ABSTRACT & COMMENTARY
Should the Physician Go Where the Sun Does Not?
By Rahul Gupta, MD, MPH, FACP
Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
In a meta-analysis of multiple prospective cohort studies, the lowest vitamin D metabolite (25-hydroxyvitamin D) quintile was associated with increased all-cause mortality, cardiovascular mortality, and cancer mortality.
Schöttker B, et al. Vitamin D and mortality: Meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States. BMJ 2014;348:g3656.
Vitamin D is well known as the primary regulator of mineral and bone density. In addition to the key role it plays in the maintenance of musculoskeletal health, vitamin D has also emerged as a regulator of several non-skeletal systems’ cellular processes, including immune, cardiovascular, and metabolic systems.1 While it can be obtained through supplements and food supply, the main source of vitamin D remains endogenous through its production in the skin under the influence of solar ultraviolet B (UVB) radiation. The most commonly measured vitamin D metabolite is serum 25-hydroxyvitamin D (25(OH)D) because of its longer half-life (about 3 weeks) and up to 1000-fold higher serum levels compared with the physiologically active metabolite 1,25-dihydroxyvitamin D (half-life of a few hours). Studies have shown that since UVB exposure varies with the latitude of regions across the globe during the year, the mean 25(OH)D concentrations of populations also correspondingly fluctuate.2 Ecological studies have suggested that mortality from several potentially life-threatening diseases such as cancer, cardiovascular diseases, and diabetes mellitus would increase with increasing latitude, in other words, with residence increasingly distant from the equator.3 Such data question the role of solar UVB radiation and vitamin D in reducing the risk of a large number of cancers and other chronic illnesses. However, it is unclear if and to what extent such influences on production and maintenance of sufficient vitamin D concentrations affect the prognostic association of low 25(OH)D concentrations with mortality.
To conduct their meta-analysis, Schöttker et al collected data from seven population-based cohorts from the United States and across Europe. All cohorts included a total of 26,018 men and women and all age groups (50-79 years), with the exception of one study that only recruited in the age range 70-79 years. The median follow-up time in individual cohorts varied between a little over 4 to almost 16 years, during which 6695 study participants died, including 2624 deaths from cardiovascular diseases and 2227 deaths from cancer.
Researchers found that the all-cause mortality was 1.57-fold higher (95% confidence interval, 1.36-1.81) among participants in the lowest quintile of serum vitamin D levels than among those in the highest quintile. Results were similar for cardiovascular-related mortality in patients with and without known cardiovascular disease (risk ratios, 1.7 and 1.4, respectively) and for cancer-related mortality in patients with histories of cancer (risk ratio, 1.7) but not in those without prior cancer. Analyses in which data were stratified by risk factors for vitamin D deficiency yielded similar results. No strong age, sex, season, or country-specific differences could be detected.
COMMENTARY
Reports from across the world indicate that hypovitaminosis D is widespread and is re-emerging as a major health problem globally.4 There may be several causes of vitamin D deficiency, including decreased dietary intake or absorption, reduced solar UVB exposure, reduced endogenous synthesis (reduced hydroxylation in liver and/or kidneys), end-organ resistance, or increased hepatic catabolism. In their meta-analysis, Schöttker et al found that people with the lowest 20% of vitamin D levels had almost 1.6 times increased mortality compared to people in the top 20%. Furthermore, there appeared to be a dose response relationship, in that the highest mortality was found in people with the lowest vitamin D levels, and mortality rate decreased as vitamin D levels rose. However, these results are from epidemiological studies. This means that causation cannot be shown. It could be possible that factors such as preexisting medical conditions could have caused participants to stay indoors, thereby reducing the amount of time spent outside in the sun. The question of causality could be best answered by conducting randomized, controlled trials and some of these are ongoing.
Until we know more, it would be most optimum to follow current recommended guidelines for vitamin D supplementation, which themselves seem to have no clear consensus on the ideal cutoff values for vitamin D deficiency. According to the Institute of Medicine, a recommended daily allowance of 600 IU/d for ages 1-70 years and 800 IU/d for ages ≥ 71 years, corresponding to a serum 25(OH)D level of at least 20 ng/mL (50 nmol/L), meet the requirements of at least 97.5% of the population.5 This recommendation assumes minimal sun exposure. However, other experts suggest a minimum level of 30 ng/mL (75 nmol/L) is necessary in older adults. Eventually, there may come a day when, supported by evidence, physicians across the globe may be prescribing varying doses of vitamin D supplementation based on geographic region, sex, and season. For now, we should pick one national recommendation on vitamin D supplementation and stick to it.
REFERENCES
- Guerrieri-Gonzaga A, Gandini S. Vitamin D and overall mortality. Pigment Cell Melanoma Res 2013;26:16-28.
- Durazo-Arvizu RA, et al. 25-hydroxyvitamin D in African-origin populations at varying latitudes challenges the construct of a physiologic norm. Am J Clin Nutr 2014; Jul 9. [Epub ahead of print].
- Grant WB. Ecologic studies of solar UV-B radiation and cancer mortality rates. Recent Results Cancer Res 2003;164:371-377.
- Mithal A, et al. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int 2009;20:1807-1820.
- Ross AC, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011;96:53-58.
