Vitamin D metabolism

1
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

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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

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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 200785860-8
• One in 8 white, 1 in 4 African Caribbean, 1 in 3
  Asian adults are vit D deficient. Ann Clin
  Biochem 2006 43468-73

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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)

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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 (1260 IU/L)
• Egg yolk (20 IU)
• Mushrooms (small quantities)

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Table 2 Recommended Dietary Allowances (RDAs)
for Vitamin D 1
Age Male Female Pregnancy Lactation
012 months 400 IU(10 mcg) 400 IU(10 mcg)    
113 years 600 IU(15 mcg) 600 IU(15 mcg)    
1418 years 600 IU(15 mcg) 600 IU(15 mcg) 600 IU(15 mcg) 600 IU(15 mcg)
1950 years 600 IU(15 mcg) 600 IU(15 mcg) 600 IU(15 mcg) 600 IU(15 mcg)
5170 years 600 IU(15 mcg) 600 IU(15 mcg)    
gt70 years 800 IU(20 mcg) 800 IU(20 mcg)    
Adequate Intake (AI)
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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.
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Physiology

• 1,25-D
• Intestine marked increase in calcium absorption,
  less significant increase in phosphorus
  absorption ( most dietary phosphorus absorption
  is vitamin Dindependent)
• 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.

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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

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Causes of Rickets

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

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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)

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Clinical features General

• Failure to thrive  
• Listlessness  
• Protruding abdomen  
• Muscle weakness (especially proximal)  
• Fractures

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Clinical features Head  

• Craniotabes 
• Frontal bossing  
• Delayed fontanelle closure  
• Delayed dentition caries  
• Alopecia (vitamin Ddependent rickets type 2)

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Clinical features Chest

• Rachitic rosary  
• Harrison groove 
• Respiratory infections and atelectasis

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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)  

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Clinical features Back

• Scoliosis 
• Kyphosis  
• Lordosis

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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 63 690-691
   

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(A) a normal child (B) a child with rickets
metaphyseal fraying and cupping of the distal
radius and ulna.
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Cupping and fraying
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Rosary beads of rickets
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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.
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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 Ddependent 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
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Consequences of untreated vitamin D deficiency

• Skeletal complications
• Musculoskeletal pain particularly in adolescence.
  Arch Dis Child 201196694-6
• Reduced whole body bone mineral content and bone
  mass even at 9 years of age. Lancet 2006
  36736-43
• Hypertension, hyperglycaemia and metabolic
  syndrome in adolescents. Pediatrics 2009 Aug 3
• Type 1 diabetes, multiple sclerosis, malignancy
  and schizophrenia. Pediatrics 2008122398-417
• Cardiomyopathy (3 deaths in the last 10 years in
  UK). Heart 200894581-4

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Threshold for intervention for vit D deficiency

• 25-hydroxyvitamin D level reliably determine vit
  D status. Nutr Rev 200866S153-64
• lt25 nmol/l severe deficiency treat
• 25-50 nmol/l insufficiency supplementation
• 51-75 nmol/l sufficiency lifestyle advice
• gt250 nmol/l excess stop treatment
• Arch Dis Child 2011,96614-615

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Prevention of vit D deficiency in UK

• Huge economic burden and preventive strategies
  are cost effective. Prog Biophys Mol Biol
  200999104-13
• Healthy Start scheme 2006. http//www.healthystart
  .nhs.uk
• 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

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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. 2007. http//www.sacn.gov.
  uk
• 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

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Vit D preparations

• Ergocalciferol (yeast derived D2)
• Oily solution 3000 IU/ ml
• Tablets 10 000 IU or 50 000 IU
• Tablets calcium 400 mg and vitamin D 400 IU
• Parenteral 300 000 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 20 000 IU
• Alfacalcidol (one Alpha Hydroxycolecalciferol)
• Oral/IV in persistent cases, renal, cholestatic
  liver disease

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Treatment of deficiency

• lt 6months 3000 IU daily for 8-12 weeks
• gt 6 months 6000 IU daily for 8-12 weeks
• gt 1 year 300,000600,000 IU orally or
  intramuscularly as 24 doses over 1 day
• Adequate dietary calcium and phosphorus
• Daily vitamin D intake of 400 IU/day

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Treatment of insufficiency

• lt 6 months 200-400 IU daily
• gt 6 months 400-800 IU daily

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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?

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Question time
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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

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Thank you