1. Dr Salah Mansy Consultant Paediatrician Conquest Hospital
Vitamin D metabolism
Dr Salah Mansy
Consultant Paediatrician
Conquest Hospital

2. Objectives Understand physiology and pathophysiology of vitamin D
Clinical presentations of vit D deficiency/insufficiency
Prevention and treatment of vit D deficiency/insufficiency
Thoughts for the future

3. Human skeleton
Protein matrix: osteoid (90%), osteocalcin and other proteins
calcium phosphate, calcium carbonate, sodium, magnesium, and citrate
Dynamic

4. Definitions
Rickets: only in growing children. Poor mineralisation before fusion of the epiphyses.
Osteomalacia: poor mineralization at all ages.
All patients with rickets have osteomalacia, but not all patients with osteomalacia have rickets
Osteoporosis: poor mineralization and loss of bone volume

5. Epidemiology
A disease of 19th and 20th century in northern Europe and the United States
Resurgence of vitamin D deficiency in UK
Recent prevalence data in UK children is lacking
Adult study
46.6% of white adults are vit D deficient. Am J Clin Nutr 2007;85:860-8
One in 8 white, 1 in 4 African Caribbean, 1 in 3 Asian adults are vit D deficient. Ann Clin Biochem 2006; 43:468-73

6. Risk factors Exclusively breast fed
Multiple short interval pregnancies
Vegetarian (or other non-fish eating) diet
Lack of sunlight exposure
Cultural influence on dress
Sedentary indoors lifestyle
Sunscreen use
Fear of cancer
Pigmented skin
Obesity
Malabsorption, short bowl or cholestatic liver disease
Use of anticonvulsants, rifampicin, cholestyramin, glucocorticoids or highly active antiretroviral treatment (HAART)

7. Sources Ultraviolet B sunlight exposure 90% of supply Oily fish
Cod liver oils
Infant formula milk (400 IU/L)
some breakfast cereals, breads and margarine
Breast milk: low (12–60 IU/L)
Egg yolk (20 IU)
Mushrooms (small quantities)

8. Table 2: Recommended Dietary Allowances (RDAs) for Vitamin D [1]
Age
Male
Female
Pregnancy
Lactation
0–12 months*
400 IU (10 mcg)
1–13 years
600 IU (15 mcg)
14–18 years
19–50 years
51–70 years
>70 years
800 IU (20 mcg)
* Adequate Intake (AI)

9. The metabolic pathway of vitamin D, indicating its conversion to the hormone 1,25(OH)2D3 and to 24,25(OH)2D3. Vitamin D2 (ergosterol), of plant origin, appears to undergo similar metabolic steps.

10. Physiology
1,25-D:
Intestine: marked increase in calcium absorption, less significant increase in phosphorus absorption ( most dietary phosphorus absorption is vitamin D–independent)
Bone resorption
PTH secretion suppression (negative feedback loop)
Kidney: inhibits its own synthesis and increases the synthesis of inactive metabolites
25-D is the standard method for determining a patient's vitamin D status because there is little regulation of the liver hydroxylation step.

11. Physiology
Parathyroid hormone (PTH) and vitamin D are the principal regulators of calcium homeostasis
Calcitonin and PTH-related peptide (PTHrP) are important primarily in the fetus.
Phosphate homeostasis is regulated by the kidneys because intestinal phosphate absorption is nearly complete and renal excretion determines the serum level

12. Causes of Rickets Vitamin D deficiency Calcium deficiency
Nutritional vitamin D deficiency
Congenital vitamin D deficiency
Secondary vitamin D deficiency 
Malabsorption 
Increased degradation 
Decreased liver 25-hydroxylase
Vitamin D–dependent rickets type 1
Vitamin D–dependent rickets type 2
Chronic renal failure
Calcium deficiency
Intake
Absorption
Rickets of prematurity
Phosphate deficiency
Renal diseases
Renal tubular acidosis

13. Diagnosis: History
History of poor growth, delayed walking, waddling gait, dental caries, pneumonia, and hypocalcaemia symptoms
Decrease dietary intake
Decrease skin synthesis: clothing, skin pigmentation, sun screen, season
Malabsorption due to liver or intestinal disease
Renal disease
Drugs e.g. Phenobarbital, phenytoin, aluminium-containing antacids, rifampicin, cholestyramin, glucocorticoids or highly active antiretroviral treatment (HAART)
Maternal risk factors for nutritional vitamin D deficiency
Family history of genetic disorders, leg deformities, difficulties with walking, or unexplained short stature , unexplained sibling death (Cystinosis)

14. Clinical features: General
Failure to thrive  
Listlessness  
Protruding abdomen  
Muscle weakness (especially proximal)  
Fractures

15. Clinical features: Head
Craniotabes 
Frontal bossing  
Delayed fontanelle closure  
Delayed dentition; caries  
Alopecia (vitamin D–dependent rickets type 2)

16. Clinical features: Chest
Rachitic rosary  
Harrison groove 
Respiratory infections and atelectasis

17. Clinical features: Extremities
Leg pain
Enlargement of wrists and ankles  
Valgus or varus deformities 
Coxa vara  
Anterior bowing of the tibia and femur   
Windswept deformity (combination of valgus deformity of 1 leg with varus deformity of the other leg)  

18. Clinical features: Back
Scoliosis 
Kyphosis  
Lordosis

19. Clinical features: Hypocalcaemia symptoms
Tetany  
Stridor due to laryngeal spasm
Seizures Stebbing C, Mansy S, Kanabar D (2002) The first reported presentation of rickets with metabolic seizures. Hospital Medicine 63:  

20. (A) a normal child
(B) a child with rickets: metaphyseal fraying and cupping of the distal radius and ulna.

21. Cupping and fraying

22. Rosary beads of rickets

23. X-rays of the knees in a 7 yr old girl with distal renal tubular acidosis and rickets. A, At initial presentation, there is widening of the growth plate and metaphyseal fraying. B, Dramatic improvement after 4 mo of therapy with alkali.

24. a two-year old rickets sufferer, with a marked genu varum, (bowing of the femurs) and decreased bone opacity, suggesting poor bone mineralization

25. VDDR: vitamin D–dependent rickets
XLH: X-linked hypophosphatemic rickets
ADHR: autosomal dominant hypophosphatemic rickets
HHRH: hereditary hypophosphatemic rickets with hypercalicuria
Pi: phosphorus
RD: relatively decreased (because it should be increased given the concurrent hypophosphatemia

26. Consequences of untreated vitamin D deficiency
Skeletal complications
Musculoskeletal pain particularly in adolescence. Arch Dis Child 2011;96:694-6
Reduced whole body bone mineral content and bone mass even at 9 years of age. Lancet 2006; 367:36-43
Hypertension, hyperglycaemia and metabolic syndrome in adolescents. Pediatrics 2009 Aug 3
Type 1 diabetes, multiple sclerosis, malignancy and schizophrenia. Pediatrics 2008;122:
Cardiomyopathy (3 deaths in the last 10 years in UK). Heart 2008;94:581-4

27. Threshold for intervention for vit D deficiency
25-hydroxyvitamin D level reliably determine vit D status. Nutr Rev 2008;66:S153-64
<25 nmol/l = severe deficiency = treat
25-50 nmol/l = insufficiency = supplementation
51-75 nmol/l = sufficiency = lifestyle advice
>250 nmol/l = excess = stop treatment
Arch Dis Child 2011,96:

28. Prevention of vit D deficiency in UK
Huge economic burden and preventive strategies are cost effective. Prog Biophys Mol Biol 2009;99:104-13
Healthy Start scheme
Free vit D to economically disadvantaged children and young mothers
Restrictive qualification criterion for supplements
Only children under 4
Only mothers with a very limited income
Asylum seekers are not entitled
Inconsistent dissemination of message regarding supplementation to pregnant women
Poor availability of supplements

29. Prevention of vit D deficiency in UK
Recommendations for vit D supplementation have not generally been implemented. Update on Vitamin D. Position Statement by the Scientific Advisory Committee on Nutrician
Better targeting of health resources to antenatal care, pregnant mothers and at risk children
Extending the range of food fortified with vit D
Clarification of the risk associated with UV radiation against the risk of deficient vit D synthesis

30. Vit D preparations Ergocalciferol (yeast derived D2)
Oily solution 3000 IU/ ml
Tablets IU or IU
Tablets calcium 400 mg and vitamin D 400 IU
Parenteral IU/ ml
Colecalciferol (fish or lanoline derived D3)
Dalvit 400 IU/ 0.6 ml
Abidec 400 IU / 0.6ml
Healthy Start vitamin drops 300 IU/ 5drops
Tablets IU
Alfacalcidol (one Alpha Hydroxycolecalciferol)
Oral/IV in persistent cases, renal, cholestatic liver disease

31. Treatment of deficiency
< 6months: 3000 IU daily for 8-12 weeks
> 6 months: 6000 IU daily for 8-12 weeks
> 1 year: 300,000–600,000 IU orally or intramuscularly as 2–4 doses over 1 day
Adequate dietary calcium and phosphorus
Daily vitamin D intake of 400 IU/day

32. Treatment of insufficiency
< 6 months: IU daily
> 6 months IU daily

33. Unanswered questions
Would eradication of vitamin D insufficiency in the UK reduce cancer incidence and improve cancer outcome?
Does poor vitamin D status cause obesity, or is it a consequence of obesity?
Are individuals genetically susceptible to vitamin D insufficiency or toxicity?
How much does vitamin D insufficiency contributes to north/south health inequalities?

34. Question time

35. Summary points Vitamin D insufficiency is common in UK
Vitamin D deficiency presentation is different in different age group
Vitamin D deficiency is easy to treat
Vitamin D is linked to other health problems e.g. cardiovascular, DM type 2 etc.
Vitamin D insufficiency is preventable however robust measures are not yet in place

36. Thank you