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The Health Benefits of Vitamin D

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Title: The Health Benefits of Vitamin D


1
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
2
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)

3
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

4
Annual Number of Vitamin D Publications Listed at
Pubmed.gov
5
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
    1,25-dihydroxyvitamin 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.

6
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 one-third.
  • 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.

7
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.

8
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.

9
All-cause Mortality Rate Hazard Ratio vs.
Follow-up Period
95 CI
Grant, Dermato- Endocrinology 2012 4(2)
Regression fit
95 CI
10
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.

11
Hills 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)

12
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.

13
Colon cancer mortality rates, males, 1970-94
Index of annual solar radiation
14
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15
Higher UVB in the west is due to higher surface
elevation and thinner stratospheric ozone layer
16
19 Vitamin D-Sensitive Cancers (from several
ecological and observational studies)
  • Vitamin D-sensitive cancers with
    moderate-to-strong 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 Hodgkins and non-Hodgkins lymphoma,
    leukemia
  • Miscellaneous melanoma

17
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.

18
Observational Studies of Breast and Colorectal
Cancer vs. Serum 25(OH)D
  • Observational studies provide useful data for
    determining the serum 25(OH)D concentration-cancer
    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.

19
Breast Cancer Incidence vs. Follow-up Period
Only studies with follow-up periods less than
three years found statistically significant
inverse correlations
20
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
21
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-Hodgkins
    lymphoma.

22
(No Transcript)
23
Can Vitamin D Explain Cancer Disparities?
  • There are 13 types of cancer for which
    African-Americans have lower survival rates than
    white-Americans 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

24
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 Jul97(7)2315-24.

25
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

26
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 (1a-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.

27
1-25-dihydroxyvitamin D - 2
  • Immunocompromised mice bearing MCF-7 breast
    cancer xenografts showed significant tumor
    shrinkage (gt50) 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.

28
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
    Jun153(6)2576-87.

29
Hills 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

30
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.

31
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.

32
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
    Feb86(1)35-47.
  • Cannell JJ, et al. Epidemic influenza and
    vitamin D. Epidemiol Infect. 2006
    Dec134(6)1129-40.

33
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
    May91(5)1255-60.

34
Hospital-Acquired Infections (HAIs)
  • There are many types of HAIs
  • Bacteremia, bacterial sepsis, Clostridium
    difficile, pneumonia, surgical site infections,
    catheter-associated 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
    20124(2)167-175

35
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. 20113(3)193-198.

36
Dental Rank vs. Solar UVB Dose in July
37
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.

38
Meta-analysis of CVD Incidence Rate vs. 25(OH)D
Concentration
Data from Dobnig, 2008 Giovannucci, 2008
Ginde, 2009 Kilkkinen, 2009
39
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 Jun61(6)591-8

40
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,
    pre-eclampsia, premature delivery, and low birth
    weight.
  • Treatment of PD sometimes reduces adverse
    pregnancy outcomes, sometimes does not.

41
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 Oct26(10)2341-57.

42
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
    20124(2)

43
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 Plt0.001) for
    CV events and 1.72 (95 CI 1.5-1.98 Plt0.001)
    for coronary heart disease (CHD).

44
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 Plt0.001) for CV events
    (N??9), 3.43 (95 CI 2.46-4.77 Plt0.001) 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. 20127(9)e43673.

45
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 meta-analysis, 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.

46
U-shaped 25(OH)D Concentration-Health Outcome
Relations
  • There have been a number of reports that U-shaped
    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

47
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.

48
List of Vitamin D-Sensitive Diseases A-E
Acne Acute lower respiratory infection Alzheimers
disease Amyotrophic lateral sclerosis Anaphylaxis
Anemia Ankylosing spondylitis Anxiety Asthma Athe
rsclerosis Autism Bacterial vaginosis Biliary
cirrhosis, primary (PBC) Birth defects Bones
fractures Bones - osteopenia
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
Bones osteoporosis Bones Pagets disease?
Bones rickets Brain injury, traumatic Bronchitis
Cancer 20 types (Bladder, breast, cervical,
colorectal, endometrial, esophageal, gallbladder,
gastric, Hodgkins lymphoma, leukemia, lung,
melanoma, multiple myeloma, non-Hodgkins
lymphoma, ovarian, pancreatic, prostate, renal,
vulvar) Cardiovascular disease Celiac
disease Cerebrovascular disease Chronic kidney
disease Chronic liver disease
49
List of Vitamin D-Sensitive Diseases F-V
Fertility, regular menses Fibromyalgia Hashimoto's
thyroiditis (HT) Headache Hearing
loss Hepatitis HIV/AIDS Hypercalcemia Hyperparathy
roidism Hypertension Inflammatory bowel disease
Influenza, type A Insulin resistance Ischemic
cardiac arrhythmias Kidney stones
Premature birth and low birth weight Psoriatic
arthritis Renal failure Renal osteodystrophy Rheum
atoid arthritis Respiratory syncytial virus
Schizophrenia Sepsis/septicemia Sickle cell
disease Systemic sclerosis Tonsillitis
Tuberculosis Thrombosis Uterine leiomyomas
(fibroids) Vascular dementia Vitiligo vulgaris108
Lupus Macular degeneration Meningitis Metabolic
disease Mononucleosis Multiple sclerosis Muscle
strength Osteoarthritis Pancreatis Parkinsons
disease Pelvic floor status Periodontal
disease Peripheral artery disease Pneumonia Polycy
stic ovary syndrome Post herpetic neuralgia
Preeclampsia
50
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

51
Increase in Serum 25(OH)D from Vitamin D
Supplementation
Garland et al., Anticancer Research, 2011
52
Testing Serum 25(OH)D is Suggested
Garland et al., Anticancer Research, 2011
53
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.
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