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Vitamin D
Zulf MughalZulf Mughal
Consultant in Paediatric Bone Disorders
Department of Paediatric Endocriology
Royal Manchester Children's Hospital
ManchesterManchester
M13 0JHM13 0JH
Bone Study Day, 28th September 2012
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
Vitamin D: Sources & Metabolism
Sources & Metabolism of Vitamin DSources & Metabolism of Vitamin D
Solar UVB (280-310nm)
Endogenous Vitamin D3
Dietary sourceVitamin D2 & D3
Oily fish, eggs, fortified foods e.g:
Infant formulas
Cereals
LiverLiver
25-Hydroxyvitamin D (major circulating metabolite)
1,25-Dihydroxyvitamin D
KidneyKidney
1α hydroxylase (CYP27B1)
PTH (+) ↓ P (+) FGF23 (-)
(7-dehydoxycholesterol)(7-dehydoxycholesterol)
DBP
25-hydroxylase (CYP2R1)
24-hydroxylase (CYP24A1)
DBP
24,25-hydroxyvitamin D
Calcitroic acid
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 & osteoidMineralisation of the growth plate & osteoid
Normal Growth Plate Rachitic Growth Plate
Low Calciumor
Low Phosphorous
Radiograph showingRachitic Changes
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
Ethnicity
Asians
Caucasians
Maternal 25(OH)D(ng/ml)
6050403020100
Cor
d 25
(OH
)D(n
g/m
l)
50
40
30
20
10
0
R=0.98 (p<0.001)
Maternal & Cord 25-Hydroxyvitamin D Concentrations
Vitamin D stores acquired during fetal life last ~ 8 weeksVitamin D stores acquired during fetal life last ~ 8 weeks
Lau 2001 (Unpublished)
N = 22
Cutaneous Vitamin D Synthesis
15 South Asians
109 Whites
Farrar et al Am J Clin Nutr. 2011;94(5):1219-24.
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
Criteria or Definition of Vitamin D Deficiency
Definition of vitamin D deficiency & sufficiency based on serum 25(OH)D concentrations
Vitamin D Deficiency & InsufficiencyVitamin D Deficiency & Insufficiency
Davies JH & Shaw NJ. Arch Dis Child. 2010 Jul 23. [Epub ahead of print]
Low Calcium Diet & Vitamin D DeficiencyLow 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% 0%
Dietary vitamin D intake (µg/day) 0.17 1.3
% Ca intake (mg/day) - dairy products 65 (31-76) 401 (195 - 594)
Total Ca intake (mg/day) 449 (356 - 538) Data not available
Khadilkar, Das, Sayyad, Sanwalka, Bhandari, Khadilkar, Das, Sayyad, Sanwalka, Bhandari, KhadilkarKhadilkar, , MughalMughal. . Low Calcium intake & Low Calcium intake & Hypovitaminosis DHypovitaminosis D in Adolescent in Adolescent GirlsGirls. Archives of Disease in Childhood. 2007 ;92(11):1045. Archives of Disease in Childhood. 2007 ;92(11):1045
Low Calcium Diet & Vitamin D DeficiencyLow Calcium Diet & Vitamin D Deficiency
Low Calcium & High Fibre Diet and Vitamin D StatusLow Calcium & High Fibre Diet and Vitamin D Status
Vitamin D Dietary Ca
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
DIETARY CALCIUM INTAKE
1 ml ~ 1mg
1 pot ~ 150 mg
~ 35 mg/slice
1 Bowl ~ 80 mg
1 oz ~ 200 mg
RNI (mg/day) in the UK
Infants up to 1 yr 525
Children 1- 3 yrs 350
Children 2-6 yrs 450
Children 7-10 yrs 550
Adolescent boys 11-18 yrs 1000
Adolescent girls 11-18 yrs 800
Vitamin D Deficiency & Muscle
DIAGNOSISDIAGNOSIS: : Severe vitamin D deficiency & low calcium intakeSevere vitamin D deficiency & low calcium intake
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
Rx:Rx: Single orally dose 180, 000 IU Vitamin D3 + 500mg/day Ca supplementSingle orally dose 180, 000 IU Vitamin D3 + 500mg/day Ca supplement
Vitamin D Deficiency & MyopathyVitamin D Deficiency & Myopathy
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
8th April 09 5th May 09
Life threatening Cardiomyopathy in Early InfancyLife threatening Cardiomyopathy in Early Infancy
Maiya S et al .Hypocalcaemia and Vitamin D deficiency: an important, but preventable cause of life threatening infant heart failure.Heart. 2007 Aug 9; [Epub]
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) 1.50 (1.07 – 1.74) 2.17 – 2.44
PTH (pmol/L) 34.3 (8.9 – 102) 0.7 – 5.6
25OHD (nmol/L) 18.5 (0.00 – 46) >50
Fractional shortening (%) 10 (5-18) 28 – 45
Left ventricular end diastolic
dimension Z score 4.1 (3.1-7) -2 < +2
Non-Musculoskeletal Consequences of Vitamin D Deficiency
Holick BMJ June 2008;336:1318-1319
Possible Consequences of Vitamin D DeficiencyPossible Consequences of Vitamin D Deficiency
Vitamin D & Innate ImmunityVitamin D & Innate Immunity
Adequate serum 25(OH)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
Vitamin D Deficiency & Pneumonia
New RMCH July 2009New RMCH July 2009
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
Effects of Vitamin D supplementation in children diagnosed with pneumonia in Kabul: A randomised controlled trial
0.00
0.25
0.50
0.75
1.00
Pro
port
ion
of c
hild
ren
204 162(37) 121(35) 0(15)Vitamin D211 156(52) 104(45) 0(19)Placebo
Number at risk (no of episodes)
0 30 60 90Time since recruitment (days)
Placebo
Vitamin D
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
Vitamin D Supplementation to Infants in Kabul had NO effect on the Vitamin D Supplementation to Infants in Kabul had NO effect on the incidence of Pneumonia: incidence of Pneumonia: A randomised controlled trialA randomised controlled trial
0.50
0.75
1.00
Pro
por
tion
of c
hild
ren
1477 1375(88) 1252(82) 1199(14) 1169(9) 1099(39) 0(13)Placebo1485 1362(94) 1246(81) 1217(8) 1183(11) 1086(50) 0(16)Vitamin D
Number at risk (no of episodes)
0 90 180 270 360 450 540Time since recruitment (days)
Vitamin D
Placebo
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):1419-27
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!
