vitamin d zulf mughal consultant in paediatric bone disorders department of paediatric endocriology...

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Lau 2001 (Unpublished)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!

Thank You

zulf.mughal@cmft.nhs.ukzulf.mughal@cmft.nhs.uk