Vitamin D in Health and

Disease
Andrew Davison
Department of Clinical Biochemistry & Metabolic Medicine
Royal Liverpool & Broadgreen University Hospitals Trust
Outline
• Significance of Vitamin D

• Biochemistry of Vitamin D

• Role of vitamin D in health

• Vitamin D deficiency

• Interpretation of vitamin D

• Management of disorders of vitamin D metabolism

Significance of vitamin D
Vitamin D requests
The number of 25-hydroxyvitamin D assays
performed by one major reference laboratory
increased by 50% in the fourth quarter of 2009 as
compared with the same quarter in 2008, and it is
expected that several million tests will be
performed this year
(Parker-Pope T. The miracle of vitamin D: sound science or hype?
New York Times, Feb. 1, 2010).

Winter and spring 25(OH)D
concentrations <25, <40, and <75
nmol/L were found in 15.5%, 46.6%,
and 87.1% of participants

Summer and autumn – 3.2%,
15.4%, and 60.9%, respectively
Hypovitaminosis D in British adults at age 45y:
nationwide cohort study of dietary and lifestyle
predictors.
 More than 50% of the adult
population has insufficient levels
of vitamin D

 16% have severe deficiency
during winter and spring

 The survey also demonstrated a
gradient of prevalence across the
UK, with highest rates in
Scotland, Northern England, and
Northern Ireland.
Hyppönen E, Power C. Am J Clin Nutr 2007;85:860-8
Bowden S A et al. Pediatrics 2008;121:e1585-e1590

Prevalence of Vitamin D deficiency in age groups
Challenges
• No National Guidelines on investigation and
management of vitamin D deficiency

• Laboratories do not have uniform cut-offs to
define optimal levels

• Vitamin D is widely prescribed but uncertainty
remains around optimal dose
Biochemistry of vitamin D
Metabolism, Actions
Where does Vitamin D come from?
Pearce SHS, Cheetham TD. BMJ 2010:340;340-347
Vitamin D
Metabolism
How different are vitamin D2 and D3?

Holick MF. N Engl J Med 2007;357:266-81.
Calcium absorption
Gut
Kidney
Mechanism of action of 1,25(OH)D
VDRE
VDR
C
C
VDR C
VDR C
VDRE
mRNA
Proteins
CaBP ALP
IL-2
C: Calcitriol – 1,25(OH)
2
D
VDR: Vitamin D receptor
CaBP: calcium binding protein
Vitamin D metabolites
25(OH) D 1,25(OH)D
Source Liver Kidney,
placenta,
macrophages
Half Life 3-4 weeks 4-6hours
Regulation D2/D3 PTH,
phosphate,
FGF-23
Metabolite Major
circulatory
Biologically
active
• Circulate in plasma
bound to globulin or
vitamin D binding
protein (DBP) and to a
lesser extent to
albumin.

• Over 96% is eliminated
ultimately through the
bile into faeces
(calcitroic acid).

ROLE OF VITAMIN D
Musculoskeletal/Non-musculoskeletal Effects
VDR C
VDR
C*
VDR**
C
mRNA
Proteins
Calcium
*C or calcitriol: 1,25(OH) D
**VDR: vitamin D receptor
Musculoskeletal Effects


Vit D
• Improves Muscle Strength
Vit D
• Reduces Falls
Vit D
• Reduces non-vertebral Fractures
• Myopathy from severe vitamin D deficiency is reversible
with vitamin D supplementation.
Calcif Tissue Int 2000;66:419-24.

• Trials of older individuals at risk for vitamin D deficiency,
vitamin D supplementation improved muscle strength,
function, and balance in a dose-related pattern.
J Bone Miner Res 2003;18:343-51
Osteoporos Int 2009;20:315-22.


Holick MF. N Engl J Med 2007;357:266-81.
Non-Musculoskeletal Effects

Evidence
Colon
Cancer
• Cancer
Epidemiol
Biomarker
s Prev
2004;13:15
02–8
• Cancer
Epidemiol
• Biomarker
s
Prev2006;1
5:2467–72
Hypert
ension
• Hyperte
nsion
2007;19:
19
• MI
• Arch
Intern
Med
2008;168:
1174–80
Infections
• Science
2006;23:23



• Diabetes
• Am J Clin Nutr
2004;79:820–
5
•Vitamin D
deficiency has
also been found
to be associated
with non-
musculoskeletal
conditions.
Nutrition Rev
2008;66:S182-S194
Mortality
Arch Intern
Med
2007;
167:
1730–7
VITAMIN D DEFICIENCY
Epidemiology, Deficiency, Etiology, clinical presentation, risk factors
Epidemiology
• World wide prevalence of Vitamin D deficiency
 Lack of sunshine
 Pigmented skin
 Poor availability of dietary sources.

• Ultraviolet B solar irradiation (major source vitamin D)
 Latitude
 time of year/ day
 Skin pigmentation
Pearce SHS, Cheetham TD. BMJ 2010:340;340-347
Risk factors for vitamin D deficiency

Latitude >35°
• Sunlight is not able to
produce vitamin D all year
round.
• “Vitamin D winter”
The body depends on
vitamin D stores or on
dietary intake.

• Latitude <35°
• Sunlight is able to produce
vitamin D in the skin all year
round.
• “Low Vitamin D status”
 Skin pigmentation
 Seasonal
 Clothing
 Elderly
 obesity
 Poor dietary intake

USA: 50-80%(10-30ng/ml or 25-
75nmol/L)
Holick et al.
Arch Intern Med
2009;169: 626-32
USA: 42% of 15- to 49-year old black
girls and women
(<20ng/ml or 50nmol/L)

Third NHANES, 1988-
1994. Am J Clin
Nutr 2002;76:18792.

UK: 50%during winter and spring
(10-20ng/ml or 25-50nmol/L)

Hyppönen E et al. Am J
Clin Nutr
2007;85:860-8.

Saudi Arabia, United Arab Emirates,
Australia, Turkey, India, Lebanon:
30-50% children and adults
(<20ng/ml or 50nmol/L)


Ann Nutr Metab
1984;28:181-5.
Am J Clin Nutr
2005;82:477-82.


1 billion people worldwide have vitamin D deficiency or insufficiency.(>30ng/ml
or 75nmol/L is optimal levels) Mayo Clin Proc 2006;81:353-73.
Holick MF. N Engl J Med 2007;357:266-81.
Holick MF. N Engl J Med 2007;357:266-81.
Clinical Presentation
Skeletal abnormalities

• Rickets (children)
– Bone deformities

• Adults (osteomalacia)
– Muscle pain
– Proximal muscle
myopathies
– Tetany
Non skeletal abnormalities

• Cancer – prostate, breast
• Autoimmune conditions
• Cardiovascular disease
• Infectious disease
• Diabetes


Bone Metabolic Disorders
Bone Fractures
Consequences of Vitamin D deficiency

Biochemical Investigation of Vitamin D Deficiency
• Increased serum alkaline phosphatase, indicating increased osteoblast activity, is the
most common abnormality (note: alkaline phosphatase is elevated during pubertal
skeletal growth).

• Serum calcium is usually normal, in association with secondary hyperparathyroidism and
a raised PTH, but may be low in severe cases.

• Serum phosphate may be low, owing to increased PTH-dependent phosphaturia, though
this is variable.

• Serum 25OHD is usually low (the exception being vitamin D-resistant rickets). Serum
1,25(OH)2D levels are also usually low, especially in VDDR type 1.

• X-rays are often normal in adults, but may show defective mineralization, especially in
the pelvis, long bones and ribs, with pseudofractures or 'Looser's zones' - linear areas of
low density surrounded by sclerotic borders.

• Iliac crest biopsy with double tetracycline labelling is occasionally necessary if
biochemical tests are equivocal.

• Serum fibroblast FGF-23 is sometimes elevated in tumour-associated osteomalacia
Biochemical diagnosis of Vitamin D Deficiency
25(OH)D


ALP

Serum Calcium
PTH
1,25(OH)D
D3
25(OH)D 1,25(OH)
2
D
Reliable marker of nutritional status Poor indicator of nutritional
status
Depends upon D2/D3 Tight regulation
Long Half life (2-3 weeks) Short half life (4-6h)
Reflects deficiency at an early stage

Levels increase/normal
deficiency
INTERPRETATION OF VITAMIN D
STATUS
Stratification, optimal cut off
Pearce SHS, Cheetham TD. BMJ 2010:340;340-347
Serum 25-hydroxyvitamin D in Health & Disease
Management of vitamin D
deficiency
Vitamin D supplementation, lifestyle advice
Pearce SHS, Cheetham TD. BMJ 2010:340;340-347
• Vitamin D3 is preferred over vitamin D2 or active vitamin D
preparations.

• The daily oral preparation of vitamin D supplement is preferred
over intermittent oral or intramuscular doses.

• 25(OH)D levels should be measured 6 monthly in patients (vitamin
D deficiency or insufficiency) on vitamin D therapy until optimal
levels are reached. Thereafter, check levels yearly.

• In elderly >65 years or those <65 years with history of osteoporosis
or fractures optimal 25(OH)D levels to be achieved should be
between 75-100nmol/L.

• Calcium supplements combined with vitamin D are preferred in
those with a dietary calcium intake below 1000mg/day.
Mersey Vitamin D Guidelines, 2012
Mersey Vitamin D Guidelines, 2012
Mersey Vitamin D Guidelines, 2012
• The major natural source of vitamin D is from skin synthesis following
ultraviolet B solar irradiation.

• In a fair skinned person, 20 to 30 minutes of sunlight exposure on the face
and forearms at midday is estimated to generate the equivalent of around
2000 IU of vitamin D. Two or three such exposures a week are sufficient to
achieve healthy vitamin D levels in summer.

• For individuals with pigmented skin and, to a lesser extent, the elderly,
exposure time or frequency need to be increased twofold to 10-fold to get
the same level of vitamin D synthesis as fair skinned young individuals.

• Only a relatively small number of foods contain substantial amounts of
vitamin D, the most significant dietary sources being oily fish eg trout,
salmon, mackerel, herring, sardines, anchovies, pilchards and fresh tuna.


Lifestyle Advice

Pearce SHS, Cheetham TD. BMJ 2010:340;340-347
Preparations of Calciferol in the UK