Vitamin D Deficiency

VITAMIN D DEFICIENCY
Dr Neera Agarwal
Consultant Physician - Cwm Taf Health Board

Honorary Senior Lecturer – School of Medicine, Cardiff University
February 2013
Content
 Source
 Physiology & metabolism
 Deficiency & resistance
 Requirements & Treatment
 ‘Extra-skeletal’ effects
History
 1600s 1st description of rickets by Whistler & Glisson
 1918 Sir Edward Mellanby linked with fat-soluble

nutrient
 1923 Goldblatt & Soames demonstrated exposure to

sunlight or UV light produced a substance with
similar properties
 1936 Identification of Vitamin D by Windaus

Modern Day Interest
 Vitamin D & metabolites

 Significant role in calcium homeostasis & bone metabolism
 Deficiency
 Rickets in children
 Osteomalacia in adults
 Rickets ? rare in most developed populations

Vitamin D Deficiency
 Subclinical deficiency
 Silent epidemic.
 Present in approximately 30% to 50% of the general population.
 More prevalent in elderly, women of child bearing age and

infants.
 Often unrecognized by clinicians.
 May contribute to development of osteoporosis & increased risk

of fractures related to falls in the elderly.
Vitamin D
 ‘Calciferol’
 Generic terms for a group of lipid-soluble

compounds with a 4-ring cholesterol backbone
Sources Of Vitamin D
 Sunlight (UV)
 Intestinal absorption (only ~20%)

 Oily fish
 Fortified milk / bread / cereal
 Supplements
Absorption & Metabolism
 Affected by fat malabsorption

 Pancreatic insufficiency
 CF
 Cholestatic liver disease
 Coeliac
 Crohn’s
Vitamin D Metabolism
 Skin
 UV light photo-isomerises provitamin D to D3 (cholecalciferol)
 Transported by Vit D binding proteins to liver
 Intestine
 Absorbed by enterocytes & packaged into chylomicrons
 Transported to liver by portal circulation
 Hydroxylated in liver to 25-ODH
 Further in kidneys to 1,25-OHD
 Physiologically active
Vitamin D Metabolism
Deficiency & Resistance
 Impaired availability of Vit D

 Lack of sun exposure, can be seasonal
 Fat malabsorptive states
 Impaired liver hydroxylation to 25-OHD
 Impaired renal hydroxylation to 1,25-OHD
 End-organ insensitivity to Vit D metabolites

 Hereditary Vit D resistant rickets
 Glucocorticoids – inhibit intestinal Vit D dependent calcium absorption

Consequences of Vitamin D Deficiency
 Reduced intestinal absorption of calcium &

phosphorus
 Hypophosphataemia precedes hypocalciaemia
 Secondary hyperparathyroidism
 Bone demineralisation
 Osteomalacia / rickets
Rickets
Osteomalacia
 After closure of epiphyseal plates

 Impaired mineralisation
 Fractures
 Lab tests
 Low calcium & phosphate
 High ALP
 X-rays
 Diffuse bone lucencies
Associated Clinical Conditions
 Muscle Weakness and Falls

 Proximal muscle weakness
 Chronic muscle aches
 Myopathy
 Increase in falls
 Recent studies suggest that vitamin D supplementation at doses

between 700 and 800 IU/d in a vitamin D-deficient elderly
population can significantly reduce the incidence of falls.
 Bone Density and Fractures

 Risk of osteoporosis may be reduced with adequate intake
of vitamin D and calcium.
 Studies support the concept that vitamin D at doses

between 700 and 800 IU/d with calcium supplementation
effectively increase hip bone density and reduced fracture
risk, whereas lower vitamin D doses may have less effect.
 Role in Cancer Prevention

 Low intake of vitamin D and calcium has been associated with an
increased risk of non-Hodgkin lymphomas, colon, ovarian, breast,
prostate, and other cancers.
 The anti-cancer activity of vitamin D
 a nuclear transcription factor that regulates cell growth,

differentiation, & apoptosis, central to the development of cancer
 Vitamin D is not currently recommended for reducing cancer risk

 Autoimmune Disease
 Vitamin D supplementation is associated with a lower risk of autoimmune
diseases.
 In a Finnish birth cohort study of 10,821 children, supplementation with

vitamin D at 2000 IU/d reduced the risk of type 1 diabetes by
approximately 78%, whereas children who were at risk for rickets had a 3-
fold higher risk for type 1 diabetes.
 In a case-control study of 7 million US military personnel, high circulating

levels of vitamin D were associated with a lower risk of multiple sclerosis.
 Similar associations have also been described for vitamin D levels and
rheumatoid arthritis.
 Role in Cardiovascular Diseases

 Vitamin D deficiency activates the renin-angiotensin-
aldosterone system and can predispose to hypertension
and left ventricular hypertrophy.
 Additionally, vitamin D deficiency causes an increase in

parathyroid hormone, which increases insulin resistance
secondary to down regulation of insulin receptors and is
associated with diabetes, hypertension, inflammation, and
increased cardiovascular risk.
 Role in Reproductive Health

 Vitamin D deficiency early in pregnancy is associated with a
five-fold increased risk of preeclampsia.
 Role in All Cause Mortality
 Researchers concluded that having low levels of vitamin D

(<17.8 ng/mL) was independently associated with an
increase in all-cause mortality in the general population.
At-Risk Groups
 Elderly
 Stores decline with age
 Winter
 House-bound or institutionalised
 Poor nutritional intake
 Impaired absorption
 CKD
At-Risk Groups
 Children
 Exclusively breast-fed infants
 Variable dietary intake
 Vegetarian or fish-free diet
 Ethnic background
 Women treated for osteoporosis

At-Risk Groups
 Healthy adults
 Immigrants
 Winter (1 in 6 UK adults)
 Boston study – Holick et al, 2002
 36% vs. 4% of healthy volunteers with normal Vit D

concentration at start & end of winter season
At-Risk Groups
 Hospitalised patients
 Age
 Sun exposure
 Intake
 Renal injury
 Burns victims
 22-42% prevalence in US studies

Assessment
Investigations
Diagnosis
Vitamin D Measurements
Interpretation Vit D Level (nmol/l) Action

Deficiency < 25 Replace Vit D
Loading dose followed by maintenance

Insufficient 25-50 Consider replacement if:
• Glucocorticoids
• Osteopenia/osteoporosis
• 2° HPTH
• Hypocalcaemia
• CKD
Maintenance dose
Replete >50 No need for replacement or continue
dose
Toxic >150 Check calcium
Stop treatment
Vitamin D Preparations
 (assuming normal renal function)

 Cholecalciferol
 D3
 Natural molecule in man
 Ergocalciferol
 D2
 Plant-derived
 Less effective than D3 preparations

Vitamin D Preparations
Vitamin D Supplementation
Deficiency (<25 nmol/l or 10 mcg/l)
 Oral Therapy
 1st line agent:
Fultium-D3 ® (Cholecalciferol) 800 iu capsules x4/d (licensed product) - 3200 iu daily

for 8-12 weeks.
 2nd line:
Dekristol® (Cholecalciferol) capsules 20,000 units (unlicensed import). Prescribe 1

capsule (20,000 units) once per week for 8-12 weeks.
Where oral therapy not appropriate

Ergocalciferol 300,000 (or 600,000) iu single dose by intramuscular injection. The
injection is gelatin free and may be preferred for some populations.
Deficiency (<25 nmol/l or 10 mcg/l)
 Oral Therapy
 1st line agent:
Fultium-D3 ® (Cholecalciferol) 800 iu capsules x4/d (licensed product) - 3200 iu daily

for 8-12 weeks.
 2nd line:
Dekristol® (Cholecalciferol) capsules 20,000 units (unlicensed import). Prescribe 1

capsule (20,000 units) once per week for 8-12 weeks.
 Where oral therapy not appropriate (e.g. malabsorption states)

 Ergocalciferol 300,000 (or 600,000) iu single dose by intramuscular injection. The
injection is gelatin free and may be preferred for some populations.
Insufficiency (25-50 nmol/l or 10-20 mcg/l) or for long-term maintenance

following rx of deficiency
 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.
Combined calcium & vitamin D supplements
 Calcium component usually unnecessary in primary

vitamin D deficiency
 Less palatable ? affects compliance
 Dual replacement required where there is severe

deficiency accompanied by hypocalcaemia leading to
secondary hyperparathyroidism
 appropriate for the management of osteoporosis and in

the frail elderly.
Alfacalcidol/Calcitriol
 Alfacalcidol (1 alpha- vitamin D) and Calcitriol have

no routine place in the management of primary
vitamin D deficiency
 Reserved for use in renal disease, liver disease and

hypoparathyroidism.
Monitoring
 1 month
 Bone and renal profile
 3 months
 Bone and renal profile, vitamin D, and plasma parathyroid
hormone.
 Once vitamin D replacement is optimised no further

measurement of vitamin D is necessary.
Conclusion
 Commoner than we think!
 Can be prevented:
 Promote awareness, especially in high-risk groups
 Sun-exposure
 Safe, 10-15 minutes per day (longer with darker skin)
 Adequate intake of fortified products in diet

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VITAMIN D DEFICIENCY

Consultant Physician - Cwm Taf Health Board

 Physiology & metabolism

 Deficiency & resistance

 Requirements & Treatment

 1600s 1st description of rickets by Whistler & Glisson

 1918 Sir Edward Mellanby linked with fat-soluble

 1923 Goldblatt & Soames demonstrated exposure to

 1936 Identification of Vitamin D by Windaus

 Vitamin D & metabolites

 Rickets ? rare in most developed populations

 Present in approximately 30% to 50% of the general population.

 More prevalent in elderly, women of child bearing age and

 Often unrecognized by clinicians.

 May contribute to development of osteoporosis & increased risk

 Generic terms for a group of lipid-soluble

 Intestinal absorption (only ~20%)

 Fortified milk / bread / cereal

 Affected by fat malabsorption

 Cholestatic liver disease

 Transported by Vit D binding proteins to liver

 Transported to liver by portal circulation

 Hydroxylated in liver to 25-ODH

 Further in kidneys to 1,25-OHD

 Impaired availability of Vit D

 Fat malabsorptive states

 Impaired liver hydroxylation to 25-OHD

 Impaired renal hydroxylation to 1,25-OHD

 End-organ insensitivity to Vit D metabolites

 Glucocorticoids – inhibit intestinal Vit D dependent calcium absorption

 Reduced intestinal absorption of calcium &

 Hypophosphataemia precedes hypocalciaemia

 After closure of epiphyseal plates

 Muscle Weakness and Falls

 Chronic muscle aches

 Recent studies suggest that vitamin D supplementation at doses

 Bone Density and Fractures

 Studies support the concept that vitamin D at doses

 Role in Cancer Prevention

 The anti-cancer activity of vitamin D

 a nuclear transcription factor that regulates cell growth,

 Vitamin D is not currently recommended for reducing cancer risk

 In a Finnish birth cohort study of 10,821 children, supplementation with

 In a case-control study of 7 million US military personnel, high circulating

 Role in Cardiovascular Diseases

 Additionally, vitamin D deficiency causes an increase in

 Role in Reproductive Health

 Role in All Cause Mortality

 Researchers concluded that having low levels of vitamin D

 Poor nutritional intake

 Variable dietary intake

 Vegetarian or fish-free diet

 Women treated for osteoporosis

 Boston study – Holick et al, 2002

 36% vs. 4% of healthy volunteers with normal Vit D

 22-42% prevalence in US studies

Interpretation Vit D Level (nmol/l) Action

Loading dose followed by maintenance

 (assuming normal renal function)

 Natural molecule in man