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Review

Vitamin D and child health:

part 2 (extraskeletal and other aspects)
Nick J Shaw,1 M Zulf Mughal2
1
Department of Endocrinology ABSTRACT diabetes, metabolic syndrome, multiple sclerosis
and Diabetes, Birmingham The rst part of this review focused on the skeletal and Crohns disease. The implication that an indivi-
Childrens Hospital,
Birmingham, UK
aspects of vitamin D. This second part reviews some of duals vitamin D status might inuence their risk of
2
Department of Endocrinology, the available evidence that vitamin D may have a such disorders has generated a lot of interest and
Royal Manchester Childrens physiological extraskeletal role beyond its traditional there have been numerous publications as a conse-
Hospital, Manchester, UK effect on the skeleton. This aspect has inuenced the quence. It is proposed to selectively present some
denition of vitamin D deciency and what level of of the studies that have arisen from this line of
Correspondence to
Dr Nicholas J Shaw, vitamin D should be regarded as optimal. The work.
Department of Endocrinology recognition of the prevalence of vitamin D deciency and
and Diabetes, Birmingham insufciency has led to debate as to whether and how Type 1 diabetes
Childrens Hospital, Steelhouse we should be treating asymptomatic individuals. This
Lane, Birmingham B4 6NH, Several studies have suggested that the risk of devel-
UK; nick.shaw@bch.nhs.uk review discusses the potential extraskeletal effects of oping type 1 diabetes is related to vitamin D status
vitamin D, the denition of vitamin D deciency and our and that vitamin D supplementation in infancy may
Received 24 November 2012 thoughts on indications for measurement and treatment. reduce that risk. Experimental evidence has demon-
Revised 18 February 2013
strated that the risk of developing type 1 diabetes in
Accepted 20 February 2013
Published Online First the non-obese diabetic mouse can be reduced with
14 March 2013 INTRODUCTION vitamin D supplements.4 A cohort study from
Initial evidence for an extraskeletal action for Finland of over 10 000 children followed for up to
vitamin D arose in the 1980s when it was observed 31 years identied that those who received 2000 IU
that elevated levels of the active form of vitamin D, of vitamin D daily during infancy had a 78% reduc-
1,25-dihydroxyvitamin D3(1,25(OH)2D3) were tion in the risk of developing type 1 diabetes.5
seen in individuals with granulomatous disorders However, the weaknesses of this study included no
such as sarcoidosis who developed hypercalcae- objective measurements of vitamin D levels and a
mia.1 It was identied that this increased synthesis failure to control for potentially important confound-
of 1,25(OH)2D3 was due to extrarenal expression ing factors such as duration of breast feeding and age
of the enzyme, 1- hydroxylase, which activates 25 of weaning. A systematic review and meta-analysis
hydroxyvitamin D (25OHD). This enzyme was which included an additional four case-control
being expressed by disease associated macrophages studies concluded that children who had been supple-
rather than in its classical location of the proximal mented with vitamin D had a 29% reduction in risk
renal tubule. Similar extrarenal expression of 1- of type 1 diabetes compared with non-supplemented
hydroxylase was seen in other granulomatous disor- peers.6 However, all of these studies were based on
ders associated with hypercalcaemia including sub- historical recall by parents regarding vitamin D sup-
cutaneous fat necrosis seen in newly born infants.2 plementation with no objective measurements of
Subsequently other work demonstrated expres- vitamin D status. The authors felt that although there
sion of the vitamin D receptor in a number of cell was an association no concrete conclusions could be
types that were not directly involved in the classical made with the need for adequately powered rando-
endocrine functions of vitamin D. This led to the mised controlled trials to establish causality.
observation that 1,25(OH)2D3 was important in
cell proliferation. This antiproliferative action of Insulin resistance
1,25(OH)2D3 has been explored as a potential A number of studies have suggested a relationship
therapeutic strategy for a variety of common forms exists between vitamin D deciency and disorders
of cancer. Such a role is now exploited in the man- related to insulin resistance.
agement of psoriasis where synthetic analogues of Several cross-sectional studies have suggested
1,25(OH)2D3 are used to reduce skin turnover. there is an association between vitamin D status and
Another line of evidence was from epidemio- risk of impaired glucose metabolism. A survey of
logical studies that demonstrated that individuals over 7000 white Caucasian adults aged 45 years
living at higher latitudes had an increased risk of a who were being followed up as part of the 1958
variety of disorders. These included malignancies British Birth Cohort demonstrated an inverse rela-
such as cancer of the colon, breast, prostate, pan- tionship between their 25OHD levels and glycated
http://dx.doi.org/10.1136/ creas, ovary and Hodgkins lymphoma. Levels of haemoglobin.7 This was particularly noted for indi-
archdischild-2011-301264 25OHD below 50 nmol/l were associated with a viduals with 25OHD levels <65 nmol/l. Obese sub-
30%50% increased risk of developing cancer of jects were more likely to have low 25OHD levels
the colon, prostate or breast as well as a higher and this relationship was attenuated after adjustment
To cite: Shaw NJ, mortality.3 Non-malignant conditions that were for body mass index (BMI) and waist circumference.
Mughal MZ. Arch Dis Child similarly associated with an increased risk at higher In the large US National Health and Nutrition
2013;98:368372. latitude and lower 25OHD status include type 1 Examination Survey of adults conducted between

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2001 and 2004, serum 25OHD was inversely associated with the as a marker of ability to restrict the growth of Mycobacterium
prevalence of diabetes and insulin resistance in non-Hispanic bovis was 20% lower in the subjects who received vitamin
whites and Mexican-Americans but not in non-Hispanic blacks.8 D. No signicant differences were seen in the ability to stimu-
A study of the 3577 adolescents who participated in the same late the secretion of interferon , a marker of protective immun-
survey demonstrated an inverse association between 25OHD ity to M tuberculosis.
levels and fasting glucose and systolic blood pressure after adjust- The potential benet of vitamin D supplementation in the
ment for potential confounders such as age, gender, race, phys- treatment of active pulmonary tuberculosis was examined in a
ical activity and BMI.9 There was an OR of 3.9 for metabolic placebo controlled trial of 146 adults who were randomised to
syndrome for those in the lowest quartile for 25OHD receive four doses of 2.5 mg (100 000 units) of vitamin D3 or
(<37.5 nmol/l) compared with the highest quartile (>65 nmol/l). placebo from baseline to 6 weeks after starting standard antitu-
A further study of 85 children in Philadelphia, 57% of whom berculosis chemotherapy.19 The primary outcome was time to
were obese, demonstrated that lower 25OHD levels were asso- sputum culture conversion, a marker of long term treatment
ciated with higher fasting blood glucose, insulin and insulin response. The median time was 36 days in the vitamin D group
resistance after adjustment for puberty and BMI z-score.10 as opposed to 43.5 days in the placebo group which did not
There have been several prospective studies that have pro- achieve statistical signicance. A subsequent subgroup analysis
duced differing results. A UK study of 524 non-diabetic adults of 95 participants who fullled the per-protocol analysis
age 4069 years demonstrated that the baseline 25OHD level demonstrated a signicant reduction in the median time to
was inversely related to the risk of hyperglycaemia and insulin sputum smear conversion in the vitamin D treated group.
resistance 10 years later even after adjustment for BMI.11 In the Vitamin D enhanced the suppressive effect of treatment on
Nurses Health Study conducted in the USA, an inverse associ- monocyte count, inammatory markers and antigen-stimulated
ation was seen between dietary vitamin D intake and the risk of Th1 cytokine responses.20
type 2 diabetes.12 However, a study from the Womens Health The role of vitamin D supplementation in the treatment of
Initiative of 5140 women did not identify a signicant associ- pneumonia in children was explored in a placebo controlled
ation of 25OHD concentrations with risk of developing type 2 trial in Kabul, Afghanistan.21 A total of 453 children aged
diabetes over a mean follow-up period of 7.3 years.13 1 month3 years who were diagnosed with pneumonia at an
There have been a limited number of intervention studies as outpatient clinic were randomised to receive a single oral dose
yet which have examined the impact of vitamin D supplementa- of 100 000 units of vitamin D3 or placebo. No signicant differ-
tion on glucose homeostasis. A placebo controlled trial of ence was seen in the mean number of days to recovery from
vitamin D and calcium supplementation undertaken primarily pneumonia but the risk of a repeat episode of pneumonia was
for bone-related outcomes showed no effect on glycaemia or reduced in the intervention group with a relative risk of 0.78.
insulin resistance in adults with normal glucose tolerance at An additional study from the same group has examined the
baseline.14 However, vitamin D and calcium supplementation in role of vitamin D supplementation in the prevention of pneu-
those with impaired fasting glucose showed a lower rise in monia in children. Children aged 111 months were randomly
fasting glucose and insulin resistance at 3 years compared with allocated to receive 100 000 units or placebo every 3 months
placebo. for 18 months. There was no difference in the incidence of
pneumonia with repeat episodes of pneumonia being signi-
Innate immunity cantly higher in the vitamin D treated group.22
There have been a number of lines of evidence to suggest that A study from Delhi examined the impact of vitamin D supple-
vitamin D plays a role in innate immunity. A case control study mentation on low birthweight infants.23 Over 2000 term infants
from Ethiopia of young children admitted to hospital showed with birth weights less than 2.5 kg were randomised to receive
that 42% of those with pneumonia had rickets in comparison 1400 units of vitamin D3 per week or placebo for the rst
with only 4% in the controls.15 A potential link between 6 months of life. No signicant differences in hospital admis-
vitamin D deciency and risk of tuberculosis has been the sions, outpatient clinic visits or mortality were seen during this
subject of several studies. A systematic review and meta-analysis time although the vitamin D treated group had higher weights,
identied seven eligible studies with the pooled effect demon- lengths and arm circumference at 6 months.
strating a probability of 70% that a healthy individual would
have a higher vitamin D level than an untreated individual with Muscle function
tuberculosis.16 A recognised clinical manifestation of vitamin D deciency is
More direct evidence of a link came from a study that muscle weakness which may coexist with skeletal features such
demonstrated the presence of a vitamin D response element in as rickets and hypocalcaemia or on occasions may be the
the promoter of the gene for cathelicidin, an important anti- primary presenting feature.
microbial peptide which has a role in the killing of intracellular This particularly affects proximal muscles with symptoms
Mycobacterium tuberculosis.17 Subsequent studies showed that such as delayed onset of walking in infants and difculty climb-
administration of 1,25(OH)2D3 to human macrophages infected ing stairs in adolescents. A particularly severe example of
with M tuberculosis reduced the number of viable bacilli. Serum muscle dysfunction in infants is cardiomyopathy with one
from African-American subjects who had lower levels of report detailing 16 infants who presented to four cardiology
25OHD was less able to induce cathelicidin mRNA than serum centres in the UK over a 6-year period.24 Six of these infants
from white Caucasian subjects who had higher 25OHD levels. had a cardiac arrest, two were referred for cardiac transplant-
Addition of 25OHD to the serum of the African-American sub- ation and there were three deaths.
jects restored the induction of cathelicidin mRNA. Additional in A cross-sectional study of muscle function in relation to
vitro evidence was provided by a study of 192 healthy adult TB vitamin D status in 99 postmenarchal adolescent girls used
contacts who were randomised to receive a single large dose jumping mechanography to assess muscle force and power.25
(2.5 mg, 100 000 units) of vitamin D2 or placebo.18 Follow-up Despite a median serum vitamin D level of 21.3 nmol/l, none of
at 6 weeks demonstrated that the 24 h BCG luminescence ratio the participants had clinical symptoms of vitamin D deciency.

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A positive relationship was seen between the 25OHD level and require a daily vitamin D intake of 1000 IU.33 The relationship
jump velocity, jump height, force and power. A subsequent ran- between serum concentrations of vitamin D and parathyroid
domised placebo controlled trial in these adolescents used four hormone (PTH) has been the focus of a number of studies.
doses of 150 000 units of vitamin D2 given at 3-month intervals These have shown an inverse relationship between vitamin D
for 1 year.26 No signicant advantages were seen in the vitamin and PTH with levels of serum PTH not starting to plateau until
D treated group for muscle force and power although the ef- serum concentrations of vitamin D of 75100 nmol/l are
ciency of the jump increased by 5% in the treated group. The achieved.34 Many of these studies have been undertaken in
apparent lack of effect seen in this study was potentially related adults with limited studies in children to date. One such study
to the participants being postpubertal as another randomised undertaken in adolescents in Boston demonstrated that a
trial did show signicant improvements in lean body mass vitamin D level of less than 37.5 nmol/l was associated with a
assessed by dual energy X-ray absorptiometry (DXA) in preme- rise in serum PTH concentrations.35 Similar work undertaken in
narchal girls who received vitamin D although there were no Birmingham has shown a similar threshold of 37.5 nmol/l (sub-
signicant effects on grip strength.27 mitted for publication). A study from India of 760 healthy
There are many other studies that have examined potential schoolchildren demonstrated that serum PTH levels started to
extraskeletal benets of vitamin D. Although there are currently rise when vitamin D concentrations fell below 25 nmol/l.36 A
many studies that have demonstrated associations with vitamin D recent analysis of the vitamin D and PTH relationship in over
status there is limited evidence at present of causation when 300 000 adults aged 20 to over 60 years has provided some
examined in intervention studies. interesting observations.37 They were unable to demonstrate a
There is a need for large randomised controlled trials to threshold level above which increasing 25 OH vitamin D fails to
determine the role of vitamin D on extraskeletal outcomes. One further suppress PTH. Using a level of 50 nmol/l to dene suf-
such ongoing study in adults in the USA (the VITAL trial) is ciency, they found that 27% of individuals fell below this level.
examining the impact of daily supplementation of 2000 IU of They were also able to demonstrate a clear age dependent rela-
vitamin D or placebo over 5 years on a number of outcomes tionship with elevated PTH levels being seen with advancing
including diabetes, heart disease, cancer and stroke. Similar age for the same level of 25 OH vitamin D.
studies are required in children and adolescents before we can These observations reinforce the importance of undertaking
make any judgements as to whether vitamin D status has a sig- paediatric studies without automatically adopting vitamin D
nicant role beyond the skeleton. thresholds based on adult studies. We are aware of many chil-
dren and adolescents who have levels of vitamin D below
DEFINITION AND PREVALENCE OF VITAMIN D DEFICIENCY 25 nmol/l with no abnormality of bone biochemistry. For
There have been a number of consensus statements or guidelines example, work undertaken in 37 adolescent girls in an inner
in recent years which have included denitions of vitamin D de- city school in Manchester showed a median vitamin D level of
ciency. It is generally agreed that the serum concentration of 14.8 nmol/l with only three girls having a serum PTH value
25OHD is the best marker of an individuals vitamin D status as it above the reference range.38 A similar observation was seen in
is the major circulating form of vitamin D and reects the combin- the large US study with 49% of subjects with vitamin D levels
ation of dietary intake and cutaneous skin synthesis. However, dif- below 25 nmol/l having normal PTH levels.37
ferent thresholds for what level of 25 OH vitamin D is considered The report from the Institute of Medicine concluded that
to reect deciency are used. For example, the Institute of there was insufcient evidence of causality for extraskeletal
Medicine report on dietary reference intake for vitamin D pub- actions of vitamin D and that bone health was the only outcome
lished in 201028 dened a level of 50 nmol/l as meeting the needs whereby causality was established.28 A similar conclusion was
of 97.5% of the population whereas the Endocrine Society reached in a consensus vitamin D position statement represent-
Clinical Practice Guideline published in 2011 dened vitamin D ing the views of a number of specialist organisations in the UK
deciency as a level <50 nmol/l with levels between 52.5 and including dermatology, cancer, cardiovascular disease, diabetes,
72.5 nmol/l regarded as vitamin D insufciency and levels greater multiple sclerosis and osteoporosis. This consensus felt that
than 72.5 nmol/l being regarded as optimal.29 In relation to chil- levels of vitamin D less than 25 nmol/l represented deciency.39
dren and adolescents, the Lawson Wilkins Paediatric Endocrine Our own view is that vitamin D deciency should be dened as
Society of North America in 2008 dened deciency as levels a level less than 25 nmol/l with vitamin D insufciency being
<37.5 nmol/l and insufciency as levels between 37.5 and dened as levels between 25 and 50 nmol/l.40
50 nmol/l.30 A widely read review article in the UK published in A number of studies have examined the prevalence of vitamin D
2010 dened deciency as a level <25 nmol/l and insufciency as deciency or insufciency. In a study of white British adults aged
a level between 25 and 50 nmol/l.31 An obvious consequence of 45 years, 46.6% had vitamin D insufciency (dened as less than
differing thresholds to dene deciency is that treatment guide- 40 nmol/l) and 15.5% had severe deciency (less than 25 nmol/l)
lines will use different levels to advocate treatment with pharmaco- during winter or spring.41 A study undertaken in adults attending
logical doses of vitamin D. We are currently aware of two local an inner city hospital in Birmingham showed that one in eight
treatment guidelines one of which advocates aiming to achieve a white subjects had vitamin D levels less than 25 nmol/l with similar
25OHD level of 50 nmol/l and the other recommends 75 nmol/l. levels being seen in one in four African-Caribbean and one in three
What is the basis for determining what represents an adequate Asian subjects.42 This study was undertaken at the end of the
vitamin D status? Traditionally, vitamin D deciency has been summer when it would be anticipated that vitamin D levels would
dened as the level below which rickets or osteomalacia may be be at their highest. A study of healthy adolescents in Boston, USA,
seen which for many years has been set at 25 nmol/l.32 identied that 42% had vitamin D insufciency (levels <50 nmol/
However, interest in other outcomes has suggested higher l) with 24.1% having vitamin D deciency (less than 37.5 nmol/
thresholds. For example, a review of optimal vitamin D concen- l).35 The highest prevalence of vitamin D deciency (35.9%) was
trations in relation to bone density, fractures in the elderly, peri- seen in the African-American subjects. An analysis of the data on
odontal disease and colorectal cancer concluded that for all children aged 418 years from the UK National Diet and Nutrition
endpoints levels of 75100 nmol/l were best which would Survey of 1997/8 showed that 35% had evidence of vitamin D

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insufciency (levels <50 nmol/l) with an increased risk if adoles- should achieve a vitamin D level > 50 nmol/l and should result
cent (OR 3.6) and of non-white ethnicity (OR 37.0).43 Recent data in resolution of symptoms due to vitamin D deciency.
from the same survey undertaken in 2008 show that the median There are occasional reports of children who have been
vitamin D level in boys aged 1118 years was 42.4 nmol/l and in treated with standard pharmacological doses of vitamin D who
girls was 36.8 nmol/l.44 It is clear that given the high prevalence of have developed hypercalcaemia. It is therefore important to
vitamin D deciency or insufciency that routine measurements of limit treatment to clearly dened indications as we have out-
vitamin D in subjects attending hospitals or seen in general practice lined to maximise the benet to risk ratio.46 Once an individual
will identify many abnormal results. It is therefore necessary to has been treated for symptomatic vitamin D deciency they
focus such requests as to whether they are likely to be related to the should be advised to continue a multivitamin supplement con-
presenting complaint. taining vitamin D in a dose of 400 IU daily to prevent a recur-
rence of vitamin D deciency.
Currently the evidence for treating asymptomatic children and
WHEN TO MEASURE VITAMIN D AND WHEN TO TREAT adolescents with evidence of vitamin D deciency (<25 nmol/l)
As previously indicated we believe that there is currently limited and insufciency (2550 nmol/l) is limited and therefore we feel
evidence of extraskeletal benets of vitamin D in children. We that such individuals should not receive pharmacological doses of
therefore feel that the primary reasons for requesting a vitamin vitamin D but should be given lifestyle advice including recom-
D measurement should relate to symptoms and signs relating to mendations regarding safe sunlight exposure and vitamin D sup-
the effects of vitamin D on the skeleton or muscle function. plementation. It is clear there is a huge prevalence of vitamin D
These are listed in box 1. A measurement and identication of insufciency and deciency in the childhood and adolescent popu-
an abnormal vitamin D level outside these indications requires lation which needs to be addressed by concerted public health
careful consideration as to whether the presenting symptoms interventions. It is mandatory that current public health recom-
and signs are likely to be related to vitamin D deciency or are a mendations for vitamin D supplementation for pregnant and
coincidental nding. breastfeeding women and all infants and young children up to the
Similarly we believe that treatment with pharmacological doses age of 5 years are implemented to prevent the risk of rickets and
of vitamin D should be reserved for individuals with symptom- hypocalcaemic seizures in infants and toddlers.
atic vitamin D deciency who are likely to have vitamin D levels
of less than 25 nmol/l. Current treatment schedules related to age SUMMARY
are listed in box 1 of the rst section of this review.45 Such doses These reviews have summarised current issues relevant to the
impact of vitamin D on a variety of aspects of child health:
Factors responsible for worldwide resurgence of rickets
among infants and adolescents are complex and include:
Box 1 Indications for measurement of vitamin D residence in northern or southern latitudes, voluntary
avoidance of exposure to solar ultraviolet B (UVB) radi-
Symptoms and signs of rickets/osteomalacia ation, genetic factors, maternal vitamin D deciency
Progressive bowing deformity of legs during pregnancy and prolonged breast feeding without
Waddling gait provision of vitamin D supplements.
Abnormal knock knee deformity (intermalleolar distance Provision of low dose (400 IU or 10 daily) vitamin D
>5 cm) supplements to newborns and infants is effective in redu-
Swelling of wrists and costochondral junctions (rachitic cing the prevalence of vitamin D deciency rickets in this
rosary) age group.
Prolonged bone pain (>3 months duration) Further research is indicated to provide accurate data on
Symptoms and signs of muscle weakness the incidence of rickets and other manifestations of symp-
Delayed walking tomatic vitamin D deciency in children in the UK.
Difculty climbing stairs The impact of maternal vitamin D deciency on bone
Cardiomyopathy in an infant health in infants requires further investigation. Such work
Abnormal bone prole or x-rays is likely to require studies in relevant animal models.
Low plasma calcium or phosphate Severe vitamin D deciency in the perinatal period and
Raised alkaline phosphatase early infancy may result in cardiomyopathy. It may also
Osteopenia or changes of rickets on x-ray cause myopathy of skeletal muscle, which in toddlers may
Pathological fractures manifest as delayed motor development.
Disorders impacting on vitamin D metabolism Further research into potential extraskeletal aspects of
Chronic renal failure vitamin D is likely to emerge that will help clarify current
Chronic liver disease knowledge. However, until there is evidence that vitamin D
Malabsorption syndromes, for example, cystic brosis, is benecial beyond its effects on the skeleton, we do not
Crohns disease, coeliac disease feel there should be widespread vitamin D supplementation
Older anticonvulsants, for example, phenobarbitone, of the population.
phenytoin, carbamezapine
Competing interests None.
Children with bone disease in whom correcting vitamin D
deciency prior to specic treatment would be indicated Provenance and peer review Commissioned; externally peer reviewed.
Osteogenesis imperfecta
Idiopathic juvenile osteoporosis REFERENCES
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372 Shaw NJ, et al. Arch Dis Child 2013;98:368372. doi:10.1136/archdischild-2012-302585

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Vitamin D and child health: part 2

(extraskeletal and other aspects)
Nick J Shaw and M Zulf Mughal

Arch Dis Child 2013 98: 368-372 originally published online March 14,
2013
doi: 10.1136/archdischild-2012-302585

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