1. Bone Study Day, 28th September 2012
Vitamin D
Zulf Mughal
Consultant in Paediatric Bone Disorders
Department of Paediatric Endocriology
Royal Manchester Children's Hospital
Manchester
M13 0JH
Bone Study Day, 28th September 2012

2. Overview Sources & Metabolism of Vitamin D
Musculoskeletal consequences of Vitamin D deficiency
Non-musculoskeletal associations of Vitamin D deficiency
The Criteria or Definition of Vitamin D deficiency
Prevention of Vitamin D deficiency

3. Vitamin D: Sources & Metabolism

4. Sources & Metabolism of Vitamin D (7-dehydoxycholesterol)
Solar UVB ( nm)
Endogenous
Vitamin D3
Dietary source
Vitamin D2 & D3
Oily fish, eggs,
fortified foods e.g:
Infant formulas
Cereals
Liver
25-Hydroxyvitamin D
(major circulating metabolite)
1,25-Dihydroxyvitamin D
DBP
25-hydroxylase
(CYP2R1)
(7-dehydoxycholesterol)
DBP
Kidney
24,25-hydroxyvitamin D
PTH (+)
↓ P (+)
FGF23 (-)
1α hydroxylase
(CYP27B1)
24-hydroxylase
(CYP24A1)
Calcitroic acid

5. Roles of 1,25-Dihydroxyvitamin D in Bone Mineral Homeostasis
Stimulates GI calcium absorption
Promotes renal calcium re-absorption
Stimulates GI phosphorous absorption
Calcium homeostasis: together with PTH it mobilises calcium from skeletal stores
Mineralisation of the growth plate & osteoid
Low Calcium or
Low Phosphorous
Radiograph showing
Rachitic Changes
Normal Growth Plate
Rachitic Growth Plate

6. Factors which contribute to development of Vitamin D deficiency
Residence in Northern or Southern Latitudes
Pigmented skin
Sun blocking creams – Factor 8 ↓ Vit D synthesis by >95%
Sunshine avoidance for religious or cultural reasons
Cloud Cover & Atmospheric Pollution
Obesity
Genetic propensity
An independent protective effect of meat consumption
Low dietary Calcium & High Fibre diets

7. Maternal & Cord 25-Hydroxyvitamin D Concentrations
R=0.98 (p<0.001)
N = 22
Lau 2001 (Unpublished)
Vitamin D stores acquired during fetal life last ~ 8 weeks

8. Cutaneous Vitamin D Synthesis

9. Serum 25(OH) Levels after Simulated Summer Sunlight Exposures
in Whites & South Asians
South Asians need 4 times longer Exposure
2 Hours of Summer Sunlight Exposure 3 x Week
109 Whites
15 South Asians
Farrar et al Am J Clin Nutr. 2011;94(5):

10. Criteria or Definition of Vitamin D Deficiency

11. Vitamin D Deficiency & Insufficiency
Definition of vitamin D deficiency & sufficiency based on serum 25(OH)D concentrations
Davies JH & Shaw NJ. Arch Dis Child Jul 23. [Epub ahead of print]

12. Low Calcium Diet & Vitamin D Deficiency

13. Low Calcium Diet & Vitamin D Deficiency
Pune (18.340N)
N = 50
Manchester (54.40N)
N=51
Age (years)
14.7 ± 0.7
15.3 ± 0.4
Serum 25OHD concentrations < 12 ng/ml
70%
73%
PTH > upper end of the reference range
48% 6%
Serum calcium concentration < 2.2 mmol/l (%)
74% 0%
Non-specific aches and pains (%)
76%
26%
Genu Varum or Genu Valgum (%)
44%
Dietary vitamin D intake (µg/day)
0.17
1.3
% Ca intake (mg/day) - dairy products
65 (31-76)
401 ( )
Total Ca intake (mg/day)
449 ( )
Data not available
Khadilkar, Das, Sayyad, Sanwalka, Bhandari, Khadilkar, Mughal. Low Calcium intake & Hypovitaminosis D in Adolescent Girls. Archives of Disease in Childhood ;92(11):1045

14. Low Calcium & High Fibre Diet and Vitamin D Status
High fibre & phytic acid reduce dietary Ca intake
Low Ca intake leads to secondary hyperparathyroidism & raised serum
1,25(OH)2D concentration
Raised serum 1,25(OH)2D concentration degrades 25OHD to inactive
24,25-dihydroxyvitamin D, thereby depleting body stores of vitamin D
Clements et al. Nature 1987;325:62–5
Vitamin D
Dietary Ca

15. DIETARY CALCIUM INTAKE
1 ml ~ 1mg
RNI (mg/day) in the UK
Infants up to 1 yr
Children 1- 3 yrs
Children 2-6 yrs
Children 7-10 yrs
Adolescent boys yrs 1000
Adolescent girls yrs 800
1 oz ~ 200 mg
1 pot ~ 150 mg
~ 35 mg/slice
1 Bowl ~ 80 mg

16. Vitamin D Deficiency & Muscle

17. Vitamin D Deficiency & Myopathy
8th April th May 09
Pre Rx
Post Rx
25(OH)D (ng/ml)
<2
27.1
PTH (ng/ml)
(10-60)
593 90
Calcium (mmol/l)
(2.15 – 2.65)
1.38
2.23
Phosphate (mmol/l)
(1.0 – 1.8)
1.68
1.43
Alk Phos (I/U)
1020
592
14 year old female
Limb pains
Difficulty walking & Climbing stairs
Life long intolerance of dairy products (Ca intake <300 mg/day)
Arrived from Saudi Arabia 8 months ago
DIAGNOSIS: Severe vitamin D deficiency & low calcium intake
Rx: Single orally dose 180, 000 IU Vitamin D mg/day Ca supplement

18. Life threatening Cardiomyopathy in Early Infancy
16 infants (6 South Asian, 10 Black ethnicity) admitted to GOS with Heart Failure
Median age 5.3 months (3 weeks - 8 months);12 exclusively breast-fed
12 needed inotropic support
8 ventilated & 2 needed ECMO
2 referred for cardiac transplantation
6 suffered a cardiac arrest & 3 died!
Median (range) Reference range
Calcium (mmol/L) (1.07 – 1.74) – 2.44
PTH (pmol/L) (8.9 – 102) – 5.6
25OHD (nmol/L) (0.00 – 46) >50
Fractional shortening (%) 10 (5-18) – 45
Left ventricular end diastolic
dimension Z score (3.1-7) < +2
Maiya S et al .Hypocalcaemia and Vitamin D deficiency: an important, but preventable cause of life threatening infant heart failure.Heart Aug 9; [Epub]

19. Non-Musculoskeletal Consequences of Vitamin D Deficiency

20. Possible Consequences of Vitamin D Deficiency
Holick BMJ June 2008;336:

21. Vitamin D & Innate Immunity
Toll like receptors recognise pathogens 
 expression of VDR & CYP27B1 enzyme
25(OH)D  1,25(OH)2D
1,25(HO)2D leads to production of
antimicrobial proteins (AMPs)
AMPs (e.g. Cathelcidin) important role in
defence against bacterial & viral infections
Adequate serum 25(OH)D

22. Vitamin D Deficiency & Pneumonia
New RMCH July 2009

23. Tropical Medicine & International Health 2010;15 (10), 1148–1155
Effects of Vitamin D supplementation in children diagnosed with pneumonia in Kabul: A randomised controlled trial
Proportion of children free of a repeat episode of pneumonia up to 90 days post-treatment
Rx of 1-36 month olds with 100,000 i.u.
Vitamin D3/Placebo + antibiotics
DID NOT reduce the duration
of illness
(p=0.17)
DID reduce readmission to
hospital with pneumonia
(p=0.01)
Manaseki-Holland S, Qader G, Masher M I, Bruce J. Mughal M Z, Chandramohan D, Walraven G,
Effects of Vitamin D supplementation to children diagnosed with pneumonia in Kabul:  A randomised controlled trial.
Tropical Medicine & International Health 2010;15 (10), 1148–1155

24. Vitamin D Supplementation to Infants in Kabul had NO effect on the incidence of Pneumonia: A randomised controlled trial
Proportion of Children without First or Only Episode of X-Ray Confirmed Severe & Non-Severe Pneumonia
3,406 infants randomised to 100,000 i.u. Vitamin D3 or Placebo
every 3-monthly, for 18 months
Subjects visited fortnightly to assess their health status
Subjects with signs of pneumonia had a chest radiograph to confirm the diagnosis of pneumonia.
No difference in the incidence of pneumonia between the vitamin D and the placebo group
Manaseki-Holland, Maroof, Bruce, Mughal, Masher, Bhutta, Walraven, Chandramohan Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial LANCET .2012;14;379(9824):

25. Summary Subclinical vitamin D deficiency is very common in the UK
Severe vitamin D deficiency is associated skeletal muscle weakness & cardiomyopathy.
No clear definition of vitamin D deficiency based on serum 25(OH)D levels in children.
Pragmatic lower limit of vitamin D sufficiency – 20 ng/ml or 50 nmol/l.
Adequate dietary calcium intake is important in order to prevent vitamin D breakdown.
Musculoskeletal symptoms of vitamin D deficiency are less likely to occur when dietary calcium intake is adequate & serum PTH is normal.
Vitamin D deficiency may be associated with increased risk of infections, autoimmune disorders, respiratory diseases & certain cancers. RCTs needed to confirm these associations!

26. Thank You