Vitamin D Deficiency
Relevant Physiology
Vitamin D is a fat-soluble vitamin that acts primarily to increase calcium and phosphorus absorption from the GI tract.
Key terms and concepts:
- Vitamin D enters the body in 2 main precursor forms (native vitamin D):
- Vitamin D3 (colecalciferol) – mainly produced by the skin from 7-dehydrocholesterol following UVB exposure, also obtained from animal-based foods and supplements
- Vitamin D2 (ergocalciferol) – mainly obtained from fungi, fortified foods and supplements
- 25-hydroxyvitamin D (calcifediol) = the intermediate and main circulating form of vitamin D
- Also referred to as: 25(OH)D
- 1,25-dihydroxyvitamin D (calcitriol) = biologically active form of vitamin D
- Also referred to as: 1,25(OH)₂D
Learning aid: The terms 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D are umbrella terms that include metabolites derived from both vitamin D₂ and vitamin D₃. For example, there are 25-hydroxyvitamin D₂, 25-hydroxyvitamin D₃, 25-dihydroxyvitamin D2, and 25-dihydroxyvitamin D3.
These distinctions are usually omitted because both forms undergo the same activation pathway and have similar physiological roles.
The pathway of vitamin D activation:
| Step | Conversion | Site of conversion | Involved enzyme |
|---|---|---|---|
| 1 | Vitamin D3 (colecalciferol) and Vitamin D2 (ergocalciferol) → 25-hydroxyvitamin D (calcifediol) | Liver | 25-hydroxylase |
| 2 | 25-hydroxyvitamin D (calcifediol) → 1,25-dihydroxyvitamin D (calcitriol) (active form of vitamin D) | Kidney | 1α-hydroxylase |
Causes and Risk Factors
In the UK, 80-90% of vitamin D is derived from skin exposure to sunlight (endogenous synthesis), 10-20% is derived from diet.
Causes of vitamin D deficiency
- Inadequate sun (UVB) exposure
- Causes of GI malabsorption (e.g. Coeliac disease, IBD, cystic fibrosis)
- Severe liver failure
- End-stage chronic kidney disease
- Hereditary vitamin D-deficiency rickets
- Drugs (orlistat, antiepileptic drugs, etc.)
Risk factors:
- ≥65 y/o
- Low / no exposure to sun
- Darker skin pigmentation
- Pregnant / breastfeeding
- Obese (BMI >30)
Clinical Manifestation
Vitamin D deficiency is commonly asymptomatic.
Prolonged and untreated vitamin D deficiency can cause:
- Osteomalacia (in adults) or rickets (in children)
- Secondary hyperparathyroidism (a compensatory response to reduced vitamin D-mediated GI calcium absorption)
- Hypocalcaemia (only seen in severe vitamin D deficiency and when the compensatory mechanism fails)
Investigation and Diagnosis
Test of choice: serum 25-hydroxyvitamin D
Serum 25-hydroxyvitamin D is the best indicator of vitamin D deficiency, as it has a longer half-life (~2-3 weeks) and is the major circulating form of vitamin D, reflecting the body’s vitamin D storage.
Although 1,25-dihydroxyvitamin D is the active hormone form, it has a short half-life (~4-6 hours). Its level may remain normal or elevated even in vitamin D deficiency, due to secondary hyperparathyroidism increasing conversion.
Indications for checking vitamin D level (ANY of the following):
- Symptomatic
- Suspected bone disease that may improve with vitamin D treatment
- Bone disease that requires vitamin D deficiency correction prior to treatment
Do not routinely test for vitamin D deficiency in asymptomatic patients.
- Asymptomatic patient at higher risk of vitamin D deficiency does NOT need testing (they can just be started on oral vitamin D supplement)
- Patients being treated with antiresorptive agent and vitamin D supplements do NOT need testing
Management
Most cases of vitamin D deficiency are prevented and treated with colecalciferol (vitamin D₃). Ergocalciferol (vitamin D₂) is an alternative but is less commonly used. Therefore, when this article refers to “oral vitamin D”, it generally means vitamin D₃ or vitamin D₂ – the native or precursor forms of vitamin D.
Activated vitamin D preparations (calcitriol or 1,25-dihydroxyvitamin D) are not routinely used for uncomplicated vitamin D deficiency. Notable indications include:
- In patients with CKD stage 4 or 5 (eGFR <30) when vitamin D deficiency has been corrected, but CKD-MBD persist (see the Chronic Kidney Disease (CKD) article for more information)
- In hypoparathyroidism (see the Hypoparathyroidism article for more information)
Treating Established Vitamin D Deficiency
Offer lifestyle advice:
- Safe sunlight exposure
- Dietary advice on vitamin D and calcium intake
Offer oral vitamin D supplements:
- For rapid correction → loading dose (total of 300,000 IU over 6-10 weeks) followed by maintenance therapy (800-2,000 IU daily)
- For non-urgent correction → maintenance therapy (800-2,000 IU daily)
Also, assess the need for calcium supplementation:
- If there is dietary insufficiency → advise to increase dietary calcium intake
- If dietary change not appropriate → calcium supplementation
NICE CKS states to seek specialist advice / arrange referral before starting vitamin D treatment in the following conditions.
Combination calcium and vitamin D preparations (e.g. Calcichew D3®) are NOT recommended for people needing high-dose vitamin D treatment, as they contain very low levels of vitamin D (200-400 IU per tablet) and may increase the risk of hypercalcaemia.
Preventing Vitamin D Deficiency
Offer lifestyle advice:
- Safe sunlight exposure
- Dietary advice on vitamin D and calcium intake
Consider oral vitamin D supplements (400 IU daily):
- ≥65 y/o with risk factors for vitamin D deficiency should take a daily vitamin D supplement
- All other adults should consider taking a daily vitamin D supplement, particularly in autumn and winter
References