Guideline on the Diagnosis and Management of Vitamin D Deficiency in Adults

Aims of Guideline
1) Advice on the diagnosis and management of Vitamin D deficiency in adults. 2. Overview of the investigation of suspected Vitamin D deficiency. 3) Overview of the treatment of Vitamin Deficiency

Vitamin D physiology
Vitamin D3 (Colecalciferol) is synthesised in the skin through the action of ultraviolet light on cholesterol. Colecalciferol is also available in the diet, and largely obtained from oily fish and some fortified cereals. It is unusual to get more than 20% of total intake from a normal diet. Yet the UK is without adequate UV exposure from October to April to permit sufficient production of vitamin D. The recommended daily intake of vitamin D is 400units/d yet this is only sufficient to prevent severe vitamin D deficiency and in the absence of adequate photosynthesis of vitamin D is likely to be an inadequate replacement. (1-4) Vitamin D is converted in the liver to 25OH Vitamin D3 which is the major storage form and is the molecule measured in the laboratory when requesting Vitamin D. Further hydroxylation of 25OH Vitamin D3 by the kidney results in the production of the metabolically active 1,25 DiOH Vitamin D3 and involves parathyroid hormone (PTH). This is a self-regulating process, with evidence of Vitamin D deficiency being manifest through higher concentrations of PTH. At present, most of our knowledge and evidence base for management of Vitamin D related issues comes from effects on bone metabolism with evidence of decreased bone density and increased fracture risk associated with vitamin D insufficiency. However, emerging evidence implicates Vitamin D deficiency with increased risk of type 2 diabetes, hypertension, cancer and multiple sclerosis yet any positive effects of replacement are as yet unknown (3).

Risk factors for Vitamin D deficiency

Vitamin D deficiency is very common in the UK with some studies suggesting that up to 50% of the UK population are insufficient and 1 in 6 adults having severe deficiency during winter months (1 !"# $ome individuals are more prone to vitamin D deficiency due to ris% factors# Inadequate UV light exposure Occlusive garments Pigmented skin Institutionalised or housebound GI effects Metabolic risk

Vegetarian (or fish-free diet) Malabsorption, short bowel or cholestatic liver disease Cholestyramine use

Elderly Drugs (Rifampicin, anticonvulsants, HAART therapy, glucocorticoids). Liver disease Multiple, short interval pregnancies

linical features of Vitamin D deficiency

!"M#$%M! and !IG&! Muscle aches and bone pains Proximal myopathy Hypocalcaemia, a later effect

Assessing the patient

#opulation screening by measuring Vitamin D concentrations is not 'ustified but consider measuring (itamin D in )high risk* patients presenting +ith symptoms ,as abo(e-.

#atient characteristics
Healthy, no risk factors, symptom free

Ad(ice and management

No investigations required Lifestyle advice Consider preventive therapies Lifestyle advice Consider long term preventative therapies Lifestyle advice Investigations Therapeutic intervention Long term preventative treatment

Risk /actors %nly

Risk factors A&D symptoms/signs

In(estigations
$est
Renal function Liver function tests FBC Parathyroid hormone Calcium, Phosphate Alkaline phosphatase 25-OH Vitamin D concentrations

Reason
Exclude renal disease Iron deficiency commonly co-exists

Diagnosis

Measurement 0 Interpretation of serum 123 hydroxy(itamin D

Adults Vitamin D deficiency can be diagnosed by requesting a 25-OH vitamin D concentration. The following table defines deficiency and insufficiency. In vitamin D deficiency, there is no requirement to measure 1,25 di-hydroxy vitamin D concentrations as its half life is relatively short and this does not adequately reflect vitamin D stores.

!erum 123hydroxy(itamin D concentrations4 status and management 567 mcg89 ,512 nmol8lDeficiency: ;igh dose treatment initially ,<177 iu daily for =361 +eeks-4 then long term maintenance treatment required ,6>77 iu8d-. Insufficiency: long term maintenance treatment ,6>77 iu8d;ealthy4 gi(e lifestyle ad(ice %ptimal

67317 mcg89 ,12327 nmol8l-

17 ? <7 mcg89 ,273@2 nmol8lA<7 mcg89,A@2 nmol8l-

onsider referral for specialist ad(ice in the follo+ing groups.

Atypical clinical manifestations or biochemistry Deficiency due to malabsorption /ailure to respond to treatment after < months /ocal bone pain 9i(er disease4 9ymphoma4 Metastatic cancer #arathyroid disorders Renal disease4 Renal stones Unexplained +eight loss

Ad(ice on prescribing of Vitamin D for Adults

Daily treatment with Vitamin D (either Cholecalciferol or Ergocalciferol) is associated with a rise in measured vitamin D concentrations, representing an increased amount of stored Vitamin D. Typically a 1000iu of vitamin D3 will raise 25OH Vitamin D concentrations by 25 nmol/l (10 mcg/L) (2). Provided basic investigations are normal, Vitamin D toxicity is rare and is only seen when concentrations exceed 500 nmol/l (200 mcg/L). Extremely large daily doses in excess of 10,000 units (250mcg) are generally required to achieve this (5). Except in toxicity, Vitamin D therapy rarely produces an elevated calcium concentration. There are many vitamin D formulations available and much has been published on the expense of specials where in some circumstances the price is many multiples of the actual cost. Currently, there is only one MHRA licensed vitamin D3 formulation Fultium D3. Based

upon the stringent licensing requirements of the MHRA and the specified NHS price (3.60), our guidance advocates the use of this preparation. Alternatives include Dekristol which is used weekly although is an unlicensed and hence 'special'.

Ad(ice and management

)Deficiency* in adults ,512 nmol8l ,567 mcg89-Oral Therapy 1st line agent: Fultium-D3 (Cholecalciferol) 800 iu capsules x4/d (licensed product) - 3200 iu daily for 8-12 weeks. 1nd line: Dekristol (Cholecalciferol) capsules 20,000 units [unlicensed import]. Prescribe 1 capsule (20,000 units) once per week for 8-12 weeks.

%nce corrected remember to s+itch to long term maintenance treatment as directed belo+.
Where oral therapy not appropriate Ergocalciferol 300,000 (or 600,000) iu single dose by intramuscular injection (4). The injection is gelatin free and may be preferred for some populations. Then give long term maintenance treatment below.

)Insufficiency* in adults ,67317 mcg89 ,12 ? 27 nmol8l-%R long term maintenance therapy follo+ing treatment of deficiency in adults
1st line therapy: Fultium-D3 800iu capsules x2/d (licensed) - 1600iu per day (a dose between 1000 2000 units daily is appropriate). 2nd line: Prescribe Dekristol capsules 20 000 units [unlicensed import]. Prescribe 1 capsule (20,000 units) once per fortnight.

Alternatively where oral therapy not appropriate Ergocalciferol 300,000 international units single dose by intramuscular injection once or twice a YEAR (4).

;ealthy4 no risk factors4 symptom free

(Intake and synthesis presumed adequate) Lifestyle advice. Can consider daily self-treatment with Colecalciferol of 400-800 iu daily amount likely to prevent rickets, but unlikely to significantly raise vitamin D concentrations to optimal in most people.

Intestinal Malabsorption8 hronic li(er disease

Vitamin D deficiency in intestinal malabsorption or in chronic liver disease often requires higher doses of pharmacological vitamin D than for primary deficiency (see BNF). One editorial suggests ergocalciferol 300,000 iu by intramuscular injection monthly for 3 months, followed by 300,000 iu by intramuscular injection once or twice a year (2).

ombined

alcium and Vitamin D products

Confining guidance to vitamin D deficiency, prescribers should avoid giving combined calcium and vitamin D preparations in the long term because the calcium component is usually unnecessary, reduces palatability and hence compliance (1,2). Where there is severe deficiency accompanied by hypocalcaemia, leading to secondary hyperparathyroidism, treatment with Vitamin D should be accompanied at least initially by Calcium supplementation 1-2 grams daily consider referral for advice. Much more vigilant monitoring of calcium concentrations is required to prevent hypercalcaemia. Combinedcalciumand vitaminD preparationsare appropriatefor the managementof osteoporosisand in the frail elderly.

!upplementary Information
Monitoring requirements
&ot all patients re'uire monitoring of their vitamin D concentrations# (ndividuals that have ris% factors and are )eing treated with supplemental treatment do not need to have their vitamin D concentrations measured# Consider monitoring of patients receiving therapy for vitamin D deficiency when there is the suspicion of malabsorption and when symptoms do not resolve with treatment. Consider referral to secondary care in such patients. 1 month: Request serum calcium and renal profile 3 months: Request bone and renal profile, vitamin D, and plasma parathyroid hormone.

Once vitamin D replacement is optimised no further measurement of vitamin D is necessary.

A(ailable Vitamin D preparations

Colecalciferol (Vitamin D3) is the natural molecule manufactured in man whereas Ergocalciferol (Vitamin D2) is derived from plants. A licensedformulationexistsfor VitaminD3 FultiumD3 800iucapsules).Vitamin D2 is less effective than Vitamin D3. This guideline would endorse supplementation with Colecalciferol in preference to Ergocalciferol based on the above plus the majority of evidence for Vitamin D replacement is based on Colecalciferol. The BNF currently lists two single ingredient products of high dose ergocalciferol (e.g. Ergocalciferol tablets 10,000 & 50,000 international units) (3). Due to ongoing supply problems neither of these preparations are currently available in the UK.

!upplies of higher dose (itamin D preparations:

#referred product: Cholecalciferol capsules are the more readily available and the cheaper preparation.
The only currently licensed Cholecalciferol product in the UK is /ultium3D< *00iu capsule + ,-#60 per -0 ta)lets ((nternis .harmaceuticals ltd !-/ 0egents .ar% 0d 1ondon &- -12"# 3he product is Kosher and 4alal although does contain 5rachnis oil so should not )e given to those with peanut allergy#

In'ection There is a licensed UK injection of ergocalciferol. This is gelatin free and is currently available. An intermittent regimen for vitamin D deficiency would be off-label (see previously). Ergocalciferol, 7.5 mg (300 000 units)/mL in oil, Injection for intramuscular use only. 1-mL amp = 7.45, 2-mL amp = 8.95.

Due to the exorbitant cost of some of these preparations ,e.g. up to B277 for <7ml- they should &%$ be routinely prescribed. A named patient supply of an unlicensed liquid preparation of (itamin D should only be used in exceptional circumstances +here patients are unable to use olecalciferol capsules or the in'ection abo(e ,e.g. #CG feeding 0 needle phobic-.

Alfacalcidol8 alcitriol ,!pecialist initiation onlyAlfacalcidol (1 alpha- vitamin D) and Calcitriol have no routine place in the management of primary vitamin D deficiency and should be reserved for use in renal disease, liver disease and hypoparathyroidism.

#regnancy 0 Dreastfeeding
Breast milk from women taking pharmacological doses of vitamin D can cause hypercalcaemia if given to an infant (additional monitoring is required). Doses of approximately 4000iu/d have been shown to provide adequate vitamin D concentrations (6). High dose intermittent regimes are not suitable in pregnancy, and daily dosing is preferred: Deficiency in adults: Fultium-D3 2400 iu/d daily (unlicensed use) for 8-12 weeks.

Insufficiency in adults or maintenance following deficiency: 800-2000 iu daily

References: 1. Primary vitamin D deficiency in adults. Drug and Therapeutics Bulletin 2006; 44(4): 25-29 2. Pearce SHS, Cheetham TD. Diagnosis and management of Vitamin D deficiency. BMJ 2010;340:b566. 3. British National Formulary. Ed 58: Sept 2009. Available online at www.bnf.org 4. European Commission. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Concentration of Vitamin D (expressed on 4 December 2002). SCF/CS/NUT/UPPLEV/38 Final. http://europa.eu.int/comm/food/fs/sc/scf/index_en.html 5. Hathcock JN et al. Risk assessment of vitamin D. American Journal of Clinical Nutrition, Vol. 85, No. 1, 6- 18, January 2007. 6. Hollis BW et al (2011) Vitamin D supplementation during pregnancy: Double blind, randomized clinical trial o
sa ety and e ecti!eness" # Bone $iner %es" 2011 #un 2&" doi: 10"1002'(bmr")*+" ,-pub a.ead o print/

9eads for this policy: Dr E! Da(ies4 onsultant Cndocrinologist4 Uni(ersity ;ospital of Fales4 ardiff Dr E ;ar(ey4 onsultant Cndocrinologist and Diabetologist4 !enior 9ecturer4 ardiff Uni(ersity and Frexham Maelor ;ospital. Dr D #rice4 onsultant Diabetologist Cndocrinologist4 Morriston ;ospital4 !+ansea Dr arol C(ans4 Diochemist4 U;F4 ardiff Ackno+ledgements Cast 9ancashire ;ealth Cconomy Guideline. Diagnosis and Management of Vitamin D Deficiency for &on3!pecialists