Overview. Musculoskeletal consequences of Vitamin D deficiency. Non-musculoskeletal associations of Vitamin D deficiency

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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, 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 ( nm) Endogenous Vitamin D 3 (7-dehydoxycholesterol) DBP Liver 25-hydroxylase (CYP2R1) Dietary source Vitamin D 2 & D 3 Oily fish, eggs, fortified foods e.g: Infant formulas DBP 25-Hydroxyvitamin D (major circulating metabolite) Kidney 24,25-hydroxyvitamin D Cereals 24-hydroxylase (CYP24A1) 1α hydroxylase (CYP27B1) PTH (+) P (+) FGF23 (-) Calcitroic acid 1,25-Dihydroxyvitamin D

5 Low Calcium or Low Phosphorous Normal Growth Plate Radiograph showing Rachitic Changes 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 50 Cord 25(OH)D(ng/ml) R=0.98 (p<0.001) N = 22 Ethnicity Asians Caucasians Maternal 25(OH)D(ng/ml) Lau 2001 (Unpublished) Vitamin D stores acquired during fetal life last ~ 8 weeks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 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 ( N) N = 50 Manchester ( N) N=51 Age (years) 14.7 ± ± 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) % 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 525 Children 1-3 yrs 350 Children 2-6 yrs 450 Children 7-10 yrs 550 Adolescent boys yrs 1000 Adolescent girls yrs oz ~ 200 mg 1 pot ~ 150 mg ~ 35 mg/slice 1 Bowl ~ 80 mg

16 Vitamin D Deficiency & Muscle

17 Vitamin D Deficiency & Myopathy 8 th April 09 5 th May 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 Pre Rx Post Rx 25(OH)D (ng/ml) < PTH (ng/ml) (10-60) Calcium (mmol/l) ( ) Phosphate (mmol/l) ( ) Alk Phos (I/U) 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) 1.50 ( ) PTH (pmol/l) 34.3 ( ) OHD (nmol/l) 18.5 ( ) >50 Fractional shortening (%) 10 (5-18) 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 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 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 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) Proportion of children Placebo Vitamin D DID reduce readmission to hospital with pneumonia Time since recruitment (days) Number at risk (no of episodes) (p=0.01) Placebo 211 (52) 156 (45) 104 (19) 0 Vitamin D 204 (37) 162 (35) 121 (15) 0 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),

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 Proportion of children Vitamin D Placebo Time since recruitment (days) Number at risk (no of episodes) Vitamin D 1485 (94) 1362 (81) 1246 (8) 1217 (11) 1183 (50) 1086 (16) 0 Placebo 1477 (88) 1375 (82) 1252 (14) 1199 (9) 1169 (39) 1099 (13) 0 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