Download Vitamin D deficiency

Optimal Nutrition and Adaptive Potential:
Function of Dietary Supplements
Vitamin D: Health Benefits And
Reduction Of Disease Risk
Susan J. Whiting PhD
University of
Saskatchewan
CANADA
What’s Important About Vitamin D
METABOLISM
New knowledge of vitamin D in past 10 years
- Importance of intermediate 25hydroxyvitamin D
- Need to provide vitamin D to all tissues, not
just for bone
Dietary requirements need to be changed to
meet the newly discovered health benefits
3
Importance of 25(OH)D
•
•
•
•
Transport form of vitamin D
Is directly correlated with vitamin D stores
Not active metabolite
Is the only substrate for 1,25D
- 1,25D made in kidney for endocrine [calcium
and phosphate] metabolism
- 1,25D made in other cells for autocrine uses
• Serum 25(OH)D levels are measured for
status
4
25(OH)D is substrate for 1,25D in
paracrine/autocrine and endocrine reactions
5
Holick M. N Engl J Med 2007;357:266-281
What’s Important About Vitamin D
HEALTH BENEFITS
Bone: ↓ fractures ↓ ricketic bones
Muscle strength and balance: ↓ falls
Pain: ↓ rickets and Osteomalacia
Immunity: ↓ recent colds and flu; ↓ Tuberculosis
Autoimmunity: ↓ Multiple sclerosis, Type 1
diabetes
Cardiovascular and Diabetes: ↓ blood pressure;
↓ insulin resistance
Cell growth: ↓ cancer (colorectal, breast)
Figure illustrates multiple causes and multiple outcomes of
deficiency: from head to toe. Holick 2008
7
Vitamin D Status and Disease
Serum
25(OH)D
< 20 nmol/L
(<8 ng/ml)
30 nmol/L
(< 12 ng.ml)
EFFECT
Vitamin D deficiency (rickets or
osteomalacia
Not at risk for classical clinical deficiency
– “old” threshold to define deficiency
75 nmol/L
New threshold for vitamin D:
(30 ng/ml)
maximal calcium absorption; improved
balance and muscle strength  fracture
and falls reduction
90-100 nmol/L Further reduction in risk for many
(35-40 ng/ml) chronic conditions such as cancer
>250 nmol/L Potential adverse effects seen above this
(> 100 ng/ml) level (hypercalcemia)
Vitamin D’s role in so many disease
processes has biological plausibility
Endocrine Pathway: vitamin D promotes calcium
and phosphate absorption; each of these
minerals is important for healthy bone, muscle,
cardiovascular, brain tissues.
Paracrine/autocrine Pathway: 1,25D is a
transcription factor in cells
- Cell differentiation, immunity
9
Optimal Calcium Absorption
A function of 25(OH)D level: Heaney 07
10
Improvement of Physical Performance in
Older Adults is Related to serum 25(OH)D
= sum score walking test, chair stands, tandem stand
=> better balance, less falls
11
Wicherts ‘07
What’s Important About Vitamin D
HIGHER REQUIREMENT
Revised requirements are needed
New knowledge of vitamin D in past 10 years
- ↑Intake to provide vitamin D to all tissues to
satisfy need for higher levels of 25(OH)D
Dietary requirements need to be changed
- To meet the newly discovered health benefits
- To acknowledge lack of adequate sun (UVB)
exposure
Relative Risk of incident cancer
1100 IU Vitamin D per day reduces
Relative Risk of any cancer
1.2
25(OH)D = 71 nmol/L
1
0.8
25(OH)D = 71 nmol/L
0.6
25(OH)D = 96 nmol/L
0.4
NS
NS
P=0.01
0.2
P<0.005
0
Placebo
Calcium Alone
All 4 years
Calcium + Vitamin D
Without first year
13
Lappe et al., 2007
Studies Corroborate Cancer
Prevention with vitamin D
• Garland 2007:
– Reduce breast cancer risk by 50% when
25(OH)D > 130 nmol/L
– Reduce colon cancer risk by 50% if 25(OH)D
> 85 nmol/L
• Freedman 2007:
– Colon cancer risk reduced by 28% if 25(OH)D
is 80 nmol/L or higher
14
Vitamin D Effective at Reducing
Fractures and Falls
Cranney et al., 2007 performed metaanalysis of literature commissioned by NIH
Findings significant in long-term care:
• Vitamin D and calcium ↓ risk of fracture
• Vitamin D and calcium ↓ risk of falls
Most studies used 800-1000 IU Vitamin D and
500-1200 mg calcium and subjects were
mainly white postmenopausal women
15
Vitamin D Effective at Reducing
Fractures and Falls
Bischoff-Ferrari, 2009 re-analysed studies that
Cranney and others had used, adjusting for
received dose (i.e., removing those with low
levels of supplementation or use of vitamin D2)
For studies where received dose was > 400IU,
fracture risk in community and institutionalized
adults showed Vitamin D ↓ risk of hip fractures
and nonvertebral fractures.
16
Higher dose trials:
Vertebral (top) and
hip fracture
reduction (bottom).
Final Relative Risk
(RR) show
significant
reduction. in
fractures.
Bischoff-Ferrari et
al. Arch Int Med
March23/09
What’s Important About Vitamin D
DIETARY INTAKES
Why dietary intakes are not keeping up with
requirements:
Loss of sun exposure: no longer our major
source of D
Lack of D in the diet: few natural sources
Food fortification: risks and benefits; need to
have staple foods
Supplementation: now encouraged for all
Canadians (2007)
Vitamin D Status and Disease
Serum
25(OH)D
< 20 nmol/L
(<8 ng/ml)
30 nmol/L
(< 12 ng.ml)
Dietary Intakes needed for effect
Vitamin D deficiency (rickets or
osteomalacia
Not at risk for classical clinical deficiency
200 IU
75 nmol/L
New threshold for vitamin D:
(30 ng/ml)
maximal calcium absorption; improved
balance and muscle strength > 400 IU
(500 IU to maintain; 5000 IU to replete)
90-100 nmol/L Further reduction in risk for many
(35-40 ng/ml) chronic conditions + 2000 IU
>250 nmol/L Potential adverse effects seen above this
(> 100 ng/ml) level (hypercalcemia) > 10,000 IU
How Much Dietary Vitamin D will
maintain 25(OH)D > 75 nmol/L?
Need for vitamin D related to degree of sun
exposure:
• Complete lack of sun exposure:
= Determine need for vitamin D to replete then maintain
25(OH)D
• Seasonal lack of sun exposure:
= Determine need for vitamin D to maintain 25(OH)D
that was obtained in summer
20
500 IU maintains 25(OH)D
in winter – Germany
Year 1
Year 2
30 ng/ml =75 nmol/L
Vitamin D
Intervention: 500
IU/ d
21
Meier et al., JBoneMinerRes 2004
Vitamin D intake to attain a desired
serum 25-hydroxyvitamin D
concentration: Aloia et al. 2008
• Gave doses of vitamin D to white and
black American adults in winter, to
determine how much D was needed to
raise 25(OH)D above 75 nmol/L
=> a dose of 5000 IU needed to ensure all
those entering study below 55 nmol/L;
needed to be given for 9-18 weeks to
replete.
22
Irish study of vitamin D supplementation for 22
weeks in older adults at latitude 51°
~600 IU enough to reach 75 nmol/L for half of population
~1600 IU to reach 75 nmol/L for 97.5% of population
80
70
60
25(OH)D
nmol/L 50
before winter
after winter
40
30
20
10
0
placebo
Cashman et al., AJCN 2008
200 IU
400 IU
600 IU
Physiological Factors Affecting
Need for Vitamin D
Age:
– less skin synthesis; less ability to make 1,25D
Body Size and /or body fatness
– Need is relative to body size
– Adipose may “hoard” D and make less
accessible to blood
Life stage: pregnancy and lactation
Skin pigmentation
– Melanin is natural sunscreen
24
Persons with higher body fat have lower vitamin D
status: is it metabolic or sun avoidance?
Serum 25(OH)D concentration from the National Health and Nutrition
Examination Survey (NHANES) 1988-1994 by body fat quartile (Q) for nonHispanic white women aged 20-49 y. Serum 25(OH)D means are age-adjusted
25
Yetley, E. A Am J Clin Nutr 2008;88:558S-564S
Supplements improve intake of older Canadians
from 200 to 400 IU (2004 survey data)
Mean intake of vitamin D supplement (µg/d)
Usual vitamin D intake (µg/d) from food
micrograms
Vitamin D intake form food & supplement(µg/d)
14
12
10
8
6
4
2
0
19-30 M
19-30 F
31-50 M
31-50 F
51-70 M
51-70 F
71 & Over M 71 & Over F
26
Environmental Factors Affecting
Need for Vitamin D
Factors related to ↓sun exposure
•
•
•
•
Latitude > 40° gives a long “vitamin D winter”
Clothing, sun screens block UVB
Pollution, cloudy weather reduce UVB exposure
Working or staying indoors from 10am-3pm
It is now not possible to assume that sun
exposure provides us with all the
vitamin D we need in Canada
27
Estimated Times to make 1000 IU if
expose 25% of body surface
Webb & Engelsen 2006: assumes cloudless day
Skin Type
I II III IV VVI -
White burns easily
White – mostly burns
White - mostly tans
Mediterranean
East Asian
African
Time (minutes) at
noon June 21
At 62.5 ºN
7
9
11
16
21
36
28
Estimated Times to make 1000 IU if
expose 25% of body surface
Webb & Engelsen 2006: assumes cloudless day
Skin Type
I II III IV VVI -
White burns easily
White – mostly burns
White - mostly tans
Mediterranean
East Asian
African
Time (minutes) at
noon March 21
At 62.5 ºN
44
55
67
106
163
n/a
29
Prevalence (%) of low serum 25(OH)D
In USA 2000-2004
Yetley, E. A. Am J Clin Nutr 2008;88:558S-564S
30
Groups Recommending Vitamin
D Supplements of 25 µg (1000 IU)
• USDA in 2005 Dietary Guidelines
= those who are older or those who lack sun-exposure
• Canadian Dermatology Association
– as this group promotes sun avoidance
• Canadian Cancer Society
– in winter and all year for those at-risk
• National Osteoporosis Foundation 2008
– for adults who are at-risk for vitamin D deficiency
31
Canada’s Food Guide (2007)
recommends vitamin D supplementation
• Recommends all adults
over 50 years take a
supplement of 400 IU
• This document is
“policy” for diet-based
programs such as
nursing homes and
hospitals
32
What’s Important About Vitamin D
SAFETY
In 1997, for USA and Canada, estimates of
the highest safest amount was published
(Upper Level = safe, but risk of adverse
effects begins with intake about this
amount)
Since this time, many have criticized the
value that was set for adults
33
Upper Level (UL) for vitamin D
Reference
Upper Level (UL)
DRI, 1997
1y+
1y+
50 µg (2000 IU)
20 µg (800 IU)
Hathcock et al.
2007 review of
evidence
> 19 y
250 µg (10,000 IU)
34
Safety of Vitamin D
• There is a UL for vitamin D of 50 µg (2000 IU) in
USA/Canada
– UL of 1000 IU for infants
• By definition a UL is safe
• Experts say intakes of ~10,000 IU/day, which
can bring 25(OH)D up to 250 nmol/L, are safe
• For repletion, intakes above the UL are required
and necessary
35
Vitamin D Toxicity
• At 25(OH)D levels above > 375 nmol/L,
hypercalciuria or hypercalcemia may occur
• All known cases are from labelling errors, faulty
manufacturing, dosing errors or excessive
dosing by health provider; none from accidental
supplement use
– With large repletion doses, monitoring is advised
• Overdoses: resolve with withdrawal of product
and sun avoidance
36
Vitamin D Hypersensitivity
• Tissues in autocrine/paracrine pathway
overproduce 1,25D which is released into blood
and acts to cause hypercalemia
– Granulomatous disease (e.g., sarcoidosis) and
lymphoma
– Diagnosis: elevated serum calcium, elevated 1,25D
– So-called Marshall Protocol not proven
• Treated by avoiding D in foods/supplements and
avoiding sun exposure
– Controversial as these patients become vitamin D
deficient
37
What’s Important About Vitamin D
PUBLIC WELL-BEING
Prevention of chronic conditions:
• Improved quality of life for the individual
– Decrease risk of many chronic diseases
– Immediate impact: colds and influenza risk
• Economic benefit to government
38
On the Epidemiology of Influenza
Cannell et al. Virology J. 2008 5:29
• Innate immunity: 1,25D ↑synthesis of
AMPs that exhibit rapid and broadspectrum antimicrobial activity against
bacteria, viruses and fungi.
• Humans make beta-defensin 2 and
cathelicidin that directly disable
microorganisms (irreversible damage to
lipoprotein membranes) and indirectly as
chemo-attractants for macrophages and
neutrophils.
Vitamin D status can affect innate
immunity and therefore colds, flu,
and other infectious diseases
• Cathelicidin also plays a role in epithelial
repair by triggering epithelial growth and
angiogenesis while beta-Defensin 3
inhibits influenza haemagglutinin A
mediated fusion.
• In the macrophage, the presence of 1,25D
may suppress the pro-inflammatory
cytokines.
Incidence of reported cold/influenza symptoms
according to season: northern USA
The 104 subjects in the placebo group (light shade)
reported cold and flu symptoms year around with the
most symptoms in the winter. Vitamin D-treated subjects
reported very few incidences.
Aloia JF, Li-Ng M: Epidemic influenza and vitamin D. Epidemiol Infect 2007;
135: 1095–1096
Estimated benefit of improved vitamin D
status in reducing economic burden of
disease in western Europe
Grant et al. 2009 Prog Biophys Mol Biol
• Raise 25(OH)D
levels to 100
nmol/L, using a
supplement:
consider direct
and indirect
costs, plus cost
of supplement,
to find net
saving.
200
180
160
Millions
of Euros
140
120
100
80
Direct Indirect
Total
Net
saving
Conclusions
The amount of vitamin D needed to protect against
bone loss, cancer, poor immunity, diabetes and
cardiovascular disease exceeds what we can get
from diet.
Sun-induced synthesis of vitamin D is compromised
during winter and with many factors (clothing,
being indoors) that prevent UVB radiation
reaching skin.
The amount needed to maintain healthy levels
year-round can be met only by supplementation