Is Hypovitaminosis D one of the Environmental Risk Factors for Multiple Sclerosis?

Charles Pierrot-Deseilligny; Jean-Claude Souberbielle

Disclosures

Brain. 2010;133(7):1869-1888. 

In This Article

Epidemiological Findings

Effect of Latitude on the Risk of Multiple Sclerosis

The effect of latitude on the risk of multiple sclerosis has long been known and is universally acknowledged, the prevalence of the disease being minimal at the equator and increasing with either North or South latitude (Handel et al., 2010) (Fig. 3). This effect is observed on a world scale (Gale and Martyn, 1995; Alonso and Hernan, 2008; Sloka et al., 2009), at a continental level (Kurtzke, 1995; Puggliatti et al., 2006), in large countries, such as the USA (Kurtzke et al., 1985, Kurtzke, 2008), the former Soviet Union (Boiko et al., 1995) and Australia (Van der Mei et al., 2001; Taylor et al., 2010) and even in comparatively small countries such as New Zealand (Taylor et al., 2008) and France (Vukusic et al., 2007). The study by Vukusic et al. (2007) involved French farmers, who represent 7% of the French population, and the mean multiple sclerosis prevalence was 65 per 100 000. For the 22 administrative regions of France (Fig. 4A), a geographical gradient of prevalence existed between North–East regions, intermediate and South and West regions (P < 0.001). However, the marked obliquity of the main geographical axes of these three zones of regions (Fig. 4A) suggests that this significance was not simply due to the latitude of these regions but also resulted from a more complicated factor, such as the climate (Ebers, 2008, 2009). French farmers represent a 'nearly ideal' (Ebers, 2008) population for the discussion of a possible climatic impact on multiple sclerosis since (i) being mostly Caucasian, they have a degree of ethnic homogeneity; (ii) they usually remain in the same region throughout their lives; (iii) they are evenly distributed throughout the country; and (iv) they spend a large part of their time outdoors, with consequently a marked exposure to the effect of climate. Thus, in this relatively homogeneous population, the only notable variable that might have influenced multiple sclerosis prevalence would appear to be the climate, since there is a very marked sunshine contrast between the North–East and South–West of France (see below). In another recent study also involving multiple sclerosis patients in France, more extensive data were obtained from national health insurance records, representing 82% of the French population and 46 926 patients with multiple sclerosis, with a mean prevalence of 95 per 100 000 (Fromont et al., 2009). In this study, the results were analysed in the 95 administrative divisions of France (called 'départements'), which are much smaller than the 22 administrative regions referred to above. A difference in prevalence also existed between the North–East and the South–West but, even though the data were more complete, no geographical gradient was found, in contrast to the farmers' study: this is possibly because the general population is (i) less ethnically homogeneous, (ii) less geographically stable, (iii) more unevenly distributed throughout the country and (iv) much more diversified in terms of lifestyle, with therefore a less marked climatic impact than in farmers. This last factor might also explain the overall lower prevalence of multiple sclerosis in farmers. Lastly, we will not deal here with the well known effects on multiple sclerosis prevalence of migrations that occurred during the first two decades of life from a region of high prevalence to a region of low prevalence, or inversely, since such effects appear to result obligatorily from the action of environmental risk factors, which most likely include climatic factors and/or a role of past infections (Gale and Martyn, 1995; Hammond et al., 2000; Ascherio and Munger, 2007a, b; Handel et al., 2010; McDowell et al., 2010); in particular, there appears to be a beneficial climatic effect for young adults who have migrated (after the age of 15–20 years) from a high-latitude region (of high multiple sclerosis prevalence) to a sunnier, lower-latitude region (of low multiple sclerosis prevalence). In conclusion, latitude globally influences the risk for multiple sclerosis (Fig. 3, link A–D), but other intermediate factors might be involved between latitude and this risk.

Effect of Exposure to Sun on the Risk of Multiple Sclerosis

The first studies in this field were based on questionnaires, i.e. the amount of time spent outdoors during holidays and weekends during the first two decades of life in patients with multiple sclerosis and control subjects. The risk of multiple sclerosis was significantly lower in those subjects who spent the most time outdoors during their youth (Acheson et al., 1960; van der Mei et al., 2003; Kampman et al., 2007; Dwyer et al., 2008; Sloka et al., 2008), including within pairs of monozygotic twins (Islam et al., 2007). These results are also supported by studies of skin actinic activity, measured on the back of the hand and reflecting total accumulated exposure to sun; the subjects who had the highest level of actinic activity also had the lowest multiple sclerosis risk (van der Mei et al., 2003; Lucas et al., 2008).

In a second type of study, there were very strong correlations between multiple sclerosis prevalence in the different States of the USA or multiple sclerosis prevalence in nine large-scale areas of North America and the corresponding mean annual amounts of UV in these areas (Beretich and Beretich, 2009). In recent preliminary results based on a meta-analysis performed on 52 studies from various countries around the world, a very highly significant link (P < 10–8) existed between multiple sclerosis prevalence and the annual amount of UV in the different countries, this link being moreover 20 times more significant than that existing between multiple sclerosis prevalence and simple latitude (Sloka et al., 2009). In France, sunshine maps show large climate areas analogous to those of the main zones of multiple sclerosis prevalence identified in farmers by Vukusic et al. (2007) (Ebers, 2008, 2009; Handel et al., 2010). This analysis has been extended here, using a method similar to that reported by Beretich and Beretich (2009) i.e. crossing figures for regional multiple sclerosis prevalence in French farmers with those of the average annual global regional solar irradiation determined from climatic maps provided by a European Environmental Institute (Suri et al., 2007) (Fig. 4A); the correlation is highly significant (Pearson test, r = –0.812, P = 0.0000041) (Fig. 4B). Moreover, it should be noted that this correlation between regional multiple sclerosis prevalence and regional sunshine (Fig. 3, link B–D) appears to be more significant than that existing between regional multiple sclerosis prevalence and mean regional latitude (Pearson's test: r = 0.688, P = 0.00042) (Fig. 3, link A–D), which is confirmed using a linear regression model (P < 0.004). Thus, in this example of France as well world-wide (Sloka et al., 2009), the risk of multiple sclerosis appears to be more influenced by sun exposure than simply by latitude. Furthermore, at identical latitudes, the risk of multiple sclerosis is lower in the sunniest regions (van Amerogen et al., 2004; van der Mei et al., 2007a, b), in particular in high-altitude regions compared to lowland regions (Kurtzke, 1967). These multiple and diverse studies consistently support the hypothesis that exposure to sun influences the risk of multiple sclerosis (Fig. 3, link B–D).

Effect of Vitamin D Status on the Risk of Multiple Sclerosis

In some studies, oral intake of vitamin D in the form of diverse vitamin supplements (Munger et al., 2004) or oily fish (Kampmann et al., 2007; Kampmann and Brustad, 2008) was found to be linked with a lower risk of multiple sclerosis. However, it cannot be ruled out that associated factors existed in these studies. Of greater significance, since it was based on the serum level of vitamin D itself, was a study performed in young American soldiers who had given at least two serum samples a few years before the onset of any neurological symptoms during their military service (Munger et al., 2006). Those with levels of vitamin D in the highest quintile (i.e. between 99 and 152 nmol/l) had a significantly lower risk of multiple sclerosis than those with the lowest levels of vitamin D (i.e. between 15 and 63 nmol/l) (P < 0.01).

Crossing the figures for regional multiple sclerosis prevalence in French farmers (Vukusic et al., 2007) with those of the mean serum levels of vitamin D reported by Chapuy et al. (1996) in normal adults of nine French regions (Fig. 4A), a significant correlation was found (Pearson's test, r = –0.832, P = 0.0054) (Fig. 4C), which suggests that an indirect link may exist between these two variables involving populations living in analogous regions (Pierrot-Deseilligny, 2009) (Fig. 3, link C–D). However, further epidemiological studies are now required to correlate regional multiple sclerosis prevalence with regional serum levels of vitamin D in patients with multiple sclerosis. Lastly, other epidemiological results may be cited here: the risk of multiple sclerosis is lower for births in autumn (mainly in November) and higher for births in spring (mainly in May) (Templer et al., 1992; Willer et al., 2005; Sotgiu et al., 2006; Bayes et al., 2009; Fernandes de Abreu et al., 2009; Ramagopalan et al., 2009b), which is also correlated with the presence of a familial risk factor (Stogiu et al., 2006) or with the phenotype HLA-DRB1 (Ramagopalan et al., 2009b). These results may be related to the vitamin D status of pregnant women (Willer et al., 2005; Salzer et al., 2010), since 25(OH)D serum levels are at their highest in autumn and their lowest in spring (Handel et al., 2010). Accordingly, various results suggest that vitamin D status also influences the risk of multiple sclerosis (Fig. 3, link C–D).

Epidemiological Synthesis of the Climatic Risk of Multiple Sclerosis

It should be noted that among the three links connecting environmental factors to the risk of multiple sclerosis (Fig. 3, vertical links A–D, B–D and C–D), the last one (link C–D) does not yet appear to be as strong as the other two. However, two types of indirect arguments reinforce the likelihood of a link between vitamin D status and the risk of multiple sclerosis. First, there is a very solid connection between latitude and exposure to the sun (Fig. 3, link A–B), which is a geographical reality observed all around the globe, including in France, between mean regional latitude and mean regional sunshine (Pearson's test: r = –0.889, P = 3.17 × 10–8). Furthermore, the connection between exposure to the sun and vitamin D status is also strong (Fig. 3, link B–C), both at the individual level, which is elementary physiology (Armas et al., 2007) and at the population scale (Chapuy et al., 1996). There are also direct correlations between latitude and serum level of vitamin D (i.e. vitamin D status) (Fig. 3, link A–C) in France (Chapuy et al., 1996) and on a world scale (Hagenau et al., 2009). Therefore, the chain of links existing between the three environmental factors (Fig. 3, horizontal chain A–B–C)—i.e. latitude, exposure to sun and vitamin D status—appears to be strong, representing a whole set of arguments converging on the same final factor, namely vitamin D status, which thus indirectly reinforces its subsequent link with the risk of multiple sclerosis (Fig. 3, link C'–D).

The second type of indirect arguments supporting the existence of this last link (Fig. 3, link C–D) stem from the current absence of a consistent, truly documented alternative hypothesis to that of vitamin D. For the first link (Fig. 3, link A–D), latitude is so general a factor as to suggest that another as yet unknown intermediate factor might exist to account for the risk of multiple sclerosis, a factor termed 'X' here (Fig. 3). Several factors such as urbanization, Western lifestyle or viral infections have been proposed as a potential intermediate factor 'X' between latitude and the risk of multiple sclerosis. However, the first two factors are barely dissociable from the lack of sunshine and the third one cannot alone explain all the environmental risk factors (see above the first chapter on the different environmental risk factors and also the summarized epidemiological results of migrations on the risk of multiple sclerosis). Furthermore, given the strength of the link that exists between latitude and exposure to the sun, it seems much more likely that the main factor 'X' is in fact exposure to the sun, as also suggested by the results observed in France (Fig. 3, link A–B) and at the world level (Sloka et al., 2009). Concerning another possible but as yet unknown intermediate factor between exposure to the sun and the risk of multiple sclerosis (Fig. 3, link B–D), old and still rather vague hypotheses about general immunological effects of sunshine itself, through UVB (Loser and Beissert, 2009), or even of mere sunlight (via the eyes and vision) (Mehta, 2010) have thus far not succeeded in ruling out an associated role of vitamin D. Be that as it may, the UVB-vitamin D immunological hypothesis and another immunological mechanism potentially resulting only from UVB, for which there are no currently available original human data, are not in fact mutually exclusive, with, therefore, possibly two parallel immunological effects originating from sunshine-UVB action. Moreover, these two immunological effects resulting from sunshine might both involve the active metabolite of vitamin D i.e. 1,25(OH)2D, which (i) for the classical stimulation of vitamin D by UVB, is produced at the end of successive transformations (in the skin, liver and kidney); and (ii) in the case of the specific UVB mechanism, could be elicited directly within the skin (Lehman et al., 2001) and initiate another, parallel immunosuppressive mechanism subsequently involving the draining lymph nodes and the general immune system (Gorman et al., 2007; Loser and Beissert, 2009 and see the Experimental results section above). It remains to be determined whether this second mechanism depends solely on UVB or may also be influenced by the general vitamin D status. In temperate and Nordic countries, besides the role of sunshine, other confounders may exist such as Western lifestyle or diet but, as mentioned above, the former is barely dissociable from the question of lack of sunshine and the latter does not appear to play a major role in the total vitamin D supply and requirements. Therefore, the absence of a genuine consistent alternative hypothesis to explain the effects of both latitude and exposure to the sun on the risk of multiple sclerosis also indirectly reinforces, at least for the time being, the existence of a link between vitamin D status and this risk (Fig. 3, link C''–D).

Taken together, these multiple results and direct or indirect arguments suggest that a chain of influence may exist between latitude, exposure to the sun, vitamin D status and the risk of multiple sclerosis (Fig. 3, chain A–B–C–D) and that sunlight influences not only the vitamin D status in the general population but probably also, mainly through this intermediate factor, the risk of multiple sclerosis in this population (Fig. 3, chain A'–B–C–D). Vitamin D appears in fact to be the best candidate for the last link in this chain since it is located precisely at the interface between the organism, in which it permanently circulates, and the environment, which obviously influences it.

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