Epidemiological evidence for a role of UV-induced Vitamin D in by zhangyun


									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
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.

I am pleased to acknowledge funding from
   these organizations:
    UV Foundation (McLean, Virginia)
    The Vitamin D Society (Canada)
    The European Sunlight Association

Cancer  Ecologic and cohort studies
         Internal cancers after diagnosis of skin cancer
         Prospective supplementation study
Respiratory viral diseases / implications for other
         Autoimmune diseases
         Viral infections, cancer risk
Effect of vitamin D on mortality rates
Vitamin D sources and cautions

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 25-
 hydroxyvitamin D3 (calcidiol), the circulating
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
    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.
                     300    350         350

350                                           300




       Colon cancer mortality rates,
       males, 1970-94
UVB Doses (kJ/M2)
   for July 1992
  breast          prostate

kidney, urinary
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
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
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
    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
                                              Colon Cancer Risk Ratio vs. Lung Cancer Risk Ratio
                                                After Diagnosis of Nonmelanoma Skin Cancer

Colon Colon Cancer Risk Ratio Ratio
      Cancer Risk

                                                                                                       When adjusted for smoking,
                                      1                                                                diagnosis of NMSC is significantly
                                                                                                       inversely correlated with
                                                                                                       colon cancer risk
                                                                                                       (lung cancer risk ratio = 1.0)
                                          0                           1                            2

                                                      LungLung Cancer Risk RatioRatio
                                                           Cancer Risk
Prostate cancer vs. NMSC

In sunny countries, diagnosis of NMSC is
   associated with reduced risk of prostate
    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
    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
    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
    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 1000-
  2000 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.
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
    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 (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
    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
             Sclerosis Prevalence for Forces vs. KC Veterans
    Multipleat Time of Entery into the Armed US WWIILatitude
    at Time of Entry into the Armed Forces Versus Latitude

 MS Prevalence (relative units)
MS Prevalence (relative units)









                                        25   30       35          40         45   50

                                                  Latitude (degrees North)
                                                    Latitude (degrees N)
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
    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
         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
    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

                                   605-Vitamin D, SF readings


   Vitamin D/min





                        0   50      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

Vitamin D supplements:
 The safest and most reliable source of vitamin D3 is
 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.

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
    Generalized weakness and fatigue;
    Central nervous system: confusion, difficulty in
     concentration, drowsiness, apathy, and coma;
    Neuropsychiatric symptoms include depression and
    Heart effects, kidney function problems;
    Ectopic soft tissue calcification

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
Suggestions for further reading

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