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The Health Benefits of Vitamin D

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.

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The Health Benefits of Vitamin D

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  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. 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)

  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. 300 300 350 350 300 350 300 350 400 400 450 500 500 450 Colon cancer mortality rates, males, 1970-94; Index of annual solar radiation

  14. Higher UVB in the west is due to higher surface elevation and thinner stratospheric ozone layer

  15. 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: Hodgkin’s and non-Hodgkin’s lymphoma, leukemia • Miscellaneous: melanoma

  16. 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.

  17. 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.

  18. Breast Cancer Incidence vs. Follow-up Period Only studies with follow-up periods less than three years found statistically significant inverse correlations

  19. 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

  20. 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.

  21. 1.37 1.35 ptrend = 0.02 0.94 HR = 0.81 HR = 0.81 HR = 0.52 0.49 0.48 0.29 Colon Cancer Survival Referent 1.0 0.9 0.8 0.7 0.6 Hazard ratios (all cause mortality) 0.5 0.4 0.3 0.2 0.1 16.5 ng/mL (+ 0.4) 28.9 ng/mL (+ 0.3) 40.0 ng/mL (+ 0.8) 23.6 ng/mL (+ 0.2) 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.

  22. 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

  23. 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.

  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

  25. 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.

  26. 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.

  27. 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.

  28. 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

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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 2012;4(2):167-175

  34. 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.

  35. Dental Rank vs. Solar UVB Dose in July

  36. 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.

  37. Meta-analysis of CVD Incidence Rate vs. 25(OH)D Concentration Data from Dobnig, 2008; Giovannucci, 2008; Ginde, 2009; Kilkkinen, 2009

  38. 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

  39. 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.

  40. 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.

  41. 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)

  42. 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: 1.5-1.98; P<0.001) for coronary heart disease (CHD).

  43. 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.

  44. 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.

  45. 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

  46. 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.

  47. List of Vitamin D-Sensitive Diseases A-E Acne Acute lower respiratory infection Alzheimer’s disease Amyotrophic lateral sclerosisAnaphylaxis Anemia Ankylosing spondylitis Anxiety Asthma Athersclerosis 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 – 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

  48. 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 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 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

  49. 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

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