63). The pediatric (56). The second included 132 1-month-old term infants
experience with stoss therapy indicates that single doses of randomized to receive vitamin D3 at 400, 800, 1200, and
600 000 IU in infants with rickets were associated with 1600 IU/d for 11 months. Again, no harm was docu-
high rates of hypercalcemia, whereas doses in the range of mented (59). High doses at 1600 IU/d did not result in
100 000 to 200 000 IU had no ill effects (64 67). Hyper- improved skeletal outcomes despite mean 25OHD con-
calcemia was also observed in a few infants who received centrations of 72 ng/mL (measured by liquid chromatog-
single doses of 300 000 IU (65). More recently, a number raphy tandem mass spectrometry). Of interest, 25OHD
of trials in healthy children tested vitamin D doses at the concentrations were also measured for safety purposes
upper levels set by the IOM and with the goal of increasing during the course of the trial by an immunoassay, which
serum concentrations above 30 ng/mL. Specifically, Gor- provided readings frequently above 100 ng/mL resulting
don et al (68) randomized 40 infants and toddlers with in premature discontinuation of this arm (59). These
25OHD levels 20 ng/mL to either 2000 IU vitamin D2 or events underscore the variability among vitamin D assays.
D3 daily or 50 000 IU D2 weekly for 6 weeks. Only a few The authors concluded that the dose of 1600 IU/d ex-
children attained serum 25OHD levels above 100 ng/mL, ceeded the healthy population target range of 50 ng/mL
although without a significant rise in serum calcium (68). without extra benefits.

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1136 Vogiatzi et al Risk of Vitamin D Toxicity in Pediatrics
Safety data of high vitamin D doses in older children
and adolescents are quite limited. Vitamin D3 supplemen-
tation 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 concentra-
tions 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 supplemen-
tation with doses as high as 4000 IU daily in children. The
current recommendations of 4000 IU/d as the upper tol-
erable vitamin D intake in children (Table 1) were based
on a variety of observations dated back to 1940 (57).
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 7595% of subjects
without toxicity (72). Similar findings were observed in
another randomized trial of calcium and vitamin D sup-
plementation 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 im-
mune 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 (7779).
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 recom-
mended caused no significant ill effects in children, al-
though 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 rein-
force long-term use of high-dose vitamin D therapy. Fur-
thermore, special attention should be paid to those with
high calcium intake or an underlying condition that pre-
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J Clin Endocrinol Metab, April 2014, 99(4):11321141
disposes 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 estab-
lished 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 ex-
tremely large doses, in the range of 240 000 to 4 500 000
IU, or approximately 40 000 to 560 000 IU/kg. This in-
take resulted in serum 25OHD levels in the range of 250
670 ng/mL leading to severe hypercalcemia (24 35). Se-
rum 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 ad-
ministered and the resulting serum 25OHD concentra-
tions. 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.
Beyond these cases, mild asymptomatic hypercalcemia as-
sociated with 25OHD concentrations above 75 ng/mL was re-
cently reported in three young children with rickets who re-
ceived 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 develop-
ments 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-hy-
droxylation caused by CYP24A1 loss-of-function muta-
tions lead to decreased degradation of 1,25(OH)2D and
the syndrome of idiopathic infantile hypercalcemia (IIH)
doi: 10.1210/jc.2013-3655 jcem.endojournals.org 1137

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.

(86 89). Affected individuals manifest increased sensitiv- after manufacturing errors of over-the-counter vitamin D
ity to vitamin D and may develop severe hypercalcemia formulations that contained substantially higher concen-
and hypercalciuria, even with small vitamin D doses. Al- trations than claimed on the label (14, 17, 18). Because the
though this syndrome is rare, it exemplifies the role of production of such supplements is not overseen by the
genotype on vitamin D metabolism and response to sup- Food and Drug Administration, their content can be quite
plementation. It also raises the question whether genetics variable. In a recent study, just over one-half of over-the-
should be taken into account when prescribing vitamin D, counter preparations and only one-third of the com-
a subject that warrants further studies (90). Although we pounded pills met the US Pharmacopeial Convention stan-
hope to have these answers in the future, at the moment the dards containing 90 110% of the active ingredient,
data support special consideration and evaluation of in- whereas the rest had either higher or lower concentrations
dividual cases who respond to vitamin D supplementation than expected (95).
in an unorthodox way. Pediatric reports include an outbreak of hypercalciuria
in the United Kingdom during the 1950s attributed to
overfortification of infant formula (96). However, some of
Causes of Vitamin D Intoxication these cases are now attributed to other disorders, such as
Vitamin D intoxication is a rare event. However, the exact Williams syndrome or IIH caused by CYP24A1 mutations
incidence is unclear because there are no systematic studies (86 89). Over the last decade, a number of infants with
that have addressed this question. suspected rickets who were prescribed high vitamin D
Vitamin D intoxication from dietary sources has been doses without prior measurement of 25OHD concentra-
reported over the last 20 years. Examples include acciden- tions presented with severe life-threatening hypercalcemia
tal use of veterinary vitamin D concentrate that was mis- (24, 29 32). Intoxication also occurred after intentional
taken as cooking oil (43) or excessive milk fortification (70 ingestion of products bought through the internet for
to 600 times above the state limit) by a home delivery dairy good health (28) or dosing errors because of parent
in the state of Massachusetts (91, 92). In adults, recent misinterpretation of the prescribed doses (25, 30). One
reports describe cases of accidental or intentional intake of case involved an infant who received a 30-fold overdose of
excessive vitamin D caused by a variety of circumstances vitamin D when the mother switched over-the-counter
such as misinterpretation of prescription instruction or formulations from one that contained 400 IU/mL to an-
inappropriate prescription of excessive vitamin D doses other that contained 400 IU per drop. Unaware of the
for vague musculoskeletal complaints without monitoring change in concentration, the mother continued to admin-
25OHD concentrations (14 23, 93, 94). In both the ister 1 mL, resulting in a daily vitamin D intake of 12 000
United States and Europe, intoxication has been reported IU (33).

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1138 Vogiatzi et al Risk of Vitamin D Toxicity in Pediatrics J Clin Endocrinol Metab, April 2014, 99(4):11321141

Symptoms and Diagnosis of Vitamin D
Intoxication
Children with vitamin D intoxication present with symp-
toms of hypercalcemia, such as poor appetite, weight loss,
abdominal pain, vomiting, constipation, polyuria, and
polydipsia, and in severe cases, life-threatening dehydra-
tion (24 32). Because the complaints of hypercalcemia
are nonspecific, symptoms can be present for prolonged
periods before a child worsens and comes to medical at-
tention. In some cases, the concentration of calcium in the
glomerular filtrate may exceed its solubility, resulting in
calcium precipitation in the renal tubules and nephrocal-
cinosis. 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 tu-
bular acidosis and insufficiency. Metastatic vascular cal-
cifications have also been reported (24 32).
The diagnosis of vitamin D intoxication is based on
elevated serum 25OHD concentrations, which are asso-
ciated with hypercalcemia or hypercalciuria, whereas se-
rum 1,25(OH)2D levels are normal and PTH is sup-
pressed. In contrast, hypercalcemia and hypercalciuria in
the presence of normal serum 25OHD concentrations, in-
creased 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 de-
crease 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 1.52.5 maintenance to increase the
glomerular filtration rate and calcium excretion. Intrave-
nous hydration can be combined with specific diuretics
that increase calcium excretion, such as loop diuretics.
Furosemide at 12 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 reab-
sorption at the distal tubule and, therefore, can further
exacerbate hypercalcemia.
Glucocorticoids and calcitonin can be added if symp-
tomatic hypercalcemia persists despite hydration and di-
uretics. Glucocorticoids prevent renal calcium reabsorp-
tion and inhibit the production and activity of
1,25(OH)2D, thus decreasing intestinal calcium absorp-
tion (98). Prednisone at 12 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 bi-
sphosphonates, such as pamidronate and alendronate, can
successfully lower serum calcium levels in intoxicated chil-
dren and adults (29 32, 100, 101). Doses of 5 or 10 mg
alendronate or 0.51 mg/kg/dose of pamidronate have
been used in pediatrics. In a recent series of six infants with
vitamin D intoxication, oral alendronate achieved nor-
mocalcemia 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 formu-
lations 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 formula-
tions must be recognized. Furthermore, vitamin D intox-
ication has been reported after misunderstanding of phy-
sician instructions, emphasizing the need for improved
communication regarding dosing. Based on this most re-
cent review of the literature, we suggest the following
guidelines for the prevention and management of vitamin
D excess and intoxication in pediatrics:

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doi: 10.1210/jc.2013-3655 jcem.endojournals.org 1139

1. Health care providers should be aware of the various of vitamin D deficiency in a multiracial US adolescent population:
the National Health and Nutrition Examination Survey III. Pedi-
vitamin D preparations and counsel patients on both
atrics. 2009;123(3):797 803.
desirable doses and variability among formulations. 5. Institute of Medicine. Dietary reference intakes for calcium and
2. Empirical therapy of vitamin D deficiency with high vitamin D. Washington, DC: The National Academies Press; 2011.
vitamin D doses, such as stoss therapy, is discour- 6. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary
reference intakes for calcium and vitamin D from the Institute of
aged without previous documentation of 25OHD Medicine: what clinicians need to know. J Clin Endocrinol Metab.
concentrations and monitoring of 25OHD and se- 2011;96:5358.
rum calcium levels. 7. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation,
treatment, and prevention of vitamin D deficiency: an Endocrine
3. Health care providers should consider monitoring
Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;
vitamin D levels in infants and children receiving 96:19111930.
treatment doses at the upper ranges currently rec- 8. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Guidelines for
ommended (5, 7). Although there is insufficient ev- preventing and treating vitamin D deficiency and insufficiency re-
visited. J Clin Endocrinol Metab. 2012;97:11531158.
idence to guide the frequency of such testing, we 9. Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members
suggest 25OHD measurements no more than every respond to Endocrine Society vitamin D guideline. J Clin Endocri-
6 months. nol Metab. 2012;97:1146 1152.
10. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M, Drug
4. Vitamin D excess or intoxication should be included
and Therapeutics Committee of the Lawson Wilkins Pediatric En-
in the differential of children who present with hy- docrine Society. Vitamin D deficiency in children and its manage-
percalcemia or hypercalciuria. ment: review of current knowledge and recommendations. Pedi-
5. Serum calcium concentrations should be monitored atrics. 2008;122:398 417.
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in children with serum 25OHD concentrations ciency in infants, children, and adolescents. Pediatrics. 2008;122:
above 150 ng/mL (375 nmol/L) measured by a reli- 11421152.
able assay such as liquid chromatography tandem 12. EFSA Panel on Dietetic Products, Nutrition and Allergies. Scientific
opinion on the tolerable upper intake level of vitamin D. EFSA J.
mass spectrometry.
2012;10:2813.
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and serum 25OHD and calcium levels until serum 2013;56:692701.
14. Araki T, Holick MF, Alfonso BD, et al. Vitamin D intoxication
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rors of two dietary supplements made in the United States. J Clin
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15. Ashizawa N, Arakawa S, Koide Y, Toda G, Seto S, Yano K. Hy-
Acknowledgments percalcemia due to vitamin D intoxication with clinical features
mimicking acute myocardial infarction. Intern Med. 2003;42:
We thank the following members of the Pediatric Endocrine So-
340 344.
ciety Drug and Therapeutics Committee for careful review of the 16. Granado-Lorencio F, Rubio E, Blanco-Navarro I, Prez-Sacristn
manuscript and constructive comments: Patricia Fechner, Chi- B, Rodrguez-Pena R, Garca Lpez FJ. Hypercalcemia, hypervi-
rag Kapadia, Bradley Miller, Susan Myers, Todd Nebesio, taminosis A and 3-epi-25-OH-D3 levels after consumption of an
Sripriya Raman, J. B. Quintos, David Weinstein, and Steven M. over the counter vitamin D remedy. A case report. Food Chem
Toxicol. 2012;50:2106 2108.
Willi.
17. Kaptein S, Risselada AJ, Boerma EC, Egbers PH, Nieboer P. Life-
threatening complications of vitamin D intoxication due to over-
Address all correspondence and requests for reprints to: the-counter supplements. Clin Toxicol (Phila). 2010;48:460 462.
Maria Vogiatzi, MD, Weill Cornell Medical College, Pediatric 18. Klontz KC, Acheson DW. Dietary supplement-induced vitamin D
Endocrinology, Box 103, 525 East 68th Street, New York, NY intoxication. N Engl J Med. 2007;357:308 309.
10065. E-mail: mvogiatz@med.cornell.edu. 19. Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associ-
No external funding was secured for this study. ated with an over-the-counter supplement. N Engl J Med. 2001;
Disclosure Summary: The authors have no conflicts to 345:66 67.
disclose. 20. Naik MA, Banday KA, Najar MS, Reshi AR, Bhat MA. Vitamin D
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