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RESEARCH · February 27, 2013
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- Vitamin D deficiency, serum 25-hydroxyvitamin D [25(OH)D] concentration < 30 nmol/L, was significantly associated with all-cause mortality (1.7-fold increased risk) and mortality from cardiovascular disease, cancer, and respiratory disease. There was a nonlinear inverse association between 25(OH)D concentrations and all-cause mortality.
Expert Comment
Primary Care
Peter Lin MD, CCFP
It seems that every week another vitamin D study is published. Is it really the panacea for so many medical ills?
Here, two studies look at vitamin D. The first hints at the role of vitamin D in terms of insulin resistance. Of 35 obese adolescents, half were given 4000 IU of vitamin D3 daily for 6 months. Although body mass index, glucose, and inflammatory markers did not change, fasting insulin levels were reduced. The second study measured 25(OH) vitamin D levels in over 9000 German patients and compared death rates. Investigators found that 25(OH)D concentrations < 30 nmol/L were strongly associated with all-cause, cancer, cardiovascular, and respiratory death.
PubMed indexes over 1000 articles related to vitamin D deficiency and diseases linking vitamin D to bone health, immune function, cancer, asthma, and cardiovascular disease—and the list goes on and on. So how can a simple vitamin have such huge impact on multiple systems, and is it really the cure-all?
Vitamin D has a role beyond that associated with bone health and calcium balance. It binds to VDRs (vitamin D receptors) that are located in the nuclei of many cells, and modulates the transcription and expression of DNA. This is why vitamin D deficiency seems to be associated with so many different organ systems and diseases. Think of it this way: vitamin D is like a caretaker in an office building, who turns on and off lights as necessary, and opens and closes windows and doors throughout the building. If the caretaker—vitamin D—stops working, various systems will operate inefficiently and various diseases will develop. It is not that vitamin D is a cure-all, but when it is deficient, systems fail. If there is not enough vitamin D for the immune system, a person is subject to more infections. Because vitamin D regulates cell growth, not enough may give way to uncontrolled cell growth, and hence the link to cancer.
Unfortunately, our vitamin D levels are dropping as we move out of the sun to avoid effects of global warming and cover up to avoid skin cancer. So should we be doing more studies to see what other diseases can be linked to vitamin D deficiency, or should we be investing in ways to improve our vitamin D levels? That may be the more pertinent question to ask. And how much vitamin D do we really need? Not too much to prevent rickets, but a lot more to return to normal immune function. Or maybe we will go back to taking the awful spoonful of cod liver oil; maybe Mom and Grandma did know best.
SUMMARY
PracticeUpdate Editorial Team
In addition to the established association between low vitamin D levels and risk of osteoporotic diseases, there appears to be an association with chronic conditions, including hypertension, cardiovascular disease, diabetes mellitus, cancer, infections, and autoimmune conditions. Although vitamin D3 supplementation has been reported to prevent a number of premature deaths, as shown by a 6% reduction in total mortality in a recent Cochrane Review, this was not shown when vitamin D was used without calcium supplementation.
Recently proposed Institute of Medicine (IOM) cutoffs for vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] concentrations < 30 nmol/L) and insufficiency (30−50 nmol/L) to define risk categories for mortality are under debate. This study conducted a repeated-measurement analysis of the association of liquid chromatography tandem-mass spectrometry (LC-MS/MS)–standardized 25(OH)D concentrations with all-cause, cancer, and cardiovascular and respiratory disease mortality in older adults, with particular attention given to dose–response relationships and the IOM-proposed vitamin D deficiency and insufficiency cutoffs for risk categories. Blood samples were taken at baseline and 5-year follow-up of participants in the ongoing population-based German ESTHER study, in which 9578 adults aged 50 to 74 years at baseline (mean age, 62 years; 43.8% men) were recruited by their general practitioner during routine checkup between 2000 and 2002 . At median follow-up of 9.5 years, 1083 participants had died: 350 of cardiovascular diseases, 433 of cancer, and 55 of respiratory diseases. At median 5-year follow-up, 511 participants had died; 8019 of the survivors (88.4%) responded to the questionnaire, which requested information on sociodemographic characteristics, lifestyle, and diet. In the first 5 years of follow-up, the burden of risk factors for premature mortality increased markedly, with the exception of a decrease in numbers of current smokers and those with low physical activity and low fish consumption. The proportion of participants with vitamin D deficiency remained constant between baseline and 5-year follow-up (15.1% vs 13.3%), but the proportion with vitamin D insufficiency was higher at baseline than at follow-up (43.8% vs 34.2%). According to the dose–response relation of 25(OH)D concentrations with all-cause mortality, the restricted cubic-spline curve showed increased mortality with decreased 25(OH)D concentrations less than approximately 75 nmol/L. This was significant at 50 nmol/L, with an approximate 1.2-fold higher mortality, and, at 30 nmol/L, there was an approximate 1.6-fold increased mortality. When baseline characteristics of the study population were stratified by 25(OH)D status, barring a few exceptions (male sex, history of cancer, and total cholesterol concentrations), the burden of risk factors for premature mortality increased from vitamin D sufficiency (25[OH]D > 50 nmol/L) over vitamin D insufficiency (30−50 nmol/L) to vitamin D deficiency (< 30 nmol/L).
After adjusting for age, sex, season of blood draw, regular multivitamin intake, low fish consumption, body mass index, academic education, physical activity, smoking, systolic blood pressure, chronic kidney disease, log (serum C-reactive protein concentrations), and total cholesterol, the overall mortality of participants with vitamin D deficiency (hazard ratio [HR] = 1.71; 95% CI, 1.43−2.03), or vitamin D insufficiency (HR = 1.17; 95% CI, 1.02−1.35), was significantly increased compared with that of participants with sufficient 25(OH)D concentrations (P < .05 for all).
Vitamin D deficiency was also associated with increased cardiovascular mortality (HR = 1.39; 95% CI, 1.02−1.89), cancer mortality (HR = 1.42; 95% CI, 1.08−1.88), and respiratory disease mortality (HR = 2.50; 95% CI, 1.12−5.56) (P < .05 for all). There was a nonlinear inverse association between 25(OH)D concentrations and all-cause mortality, with risk starting to increase at concentrations of < 75 nmol/L.
In this large, population-based cohort study with repeated LC-MS/MS–standardized 25(OH)D measurements, vitamin D deficiency [25(OH)D concentration < 30 nmol/L] was significantly associated with all-cause mortality (1.7-fold increased risk), and mortality from cardiovascular disease, cancer, and respiratory disease. A nonlinear inverse association was found for 25(OH)D concentrations and all-cause mortality, with mortality starting to increase slightly at concentrations < 75 nmol/L.
The American Journal of Clinical Nutrition
Am J Clin Nutr 2013 Feb 27;97(4)782-793, B Schöttker, U Haug, L Schomburg, et al
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.