Vitamin D

Simon Pearce Consultant Endocrinologist, RVI, Newcastle

Vitamin D

• Basic background • Public health • Cases & Clinical scenarios

Synthesis, activation & action

Skin Liver Kidney Active vitamin D hormone Calcium & skeletal homeostasis Immune system tissues Metabolic & vascular tissues Cellular Homeostasis & apoptosis

Vitamin D- natural sources

• Ergocalciferol – ‘Vitamin D2’ – UV irradiated fungi/ yeast • Colecalciferol – ‘Vitamin D3’ – UV irradiated plankton – UV irradiated animal skin/ fur

Vitamin D- natural sources

• >90% of humankind’s vitamin D comes from UV-B exposure of skin • 20-30 min of direct skin exposure to midday sun on face and arms, 2 or 3 times weekly provides sufficient for a fair-skinned person • Above 43 o N, the angle of sun to atmosphere filters out useful UV wavelengths between October and April.

Vitamin D- natural sources

• Sun block lotion SPF-8 prevents 95% of dermal vitamin D synthesis • Wearing a hat, veil or head scarf very substantially reduce skin vitamin D synthesis • Pigmented skin or elderly (thin skin) needs more exposure for same vit D production • Impossible to overdose on skin synthesised vitamin D; possible to sunburn

Scale of the public health problem

• Seasonal & geographic variation in prevalence of 25-OHD <40nmol/L • MRC 1958 birth cohort at age 45yrs =7437 whites • Spring nadir for 25OHD <20 nmol/L =16% <50 nmol/L =50% Hyppönen & Power 2007

Vitamin D- natural sources

• Food – Oily fish (top of the marine ecosystem) – Salmon, trout, mackerel, herring, fresh tuna, sardines, pilchards, anchovies – Fish oils (cod liver oil) • 2 portions of oily fish weekly (100-125g) sufficient to provide sufficient Vit D • Less Vitamin D in farmed fish • Heavy metals in some sea fish

Vitamin D- natural sources

• Common misconceptions – Negligible amount of vit D in milk – None in green vegetables • Small amounts in Egg yolk (20 yolks per day sufficient) • Small amount in mushrooms (100 per day sufficient) • Small amounts in animal liver (inc. seal liver) • Statutory supplementation in UK – Infant milk formula (500 IU/l) – Margarines (150-300 IU/100g)

How to determine vitamin D status?

• Measure serum 25 hydroxyvitamin D (25-OHD) – Robust marker of vit D stores – Half-life 3-4 weeks • Don’t measure 1,25 dihydroxyvitamin D – Active ‘D hormone’ – Circulating levels reflect PTH action and calcium supply – Often falsely normal or even elevated in D deficiency

How to determine vitamin D status?

25-OHD

(nmol/l)

<25 Vit D status

Deficient

25-50 50-75 >75

Insufficient Adequate Optimal

Manifestation Action

Rickets Osteomalacia Treat with high dose D Associated with disease risk Supplement with vit D Healthy Healthy Lifestyle advice None

Interpretation of serum 25-OHD

Men (n=3725) Women (n=3712) • UK-wide white cohort born 1958 Hypponen & Power 2007

Interpretation of serum 25-OHD

Men (n=3725) Women (n=3712) • UK-wide white cohort born 1958 Hypponen & Power 2007

Case 1

35 yo, Pakistani-born Lady

• Living in Fenham for 11 yrs • Migratory aches and pains, hips, legs, back during 3rd pregnancy • GP re-assured, but ? Depressed • 4/12 post partum-feels low, aches and pains persist= Fluoxetine 20mg od • Presents limping, with pain in R hip

GP did blood tests

• Calcium =1.89 mmol/l (2.12-2.6) • Alk Phos = 231 KIU/l (<120) • Rh factor negative •

Refer endocrinology

Endocrinology blood tests

• PTH 684 ng/l • 25-OH vitamin D = 7 nmol/l •

Diagnosis = Osteomalacia

Generalised Aches & Pains =not always depression

Sievenpiper J et al. BMJ

Treatment

• Oral ergocalciferol 10,000 IU daily for 3 months • Feels a lot better, aches and pains gone, smiling in clinic • But……..

• After topping up her vitamin D levels, she will need long-term maintenance – 1000 to 2000 IU calciferol daily – Regular sunlight exposure • Don’t forget the baby: who was slow to walk and had rickets with tibial deformities

NICE antenatal care guideline

Case 2

20 month old girl

• Mother reports lower limb deformity • 4th child, term birth, no problems • Breast fed until 8 months • Pain on walking, difficulty climbing stairs • Nigerian mother, asylum seeker housed in tower block • 3 older brothers born in Nigeria, no problems

• Ca 1.92 mmol/l (2.3-2.7) • PO4 1.26 mmol/l (1.1-1.85) • Alk Phos 1077 KIU/l (<375) •

Treatment

• Ergocalciferol oily solution, 3,000 IU/ml. 2mls daily • Mother and brothers, also to take supplements: Dalivit 0.6 mls daily

Healthy Start/ Sure Start

• The UK health departments recommend a daily dose of vitamins A, C and D for: – breastfed infants from 6 months (or from 1 month if there is any doubt about the mother's vitamin status during pregnancy) – formula-fed infants who are over 6 months and taking less than 500 ml infant formula per day – children under 5 years of age • This recommendation is particularly important for children who are picky or fussy eaters, those of Asian, African, Afro-Caribbean or middle eastern origin and

those living in northern areas of the UK

.

Case 3

45 yo woman

• Multiple sclerosis diagnosed age 29 • Only 2 major attacks • Feeling increasingly weak for 30 months • Painful to move legs, can’t stand up • Using wheelchair, even in house • Needs husband to pull her out of bed in morning

Fell out of bed one day

• Wedge # of L2 vertebral body • BMD measured; T score -3.4 at spine • Bone chemistry • (PTH 43)

Serum

Calcium Feb April 2.60 2.30

PO4 1.11

Alk Pase 62 25-OHD 10 0.77

48 11 • Treated with calcichew D3 one daily

• Allergic to fish; none since teenager • Not really leaving the house due to mobility • No overseas holiday for 5 yrs

Treatment

• Oral colecalciferol 20,000 IU capsules, 3 per week (Dekristol; pharmacy special order, approved by APC) • Vomiting and diarrhoea (contains fish oil!) • IM ergocalciferol 300,000 IU monthly for 3 months, • Oral vitamin D3 2 x 25ug capsules daily (2000 IU) from Holland and Barrett • 1 year later; walks unaided up to 200 m, no pain

How to determine vitamin D status?

25-OHD

(nmol/l)

<25 Vit D status

Deficient

25-50 50-75 >75

Insufficient Adequate Optimal

Manifestation Action

Rickets Osteomalacia Treat with high dose D Associated with disease risk Supplement with vit D Healthy Healthy Lifestyle advice None

Also OTC Boots (12.5 ug capsules) £2.99 for 90 Holland & Barrett (25 ug capsules) £6.99 for 100

Dosing issues

• 100 IU calciferol daily increases serum 25-OHD by 2.5 nmol/l • RDA is 400 IU (10 ug) • Increase serum 25-OHD by 10 nmol/l • Typical Newcastle patient with vitamin D insufficiency has levels between 20 and 30 nmol/l • Need to aim for 70 nmol/l or better • Toxicity seen at levels of 500 nmol/l or higher • 1- 2000 IU daily is appropriate maintenance dose (Adults)

Tips on treatment

• Most people who you suspect are D deficient, are D deficient • Supplementation is not the same as treatment • If a child has rickets, the siblings and mother should also be treated • Compliance with calcium containing preparations (calcichew D3) is poor, better to prescribe D only compounds for longterm use

The End

Questions

•

Is it worth screening all new patients from overseas at risk of vit D?

-When people first arrive, they aren ’ t deficient -Probably takes 5 years or a pregnancy to manifest severe D deficiency -Worth giving dietary/sunlight exposure advice to all at risk groups

Questions

•

Treatment- injection vs oral medication and how long for?

-Oral is better (all round); but current supply issues. -In severe deficiency a short course of monthly IM insures treatment is received -If GI problem, IM worthwhile

Questions

•

How often to monitor bloods once on treatment?

-Depends on manifestations, but maybe never or once in a year until dietary intake is no longer an issue -If Alk. Phos raised, recheck in 3 and 6 months; although it may take longer to normalise

Questions

•

When to refer?- and who to endocrine vs bone clinic

- Doubt about diagnosis; conflicting biochem (eg. Hypercalcaemia) - Failure to respond to treatment - Other nutritional issues (IDA frequently co-exists) - Childhood with bone disease - Vitamin D is actually a hormone

Questions

•

Patients with aches and pains and confirmed vit D def- should we be x-raying joints

I generally don ’ t, unless there is very localised pain (not generalised aches & pains) Pain not improved by 3 months treatment should trigger an X-ray

Dosing of colecalciferol in Autumn

10,000 U/d 5,000 U/d 1,000 U/d Placebo

From Heaney RP et al.