References for the Review were identified through searches of PubMed from 1949 to February, 2010, and Embase from 1974 to February, 2010, by use of the following search string: (“vitamin D” OR “sun exposure” OR “diet” OR “latitude”) AND “multiple sclerosis”. Bibliographies of papers and book chapters were also reviewed. Only papers published in English were considered. We did not include results presented only as abstracts. Studies were selected on the basis of relevance as judged by the
ReviewVitamin D and multiple sclerosis
Introduction
The risk of developing multiple sclerosis (MS), a relatively common cause of disability among young adults, is determined by a combination of genetic and environmental factors. The latter include Epstein-Barr virus (EBV) infection, cigarette smoking, and inadequate serum concentrations of vitamin D.1, 2 Although EBV is nearly ubiquitous, there are no effective vaccines or treatments for EBV infection, leaving smoking cessation and vitamin D supplementation as the only available interventions that might result in a reduction in the global burden of MS. Because vitamin D deficiency is endemic worldwide,3 the potential impact of vitamin D supplementation on MS incidence is profound.
The hypothesis that vitamin D deficiency is a risk factor for MS was first proposed over 30 years ago,4 and gained credibility after the discovery of the immunomodulatory effects of vitamin D.5 However, over the past few years, the epidemiological evidence of an increased MS risk among individuals with low vitamin D concentrations has achieved substantial strength, thus approaching a threshold that calls for important decision-making in terms of experimental investigations or public-health interventions. In this Review, we will provide a critical analysis of the epidemiological studies on vitamin D and MS risk or severity, and their implications for MS prevention and treatment.
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Source and metabolism
The primary form of vitamin D, colecalciferol (vitamin D3), is available from two sources: skin exposure to ultraviolet B radiation (UVB) in sunlight and diet (figure 1). UVB in the 290–315 nm range photolyses 7-dehydrocholesterol in the skin to form pre-vitamin D3, which then isomerises to colecalciferol.6 Colecalciferol (and ergocalciferol [vitamin D2]) is also available from fortified foods (eg, milk, cereal, and some orange juice and cheeses), dark fish (eg, salmon and tuna), and vitamin
Factors affecting exposure
Because melanin pigment in human skin absorbs UVB,52 black people have lower 25-hydroxyvitamin D concentrations than white people, and are often vitamin D deficient.22 However, the risk of MS in black people is lower than in white people;53 this contradiction to the vitamin D hypothesis might only occur because genetic differences could compensate for low vitamin D concentrations, as seems to be the case for bone turnover.54 Analyses of the relation between vitamin D status and MS risk are
Latitude and ecological studies
The reasons why vitamin D deficiency is thought to be a risk factor for MS are as follows: (1) MS frequency increases with increasing latitude, which is strongly inversely correlated with duration and intensity of UVB from sunlight and vitamin D concentrations;53, 64, 65, 66, 67, 68, 69 (2) prevalence of MS is lower than expected at high latitudes in populations with high consumption of vitamin-D-rich fatty fish;4, 70, 71 and (3) MS risk seems to decrease with migration from high to low
Vitamin D and MS activity and progression
Many patients with MS have deficient or insufficient vitamin D concentrations. In addition, serum 25-hydroxyvitamin D concentrations in patients with MS are lower during MS relapses than during remissions50, 87, 175 and correlate inversely with disease severity.55, 85, 176, 177 All but one175 of these results were from cross-sectional studies, and might indicate lower sun exposure in patients with severe MS, rather than a beneficial effect of vitamin D on immune responses. Although serum
Conclusions
Vitamin D supplementation in healthy individuals is emerging as a promising approach for MS prevention. In utero and early-life exposure could also be important, but there is strong evidence that vitamin D concentrations during late adolescence and young adulthood have a major effect in determining MS risk. Whereas future observational epidemiological studies, and genetic and molecular investigations, will be useful to strengthen and refine the hypothesis, evidence is approaching equipoise, at
Search strategy and selection criteria
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