Transcript Epidemiological evidence for a role of UV

Health Benefits of Vitamin D:
Prostate Cancer, Etc.
A presentation to the
Prostate Awareness Foundation
December 6, 2007
by William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center
San Francisco, California, 94109 USA
www.sunarc.org
Golden Age
 We are in the “Golden Age” of research on solar
ultraviolet-B irradiance and vitamin D.
 New findings are being reported weekly.
 If vitamin D could be patented and sold for huge profits,
you would see it advertised everywhere.
 Instead, the establishment tries to suppress the
information on vitamin D in order to maintain the high
profit rates in our disease-treatment health system.
 As John Cannell, MD, likes to say, Linus Pauling was
on the right track, but off by one letter.
Disclosure
I am pleased to acknowledge funding from
these organizations:
 UV Foundation (McLean, Virginia)
www.uvfoundation.org
 The Vitamin D Society (Canada)
www.vitamindsociety.org
 The European Sunlight Association
www.europeansunlight.eu
Outline
Definitions
Cancer  Ecologic and cohort studies
Internal cancers after diagnosis of skin cancer
Prospective supplementation study
Respiratory viral diseases / implications for other
diseases
Autoimmune diseases
Viral infections, cancer risk
Effect of vitamin D on mortality rates
Vitamin D sources and cautions
Definitions
Vitamin D3 (cholecalciferol) is made in the skin
from 7-dehydrocholesterol from ultraviolet-B
(UVB) and a thermal process.
Solar UVB extends from 290-315 nm
UVA extends from 315-400 nm
Vitamin D3 is converted in the liver to 25hydroxyvitamin D3 (calcidiol), the circulating
form.
Calcidiol is converted in the kidney and other
organs to 1,25-dihydroxyvitamin D3 (calcitriol),
the hormonal version.
Definitions, continued
Vitamin D receptors (VDRs) hold calcitriol
where it can work its magic.
VDRs come in different alleles, with some more
helpful than others.
The half life of vitamin D3 is about 4-6 weeks.
Vitamin D2 (ergocalciferol) is made from
vegetable matter, and is about half as effective
as vitamin D3; however, MDs can prescribe it
but not vitamin D3.
Studies of UVB and Cancer
Ecological Studies of UVB and Cancer Incidence and
Mortality
 Ecological studies treat populations defined geographically as
the units, averaging all data at that level.
 The Garland brothers made the first ecological study of cancer
and solar UVB in 1980.
 They saw that cancer rates were lowest in the sunniest part of
the country and highest in the least sunny part.
 They hypothesized that since vitamin D production is the most
important physiological effect of solar radiation, vitamin D was
likely the agent.
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Colon cancer mortality rates,
males, 1970-94
UVB Doses (kJ/M2)
for July 1992
breast
kidney, urinary
prostate
stomach
Cancer Risk Modifying Factors
There are a number of factors that modify
the risk of cancer.
They can often be included in studies by
means of indices.
Examples include diet, smoking, alcohol
consumption, ethnic heritage, and urban
residence.
Cancer Incidence and Mortality
Cancer incidence and mortality rates
in the United States
 Based on the incidence and mortality rate data in
the United States, ecological studies have identified
over 20 UVB/vitamin D-sensitive cancers.
 The inverse correlation is stronger for mortality
than incidence rate;
 the likely reason is that there are many risk-modifying
factors for cancer incidence and progression but few for
metastasis.
Other Risk-Modifying Factors
In our multi-factorial ecological study1 of cancer
mortality rates in the United States, we found:
 UVB: inverse for 15 types of cancer
 Smoking: risk for 10 types of cancer
 Alcohol: risk for 9 types of cancer
 Hispanic heritage: risk for 3 types of cancer
 Latitude: risk for 1 type (prostate)
1. Grant and Garland, Anticancer Research, 2006.
Diet and Cancer Risk
Diet is a very important cancer risk factor.
 For many types of cancer, animal products are
associated with increase risk, perhaps though
production of insulin-like growth factor.
 For prostate cancer, animal products are an
important risk factor, but milk and calcium are also
associated with risk, while onions, garlic, and
cooked tomatoes are associated with reduced risk.
 Those eating high amounts of onions and garlic
were found to have a 20-30% reduced risk for
prostate cancer (and many other types of cancer).
Vitamin D and Cancer Risk
Harvard cohort study on vitamin D and cancer
 Edward Giovannucci developed a vitamin D index
based on vitamin D from oral intake and UVB
production, and controlled for other factors.
 Significant inverse correlations with vitamin D were
found for colon, esophageal, oral, pancreatic, and
rectal cancer and leukemia.
 Insignificant inverse correlations were found for
bladder, gastric, lung, prostate, and renal cancer.
 They estimated that male cancer deaths could be
reduced by 29% for 1500 IU of vitamin D3/day.
UVB Irradiance
Studies based on indices of UVB irradiance rather
than vitamin D dose
 Critics of ecological studies based on solar UVB
doses related to geographic location of residence
question whether UVB dose translates to UVB
irradiance.
 There is a simple way to determine lifetime UVB
irradiance at the personal or population level:
development of non-melanoma skin cancer (NMSC)
after controlling for smoking.
Risk of Second Cancer
Meta-analysis of risk of second cancer after diagnosis of
NMSC
Risk
Cancer
Colon Colon
Cancer Risk
Ratio Ratio
Colon Cancer Risk Ratio vs. Lung Cancer Risk Ratio
After Diagnosis of Nonmelanoma Skin Cancer
2
When adjusted for smoking,
diagnosis of NMSC is significantly
inversely correlated with
colon cancer risk
(lung cancer risk ratio = 1.0)
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0
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Cancer Risk Ratio
LungLung
Cancer
Risk Ratio
2
Prostate cancer vs. NMSC
In sunny countries, diagnosis of NMSC is
associated with reduced risk of prostate
cancer1
 Basal cell carcinoma:
SIR = 0.63 (0.44-0.89)
 Squamous cell carcinoma: SIR = 0.43 (0.23-0.73)
 But not melanoma:
SIR = 1.20 (1.10-1.30)
 (SIR = standardized incidence rate with 95% confidence
intervals)
 BCC and SCC are linked to lifetime UVB irradiance;
melanoma is linked to UVA and sunburning
1 Tuohimaa
et al., 2007
Vitamin D Indices by Strength
Vitamin D indices for cancer studies in order of
strength of correlation
 Solar UVB doses
 Non-melanoma skin cancer incidence rates
 Hybrid oral intake plus UVB irradiance
 Personal sun exposure history
 Oral intake
 Pre-diagnostic serum calcidiol
 Note that most studies of pre-diagnostic serum calcidiol
have not found an inverse correlation with prostate cancer
for lags of 5 to 15 years.
Number of UVB-Cancer Studies
Number of Observational Studies on
UVB and Cancer Risk Reduction
 10+ breast, colon, ovarian, pancreatic,
prostate cancer, NHL
 7-9 esophageal, lung, rectal cancer
 5-6 renal, Hodgkin’s lymphoma
 3-4 bladder, gallbladder, gastric,
uterine corpus cancer, multiple myeloma
 2 laryngeal, oral, thyroid cancer, leukemia
 1 biliary, cervical, pleural, small intestine,
soft tissue, vulvar cancer
20 types of cancers with 2 or more studies
Vitamin D, Calcium and Cancer Risk
Recent prospective study of vitamin D3 and calcium
and cancer risk1
 Randomized, double-blind, placebo-controlled study
of post-menopausal women in Nebraska
 1100 IU of vitamin D3 and, in some cases, 1400 mg
of calcium per day, or a placebo.
 The all-cancer incidence for women over the age of
55 years at time of enrollment was reduced by 77%
between the ends of the first and fourth years of the
study. (OR = 0.23, CI: 0.09, 0.60; P < 0.005)
 The baseline serum calcidiol level for these women
was 28 ng/mL (mean value in the U.S.).
1. Lappe JM et al. Vitamin D and calcium supplementation reduces cancer risk: results of a
randomized trial. Am J Clin Nutr 2007 Jun; 85(6): 1586-91.
Dose-Response Relations
It is important to determine the dose-response
relations between vitamin D and cancer risk:
 To verify that the effect is causal;
 To be able to make policy recommendations.
This has been done for breast and colorectal
cancer through meta-analyses of published
studies of prediagnostic serum calcidiol.
 1500 IU/day for 50% reduction in colorectal cancer;
 3600 IU/day for 50% reduction in breast cancer.
Gorham et al., 2007
Seasonal Cancer Survival
Cancer Survival with Respect to Season of
Diagnosis
 Studies in Norway, Boston, and England have found
that those diagnosed with cancer in summer or fall
have better survival over the next 1.5-5 years.
 The most likely reason is higher levels of solar UVB
and vitamin D.
Seasonal Survival in Norway
Cancer Survival with Respect to Season of
Diagnosis in Norway1 (mortality rate differences in
southeast Norway vs. midwest winter for 36 months)
 Prostate cancer:
0.80 (0.75-0.85)*
 Breast cancer:
0.75 (0.7-0.8)*
 Colon cancer:
0.79 (0.7-0.84)*
 Lung cancer:
0.93 (0.89-0.96)*
 Hodgkin’s lymphoma: 0.80 (0.9-1.1)
* indicates statistically significant
1. Porojnicu et al., 2007.
Vitamin D Supplements
Those with cancer should consider vitamin D
supplements.
 The magnitude of the effect from just solar UVB
suggests vitamin D3 supplements of several
thousand IU per day should be considered for those
with most types of cancer.
 Those with Hodgkin’s and non-Hodgkin’s lymphoma
should be a cautious due to possible adverse
effects on calcium.
UVB-D-Cancer Causality?
A. B. Hill laid down the criteria for establishing
causality in a biological system. The most
important ones are well satisfied:
 Strength of association
 Repeated in many diverse populations
 Linear dose-response relation
 Confounding factors accounted for
 Mechanisms understood
 Experimental verification
 Cause precedes the effect
Precautionary Principle
As an alternative to the requirement for a
randomized controlled trial, we propose that a
set of well-conducted observational studies be
used, along with the precautionary principle.
The precautionary principle looks at the risks
and benefits of a policy, and if the
preponderance of the evidence supports the
policy, it is adopted.
The precautionary principle is more likely to be
used in European countries than the U.S.
Respiratory Viral Diseases
John Cannell, M.D., noticed that patients in his
ward in Atascadero had much lower rates of
influenza one winter than those in other wards.
His patients were supplementing with 10002000 IU of vitamin D3.
Cannell et al.1 hypothesized that epidemic
influenza is seasonal in part due to seasonal
variations of solar UVB and vitamin D.
. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S,
Garland CF, Giovannucci E.Epidemic influenza and vitamin D.
Epidemiol Infect. 2006 Dec;134(6):1129-40.
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Cold and Flu Prevention
Results of a prospective double blind vitamin D
supplementation study involving 208 African-American
post-menopausal women living in or near Mineola, NY.
The vertical scale refers to cases of common cold or flu.
Aloia JF, Li-Ng M. Epidemiol Infect. 2007.
Respiratory Syncytical Virus
Yusuf et al. [2007] showed that solar UVB
modulates the seasonal incidence of respiratory
syncytical virus (bronchitis) in a latitudinally
consistent manner.
Other important factors associated with increased
number of cases were temperature and relative
humidity.
 Low temperature impairs white blood cells from
getting to the surface.
 Low relative humidity makes exhaled viruses smaller.
Calcitriol and Cathelicidin
Calcitriol Induces Production of Human Cathelicidin
 The hormonal metabolite of vitamin D,
1,25-dihydroxyvitamin D (calcitriol) can induce
the production of cathelicidin, a component of the
innate immune system.
 Cathelicidin induction from vitamin D seems to
explain the beneficial role of UVB and vitamin D for
bacterial and viral infections that peak in winter.
Sepsis
Sepsis (infectious blood disease related to
bacterial and viral infections) has these
epidemiological features in the United States:
 Highest in the Northeast, lowest in the Southwest.
 Highest in winter, lowest in fall.
 Higher in black Americans than white Americans.
 Rapid increase with advancing age.
 Comorbid diseases are vitamin D sensitive.
These features are explained by the
epidemiological features of solar UVB and
vitamin D [Grant, submitted].
Autoimmune Diseases
Theoretical Extension to Autoimmune Diseases
 There are a number of diseases for which viral
infections are a risk factor.
 The virus can embed itself in various tissues and
live for many years with few symptoms.
 As the body tries to fight the infection, it may
generate an autoimmune response.
Multiple Sclerosis
Theoretical extension to multiple sclerosis (MS)
and possibly other autoimmune diseases
 Risk of MS is linked to viral diseases such as
infectious mononucleosis linked to Epstein-Barr
virus.
 UVB and vitamin D reduce the risk of MS.
 The prevalence of MS increases with increasing
latitude in Australia, Europe south of Nordic
countries, and the United States.
Multiple Sclerosis Prevalence for U.S. WWII, KC Veterans
Multiple
Sclerosis Prevalence for US WWII KC Veterans
at Time of Entery into the Armed Forces vs. Latitude
at Time of Entry into the Armed Forces Versus Latitude
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MSPrevalence
Prevalence (relative
units)
MS
(relativeunits)
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Latitude(degrees
(degrees North)
N)
Latitude
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Hypothesis for MS
The multiple sclerosis vitamin-D hypothesis:
 UVB, through production of vitamin D, reduces the
risk of MS primarily by fighting the viral infections
that lead to MS, especially in youth, when such viral
infections are more common.
 The quadratic latitudinal gradient in disease
outcome is linked to wintertime solar UVB, when
infectious diseases are more common, as opposed
to summertime UVB, which has an asymmetrical
pattern in the US.
Viral Risk of Cancer
Viral infections pose a known risk for a number of
cancer types:
 Well-known cancers
cervical, esophageal, nasopharyngeal cancer, lymphoma
 Less-well-known cancers
bladder, gastric, prostate, testicular, and thyroid cancer
Viral Infections and Cancer
Immunosuppression and cancer risk from viral
infections:
 For cervical, esophageal, and nasopharyngeal
cancer, UV-induced immunosuppression seems to
play an important role in cancer risk.
 For many of these cancers, higher solar UV is
associated with increased risk.
Vitamin D and Viruses
Vitamin D-mediated reduction in cancer risk due
to viral infections
 The mortality rate map for prostate cancer is very
similar to that for multiple sclerosis.
 Prediagnostic serum calcidiol levels are generally
not inversely correlated with prostate cancer
incidence rates.
 There are many indications that young men have
more genital infections than older men.
 Viruses can lead to cancer via inflammation.
Prostate cancer mortality rates
Viral Infections Leading to Cancer
Ecological study supports a role for vitamin D in
combating viral infections leading to cancer:
 For the cancers less well known as linked to viral
infections, they all show an increase in mortality
rate with increasing latitude in the U.S. (an index for
wintertime solar UVB/vitamin D).
 This finding suggests that vitamin D is lowest in the
season of highest viral infection rate.
 The benefit likely occurs early in life.
 Other common cancers, such as breast, colon, and
ovarian cancer, have neither such a variation nor
evidence in the literature for a viral link.
Grant, Photochem. Photobiol., in press
Vitamin D and Mortality
Low vitamin D status could be associated with higher
mortality from life-threatening conditions:
 cancer, cardiovascular disease, and diabetes mellitus
 60% to 70% of total mortality in high-income countries
We examined the risk of dying from any cause in
subjects who participated in randomized trials testing
the impact of vitamin D supplementation on any health
condition.
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18 independent randomized controlled trials
including 57,311 participants
A total of 4777 deaths from any cause occurred
Mean daily vitamin D dose was 528 IU
The summary relative risk for mortality from any cause was
0.93 (95% confidence interval, 0.87-0.99).
Autier P. Gandini S. Arch Intern Med. 2007 Sep 10;167(16):1730-7.
Benefits of 2000 IU of D3 /day
I have just completed an analysis of the estimated
health benefit of 2000 IU of vitamin D3 per day
in reducing the risk of eight diseases in
Canada: cancer, infections, autoimmune
diseases, hip fractures, and metabolic
diseases.
Conclusions:
 Mortality rate would be 12% less (range: 6-18%)
 People would live longer (1-2 years?)
 Total economic burden would be 8% less (4-12%)
Canadian Recommendation
8 June 2007, Toronto: The Canadian Cancer Society is
recommending a specific amount of Vitamin D
supplementation for Canadians to consider taking. This
first-time recommendation is based on the growing body
of evidence about the link between Vitamin D and
reducing risk for colorectal, breast and prostate cancers.
 Adults living in Canada should consider taking Vitamin D
supplementation of 1,000 IU a day during the fall and winter.
 Adults at higher risk of having lower Vitamin D levels should
consider taking vitamin D supplementation of 1,000 IU/day all
year round.
Sources of Vitamin D3
Fortified food and fish in the United States
provide about 250-300 IU of vitamin D3/day.
However, milk and orange juice are not on my list
of health foods, and cold water fatty fish are
both a dwindling resource and contain mercury
and other toxins.
Milk and Parkinson’s Disease
I have just completed an ecologic study and review of risk
factors for Parkinson’s disease (PD).
 Peroxynitrite, formed from dietary components, is
an important risk factor.
 Uric acid blocks the formation of peroxynitrite.
 Milk protein (casein) reduces the production of uric
acid, and is the strongest dietary risk factor for PD.
 Other anti-oxidants from fruits and vegetables also
reduce risk.
UVB Production of vitamin D
Ultraviolet-B irradiance
 Young fair-skinned people can make 1000 IU of
vitamin D3 in 30 minutes at noon in the Bay Area in
summer with 10% of their body exposed.
 Older people take up to 4-5 times longer.
 It is impossible to produce too much vitamin D from
UVB due to UV destruction of vitamin D and
production of inert metabolites.
Vitamin D/min
C
605-Vitamin D, SF readings
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70
Vitamin D/min
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50
40
30
20
10
0
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100
150
200
250
300
350
Day of Year
Production rates for vitamin D in San Francisco at noon
for a pale young person with 10% of the body exposed.
Skin Color Considerations
Supplements
Vitamin D supplements:
 The safest and most reliable source of vitamin D3 is
supplements.
 They should not be combined with vitamin A (max
vitamin A per day = 1500 IU).
 http://www.bio-tech-pharm.com/products/d35.html
 According to Heaney, one can use about 3600 IU/day.
 We are now recommending 1000-2000 IU/day for
prevention of disease.
 It is suggested that serum calcidiol be measured to
guide use of supplements at the higher doses.
Serum Calcidiol Levels
The consensus of scientific understanding
appears to be:
 Vitamin D deficiency is serum calcidiol levels
<20 ng/mL (50 nmol/L)
 Insufficiency in the range: 20-32 ng/mL
 Sufficiency in the range:
33-80 ng/mL
 Normal in sunny countries: 54-90 ng/mL
 Vitamin D excess:
>100 ng/mL

……………………………………………………………………………….
Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal
health: a review. Altern Med Rev. 2005;10:94-111.
Adverse Effects of UV
Known adverse effects of ultraviolet radiation are:
 Premature skin aging, brown (melanin) spots
 Basal cell carcinoma (easily treated, seldom fatal)
 Actinic keratosis (irritation of skin, can be removed
with liquid nitrogen)
 Squamous cell carcinoma (lifetime UVB exposure)
 Melanoma (early life sunburns, nevi, UVA)
Adverse Effects of Vitamin D
Documented adverse effects of vitamin D in the
literature include:
 Calcium dysregulation at high doses;
 Calcium dysregulation at normal doses for those
with granulomatous diseases due to extra-renal
production of calcitriol;
 Kidney stones in susceptible individuals?
Granulomatous Diseases
Granulomatous diseases are characterized by
masses or nodules of chronically inflamed
tissue with granulations that is usually
associated with an infective process.
Such diseases include
 infectious diseases: TB, histoplasmosis,
candidiasis, and leprosy;
 non-infectious diseases such as sarcoidosis, and
Crohn’s disease.
Lymphoma
Hypercalcemia has been reported in 5% of
patients with Hodgkin’s disease and 15% of
those with non-Hodgkin’s lymphoma.
It is not clear how extra-renal production of
calcitriol occurs in lymphoma.
However, other factors than increased calcitriol
are also involved.
Vitamin D Toxicity
Clinical manifestations of vitamin D toxicity
include:
 Generalized weakness and fatigue;
 Central nervous system: confusion, difficulty in
concentration, drowsiness, apathy, and coma;
 Neuropsychiatric symptoms include depression and
psychosis;
 Heart effects, kidney function problems;
 Ectopic soft tissue calcification
Conclusion
In summary:
 1000-2000 IU/day or more of vitamin D3 is essential
for optimal health; more if one has cancer.
 Solar UVB is the primary source of vitamin D3 for
most people, but is inadequate in the Bay Area for
reliable production of adequate vitamin D.
 Other sources include diet (inadequate), and
supplements (efficient and safest).
 Those with cancer should consider taking several
thousand IU/day.
 There are many health benefits of vitamin D3.
Solar Power Table of Contents
Chapter headings
 1. Seasons and Sunlight
 2. Free Radicals and Antioxidants
 3. Solar Power, Skin Cancer and Fat
 4. Sunlight and health: a history
 5. Solar Power and melanoma: burned by sunscreens?
Section 2: Solar Power and prevention of deadly cancers
 6. Solar Power and cancer prevention mechanisms
 7. Solar Power, breast Cancer and other women’s cancers
 8. Sunlight, Vitamin D and prostate cancer
 9. Solar Power, colon cancer and other internal cancers
Solar Power continued
Section 3: Solar Power and other major diseases and issues
 10. Boning up: Solar Power, osteoporosis, joints and pain
 11. Solar Power reduces the risk of multiple sclerosis.
 12. Solar Power, diabetes and autoimmune diseases
 13. Solar power, heart disease and high blood pressure
 14. Solar Power and a potpourri of health concerns
 15. Solar Power vs. depression and other mental disorders
 16. Solar Power and African Americans
 17. Summary
Epilogue
Suggestions for further reading
References