Transcript The Health Benefits of Vitamin D A presentation for East Tennessee State University September 18, 2012 by William B.

The Health Benefits
of Vitamin D
A presentation for
East Tennessee State University
September 18, 2012
by William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center
San Francisco, California
www.sunarc.org
Disclosure
I am pleased to acknowledge funding from these
organizations:
 Bio-Tech-Pharmacal (Fayetteville, AR)
 Sunlight Research Forum (Veldhoven, Netherlands)
 The UV Foundation (McLean, VA)
 The Vitamin D Council (San Luis Obispo, CA)
 The Vitamin D Society (Canada)
Outline
Vitamin D physiology
Epidemiological studies and randomized
controlled trials
Vitamin D and cancer
Selected vitamin D-sensitive diseases from a list
of 100 such diseases
 Infectious diseases, cardiovascular diseases
Mortality rates
U-shaped serum 25(OH)D-health outcomes
Vitamin D sources and recommendations
Annual Number of Vitamin D
Publications Listed at Pubmed.gov
4500
4000
Vitamin D publications
3500
3000
2500
2000
1500
1000
1985
1990
1995
2000
Year
2005
2010
2015
Vitamin D Physiology
 Vitamin D3 (cholecalciferol) is made by the action of
ultraviolet-B (UVB) radiation on 7-dehydrocholesterol in
the skin, followed by a thermal process.
 Solar UVB extends from 290-315 nm
(UVA extends from 315-400 nm)
 Vitamin D3 is converted in the liver to 25-hydroxyvitamin
D3 [25(OH)D], the circulating form.
 25(OH)D is converted in the kidneys to 1,25dihydroxyvitamin D3 [1,25(OH)2D3], the active form of
vitamin D, for circulation in the blood.
 It is also converted in other organs as needed, such as to
fight cancer.
Vitamin D continued
 Vitamin D receptors (VDRs) are activated by
1,25(OH)2D and affect expression of over 200 genes,
upregulating about two-thirds, downregulating onethird.
 VDRs come in different alleles, with different effects.
 The half life of 25(OH)D3 is about 4-6 weeks.
 Vitamin D is stored in adipose tissue; 25(OH)D is stored
in muscles, and along with 1,25(OH)2D, circulates in the
blood.
 Vitamin D2 (ergocalciferol) is made in mushrooms or
from yeast, and is much less effective than vitamin D3.
Types of Epidemiological Studies
There are four basic types of epidemiological
studies used to identify and quantify links
between risk-modifying factors and disease:
 Nested case-control from cohort studies – a defined
population followed for years after blood draw;
 Case-control – blood drawn at time of diagnosis;
 Cross-sectional – survey of a large population;
 Ecological – populations are defined geographically
or temporally (seasons or longitudinal); both disease
outcome and risk-modifying factors are averaged by
region or time.
Strengths and Weaknesses
 Nested case control – weakness: single serum
25(OH)D concentration at time of enrollment.
 Case-control – strength: 25(OH)D concentration at
time of diagnosis; weakness – disease state may
influence 25(OH)D concentration.
 Cross-sectional – weakness: health conditions may
affect 25(OH)D concentration.
 Ecological – strengths: solar UVB is primary vitamin
D source, large numbers of cases, many data sets,
can account for confounding factors, works well for
cancer, multiple sclerosis. Weaknesses: other
factors also affect seasonality or trends.
All-cause Mortality Rate Hazard
Ratio vs. Follow-up Period
1.2
1.1
95% CI
1
Grant, DermatoEndocrinology 2012
4(2)
Hazard ratio
0.9
Regression
fit
0.8
0.7
95% CI
0.6
0.5
0.4
0
5
10
Follow-up period (years)
15
Randomized Controlled Trials (RCTs)
 RCTs are essential for pharmaceutical drugs to
demonstrate efficacy and uncover risks.
 Many vitamin D RCTs used doses that were too low
(400 IU/day) to produce any effects.
 There have been a number of successful vitamin D
RCTs, including those for hip-fractures, all-cause
mortality rate, cancer incidence, and type A
influenza.
Hill’s Criteria for Causality in a
Biological System
A. Bradford Hill [1965] laid down criteria for
causality in a biological system . The main
criteria are:
 Strength of association
 Consistency (repeated in different populations)
 Biological gradient
 Plausibility (mechanisms)
 Experiment (e.g., randomized controlled trial)
 Analogy
 (Account for confounding factors)
Ecological Studies of UVB, Vitamin D,
Cancer
The first epidemiological study hypothesizing
that solar UVB, through production of vitamin D,
reduced the risk of cancer was published in
1980.
The brothers Cedric Garland and Frank
Garland, beginning graduate students at Johns
Hopkins School of Public Health in 1974,
looked at the map of colon cancer mortality
rates in the U.S. and saw a link to solar
radiation.
300
300
350
350
Colon cancer mortality rates,
males, 1970-94;
Index of annual solar radiation
300
350
300
350
400
400
450
500
500
450
Higher UVB in the west
is due to higher surface
elevation and thinner
stratospheric ozone layer
19 Vitamin D-Sensitive Cancers (from several
ecological and observational studies)
Vitamin D-sensitive cancers with moderate-tostrong support after accounting for other
factors:
Gastrointestinal: colon, esophageal,
gallbladder, gastric, pancreatic, rectal
Urinary: bladder, kidney; Male: prostate
Female: breast, cervical, endometrial,
ovarian, vulvar
Blood: Hodgkin’s and non-Hodgkin’s
lymphoma, leukemia
Miscellaneous: melanoma
Why Ecological Studies of Cancer Are
Powerful
Solar UVB is the primary source of vitamin D.
The risk for cancer can occur anytime in life
including youth. Studies found reduced risk for
breast and prostate cancer for UVB in youth.
Cancers generally take 15-40 years to progress
from initiation to detection or death.
Vitamin D has effects at all stages of cancer,
initiation, progression, and metastasis.
Thus, integrated serum 25(OH)D levels over
long periods of time are important in reducing
the risk of cancer incidence and death.
Observational Studies of Breast and
Colorectal Cancer vs. Serum 25(OH)D
Observational studies provide useful data for
determining the serum 25(OH)D concentrationcancer incidence rate relation for breast and
colorectal cancer.
Stronger inverse correlations between 25(OH)D
concentrations and cancer incidence are found
for case-control studies or cohort studies with
short follow-up times.
Breast Cancer Incidence vs.
Follow-up Period
1.4
1.2
Breast cancer (RR)
1
Only studies with
follow-up periods
less than three years
found statistically
significant inverse
correlations
0.8
0.6
Breast cancer (RR)
Breast 95% CI low
Breast 95% CI high
0.4
0.2
0
2
4
6
Follow-up period (years)
8
10
Meta-Analysis of Breast Cancer Risk with
Respect to Diagnostic Serum 25(OH)D
Based on five
case-control
studies from Germany,
Mexico, UK, and USA
I
I
Cancer Survival with Respect to
Serum 25(OH)D Level
 Vitamin D reduces the risk of dying from cancer by
reducing angiogenesis around tumors and reducing
metastasis.
 Higher survival rates have been reported for higher
serum 25(OH)D concentrations at time of diagnosis for
breast, colorectal, lung, ovarian, prostate cancer,
melanoma and non-Hodgkin’s lymphoma.
Colon Cancer Survival
Hazard ratios (all cause mortality)
1.35
1.0
1.37
p trend = 0.02
Referent
0.94
0.9
HR = 0.81
HR = 0.81
0.8
0.7
0.6
HR = 0.52
0.5
0.49
0.48
0.4
0.3
0.29
0.2
0.1
16.5 ng/mL
23.6 ng/mL
28.9 ng/mL
40.0 ng/mL
(+ 0.4)
(+ 0.2)
(+ 0.3)
(+ 0.8)
Mean plasma 25-hydroxyvitamin D quartiles ng/mL (+ se)
Hazard ratios for all cause mortality among 304 colorectal cancer patients by prediagnostic mean
plasma 25-hydroxyvitamin D concentration by quartiles, multiple-adjusted, Nurses Health and
Health Professionals Study Cohorts
Source: Ng K, Meyerhardt JA, Wu K, Feskanich D, Hollis BW, Giovannucci EL, Fuchs CS. Circulating 25-hydroxyvitamin D
levels and survival in patients with colorectal cancer J Clin Oncol 2008; 26: 2984-91.
Can Vitamin D Explain Cancer
Disparities?
There are 13 types of cancer for which AfricanAmericans have lower survival rates than whiteAmericans after consideration of
socioeconomic status, stage at diagnosis, and
treatment.
African-Americans have lower serum 25(OH)D
concentrations than white-Americans (16 ng/ml
vs 25 ng/ml).
This difference likely accounts for a 20%
difference in survival rates.
Grant and Peiris, Dermato-Endocrinology, 2012
Treatment of Prostate Cancer
 All subjects had a diagnosis of low-risk prostate cancer.
 Vitamin D(3) supplementation at 4000 IU/d for 1 yr.
 24 of 44 subjects (55%) showed a decrease in the
number of positive cores or decrease in Gleason score;
five subjects (11%) showed no change; 15 subjects
(34%) showed an increase in the number of positive
cores or Gleason score.
 Marshall DE, et al. Vitamin D3 supplementation at 4000
international units per day for one year results in a decrease of
positive cores at repeat biopsy in subjects with low-risk prostate
cancer under active surveillance. J Clin Endocrinol Metab. 2012
Jul;97(7):2315-24.
Mechanisms for Cancer Risk Reduction
Effects on cellular differentiation and
proliferation
Maintains epithelial cell integrity and tight
junctions between cells
Increased calcium absorption
Anti-angiogenesis
Anti-metastasis
1-25-dihydroxyvitamin D
 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) or
calcitriol], the hormonally active vitamin D metabolite,
exhibits anticancer actions in models of breast cancer
and prostate cancer.
 Because CYP27B1 (1α-hydroxylase), the enzyme
catalyzing 1,25(OH)(2)D(3) formation in the kidney, is
also expressed in extrarenal tissues, we hypothesize
that dietary vitamin D(3) will be converted to
25(OH)D(3) in the body and then to 1,25(OH)(2)D(3)
locally in the cancer microenvironment in which it will
exert autocrine/paracrine anticancer actions.
1-25-dihydroxyvitamin D - 2
Immunocompromised mice bearing MCF-7
breast cancer xenografts showed significant
tumor shrinkage (>50%) after ingestion of a
vitamin D(3)-supplemented diet (5000 IU/kg)
compared with a control diet (1000 IU/kg).
Dietary vitamin D(3) inhibition of tumor growth
was equivalent to administered calcitriol (0.025,
0.05, or 0.1 μg/mouse, three times a week).
Dietary vitamin D(3) did not increase serum
calcium, demonstrating its safety at the
concentration tested.
1-25-dihydroxyvitamin D - 3
Both calcitriol and dietary vitamin D(3) were
equipotent in suppressing estrogen synthesis
and signaling and other proinflammatory and
growth signaling pathways. These preclinical
data demonstrate the potential utility of dietary
vitamin D(3) supplementation in cancer
prevention and therapy.
 Swami S, Krishnan AV, Wang JY, Jensen K, Horst R,
Albertelli MA, Feldman D. Endocrinology. 2012
Jun;153(6):2576-87.
Hill’s Criteria Applied to Cancer
 Strength of association - yes
 Consistency (repeated in different populations) –
yes – ecological studies in Australia, China, France,
Japan, Spain, United States; case-control studies
for breast cancer in four countries
 Biological gradient – yes
 Plausibility (mechanisms) - yes
 Experiment (e.g., randomized controlled trial) – yes
(two)
 Analogy – yes, similar geographical findings for
dental caries (shown later)
 (Account for confounding factors) - yes
Infectious Diseases – Induction of
Cathelicidin and Defensins
 1,25-dihydroxyvitamin D induces production of human
cathelicidin, LL-37, a polypetide with modest
antimicrobial and potent antiendotoxin activities, and
defensins.
 There is strong evidence that LL-37 can fight bacterial
infections: dental caries, pneumonia, septicemia, TB.
 There is also evidence that LL-37 can fight some viral
infections: Epstein-Barr virus, influenza, rhinovirus.
However, the effect of vitamin D may be mediated
through modification of the cytokine production by the
innate immune system.
Infectious Diseases – Vitamin D
and Cytokines
Another important role of vitamin D is the
regulation of cytokines and related proteins.
Cytokines are proteins that deliver signals to
other cells.
Many cytokines are pro-inflammatory such as
interleukin-4 (IL-4) and IL-6.
Vitamin D shifts the cytokine balance away
from inflammatory ones.
Thus, vitamin D reduces inflammation during
infection.
Epidemic Influenza
Edgar Hope-Simpson pointed out that influenza
outbreaks were inversely correlated with solar
UV.
John Cannell, M.D., et al. hypothesized that
epidemic influenza is seasonal in part due to
seasonal variations of solar UVB and vitamin D.
However, cold temperatures and low relative
humidity in winter also affect the seasonality.
Hope-Simpson RE. The role of season in the epidemiology of
influenza. J Hyg (Lond). 1981 Feb;86(1):35-47.
Cannell JJ, et al. Epidemic influenza and vitamin D. Epidemiol
Infect. 2006 Dec;134(6):1129-40.
RCT with Vitamin D for Type A
Influenza
 “Influenza A occurred in 18 of 167 (10.8%) children in the vitamin
D(3) group compared with 31 of 167 (18.6%) children in the
placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P =
0.04]. The reduction in influenza A was more prominent in children
who had not been taking other vitamin D supplements (RR: 0.36;
95% CI: 0.17, 0.79; P = 0.006) and who started nursery school
after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children
with a previous diagnosis of asthma, asthma attacks as a
secondary outcome occurred in 2 children receiving vitamin D(3)
compared with 12 children receiving placebo (RR: 0.17; 95% CI:
0.04, 0.73; P = 0.006).”
 Urashima et al., Am J Clin Nutr. 2010 May;91(5):1255-60.
Hospital-Acquired Infections (HAIs)
There are many types of HAIs:
 Bacteremia, bacterial sepsis, Clostridium difficile,
pneumonia, surgical site infections, catheterassociated urinary tract infections, and virulent
organisms such as MRSA.
Many people arrive in hospitals due to diseases
related to low serum 25(OH)D concentrations.
Increasing serum 25(OH)D concentrations
would reduce risk of HAIs.
 Dima A. Youssef, Tamra Ranasinghe, William B. Grant
and Alan N. Peiris, Dermato-Endocrinology
2012;4(2):167-175
Dental Caries
Dental caries are caused by oral bacteria.
Vitamin D, through induction of cathelicidin,
reduces concentration of oral bacteria.
This was first shown in a study of vitamin D2
supplementation in 1928 by May Mellanby.
Several recent studies identified cathelicidin as
a way to reduce dental caries.
 Grant WB. A review of the role of solar ultraviolet-B
irradiance and vitamin D in reducing risk of dental
caries. Dermatoendocrinol. 2011;3(3):193-198.
Dental Rank vs. Solar UVB Dose in
July
50
Dental health rank, UVB <7.0 kj/m2
Dental health rank, UVB >7.0 kJ/m2
Dental health rank, UVB <7.0 kj/m2
40
30
20
10
0
3
4
5
6
7
UVB July (kJ/m2)
8
9
10
Cardiovascular Disease
Several recent observational studies found that
those with lower serum 25(OH)D had higher
risk of cardiovascular disease (coronary heart
disease and/or stroke) incidence or mortality
rate.
The mechanisms appear to include reducing
risk of metabolic disease through effects on
insulin sensitivity, blood pressure, and arterial
calcification, as well as reducing risk of
infectious diseases and inflammation.
Meta-analysis of CVD Incidence
Rate vs. 25(OH)D Concentration
CVD hazard ratio
909-Vitamin D CVD
2.4
y = 5.3864 * x^(-0.43143) R= 0.93611
2.2
CVD hazard ratio
2
1.8
1.6
Data from
Dobnig, 2008;
Giovannucci, 2008;
Ginde, 2009;
Kilkkinen, 2009
1.4
1.2
1
0.8
5
10
15
20
25
30
25(OH)D ng/mL
35
40
45
Seasonality of CVD
Risk of cardiovascular disease is about 20-25%
higher in winter than in summer.
Inflammation is an important risk factor.
Infection, such as by influenza virus, increases
inflammation through increasing production of
proinflammatory cytokines.
A study in China found cytokines associated
with influenza significantly increased among
those with acute myocardial infarction.
 Inflamm Res. 2012 Jun;61(6):591-8
Periodontal Disease (PD)
PD is characterized by tooth attachment loss
and bacteria.
PD is associated with systemic diseases such
as cardiovascular disease and diabetes.
PD is also associated with adverse pregnancy
outcomes such as gestational diabetes, preeclampsia, premature delivery, and low birth
weight.
Treatment of PD sometimes reduces adverse
pregnancy outcomes, sometimes does not.
Periodontal Disease Ramifications
Vitamin D reduces risk of PD by killing bacteria
through cathelicidin, reducing inflammation,
and reducing concentrations of Matrix
metalloproteinases (MMPs).
Thus, periodontal disease can serve as an
indication of vitamin D deficiency.
Pregnant women with PD should be advised to
take 4000 IU/d vitamin D3 and achieve a serum
25(OH)D concentration of 40 ng/ml.
 Hollis BW, et al. Vitamin D supplementation during pregnancy:
double-blind, randomized clinical trial of safety and effectiveness. J
Bone Miner Res. 2011 Oct;26(10):2341-57.
Erectile Dysfunction
 “Erectile dysfunction (ED) is a multifactorial disease,
and its causes can be neurogenic, psychogenic,
hormonal and vascular. ED is often an important
indicator of cardiovascular disease (CVD) and a
powerful early marker for asymptomatic CVD.”
 “We show here that risk factors associated with a
higher CVD risk also associate with a higher ED risk.
Such factors include diabetes mellitus, hypertension,
arterial calcification and Inflammation in the vascular
endothelium.”
 Sorenson and Grant, Dermato-Endocrinology 2012;4(2)
Diabetes and Erectile Dysfunction
A total of 3,791 CV events were reported in 3
cohort studies and 9 cross-sectional studies
(covering 22,586 subjects). Across the cohort
studies, the overall odds ratio (OR) of diabetic
men with ED versus those without ED was 1.74
(95% confidence interval [CI]: 1.34-2.27;
P<0.001) for CV events and 1.72 (95% CI: 1.51.98; P<0.001) for coronary heart disease
(CHD).
Diabetes and Erectile Dysfunction
In the cross-sectional studies, the OR of
diabetic men with ED versus those without ED
was 3.39 (95% CI: 2.58-4.44; P<0.001) for CV
events (N = 9), 3.43 (95% CI: 2.46-4.77;
P<0.001) for CHD (N = 7), and 2.63 (95% CI:
1.41-4.91; P = 0.002) for peripheral vascular
disease (N = 5).
Yamada T, et al. PLoS One. 2012;7(9):e43673.
Mortality Rate and Vitamin D
 Overall, 12 original studies were included in the review
and meta-analysis comprising 32,142 mainly elderly
study participants with measured 25(OH)D of whom
6921 died during follow-up. An inverse association
between 25(OH)D levels and all-cause mortality was
found in all but two studies that was statistically
significant in several of the individual studies. In metaanalysis, 25(OH)D levels were significantly inversely
associated with all-cause mortality with a pooled HR of
0.92 (95% confidence interval: 0.89-0.95) for a 20
nmol/l increase in 25(OH)D levels.
 Schöttker B, Ball D, Gellert C, Brenner H. Serum 25-hydroxyvitamin D
levels and overall mortality. A systematic review and meta-analysis of
prospective cohort studies. Ageing Res Rev. 2012 Feb 16.
U-shaped 25(OH)D ConcentrationHealth Outcome Relations
There have been a number of reports that Ushaped relations between serum 25(OH)D and
health outcomes.
Some of these findings do not show
statistically-significant relations.
Some are in disagreement with many other
studies of the same outcome.
Some may be due to including people who
were recently told by their physician to take
vitamin D supplements
Serum 25(OH)D and Frailty
 Two studies were reported on frailty status of elderly
Americans approximately four years after serum
25(OH)D concentration measurement.
 For men, frailty index increased as serum 25(OH)D
decreased (Ensrud, 2011).
 For women, there was a U-shaped relation (Ensrud,
2010)
 My interpretation is that the women were more likely to
be told to take vitamin D, but that doing so did not erase
adverse effects of previous vitamin D deficiency.
List of Vitamin D-Sensitive Diseases A-E
Acne
Acute lower respiratory
infection
Alzheimer’s disease
Amyotrophic lateral
sclerosis
Anaphylaxis
Anemia
Ankylosing spondylitis
Anxiety
Asthma
Athersclerosis
Autism
Bacterial vaginosis
Biliary cirrhosis, primary
(PBC)
Birth defects
Bones – fractures
Bones - osteopenia
Bones – osteoporosis
Bones – Paget’s disease?
Bones – rickets
Brain injury, traumatic
Bronchitis
Cancer – 20 types (Bladder,
breast, cervical, colorectal,
endometrial, esophageal,
gallbladder, gastric, Hodgkin’s
lymphoma, leukemia, lung,
melanoma, multiple myeloma,
non-Hodgkin’s lymphoma,
ovarian, pancreatic, prostate,
renal, vulvar)
Cardiovascular disease
Celiac disease
Cerebrovascular disease
Chronic kidney disease
Chronic liver disease
Chronic, non-specific
muscle pain
Cognitive impairment
Common cold
Epstein-Barr virus
Congestive heart failure
Chronic obstructive
pulmonary disease
Coronary heart disease
Craniotabies
Cystic fibrosis
Dental caries
Depression
Diabetes, type 1
Diabetes, type 2,
Epilepsy
List of Vitamin D-Sensitive Diseases F-V
Fertility, regular menses
Fibromyalgia
Hashimoto's thyroiditis
(HT)
Headache
Hearing loss
Hepatitis
HIV/AIDS
Hypercalcemia
Hyperparathyroidism
Hypertension
Inflammatory bowel
disease
Influenza, type A
Insulin resistance
Ischemic cardiac
arrhythmias
Kidney stones
Lupus
Macular degeneration
Meningitis
Metabolic disease
Mononucleosis
Multiple sclerosis
Muscle strength
Osteoarthritis
Pancreatis
Parkinson’s disease
Pelvic floor status
Periodontal disease
Peripheral artery disease
Pneumonia
Polycystic ovary
syndrome
Post herpetic neuralgia
Preeclampsia
Premature birth and low
birth weight
Psoriatic arthritis
Renal failure
Renal osteodystrophy
Rheumatoid arthritis
Respiratory syncytial virus
Schizophrenia
Sepsis/septicemia
Sickle cell disease
Systemic sclerosis
Tonsillitis
Tuberculosis
Thrombosis
Uterine leiomyomas
(fibroids)
Vascular dementia
Vitiligo vulgaris108
Sources of Vitamin D
 Solar UVB, especially near solar noon, with as much
skin exposed as possible, not so long as to turn pink or
red. Gradual increase in UV in spring/summer leads to
tanning and development of a SPF value of 2-4. Solar
UVB is the source of 90% of vitamin D for most
Americans.
 Supplements, 1000-4000 IU/day recommended.
 Diet, provides 250-300 IU/day in the U.S., Canada
Increase in Serum 25(OH)D from
Vitamin D Supplementation
Garland et al.,
Anticancer
Research,
2011
Testing Serum 25(OH)D is Suggested
Garland et al., Anticancer Research, 2011
Conclusion
There is enough evidence now to conclude that
serum 25(OH)D concentrations of at least 40
ng/ml, can significantly reduce the burden of
breast and many other types of cancer, other
chronic and infectious diseases, adverse
pregnancy outcomes, and increase healthy and
total life expectancy.
Solar UVB irradiance or vitamin D supplements
can be used to reach these concentrations.
It could take 1000-5000 IU/day vitamin D3
Testing serum 25(OH)D recommended.