Vitamin D deficiency is
considered to be the most common nutritional
deficiency [1] and also one of the most common
undiagnosed medical conditions in the world.
Vitamin D has evolved into a hormone that is
active throughout the body not only to regulate
calcium and bone metabolism but also to reduce
the risk of chronic diseases including auto
immune diseases, malignancies, cardiovascular
and infectious diseases. It has been estimated
that 1 billion people worldwide have vitamin D
deficiency or insufficiency [2]. Though majority
of population in India lives in areas receiving
ample sunlight throughout the year, vitamin D
deficiency is very common in all the age groups
and both the sexes across the country [3-5].
Over the last two decades,
understanding of vitamin D synthesis and its
function has changed remarkably. This led us to
re-examine the traditional concepts and current
recommendations for vitamin D supplementation,
sun light exposure and revised management
strategies for deficiency. In this review, we
discuss the current knowledge on diagnosis,
prevention and treatment of vitamin D
deficiency.
Etiology of Vitamin D
Deficiency
The prevalence of vitamin D
deficiency is 50-90 % in the Indian subcontinent
and is attributed to low dietary calcium along
with skin color and changing lifestyle [3]. Some
postulate that a deficiency of dietary calcium
rather than vitamin D deficiency is responsible
for rickets after infancy, supported by the fact
that they have a better response to treatment
with calcium alone or in combination with
vitamin D rather than vitamin D alone [6].
Vitamin D deficiency is observed among breastfed
infants at one end with dietary calcium
deficiency in older children at the other end.
Between these two extremes, it is likely that
vitamin D insufficiency and decreased calcium
intake or high phytate intake combine to induce
vitamin D deficiency and rickets, which may be
the most frequent cause of rickets globally [7]
(Table I).
TABLE I Etiology of Vitamin D Deficiency [19]
|
Decreased vitamin D synthesis |
Skin pigmentation, physical agents
blocking UVR exposure, clothing,
latitude, season, air pollution, cloud
cover, altitude |
|
Decreased nutritional intake of vitamin
|
Strict vegan diet |
|
Age and physiology related |
Elderly, obese and institutionalised |
|
Decreased maternal vitamin D stores |
Exclusive breast feeding |
|
Malabsorption |
Celiac disease, pancreatic insufficiency
(cystic fibrosis), biliary obstruction (biliary
atresia) |
|
Decreased synthesis |
Chronic liver disease |
|
Increased degradation of 25 (OH) D |
Drugs such as rifampicin, isoniazid,
anticonvulsants, glucocorticoids. |
Vitamin D deficiency is
common in infancy due to several factors such as
– decreased dietary intake, decreased cutaneous
synthesis (because of cultural and religious
practices, seasonal variation, fear of cancer,
and practice of not taking the child out,
increase in pigmentation), increasing rate of
exclusive breast feeding, and low maternal
vitamin D.
Definition of Vitamin D
Status
Definitions of vitamin D
status have been intensely debated by clinicians
and researchers alike. Vitamin D deficiency is
defined as serum levels of 25(OH)D less than 20
ng/dL whereas 21- 29 ng/dL is considered to be
insufficient by US Endocrine Society. This has
been done to utilize full advantage of all the
health benefits of vitamin D [8] (Table
II). Chapuy, et al. [9] and Malabanan,
et al. [10] concluded that those who had
25(OH)D more than 20 ng/dL had no significant
change in their PTH levels. Recently IOM
(Institute of Medicine) remarked that available
scientific evidence supports a key role of
calcium and Vitamin D in skeletal health is
consistent with cause and effect relationship
whereas evidence supporting the role of vitamin
D deficiency in extra skeletal health outcomes
is inconsistent, inconclusive and insufficient
to be considered more than "hypothesis of
emerging interest" [11]. A variety of
definitions exist in the literature [12-16].
TABLE II Vitamin D Status in Relation to 25 (OH) D Levels
|
Vitamin D status |
Levels |
|
US IOM classification [17] |
|
Severe deficiency |
<5 ng/mL |
|
Deficiency |
<15 ng/mL |
|
Sufficiency |
>20 ng/mL |
|
Risk of toxicity |
>50 ng/mL |
|
US Endocrine Society classification
[8] |
|
Deficiency |
<20 ng/mL (50 nmol/L) |
|
Insufficiency |
21-29 ng/mL (52.5–72.5) nmol/liter |
|
Sufficiency |
>30 ng/mL |
|
Toxicity |
>150 ng/mL |
|
1mcg = 40IU; 0.025 mcg is 1 IU |
It has been estimated the
serum 25(OH)D levels of 20 ng/dL meet the needs
of at least 97.5% of population across all age
groups in developed countries [17]. Hence it has
been concluded by IOM that 25(OH)D levels >20ng/dL
indicates vitamin D sufficiency [18]. Levels of
25(OH)D 15 ng/dL or less are considered as
deficiency and 5 ng/dL or less are considered as
severe deficiency [19,20].
Sufficient data are not
available to define the upper limits of normal
or dose levels above which toxicity occurs.
Previously it was thought that vitamin D
intoxication does not occur until serum levels
of 25(OH)D reach 150 to 200 ng/dL [21,22].
Recently the IOM concluded that the serum
concentrations of 25(OH)D above 30 ng/dL are not
consistently associated with increased benefits
and risks have been identified at higher levels
above 50 ng/dL [17]. There is an urgent need for
consensus derived cut off points for serum
levels of 25 (OH)D to define vitamin D status in
order to avoid problems of both over-and
under-treatment (Table II).
Measurement of Vitamin D
Levels
25(OH)D is the major
circulating form of vitamin D with a half-life
of 2-3 weeks and its levels are the best
available indicators of vitamin D status.
Although 1, 25 (OH)
2D
(calcitriol) is the active form, it has a
half-life of only 4 hours and it is not a good
indicator of vitamin D stores because (i)
vitamin D deficiency can cause PTH elevation
that induces increased 1- alpha hydroxylase
activity, which results in normal or increased
levels of 1,25 (OH)2
D; and (ii) it circulates at the
concentration that is 100-1000 fold less than
25(OH)D [23].
The assays used to measure
25(OH)D levels should be capable of measuring
both D2 (ergocalciferol) and D3 (cholecalciferol)
derivatives. The total 25(OH) D [25(OH)D2 and
25(OH)D3] levels measured by high performance
liquid chromatography (HPLC) or tandem mass
spectrometry have been reported as the gold
standard for vitamin D metabolite assay [19].
Other methods of measurement include
radio-immune assays using monoclonal antibodies
to 25(OH)D and chemiluminescent protein binding
assay.
When to Treat?: Vitamin D
therapy is necessary for infants and children
who manifest clinical features of hypocalcemia
as a result of vitamin D deficiency or rickets
and when vitamin D levels are in the deficient
range even if asymptomatic [19]. The three
stages of vitamin D deficiency are outlined in
Table III.
TABLE III Biochemical Markers of Vitamin D Deficiency
|
Stages |
Serum calcium |
Serum phosphorus |
ALP |
PTH |
25 (OH)D |
1,25 (OH)D3 |
Radiography |
|
Early |
N /¯ |
¯ |
|
|
¯ |
N |
Osteopenia |
|
Moderate |
N /¯ |
¯ |
|
|
¯ |
|
Rachitic changes 1+ |
|
Severe |
¯¯ |
¯ |
|
|
¯¯ |
/ N / |
Rachitic changes 2+ |
|
ALP: Alkaline phosphatase; PTH: Parathrmone; 25(OH)D: 25-hydroxy vitamin D; 1,25 (OH) D3: 1,25-dihydroxy vitamin D3. |
Recommended Treatment Regimen
Several therapeutic regimens
have been attempted for deficiency of vitamin D.
Short term administration of vitamin D2 or D3
2000 units daily or vitamin D2 50,000 units
weekly has yielded equivalent outcomes in the
treatment of hypovitaminosis D in young children
[24]. Common recommendations include vitamin D
1000-5000 units/day for several weeks or single
IM injection of 6 lakh units (Stoss therapy) or
50,000U of vitamin D2 weekly for 8 weeks. The
total dose of vitamin D has been reported to be
more predictive of vitamin D sufficiency rather
than the frequency of dosing (daily, weekly or
monthly) [24]. Therefore, treatment regimens for
a given patient can be individualized to ensure
compliance, since no difference in the efficacy
or safety was reported in these common treatment
regimens [24].
Lack of compliance is an
important cause for lack of response to therapy
and an option to prevent this is to administer
high dose of 1,00,000 to 6,00,000 IU over 1-5
days [25,26]. Doses of 10000 units /kg [27]
instead of smaller doses over longer period
followed by maintenance dose have also been
reported to be effective. Shah and Finberg have
successfully administered 1 lakh IU every 2
hours over 12 hours period [25]. Another
advantage of Stoss therapy is that vitamin D is
efficiently stored in adipose tissue and muscle
and is continuously converted into active form (Table
IV).
TABLE IV Treatment Regimens for Vitamin D Deficiency
Group
|
Daily regimen
(8-12 weeks) |
Weekly regimen
(8-12 weeks) |
Stoss therapy (oral or IM)
|
Maintenance
|
|
< 1 mo old |
1,000 IU |
50,000 IU |
- |
400-1,000 IU |
|
1-12 mo old |
1,000-5000 IU |
50,000 IU |
1 lakh -6 lakhs units over 1-5 days
|
400- 1,000 IU |
|
|
|
|
(Preferably 3 lakh) |
|
|
1-18 y old |
5,000 IU |
50,000 IU |
3-6 lakh units over 1-5 days
|
600-1,000 IU |
|
>18 y old |
6,000 IU |
50,000 IU |
3-6 lakh units over 1-5 days
|
1,500-2,000 IU |
|
Obese patients, patients |
6,000-10,000 |
|
|
3,000-6,000 IU |
|
with malabsorption |
IU/ day |
|
|
|
|
syndrome, or on |
|
|
|
|
|
medications affecting |
|
|
|
|
|
vitamin D |
|
|
|
|
|
* To convert (IU) to mcg of
calciferol divide by 40.
|
Stoss therapy regimens with
large oral or parenteral dose of vitamin D3 has
been shown to cause increased and sustained
higher levels of 25(OH)D levels, especially the
regimen with 6 lakh IU. Stoss therapy is safe
and can lead to hypercalcemia only at very high
doses. Doses of 1,50,000 to 3,00,000 IU can be
effective with less side effects [28].
After the completion of
treatment, vitamin D has to be continued at
800-1000 IU/day till serum alkaline phosphatase
returns to normal, followed by RDA for age
[29].Vitamin D supplements are available as both
vitamin D2 and D3. Although traditionally D2 and
D3 have been considered to be equipotent,
studies have shown that D3 may be at least 3
times more potent than D2 [30]. Hence
supplements containing D3 may be preferred.
Calcium supplementation:
Even for children who are not frankly
hypocalcemic, calcium supplements are important
for avoiding subsequent hypocalcaemia from a
decrease in bone demineralization and an
increase in bone mineralization as PTH levels
normalize (hungry bone syndrome), particularly
with Stoss therapy. Supplementation of elemental
calcium in a dose of 30-75mg/kg/day in 3 divided
doses is recommended. High doses of calcium are
necessary early in the course of therapy, after
which doses are reduced by half for next 1-2
weeks. Once vitamin D supplements have been
decreased to 400 IU /day with normal PTH and
25(OH)D, calcium supplementation is usually not
necessary [19]. Administration of parenteral
calcium is essential for symptomatic
hypocalcemia (10-20 mg of elemental calcium/kg
IV slowly over 5-10 minutes) and is usually
given as 1-2 mL/kg of calcium gluconate. This
becomes necessary in case of manifest tetany or
convulsions and repeat boluses may also be
necessary on occasion. Calcium levels should
thereafter be maintained with oral calcium
supplements.
Calcium preparations:
Calcium carbonate and citrate are the most
common forms of calcium supplements. Calcium
carbonate, the most effective form should be
taken with a meal to ensure optimal absorption.
Calcium citrate can be taken without food and is
the supplement of choice for individuals with
achlorhydria or who are taking histamine-2
blockers or Proton Pump Inhibitors since calcium
carbonate needs acid environment for calcium
absorption. Calcium lactate and gluconate are
less concentrated form of calcium and are not
practical oral supplements. The maximal dose of
elemental calcium that should be taken at a time
is 500 mg. Tolerable upper limit is 2500 mg/day
for ages 1 year and above.
In addition to calcium
supplements, 1, 25 (OH)
2D
may be necessary till calcium levels normalize (Table
V). Calcitriol is not used for Stoss
therapy, since it has a short half-life, does
not build up vitamin D stores, and is expensive.
In higher doses it may cause hypercalcemia
because of its rapid onset of action which
limits the amount that can be administered.
TABLE V Management of
Hypocalcaemia Due to Vitamin D Deficiency
|
Symptomatic hypocalcaemia due to
vitamin D deficiency
|
Asymptomatic vitamin D deficiency
|
|
IV calcium gluconate
(1-2ml/kg) (up to a maximum of 20 ml/
dose) 1-2 doses (till symptoms subside).
Then oral calcium 30-75mg/kg/day (up to
a maximum of 1-2 g/ day) in 3 divided
doses X 1-2 weeks
|
Oral calcium 30-75mg/kg/day (up to a
maximum of 1 – 2 g/ day) in 3 divided
doses X 1-2 weeks
|
|
Reduce the dose by
half and continue till PTH and vitamin D
becomes normal. Calcitriol 0.05 mcg/kg/
day (up to a maximum of 0.5 mcg/ day)
may be needed till calcium levels
normalize.
|
Reduce the dose by
half and continue till PTH and vitamin D
becomes normal. Calcitriol 0.05 mcg/kg/
day (up to a maximum of 0.5 mcg/ day)
may be needed till calcium levels
normalize.
|
Monitoring therapy:
Estimation of serum calcium, phosphorus and
serum alkaline phosphatase levels is recommended
1 month after initiation of therapy. With Stoss
therapy biochemical response is usually evident
in 1 or 2 weeks [19]. Usually calcium and
phosphorus levels become normal within 6-10 days
whereas PTH, 25(OH)D levels normalize within 1-2
months and serum alkaline phosphatase by 3-6
months. Complete radiological healing takes
longer than one month although evidence of
healing is seen within 4 weeks.
After 3 months it is
recommended to obtain serum levels of calcium,
phosphorus, magnesium, serum alkaline
phosphatase, 25(OH)D and PTH, and a repeat X-ray
if there are bone changes initially.
Subsequently 25(OH)D levels may be monitored
yearly [19]. Considering the cost of performing
laboratory tests, reserving investigations only
for those not improving (based on clinical
assessment) may be an appropriate practical
option.
Screening for Vitamin D
Deficiency
The US endocrine society
guideline recommends screening only in
population at risk, as no evidence currently
exists to support screening at all population
levels. The candidates for screening or those
who are at risk for vitamin D deficiency include
patients with few specific disorders (Table
VI) [8].
TABLE VI Whom to Screen [8]
|
i. |
Dark skinned infants who live at higher
altitude and infants born to vitamin D
deficient mothers. |
ii.
|
In the presence of nonspecific symptoms
like poor growth, gross motor
developmental delay and unusual
irritability. |
|
iii. |
Children with suspected rickets, those
with osteoporosis. |
|
iv. |
Chronic kidney disease |
|
v. |
Hepatic failure |
|
vi. |
Mal absorption syndromes. |
|
Cystic fibrosis |
|
Inflammatory bowel disease |
|
Crohn’s disease |
|
vii. |
Hyper parathyroidism |
|
viii. |
Medications |
|
1.Anticonvulsants |
|
2.Glucocorticoids |
|
3.AIDS medications |
|
4.Antifungals (ketoconazole) |
|
ix. |
Obese children and adults (BMI >
30kg/m2) |
|
x. |
Granuloma forming disorders |
|
1.Sarcoidosis |
|
2.Tuberculosis |
|
3.Histoplasmosis |
How to Screen? Serum
alkaline phosphatase has been reported to be
useful as a screening test [29], which if
elevated for age should be followed with
measurements of 25(OH)D, calcium, phosphorus and
PTH along with radiological examination of
distal ends of radius and ulna or tibia and
femur depending on the age [31]. Serum alkaline
phosphatase levels are usually <500 IU/L in
neonates and <1000 IU/L in children up to 9
years and decrease after puberty (levels of
serum alkaline phosphatase vary with the method
of estimation used). Some studies however,
indicate that though all children with
radiographic evidence of rickets have low
vitamin D levels, not all have high serum
alkaline phosphatase and the wrist radiography
may be the most reliable test for detecting
subclinical rickets [32-34]. Recent reports
suggest that serum alkaline phosphatase is a
good screening test particularly for healthy
infants and toddlers who have been breastfed for
a prolonged period [34].
Guidelines for Vitamin D
Intake
The recommended vitamin D
intake is 400 IU/day in infants less than 1 year
and 600 IU/day in children more than 1 year of
age as suggested by US IOM [17,35,36].
The dietary reference intake
for vitamin D is chosen with a margin of safety
and "over shoot" that targeted serum values to
ensure that the specified levels of intake
achieve the desired 25(OH)D levels in almost all
persons. It is assumed that there are no
contributions to serum 25(OH)D levels from sun
exposure and recommendations are applicable to
people with dark skin or negligible sun
exposure.
However, to keep the serum
levels of 25(OH)D >30 ng/dL which is considered
to be the optimal level, the US Endocrine
committee has suggested the intake of 400-1000
IU/day under 1 year of age and 600-1000 IU/day
from 1 to 18 years of age [8].
Children at risk (on
anticonvulsants, glucocorticoids, antifungals
and medications for AIDS) need 2 to 3 times the
requirement for their age.
The upper limit of vitamin D
intake as maintenance therapy which is not to be
exceeded without medical supervision is as
follows : 1000 IU/ day for infants from 6
months-1 yr; 1500 IU/day for 1-3 years; 2500
IU/day for 4-8 years, 3000 IU/day for >8 years -
4000 IU/day.
Prevention
The most important factor
determining the vitamin D status in infancy is
the maternal vitamin D status [37]. Though
practically difficult, all pregnant women should
have their 25(OH) D levels checked during the
first trimester of pregnancy. If they are
deficient they should be treated with 3000-5000
IU until 25(OH)D is more than >20 ng/dL followed
by 400 IU /daily [38].
Routine vitamin D
supplementation to all the pregnant women is
controversial [39]. Administration of high dose
of vitamin D (400-6400 IU) daily to breast
feeding mothers increases the anti-rachitic
activity of breastmilk [40,41] without causing
hypervitaminosis in the mother.
Preterm infants should be
supplemented from birth with 400-800 IU/day
because of inadequate transfer of maternal
vitamin D stores and issues associated with
prematurity such as poor feeding,
gastrointestinal difficulties impairing
absorption and sometimes liver and kidney
impairment. Consideration for universal
supplementation particularly in breastfed
infants has been suggested [42].
The preparations available in
India are; Vitamin D3 – as oral drops 400 IU/mL;
Syrup 400 IU/5mL; and Tablets as 1000 and 2000
IU in blister packing and also as sachet in
powder form with each sachet containing 60000 IU
of vitamin D3.
Supplementation in newborn
period: For infants who are exclusively
breastfed a minimum daily intake of 400 IU/day
should be initiated within a few days after
birth. Since most of the infant formulas contain
400 IU/L, infants who are on formula feeds also
need supplementation unless they consume more
than 1000 mL of formula per day.
Toddlers and adolescents:
Children who are dark skinned, veiled, exposed
to reduced sun light or who have underlying
medical condition should receive 400 IU daily to
prevent vitamin D deficiency.
Sources
Sunlight: Most of
circulating vitamin D is provided by synthesis
from skin exposure to UVB radiation and <10%
from dietary sources[43]. At solar noon the
ratio of UVB – UVA light is the highest and the
only time that enough UVB photons reach the
earth’s surface to produce vitamin D is between
1000-1500 hours in the spring, summer and fall.
The disadvantage of UVR exposure for vitamin D
generation is the induction of skin cancers,
though in dark skinned individuals, the risk for
melanoma is considerably less. Children,
particularly infants may require less sun
exposure to produce sufficient quantities of
vitamin D because of greater capacity to produce
vitamin D than older people [29].
Specker, et al. [43]
reported that exposure to sunlight for 30
min/week for infants in diaper and 2 hour /week
for fully clothed infants without hat (since
infants’ scalp contributes a major part of body
surface area) maintained vitamin D levels of
>11ng/dL. Asian children require three times the
recommended amount of sun light exposure to
maintain the vitamin D levels (because of dark
skin color). However, to maintain vitamin D
level in the sufficiency range the duration of
UVR exposure particularly in relation to time of
the day, season or skin pigmentation, remains to
be determined. Excessive exposure to sunlight
dose not lead to vitamin D toxicity.
Dietary and supplemental
sources of vitamin D: Oily fish such as
salmon, mackerel and sardines, cod liver oil,
and liver and organ meats are rich natural
sources that are not commonly consumed by
children.
Fortified foods are being
recognised as an important source of vitamin D
[44]. Fortification of milk has been found to be
a safe, effective and acceptable method [45].
However, in a setting like India, where the per
capita milk consumption is very low,
consideration for other methods of fortification
such as fortification of oil, cereal powders and
even salt needs consideration. The need for a
national food fortification program for vitamin
D has been highlighted in an earlier review
[46]. Since adequate sunlight exposure at solar
noon is difficult to achieve because of
modernisation and existing cultural practices,
supplementation and fortification may help in
preventing vitamin D deficiency and such public
health interventions need serious consideration
in the Indian context.
Contributors: All the
authors have contributed, designed and approved
the review.
Funding: None;
Competing interests: None stated.
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