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Vitamin D Zulf Mughal Consultant in Paediatric Bone Disorders Department of Paediatric Endocriology Royal Manchester Children's HospitalManchester M13.

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Presentation on theme: "Vitamin D Zulf Mughal Consultant in Paediatric Bone Disorders Department of Paediatric Endocriology Royal Manchester Children's HospitalManchester M13."— Presentation transcript:

1 Vitamin D Zulf Mughal Consultant in Paediatric Bone Disorders Department of Paediatric Endocriology Royal Manchester Children's HospitalManchester M13 0JH Bone Study Day, 28 th 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 Solar UVB (280-310nm) Endogenous Vitamin D 3 Dietary source Vitamin D 2 & D 3 Oily fish, eggs, fortified foods e.g:   Infant formulas   Cereals Liver 25-Hydroxyvitamin D (major circulating metabolite) 1,25-Dihydroxyvitamin D Kidney 1α hydroxylase (CYP27B1)   PTH (+)   ↓ P (+)   FGF23 (-) (7-dehydoxycholesterol) DBP 25-hydroxylase (CYP2R1) 24-hydroxylase (CYP24A1) DBP 24,25-hydroxyvitamin D 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 Normal Growth Plate Rachitic Growth Plate Low Calcium or Low Phosphorous Radiograph showing Rachitic Changes

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Maternal & Cord 25-Hydroxyvitamin D Concentrations Vitamin D stores acquired during fetal life last ~ 8 weeks Lau 2001 (Unpublished) N = 22

8 Cutaneous Vitamin D Synthesis

9 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

10 Criteria or Definition of Vitamin D Deficiency

11 Definition of vitamin D deficiency & sufficiency based on serum 25(OH)D concentrations Vitamin D Deficiency & Insufficiency Davies JH & Shaw NJ. Arch Dis Child. 2010 Jul 23. [Epub ahead of print]

12 Low Calcium Diet & Vitamin D Deficiency

13 Pune (18.34 0 N) N = 50 Manchester (54.4 0 N) N=51 Age (years) 14.7 ± 0.715.3 ± 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) 0.171.3 % 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, Mughal. Low Calcium intake & Hypovitaminosis D in Adolescent Girls. Archives of Disease in Childhood. 2007 ;92(11):1045 Low Calcium Diet & Vitamin D Deficiency

14 Low 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

15 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 yrs800

16 Vitamin D Deficiency & Muscle

17 DIAGNOSIS : Severe vitamin D deficiency & low calcium intake Pre RxPost 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: Single orally dose 180, 000 IU Vitamin D3 + 500mg/day Ca supplement Vitamin 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 8 th April 09 5 th May 09

18 Life 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

19 Non-Musculoskeletal Consequences of Vitamin D Deficiency

20 Holick BMJ June 2008;336:1318-1319 Possible Consequences of Vitamin D Deficiency

21 Vitamin 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) 2 D   1,25(HO) 2 D leads to production of antimicrobial proteins (AMPs)   AMPs (e.g. Cathelcidin) important role in defence against bacterial & viral infections

22 Vitamin D Deficiency & Pneumonia New RMCH July 2009

23 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

24 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 incidence of Pneumonia: A randomised controlled trial 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

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 zulf.mughal@cmft.nhs.uk


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