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Vitamin D

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

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Vitamin D

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  1. 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. Solar UVB (280-310nm) Endogenous Vitamin D3 Liver 25-Hydroxyvitamin D (major circulating metabolite) Dietary source Vitamin D2 & D3 • Oily fish, eggs, • fortified foods e.g: • Infant formulas • Cereals 1,25-Dihydroxyvitamin D Sources & Metabolism of Vitamin 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 DConcentrations 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0.001) N = 22 Lau 2001 (Unpublished) Vitamin D stores acquired during fetal life last ~ 8 weeks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):1219-24.

  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. 2010 Jul 23. [Epub ahead of print]

  12. Low Calcium Diet & Vitamin D Deficiency

  13. Low Calcium Diet & Vitamin D Deficiency Khadilkar, Das, Sayyad, Sanwalka, Bhandari, Khadilkar, Mughal. Low Calcium intake & Hypovitaminosis D in Adolescent Girls. Archives of Disease in Childhood. 2007 ;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 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 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 09 5th May 09 • 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 D3 + 500mg/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) 1.50 (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 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]

  19. Non-Musculoskeletal Consequences of Vitamin D Deficiency

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

  21. Vitamin D & Innate Immunity • 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. 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):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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