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Orthomolecular Medicine News Service, January 16, 2014
Top 20 Vitamin D Papers for 2013 by William B. Grant, PhD
(OMNS Jan 16, 2014) There were 3774 papers published in 2013 with vitamin D in the title or abstract according to pubmed.gov, up from 3099 in 2012. Among the top 20 vitamin D papers chosen to highlight for 2013 were 11 reviews, five observational studies, one geographical ecological study, one trial, one laboratory study, and one analysis of data from published results. The papers were chosen in part by the number of times they have been cited in other works as reported by Scholar.Google.com and in part based on expert opinion by vitamin D researchers. The fact that two-thirds of the papers were reviews is an indication of the relative maturity of the field. However, as noted in the discussion, the weak link in the vitamin D story is the limited number of randomized controlled trials (RCTs) reporting beneficial effects of vitamin D. As discussed in the paper by Heaney , the primary reason for this result is that vitamin D RCTs have been poorly designed and conducted in general; researchers have generally designed vitamin D RCTs based on the pharmaceutical drug model, which assumes no other source of the agent and a linear dose-response relation. These conditions are not satisfied for vitamin D. As a result, many of the trials enrolled people who had relatively high serum 25-hydroxyvitamin D [25(OH)D] levels and gave them too little vitamin D to produce a beneficial effect.
Especially Important Original Studies
A randomized controlled trial with 400 or 2000 IU/d vitamin D3 found that gene expression in white blood cells was affected by vitamin D [Hossein-nezhad et al., 2013]. There was some improvement in 291 genes and significant improvement in 66 genes. In addition, 17 vitamin D-regulated genes were found with new candidate vitamin D response elements "which have been shown to be important for transcriptional regulation, immune function, response to stress and DNA repair". This study provides strong support for the role of vitamin D in affecting risk of cancer, autoimmune disorders and cardiovascular disease.
An observational study found that serum 25(OH)D levels below 30 nmol/l (12 ng/ml) were associated with 1.0-1.6 additional cases of spontaneous preterm birth before 35 weeks' gestation per 100 births for nonwhite mothers compared to levels above 75 nmol/l (30 ng/ml) [Bodnar, 2014]. Placental inflammatory lesions played a role in this relation. It was not understood why there was no relation between serum 25(OH)D level and risk of premature birth for white mothers. This paper adds to the literature on the beneficial role of higher serum 25(OH)D levels during pregnancy.
Vrieling et al.  conducted a prospective cohort study in Germany including 2,177 incident stage I-IV postmenopausal breast cancer patients aged 50-74 years. Lower concentrations of 25(OH)D were significantly associated with an 86% higher risk of overall mortality and a 76% higher risk of distant disease in stage I-IIIa but not in stage IIIb-IV breast cancer patients. This study adds to the evidence that vitamin D plays an important role in cancer and all-cause survival.
A laboratory study identified several genes associated with triple negative/basal-like breast cancer that are regulated by vitamin D receptors [Laporta and Welsh, epub], thereby providing additional evidence that vitamin D can be useful in reducing risk of and treating breast cancer.
A pair of papers published in the open-access journal Dermato-Endocrinology discussed the evidence that solar ultraviolet-B irradiance and vitamin D reduce the risk of autism. In one, the prevalence of autism by state for those aged 6 to 17 years was found inversely correlated with summertime solar UVB doses [Grant and Cannell, 2013]. Rates for African Americans were higher than for European Americans. The variation with respect to solar UVB doses is similar to that reported previously for many types of internal cancer and dental caries in the United States. Summertime solar UVB doses in the United States are highest in the Southwest, lowest in the Northeast due to a combination of factors involving surface elevation, aerosol and cloud levels, and stratospheric ozone amounts. In the second paper, the evidence supporting the role of vitamin D in reducing the risk of autism and treating those with autism was presented and discussed. The mechanisms seem to include effects on reducing DNA mutations, anti-inflammation and antiautoimmune effects, and upregulating glutathione [Cannell and Grant, 2013]. It is not clear from either study what the relative contributions of maternal and infant serum 25(OH)D levels might be. These two papers add to the understanding of the roles of solar UVB and vitamin D in reducing risk of autism and could lead to a reduction in the epidemic of autism.
One of the roles of vitamin D is the reduction of inflammation. In a study of morbidly obese women, serum 25(OH)D levels were found inversely correlated with several indicators of inflammation including high-sensitive C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) after accounting for confounding factors including body mass index (BMI) [Bellia et al., 2013]. This study adds to the literature connecting low serum 25(OH)D level to increased risk of inflammation. This is important since inflammation is an important risk factor for many chronic diseases.
Another paper analyzed data from 21 adult cohort studies involving 42,000 participants with information on BMI, serum 25(OH)D levels, and genes related to BMI and 25(OH)D. The analysis found that each 1 kg/m(2) increase in BMI was associated with a 4.2% lower serum 25(OH)D level [Vimaleswaran, 2013]. The authors were also able to conclude that changes in serum 25(OH)D level would not affect BMI.
One of the concerns regarding taking vitamin D supplements is the possible risk of developing kidney stones. An analysis of data on 2000 participants of the GrassrootsHealth.net vitamin D testing program followed for an average of 19 months found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P?=?0.42) in the range of 20-100 ng/ml. However, higher BMI was associated with an increased risk [Nguyen et al., 2013].
Comprehensive Reviews of the Health Benefits of Vitamin D
Pludowski et al.  reviewed the evidence of health benefits of vitamin D as one of the outcomes of a vitamin D conference attended by over 500 people in Warsaw, Poland in October 2012. The evidence reviewed was primarily from observational studies. They found "Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality." This paper provided the basis for recommending serum 25(OH)D levels of at least 30 ng/ml (75 nmol/l) for Central and Eastern Europe.
Hossein-nezhad and Holick  reviewed the effects of vitamin D on the risk of chronic illnesses, including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and mortality. The authors recommend a serum 25(OH)D level of at least 30 ng/ml. This paper has open access.
The paper by Haussler et al.  summarizes the molecular mechanisms of vitamin D, with primary emphasis on the classical functions of vitamin D on intestinal calcium and phosphate absorption and effects on skeletal and calcium homeostasis, but also discussion of how the active form of vitamin D, 1,25-dihydroxyvitamin D, affects gene expression and, thus risk of chronic diseases such as cancer, cardiovascular disease, and type 2 diabetes mellitus.
The paper by Palacios and Gonzalez  presents an overview of what is known about serum 25(OH)D levels globally. Six maps are presented with data on vitamin D status (percent of population <30 nmol/l, <50 nmol/l, <75 nmol/l) by country for infants, children, adolescents, adults, pregnant or lactating women, and elders. The quality of the data (representative or individual studies) is also indicated. For pregnant or lactating women for example, values for <50 nmol/l range from 20% in Spain to 96% in India. For elders, values for <50 nmol/l are generally >50% for European countries, but are 36% for China and 91% for India.
The Actions of Vitamin D
The effects of vitamin D on gene expression are controlled by the action of the hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D on vitamin D receptors (VDRs). A paper by Carlberg and Campbell  reviews the actions of the VDR in comparison with those of other transcription factors in order to better understand the role of vitamin D on gene expression.
The Role of Vitamin D for Specific Health Outcomes
The paper by Song et al.  presents a meta-analysis of 21 prospective studies of type 2 diabetes mellitus incidence with respect to serum 25(OH)D level at time of enrollment in the studies. The studies involved a total of 76,220 participants and 4,996 incident type 2 diabetes cases. The second order fit to the data went from a relative risk of 1.00 at 35 nmol/l (14 ng/ml) to 0.45 at 150 nmol/l (60 ng/ml). This analysis provides strong support for the role of vitamin D in reducing the risk of type 2 diabetes mellitus.
Girgis and colleagues  published a comprehensive review of the role of vitamin D on skeletal muscle. It has 51 pages and 390 references. It should be the standard reference on the topic for years.
A paper by DeLuca et al.  reviewed the evidence from 225 papers for the role of vitamin D in reducing risk of nervous system diseases: Alzheimer's disease, amyotrophic lateral sclerosis, autism, multiple sclerosis, Parkinson's disease, and schizophrenia. The strongest evidence is for multiple sclerosis. They note that evidence from many types of studies finds that vitamin D plays a crucial role in cellular proliferation and differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Given the importance and devastation of neurological diseases, more research on the role of vitamin D in reducing risk of these diseases is warranted.
A Skeptical Viewpoint
One paper that has gotten considerable publicity is one calling into question the health benefits of vitamin D. Autier and colleagues published a paper comparing vitamin D randomized controlled trials to prospective studies based on health outcomes with respect to serum[25(OH)D levels [Autier et al., 2013]. While they found reasonable evidence from the observational studies that higher serum 25(OH)D levels were correlated with lower disease and mortality rates, they noted that few randomized controlled trials (RCTs) agreed with the observational studies. They also noted that inflammation is an important aspect of many diseases, but that RCTs have not shown that vitamin D can reduce inflammation. They proposed "the hypothesis that variations in 25(OH)D concentrations would essentially be a result, and not a cause, of ill health." As noted with respect to the paper by Bellia et al. , there is evidence that serum 25(OH)D levels are inversely correlated with markers of inflammation. The vitamin D RCTs conducted to date have for the most part been poorly designed and conducted as pointed out by Heaney . Vitamin D RCTs have mostly been done using the pharmaceutical drug model, paying limited attention to other sources of vitamin D, not seeking to enroll people with low serum 25(OH)D levels, supplement them with sufficient vitamin D to raise their levels to those that have significant impact on health outcome, and also measure serum 25(OH)D levels later in the study. The proper way to examine causality with respect to vitamin D is to apply Hill's criteria for causality in a biological system [Hill, 1965]. These criteria appropriate for vitamin D include strength of association, consistent findings in different populations, temporality, biological gradient, plausibility (e.g., mechanisms), coherence, experiment (e.g., RCT), and analogy. Not all criteria need be satisfied, but the more that are, the stronger the case. A number of health outcomes have been found to satisfy Hill's criteria for causality for vitamin D including many types of cancer. Unfortunately, the paper by Autier and colleagues will likely dissuade many from recommending vitamin D in their practice or using it personally.
To learn more:
Dr. William Grant directs the Sunlight, Nutrition and Health Research Center http://www.sunarc.org/ . This paper was reviewed by:
Carole A. Baggerly, Director, http://www.Grassrootshealth.net
Barbara J Boucher. MD, FRCP, Centre for Diabetes, Blizard Institute, Bart's & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK.
Michael F. Holick, MD, PhD, Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, and the Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston.
Henry Lahore, Director, http://www.vitaminDwiki.com
Pawel Pludowski, MD, Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland
Autier P, Boniol M, Pizot C, Mullie, P. Vitamin D status and ill health: a systematic review. Lancet Diabetes & Endocrinology, Early Online Publication, 6 December 2013. doi:10.1016/S2213-8587(13)70165-7.
Bellia A, Garcovich C, D'Adamo M, Lombardo M, Tesauro M, Donadel G, Gentileschi P, Lauro D, Federici M, Lauro R, Sbraccia P. Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects. Intern Emerg Med. 2013 Feb;8(1):33-40. http://link.springer.com/article/10.1007/s11739-011-0559-x
Bodnar LM, Klebanoff MA, Gernand AD, Platt RW, Parks WT, Catov JM, Simhan HN. Maternal vitamin D status and spontaneous preterm birth by placental histology in the US Collaborative Perinatal Project. Am J Epidemiol. 2014 Jan 15;179(2):168-76. http://aje.oxfordjournals.org/content/179/2/168.short
Cannell JJ, Grant WB. What is the role of vitamin D in autism? Dermatoendocrinol. March 18, 2013;5(1):199-204. https://www.landesbioscience.com/journals/dermatoendocrinology/article/24356/
Carlberg C, Campbell MJ, Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor. Steroids, Feb. 2013;78(2):127-36. http://www.sciencedirect.com/science/article/pii/S0039128X12003091
DeLuca GC, Kimball SM, Kolasinski J, Ramagopalan SV, Ebers GC. Review: the role of vitamin D in nervous system health and disease. Neuropathol Appl Neurobiol. 2013 Aug;39(5):458-84. http://onlinelibrary.wiley.com/doi/10.1111/nan.12020/abstract
Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE. The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev. 2013 Feb;34(1):33-83. http://press.endocrine.org/doi/abs/10.1210/er.2012-1012
Grant WB, Cannell JJ. Autism prevalence in the United States with respect to solar ultraviolet-B doses: An ecological study. Dermatoendocrinol. 2013;5(1):159-64. https://www.landesbioscience.com/journals/dermatoendocrinology/article/22942/
Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, Jurutka PW. Molecular mechanisms of vitamin D action. Calcif Tissue Int. 2013 Feb;92(2):77-98. http://www.researchgate.net/publication/229065129_Molecular_Mechanisms_of_Vitamin_D_Action/file/d912f50117bf975fd6.pdf
Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. January 2014;72(1):48-54. [Epub ahead of print] http://onlinelibrary.wiley.com/doi/10.1111/nure.12090/abstract
Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965 May;58:295-300. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/14283879/
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Nguyen S, Baggerly L, French C, Heaney RP, Gorham ED, Garland CF. 25-hydroxyvitamin D in the range of 20 to 100 ng/mL and incidence of kidney stones. Am J Public Health. 2013 Oct 17. [Epub ahead of print] http://ajph.aphapublications.org/doi/abs/10.2105/AJPH.2013.301368
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Song Y, Wang L, Pittas AG, Del Gobbo LC, Zhang C, Manson JE, Hu FB. Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care. 2013 May;36(5):1422-8. http://care.diabetesjournals.org/content/36/5/1422.full
Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013;10(2):e1001383. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001383
Vrieling A, Seibold P, Johnson TS, Heinz J et al. Circulating 25-hydroxyvitamin D and postmenopausal breast cancer survival: Influence of tumor characteristics and lifestyle factors? Int J Cancer. 2013 Nov 22. doi: 10.1002/ijc.28628. [Epub ahead of print] http://onlinelibrary.wiley.com/doi/10.1002/ijc.28628/abstract
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