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

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 D

Solar UVB (280-310nm)

Endogenous Vitamin D3

Dietary sourceVitamin D2 & D3

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

Normal Growth Plate Rachitic Growth Plate

Low Calcium

or

Low Phosphorous

Radiograph showing

Rachitic 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

Cord 25(OH)D(ng/ml)

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 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Lau 2001 (Unpublished)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

Criteria or Definition of Vitamin D Deficiency

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]

Low 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, Mughal. Low Calcium intake & Hypovitaminosis D in Adolescent

Girls. Archives of Disease in Childhood. 2007 ;92(11):1045

Low Calcium Diet & Vitamin D Deficiency

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

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

DIAGNOSIS: Severe 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: Single 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 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 Deficiency

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)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 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

Proportion of children

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

incidence of Pneumonia: A randomised controlled trial

0.50

0.75

1.00

Proportion of children

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.uk