by William B. Grant, PhD
Later publications Top Vitamin D Papers - 2017 Top Advances in the Understanding of Vitamin D on Human Health - Grant Jan 2019
(OMNS, Feb 13, 2017) Research on the health benefits of vitamin D continues at a rapid pace. There were 4,356 papers published in 2015 with vitamin D in the title or abstract and 4,388 in 2016 according to the listings at https://www.ncbi.nlm.nih.gov/pubmed/. Those included in this review are the tip of the iceberg. The 18 papers chosen were deemed representative of those most likely to impact medical policies and public attitudes towards vitamin D, as well as impact ongoing research. Topics highlighted in this review include:
Are there health benefits from UVB exposure not related to vitamin D?
Benefits of higher 25-hydroxyvitamin D [25(OH)D] concentrations during pregnancy and lactation
Cancer risk reduction through vitamin D supplementation
Autism spectrum disease symptoms reduced at higher 25(OH)D concentrations
Broken bones in infancy: child abuse or rickets?
Are high 25(OH)D concentrations harmful?
Public understanding of vitamin D
Increasing 25(OH)D concentrations through the food supply
Brief descriptions of the papers
During the past couple of years, there has been increased interest in the health benefits of regular sun exposure. Solar UVB exposure is the main source of vitamin D for most people. Geographical ecological studies have found lower rates for a number of diseases where solar UVB doses are higher "includ[ing] anaphylaxis/food allergy, atopic dermatitis and eczema, attention deficit hyperactivity disorder, autism, back pain, cancer, dental caries, diabetes mellitus type 1, hypertension, inflammatory bowel disease, lupus, mononucleosis, multiple sclerosis, Parkinson disease, pneumonia, rheumatoid arthritis, and sepsis."[Grant, 2016]. Observational studies have found higher 25(OH)D concentrations associated with lower risk of many diseases. The fact that vitamin D supplementation randomized controlled trials (RCTs) have not always supported these studies have led a number of researchers to investigate whether there are health benefits of sun exposure through mechanisms other than vitamin D production. Five papers exploring this question are included in the list of top vitamin D papers for 2015-2016.
One of these papers is a summary of presentations at a conference organized by GrassrootsHealth in December 2014 [Baggerly, 2015]. Videos from the conference are available at http://ucsd.tv/vitamin-d-public-health/. Most of the presentations emphasized studies of the role of vitamin D from solar UVB exposure for optimal health, with examples of reducing risk of many types of cancer, type 1 diabetes mellitus, and adverse pregnancy and birth outcomes. It was also noted that the body has several physiological adaptations to regular sun exposure that reduce risk of adverse effects such as skin cancer and melanoma.
A recent review found that the benefits of sun exposure include lower rates of various types of cancer, cardiovascular disease, Alzheimer disease/dementia, myopia and macular degeneration, diabetes and multiple sclerosis. "The message of sun avoidance must be changed to acceptance of non-burning sun exposure sufficient to achieve serum 25(OH)D concentration of 30 ng/mL or higher in the sunny season and the general benefits of UV exposure beyond those of vitamin D." [Hoel, 2016]. They also noted that part of the reason for reduced sun exposure is the change in lifestyle over the last few decades, with more time spent in cars and buildings than in the past. A greater amount of intermittent sun exposure is associated with increased risk of skin cancer and melanoma. However, the risk of these cancers is dwarfed by the reduced risk of internal cancers from sun exposure.
It is well known that death rates are higher in winter than in summer. Possible contributing factors include seasonal changes in length of day (photoperiod), solar visible or UV radiation doses, 25(OH)D concentration, and temperature. A paper published in 2015 found "more than 4,000 protein-coding mRNAs in white blood cells and adipose tissue to have seasonal expression profiles.... With regards to tissue function, the immune system has a profound pro-inflammatory transcriptomic profile during European winter, with increased levels of soluble IL-6 receptor and C-reactive protein, risk biomarkers for cardiovascular, psychiatric and autoimmune diseases that have peak incidences in winter. Circannual rhythms thus require further exploration as contributors to various aspects of human physiology and disease." [Dopico, 2015]. It will be interesting to follow additional research on this topic.
A very interesting experiment was conducted in Denmark to determine the maximal 25(OH)D concentration obtained with non-burning UVB exposure to 80% of the body [Datta, 2016]. Twenty two healthy Danish sun worshipers with similar light skin color aged 22 to 62 years participated. The baseline 25(OH)D concentration was 85±21 nmol/L (34±8 ng/mL). At the end of the nine-week treatment, the average 25(OH)D concentration was 134 nmol/L (54 ng/mL). Increases were associated with number of days, height, and vitamin D receptor gene polymorphisms. Factors limiting increases were age and constitutive skin pigmentation protection factor. Thus, this paper shows that different people increase 25(OH)D concentrations in different amounts depending on a number of personal factors.
Vitamin D3 (cholecalciferol) is produced by the action of UVB radiation on 7-dehydrocholesterol in the skin. Vitamin D then circulates in the blood and is converted to 25-dihydroxyvitamin D [25(OH)D or calcidiol] in the liver by the addition of a hydroxyl (OH) group. This is the circulating form of vitamin D that is generally measured to determine vitamin D status. Another OH group can be added by the kidneys to form 1,25-dihydroxyvitamin D [1,25(OH)2D or calcitriol]. This is the active metabolite of vitamin D. It helps regulate calcium concentrations in the blood. It can also induce production of cathelicidin, a polypeptide with antimicrobial and antiendotoxin (counteracts bacterial endotoxin) properties, which can fight infections. Most of the action of vitamin D is through calcitriol activating vitamin D receptors (VDRs). Nearly every cell in the body has a VDR! They are attached to chromosomes. When the VDR is activated, the expression of many genes is affected, some are upregulated, others downregulated. Organs that require calcitriol, such as those affected by cancer, can also convert calcidiol to calcitriol.
Results from two vitamin D supplementation RCTs conducted with pregnant women in South Carolina were reanalyzed by looking at 25(OH)D concentrations within six weeks of birth rather than vitamin D supplementation dose. The found that preterm births decreased steadily as 25(OH)D concentration increased [Wagner, 2016]. The gestation week at birth varied from 37 weeks for 25(OH)D concentration of 8 ng/mL to 39 weeks at 40 ng/mL, with no significant change above 40 ng/mL. Raising 25(OH)D concentration from 20 to 40 ng/mL reduced risk of preterm birth by 59%. It is noted that the original statistical analysis of these data sets was based solely on the vitamin D dose, which did not find a large effect. Researchers are now realizing that since vitamin D dose is not directly linked to 25(OH)D concentration while high 25(OH)D concentration is linked to very substantial health outcomes, vitamin D RCTs should be conducted and evaluated based on the improvement in 25(OH)D concentrations, not on vitamin D dose.
A vitamin D RCT of 4400 IU/d vitamin D3vs 400 IU/d vitamin D3 was conducted on pregnant women with a high risk of atopic disease in their family at three centers in the U.S. Supplementation began in weeks 10-18. The hypothesis was that higher dose of vitamin D3 would reduce the risk of developing preeclampsia. However, there was no difference in preeclampsia associated with the vitamin D doses. However, the risk of preeclampsia was a strong function of serum 25(OH)D concentration, dropping from 11% near 10 ng/mL to less than 2% near 70ng/mL [Mirzakhani, 2016]. This study is another excellent example of why the traditional vitamin D RCTs looking just at vitamin D dose can no longer be considered reliable.
In another of a series of vitamin D3 RCTs, women who were breastfeeding infants were given 400, 2400, or 6400 IU/d vitamin D3.The infants of the mothers receiving 400 IU/d vitamin D3 were given 400 IU/d vitamin D3. The 25(OH)D concentrations of the infants whose mothers were given 400 or 6400 IU/d were the same. Concentrations of 25(OH)D for infants whose mothers were given 2400 IU/d were inadequate. There were no adverse effects of 6400 IU/d [Hollis, 2015].
A meta-analysis of vitamin D or vitamin D plus calcium supplementation RCTs involving pregnant women using the Cochrane approach found supplementing pregnant women with vitamin D in a single or continued dose apparently reduced the risk of preeclampsia, low birthweight and preterm birth. However, when vitamin D and high doses of calcium are combined, the risk of preterm birth is increased. [De-Regil, 2016].
Two of the top papers reported findings on cancer incidence related to 25(OH)D or vitamin D3 supplementation. The first was a pooled analysis of cancer incidence from two studies, one a vitamin D supplementation study involving postmenopausal non-Hispanic white women living in Nebraska, the other from the voluntary cohort of non-Hispanic white female participants in GrassrootsHealth's cohort. It found that the incidence rate decreased from 2%/yr at 18 ng/mL to 0.4%/yr at 63 ng/mL [McDonnell, 2016].
The second was a conference report of the results of a four-year RCT in which postmenopausal women were given either 2000 IU/d vitamin D3 plus 1500 mg/d calcium or vitamin D and calcium placebos. Cancer incidence rates were reduced by one-third by the treatment [Lappe, 2016]. Based on previous work by the same group as well as findings in other studies, calcium supplementation may have accounted for about one-third of the decrease. Nonetheless, this study adds to the literature that vitamin D reduces risk of cancer as found in many single-country geographical studies and observational studies. Higher doses of vitamin D3 would have reduced the risk further based on findings from observational studies.
The role of vitamin D in reducing risk and/or symptoms of autism spectrum disease has been studied since John Cannell proposed the connection in 2008. Two recent papers from Egypt found beneficial effects on autism symptoms from vitamin D supplementation.
In the first study, conducted in Egypt on 122 children aged 3 to 9 years with autism spectrum disorder, autism scores were found to be inversely correlated with 25(OH)D concentration: the Childhood Autism Rating Scale (CARS) scores improved from 41 near 8 ng/mL, to 30 for 25(OH)D concentration near 25 ng/mL [Saad, 2016a]. 106 of the children participated in an open label study in which they were given 300 IU/d vitamin D3/kg/d, not to exceed 5000 IU/day over a three month period. After vitamin D therapy, significant improvements were found in most of the CARS scores.
In a vitamin D RCT, autistic children aged 3-10 years were given 300 IU/d vitamin D3/kg/d, not to exceed 5000 IU/d, over a four month period. 25(OH)D concentrations increased from a mean of 26 ng/mL to 46 ng/mL. Scores for aberrant behavior reduced by about 50%, those for autism treatment evaluation reduced by zero for communication to 50% for behavior, while social responsiveness scale improved by zero to 10% [Saad, 2016b].
John Cannell and Michael Holick published a paper pointing out that X-rays of broken bones in infants should not be used as definitive evidence of child abuse. Instead, bone biopsy should be used. X-rays miss rickets 80% of the time [Cannell, 2016]. This paper should help reduce the practice of taking infants with broken bones from parents suspected of abusing them when in fact what they need is treatment for rickets.
One of the reasons given by the Institute of Medicine for recommending that 25(OH)D concentrations for good health be only 20 ng/mL and that no more than 4000 IU/d vitamin D be taken was concern over adverse effects reported at higher 25(OH)D concentrations, often in the form of U- or J-shaped curves (i.e., higher risk at both low and high concentrations). In response, William Grant and other vitamin D researchers reviewed many of the studies reporting J- or U-shaped 25(OH)D concentration-health outcome relations . They found that many of these studies were not in agreement with other studies of the same outcome, such as for all-cause mortality rate.[Grant et al., 2016] There was little robust evidence that 25(OH)D concentrations up to 100 ng/mL (250 nmol/L) were harmful. One explanation proposed to explain the findings was that participants in the studies with high 25(OH)D concentrations may have only recently started supplementing with vitamin D, perhaps because they were advised by their physician that they had a vitamin D-deficiency disease, and that undiagnosed vitamin D-deficiency diseases were subsequently diagnosed during the study.
A paper from France found that the general public does not understand vitamin D very well. "Participants did not always accurately cite vitamin D sources (e.g., 72% only for sun exposure, fatty fish: 61%) or established health effects (e.g., bone health: 62%-78%). Conversely, they mentioned incorrect sources and health effects for which there is no consensus yet (e.g., skin cancer)." [Deschasaux, 2016].
A paper by Hayes and Cashman makes the case for increasing 25(OH)D concentrations at the population level through adding vitamin D to the food supply, either by adding vitamin D to the food or by providing vitamin D-enriched feed to livestock to increase the concentration of 25(OH)D in animal products such as meat, milk, and eggs (biofortification) [Hayes, 2016]. They point out that the general population does not take vitamin D supplements, and that with well-designed programs, people could obtain 400-800 IU/d vitamin D through the food they eat.
There is a growing consensus that optimal 25(OH)D concentrations are above 40 ng/mL (100 nmol/L). Sensible solar UVB exposure seems to be the best way to raise 25(OH)D concentrations when feasible. Taking 1000-5000 IU/d vitamin D3 when that is not feasible, for example in the winter, is a good alternative. It is also useful to have one's 25(OH)D concentration measured as there are large variations due to body and genetic factors. Both GrassrootsHealth and the Vitamin D Council offer mail-in blood spot tests at a reasonable rate. These tests are now as accurate as those performed with wet blood draw.
In the next few years, results from a number of large-scale vitamin D3 RCTs will be published. While most of the RCTs did not include 25(OH)D concentrations as important considerations in their design or conduct, it is hoped that they will, nevertheless, add additional support for the role of vitamin D for optimal health.
For more information
The following vitamin D researchers helped determine the papers included in this review: Carole A. Baggerly, Barbara J. Boucher, John J. Cannell, Kevin D. Cashman, Cedric F. Garland, Bruce W. Hollis, Samantha Kimball, Marc Sorenson, and Jean-Claude Souberbielle.
(William B. Grant directs the Sunlight, Nutrition and Health Research Center (SUNARC) in San Francisco (http://www.sunarc.org/). His PhD is in Physics from U.C. Berkeley. Dr. Grant was a senior research scientist in atmospheric sciences at the NASA Langley Research Center. He is author or coauthor of over 230 publications in peer-reviewed journals related to vitamin D.)
- Baggerly CA, Cuomo RE, French CB, Garland CF, Gorham ED, Grant WB et al. Sunlight and Vitamin D: Necessary for Public Health. J Am CollNutr. 2015;34(4):359-65. http://www.tandfonline.com/doi/full/10.1080/07315724.2015.1039866
- Cannell JJ, Holick MF. Multiple unexplained fractures in infants and child physical abuse. J Steroid BiochemMol Biol. 2016 Sep 15. pii: S0960-0760(16)30248-5. doi: 10.1016/j.jsbmb.2016.09.012. [Epub ahead of print]
- Cashman KD, Dowling KG, Škrábsková Z, Gonzalez-Gross M, Valtueña J et al. Vitamin D deficiency in Europe: pandemic? Am J ClinNutr. 2016 Apr;103(4):1033-44.
- Datta P, Philipsen PA, Olsen P, Petersen B, Johansen P, Morling N, Wulf HC. Major inter-personal variation in the increase and maximal level of 25-hydroxy vitamin Dinduced by UVB. PhotochemPhotobiol Sci. 2016 Apr;15(4):536-45.
- Deschasaux M, Souberbielle JC, Partula V, Lécuyer L, Gonzalez R et al. What Do People Know and Believe about Vitamin D? Nutrients. 2016 Nov 11;8(11). pii: E718. http://www.mdpi.com/resolver?pii=nu8110718
- De-Regil LM, Palacios C, Lombardo LK, Peña-Rosas JP. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2016 Jan 14;(1):CD008873.
- Dopico XC, Evangelou M, Ferreira RC, Guo H, Pekalski ML et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nat Commun. 2015 May 12;6:7000.
- Grant WB. The Role of geographical ecological studies in identifying diseases linked to UVB exposure and/or vitamin D. Dermato-Endocrinology. 2016 Jan 8;8(1):e1137400. http://www.tandfonline.com/doi/full/10.1080/19381980.2015.1137400
- Grant WB, Karras SN, Bischoff-Ferrari HA, Annweiler C, Boucher BJ et al. Do studies reporting 'U'-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects? Dermato-Endocrinology, 2016;8(1): e1187349. http://www.tandfonline.com/doi/full/10.1080/19381980.2016.1187349
- Hoel DG, Berwick M, de Gruijl FR, Holick MF. The risks and benefits of sun exposure 2016. Dermatoendocrinol. 2016 Oct 19;8(1):e1248325. http://www.tandfonline.com/doi/full/10.1080/19381980.2016.1248325
- Hollis BW, Wagner CL, Howard CR, Ebeling M, Shary JR et al. Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial. Pediatrics. 2015 Oct;136(4):625-34.
- Lappe J, Travers-Gustafon D, Garland C, Heaney R, Recker R, Watson P. Vitamin D3 and calcium supplementation significantly decreases cancer risk in older women. Poster 3352. 0. American Public Health Association 2016 meeting Oct 31, 2016. https://apha.confex.com/apha/144am/meetingapp.cgi/Paper/368368
- McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF et al. Serum 25-Hydroxyvitamin D Concentrations≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. PLoS One. 2016 Apr 6;11(4):e0152441. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152441
- Mirzakhani H, Litonjua AA, McElrath TF, O'Connor G, Lee-Parritz A et al. Early pregnancy vitamin D status and risk of preeclampsia. J Clin Invest. 2016 Dec 1;126(12):4702-4715.
- Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, Cannell JJ et al. Vitamin D status in autism spectrum disorders and the efficacy of vitamin D supplementation in autistic children. NutrNeurosci. 2016a Oct;19(8):346-351.
- Saad K, Abdel-Rahman AA, Elserogy YM, Al-Atram AA, El-Houfey AA et al. Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. J Child Psychol Psychiatry.2016b Nov 21.doi: 10.1111/jcpp.12652. [Epub ahead of print]
- van der Rhee HJ, de Vries E, Coebergh JW. Regular sun exposure benefits health. Med Hypotheses. 2016 Dec;97:34-37.
- Wagner CL, Baggerly C, McDonnell S, Baggerly KA, French CB. Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancy cohorts compared with South Carolina March of Dimes 2009-2011 rates. J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B ):245-51.
Editorial Review Board:
Ian Brighthope, M.D. (Australia) , Ralph K. Campbell, M.D. (USA) , Carolyn Dean, M.D., N.D. (USA) , Damien Downing, M.D. (United Kingdom) , Michael Ellis, M.D. (Australia) , Martin P. Gallagher, M.D., D.C. (USA) , Michael J. Gonzalez, N.M.D., D.Sc., Ph.D. (Puerto Rico) , William B. Grant, Ph.D. (USA) , Tonya S. Heyman, M.D. (USA) , Suzanne Humphries, M.D. (USA) , Ron Hunninghake, M.D. (USA) , Michael Janson, M.D. (USA) , Robert E. Jenkins, D.C. (USA) , Bo H. Jonsson, M.D., Ph.D. (Sweden) , Jeffrey J. Kotulski, D.O. (USA) , Peter H. Lauda, M.D. (Austria) , Thomas Levy, M.D., J.D. (USA) , Stuart Lindsey, Pharm.D. (USA) , Victor A. Marcial-Vega, M.D. (Puerto Rico) , Charles C. Mary, Jr., M.D. (USA) , Mignonne Mary, M.D. (USA), Dave McCarthy, M.D. (USA) , Joseph Mercola, D.O. (USA) , Jorge R. Miranda-Massari, Pharm.D. (Puerto Rico) , Karin Munsterhjelm-Ahumada, M.D. (Finland) , W. Todd Penberthy, Ph.D. (USA) , Jeffrey A. Ruterbusch, D.O. (USA) , Gert E. Schuitemaker, Ph.D. (Netherlands) , Thomas L. Taxman, M.D. (USA) , Jagan Nathan Vamanan, M.D. (India) , Ken Walker, M.D. (Canada) , Atsuo Yanagisawa, M.D., Ph.D. (Japan) , Anne Zauderer, D.C. (USA),
Andrew W. Saul, Ph.D. (USA), Editor-In-Chief, Robert G. Smith, Ph.D. (USA), Assistant Editor, Helen Saul Case, M.S. (USA), Assistant Editor , Michael S. Stewart, B.Sc.C.S. (USA), Technology Editor, Jason M. Saul, JD (USA), Legal Consultant
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