Vitamin DPresentation at Rossmoor

May 26, 2014William B. Grant, Ph.D.

Sunlight, Nutrition and Health Research CenterSan Francisco

wbgrant@infionline.net

I am pleased to acknowledge funding from these organizations:◦ Bio-Tech-Pharmacal (www.Bio-Tech-Pharm.com)

(Fayetteville, AR)◦ Sunlight Research Forum (Veldhoven)◦ UV Foundation (Bethesda, MD)

Disclosure

Vitamin D physiology UVB, vitamin D and cancer Autism Cardiovascular disease Infectious diseases Lower back pain All-cause mortality rates Benefits during pregnancy U-shaped relations Problems with randomized controlled trials Recent literature; vitamin D conferences Recommendations Sources of additional information

Outline

Vitamin D is produced in the skin through the action of ultraviolet-B irradiance on 7-dehydrocholesterol, producing previtamin D3, which then converts to vitamin D3 through a thermal process.

In the liver, a hydroxyl group is added to make 25-hydroxyvitamin D3.

In the kidneys and many other organs, another hydroxyl group is added to make 1,25-dihydroxyvitamin D3.

Vitamin D Production

The active metabolite, 1,25-dihydroxyvitamin D3, acts through vitamin D receptors attached to chromosomes to control gene expression, up regulating some, down regulating others.

In addition, vitamin D induces production of cathelicidin, a polypeptide with antibiotic and antiendotoxin properties.

Vitamin D Actions

The ultraviolet-B-vitamin D-cancer hypothesis was proposed by the brothers Cedric and Frank Garland in 1974 when, as graduate students at Johns Hopkins School of Public Health, noted an inverse correlation between annual sunlight doses and colon cancer mortality rates.

However, it was not published until 1980 due to the reluctance of medical journals to accept it.

Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980 Sep;9(3):227-31.

Cancer

Colon Cancer Mortality Rates, White Males, 1970-94

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Breast Cancer Mortality Rates, White Females, 1970-94

Solar UVB Doses – July 1992

From NASA’sTotal Ozone MappingSpectrometer

“Data on cancer standardized incidence ratios (SIRs) by sex and 54 occupation categories based on 1.4 million male and 1.36 million female cancer cases for 1961-2005 in the five Nordic countries provide the basis for an ecological study of the role of solar UVB in the risk of many types of cancer at high latitudes.”

Data source: Pukkala E, et al. Occupation and cancer -

follow-up of 15 million people in five Nordic countries. Acta Oncol. 2009;48(5):646-790.

Occupation and Cancer Incidence – Nordic Countries

“Lip cancer SIRs less lung cancer SIRs for men was the best index of solar UVB dose, which was weakly inversely correlated with both melanoma and nonmelanoma skin cancer (NMSC) SIRs. Lung cancer SIRs were used as the index of the effects of smoking.

Basal cell carcinoma and melanoma are more strongly related to long wave UV (UVA) and sporadic UV rather than chronic UVB.”

Nordic - 2

“For men, the UVB index was significantly inversely correlated with 14 types of internal cancer-bladder, breast, colon, gallbladder, kidney, laryngeal, liver, lung, oral, pancreatic, pharyngeal, prostate, rectal and small intestine cancer.

For women, the same UVB index was inversely correlated with bladder, breast and colon cancer. These results generally agree with findings from other studies.”

Grant WB. Dermatoendocrinol. 2012;4(2):203-11.

Nordic - 3

All Less Lung Cancer, Males

Pancreatic Cancer - Males

Breast Cancer - Females

Male UVB index used(women wear lipstick)

No factor other than vitamin D production has been proposed to explain the relationship between solar UVB doses or irradiance and cancer incidence and/or mortality rates.

Higher serum 25-hydroxyvitamin D levels have been associated with reduced risk of breast and colorectal cancer.

Mechanisms have been identified to explain how vitamin D reduces risk of cancer.

Some support from randomized controlled trials.

Is the Inverse Association with Solar UVB Due to Vitamin D Production?

Breast Cancer Incidence Odds Ratio vs. 25OHD from Case-Control Studies

Grant WB. A review of the evidence regarding the solar D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9.

Based on six case-control studies,From Germany, Mexico, UK, US

Divide by 2.5 for ng/mL

There is stronger evidence that UVB and vitamin D reduce cancer mortality rates and increase survival after diagnosis than incidence.

The likely reasons are that there are many cancer risk-modifying factors but few natural ways to limit cancer progression and metastasis.

Vitamin D reduces angiogenesis around tumors as well as metastasis.

Vitamin D and Cancer Survival Rates

Survival After Diagnosis of Cancer

Tretli S, Schwartz GG, Torjesen PA, Robsahm TE. Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study. Cancer Causes Control. 2012;23(2):363-70.

Hill’s [1965] criteria for causality for UVB and vitamin D in reducing risk of many types of cancer:◦ Strength of association – yes◦ Accounting for confounding factors - yes◦ Consistent findings in different populations – yes◦ Dose-response relation for 25(OH)D – yes◦ Mechanisms – yes◦ Experiment (RCTs) – limited, need better design◦ Analogy – yes (various cancers, other health

outcomes)

Hill’s Criteria for Causality in a Biological System

Vitamin D-sensitive cancers with moderate-to-strong support from several ecological studies after accounting for other factors:◦ Gastrointestinal: colon, esophageal, gallbladder,

gastric, pancreatic, rectal◦ Urinary: bladder, kidney◦ Male: prostate◦ Female: breast, endometrial, ovarian, vulvar◦ Blood: Hodgkin’s and non-Hodgkin’s lymphoma,

leukemia◦ Miscellaneous: brain, hepatocellular carcinoma,

lung

19 Vitamin D-Sensitive Cancers from Ecological Studies

Ecological studies have reported inverse correlations between geographical variations in solar UVB doses and incidence, prevalence, and/or mortality rates for these diseases:◦ Anaphylaxis, autism, cancers, Crohn’s disease,

dental caries, diabetes mellitus type 1, epilepsy, lower back pain, multiple sclerosis, Parkinson’s disease, pneumonia, respiratory syncytial virus, rheumatoid arthritis, sarcoidosis, and sepsis.

Ecological Studies – Geographical Variations Associated with Solar UVB

John Cannell proposed that vitamin D reduced the risk of autism based in part on higher prevalence of autism in regions with lower sunlight [Cannell, 2008].

A recent ecological study of autism prevalence among those between the ages of 6 and 17 years found significant inverse correlations with respect to solar UVB doses [Grant, Cannell, 2013].

Children with autism generally have lower 25(OH)D levels [Mostafa, 2012].

A recent paper presented an analysis of how vitamin D could affect the risk of autism through its effects on tryptophan and serotonin production [Patrick, 2014].

Cannell JJ. Med Hypotheses. 2008;70(4):750-9. Grant WB, Cannell JJ. Dermatoendocrinol. 2013;5(1):159-64. Mostafa GA, Al-Ayadhi LY. J Neuroinflammation. 2012;9:201. Patrick RP, Ames BN. FASEB J. 2014 Feb 20. [Epub ahead of print]

Autism

Autism Prevalence vs. Solar UVB

Cannell JJ, Grant WB. What is the role of vitamin D in autism? Dermatoendocrinol. 2013;5(1):199-204.

Higher rates in winter, likely a combination of effects of cold temperature and low UVB.

Nested case-control studies: strong support in a meta-analysis [Wang L, 2012]

Mechanisms have been proposed. RCTs show benefits in reducing biological

parameters related to CVD when conducted on populations with low baseline 25(OH)D levels, as in Iran.

Satisfies Hill’s criteria [Weyland, Grant, Howie-Esquivel, submitted]

Cardiovascular Disease (CVD)

Cardiovascular Disease

Divide by 2.5 for ng/mL

Vitamin D has been found to reduce the risk of several types of infectious diseases◦ Influenza◦ Pneumonia◦ Sepsis◦ Dental caries◦ Epstein-Barr virus related diseases: multiple

sclerosis, Hodgkin’s lymphoma, infectious mononucleosis

Infectious Diseases

It was first demonstrated that vitamin D could reduce the risk of dental caries in 1928 [Mellanby, 1928]. There were several ecological studies reporting on the relation between dental caries and solar UVB doses in the 1930s [Grant, 2011]. There were also controlled clinical trials of vitamin D to reduce dental caries in the 1920s through the 1940s that demonstrated significant beneficial results [Hujoel, 2013]. Unfortunately, modern dentistry has forgotten these studies. The mechanism whereby vitamin D reduces the risk of dental caries is largely through induction of cathelicidin [Grant, 2011].

Grant WB. Dermatoendocrinol. 2011;3(3):193-198. Hujoel PP. Nutrition Reviews. 2013;71(2):88-97. Mellanby M, Pattison CL. Br Med J. 1928;2(3545):1079-82. 

Dental Caries

Vitamin D deficiency was reported as a risk factor for non-specific lower back pain (LBP) in 2003 [Al Faraj, 2003; Plotnikoff, 2003]. A strong direct correlation between LBP and latitude was noted in Great Britain [Walsh, 1992]. The findings of the recent global survey of LBP [Hoy, 2014] were linked to overweight/obesity and vitamin D deficiency in a letter to the editor [Grant, 2014].

Al Faraj S, Al Mutairi K.. Spine (Phila Pa 1976). 2003;28:177-9 Grant WB. Ann Rheum Dis. Epub April 12, 2014 Hoy D, et al. Ann Rheum Dis 2014 Mar 24. Epub ahead of print Plotnikoff GA, Quigley JM. Mayo Clin Proc. 2003;78:1463- Walsh K, et l. J Epidemiol Community Health. 1992;46(3):227-

30.

Lower Back Pain

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70+0.80

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2.00Figure 3. Overall age-adjusted hazard ratios for mor-

tality, all 32 studies combined, 1966-2012

Serum 25(OH)D, ng/ml

Haz

ard

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io Garland, et al., in press

A randomized controlled trial in South Carolina found that for 4000 IU/d vitamin D3, 1,25(OH)2D levels optimized.

This helps optimize gene expression during fetal development.

It also reduces the risk of primary Cesarean section delivery, premature delivery, low birth weight, gestational diabetes, and, likely birth defects, perhaps autism.

Benefits of Vitamin D Supplementation During Pregnancy

Changes in 25(OH)D During Pregnancy from Supplementation

Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10):2341-57.

Relation of 1,25(OH)2D to 25(OH)D during Pregnancy

Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011;26(10):2341-57.

Studies that report J- or U-shaped 25(OH)D level-health outcome relations do not have any information on vitamin D supplementation.

Older women are likely to be advised to take vitamin D supplements, especially if they are at risk of osteoporosis.

Taking vitamin D supplements cannot erase the adverse health effects of years of low 25(OH)D levels.

However, there is mounting evidence that 25OHD levels >50 ng/mL are associated with risk of food allergies and prostate cancer.

U-Shaped 25OHD-Health Outcome Relations

Frailty vs. 25(OH)D Level - Women

Ensrud KE, et al. Circulating 25-hydroxyvitamin D levels And frailty status in older women. J Clin Endocrinol Metab. 2010;95:5266-73.

Frailty vs. 25(OH)D Level - Men

Ensrud KE, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59:101-6.

◦ People are enrolled and randomized as to who is given an agent, who the placebo. The study is conducted for periods of weeks to several years.

◦ RCTs are essential for pharmaceutical drugs to show both efficacy and lack of harm.

◦ Most vitamin D RCTs to date have been based on the pharmaceutical drug model (one source of agent, linear dose-response relation). These assumptions are not valid for vitamin D.

Randomized Controlled Trials

Advantages◦ Shows effect of vitamin D unambiguously?

Disadvantages◦ Participants generally have baseline 25(OH)D levels

that are too high and are supplemented with too little vitamin D to find an effect.

◦ Compliance is often poor.◦ Vitamin D is often combined with calcium.◦ These trials are costly, time consuming.◦ Other sources of vitamin D can interfere. ◦ The time of life when vitamin D is most important

for any health income is not well known.

RCTs - 2

Start with the 25(OH)D level-health outcome relation from observational studies.

Measure 25(OH)D levels and only include those with low levels (<15-20 ng/mL)

Supplement with sufficient vitamin D3 to raise 25(OH)D levels to >40 ng/mL

Also make sure that cofactors are optimized Remeasure 25(OH)D levels

Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014 Jan;72(1):48-54.

Guidelines for optimizing design and analysis of clinical studies of Vitamin D

Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality.

Autier et al., Lancet, 2014

Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality.

Autier et al., Lancet, 2014 - 2

The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.

Autier et al., Lancet, 2014 - 3

Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2(1):76-89.

Letters to the Editor in response: Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health--author's reply. [Lancet Diabetes Endocrinol. 2014]Vitamin D: chasing a myth? [Lancet Diabetes Endocrinol. 2014]Vitamin D status and ill health. [Lancet Diabetes Endocrinol. 2014]

Autier et al., Lancet, 2014 - 4

1 – Observational studies are generally prospective studies in which 25OHD levels are measured prior to disease incidence.

2 – Ecological studies are based on many years of solar UVB doses.

3 – Vitamin D does reduce inflammation. 4 – Vitamin D randomized controlled trials

have not been designed to evaluate results from observational studies for cancer and cardiovascular disease.

Arguments Against Autier’s Claim

The Golden Age of vitamin D research is over.

Ecological and observational studies have identified a large number of UVB- and vitamin D-sensitive health outcomes.

However, public health policy is based on randomized controlled trials.

Six major vitamin D randomized controlled trials are underway, to be completed by 2020

The next major review of the benefits of vitamin D will be in 2020.

Lessons from Three Vitamin D Conferences in Europe in 2014

Concern about the risk of melanoma and nonmelanoma skin cancer has led to widespread sun avoidance and use of sun block.

As a result, 25(OH)D levels have decreased in many countries during the past two decades.

For example, 25(OH)D levels in Denmark dropped from 26 ng/mL in 1993 to 21 ng/mL in 2000 to 18 ng/mL in 2007 [Skaaby et al., 2014]

UV Exposure

Try to maintain 25(OH)D levels in the range of 30-50 ng/mL.

This might take 1000-5000 IU/d vitamin D3. The only way to know 25(OH)D levels is to

have them measured. Grassrootshealth.net and

vitamindcouncil.org offer kits for 25(OH)D based on blood spots for about $70.

Recommendations

“All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.”

Arthur Schopenhauer

Vitamin D is now in stage two.

The Path to Truth

http://www.grassrootshealth.net/ http://www.healthresearchforum.org.uk/ http://www.pubmed.gov/ http://www.sunarc.org/ http://www.vitamindcouncil.org/ http://www.vitamindwiki.com/VitaminDWiki

For a copy of this presentation, wbgrant@infionline.net

Additional Resources