Vitamin D metabolism

Dr Salah MansyConsultant Paediatrician

Conquest Hospital

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

Human skeleton

Protein matrix: osteoid (90%), osteocalcin and other proteins

calcium phosphate, calcium carbonate, sodium, magnesium, and citrate

Dynamic

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

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

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)

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)

Age Male Female Pregnancy Lactation

0–12 months*400 IU

(10 mcg)

400 IU(10

mcg)   

1–13 years600 IU

(15 mcg)

600 IU(15

mcg)   

14–18 years600 IU

(15 mcg)

600 IU(15

mcg)

600 IU(15 mcg)

600 IU(15

mcg)

19–50 years600 IU

(15 mcg)

600 IU(15

mcg)

600 IU(15 mcg)

600 IU(15

mcg)

51–70 years600 IU

(15 mcg)

600 IU(15

mcg)   

>70 years800 IU

(20 mcg)

800 IU(20

mcg)   

* Adequate Intake (AI)

Table 2: Recommended Dietary Allowances (RDAs) for Vitamin D [1]

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.

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.

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

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 D–dependent rickets type 1 Vitamin D–dependent rickets type 2 Chronic renal failure

Calcium deficiency Intake Absorption Rickets of prematurity

Phosphate deficiency Intake Absorption Renal diseases Renal tubular acidosis Rickets of prematurity

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)

Clinical features: General

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

Clinical features: Head  

Craniotabes  Frontal bossing   Delayed fontanelle closure   Delayed dentition; caries   Alopecia (vitamin D–dependent rickets type

2)

Clinical features: Chest

Rachitic rosary   Harrison groove  Respiratory infections and atelectasis

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)  

Clinical features: Back

Scoliosis  Kyphosis   Lordosis

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  

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

Cupping and fraying

Rosary beads of rickets

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.

a two-year old rickets sufferer, with a marked genu varum, (bowing of the femurs) and decreased

bone opacity, suggesting poor bone mineralization

VDDR: vitamin D–dependent rickets XLH: X-linked hypophosphatemic ricketsADHR: autosomal dominant hypophosphatemic rickets HHRH: hereditary hypophosphatemic rickets with hypercalicuriaPi: phosphorusRD: relatively decreased (because it should be increased given the concurrent hypophosphatemia

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;122:398-417 Cardiomyopathy (3 deaths in the last 10 years in UK). Heart

2008;94:581-4

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 treatmentArch Dis Child 2011,96:614-615

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 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

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

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

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

Treatment of insufficiency

< 6 months: 200-400 IU daily > 6 months 400-800 IU daily

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?

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