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

Serum Levels of Vitamin D in Multiple Sclerosis

Significance of Low Serum Levels of Vitamin D

The serum levels of vitamin D are reported to be low, whatever the assays, in most patients with a relapsing-remitting form of multiple sclerosis, including at the initial stage of the disease (Soilu-Haninnen et al., 2005; Barnes et al., 2007; van der Mei et al., 2007a; Kragt et al., 2008; Smolders et al., 2008b; Soilu-Haninnen et al., 2008; Correale et al., 2009; Pierrot-Deseilligny, 2009; Steffensen et al., 2010; Mowry et al., 2010). The mean serum levels were generally between 50 and 65 nmol/l and the levels were lower in winter than in summer, but other particularities were mentioned in some of these studies. Where a control group existed, the serum levels were significantly lower in patients than in controls in some studies (Soilu-Hänninen et al., 2005; van der Mei et al., 2007b; Correale et al., 2009), but not in others (Barnes et al., 2007; Kragt et al., 2008; Soilu-Hänninen et al., 2008). Inverse correlations between the 25(OH)D serum levels and the relapse rate or the degree of disability (Expanded Disability Status Scale) were sometimes observed (Barnes et al., 2007; Van der Mei et al., 2007a; Smolders et al., 2008b; Mowry et al., 2010). It should be noted that in the study by Mowry et al. (2010), performed in 110 children (mean age: 15 years; follow-up: 30 months) with a clinically isolated syndrome or paediatric-onset multiple sclerosis, an elevation of 25 nmol/l of the 25(OH)D serum level was associated with a 34% decrease in relapse rate, which suggests a protective role of vitamin D. The 25(OH)D serum levels could also be lower during relapses than between relapses, with higher serum levels of parathyroid hormone during relapses (Soilu-Hänninen et al., 2008). These particularities will, however, require confirmatory studies and the rest of the discussion will focus on the significance of the simple decrease in the 25(OH)D serum level observed in patients with multiple sclerosis. Firstly, this decrease in the 25(OH)D serum level observed in most patients with multiple sclerosis is of crucial importance if one hypothesizes that hypovitaminosis D partly contributes to the risk of multiple sclerosis. Secondly, such a decrease is not constant since it is observed in 60–95% of patients with multiple sclerosis, depending on the study and the cut-off. If one accepts that the 25(OH)D serum level may remain durably normal in a few patients, even in winter, this fact does not in itself preclude a partial global effect of hypovitaminosis D on the risk of multiple sclerosis at the scale of a population. Indeed, the risk factors for multiple sclerosis are numerous (see above and Fig. 1) and it may be that for a few individuals with multiple sclerosis, with for example a highly unfavourable genetic disposition (including for the metabolism and effects of vitamin D) and the presence of other deleterious environmental risk factors (past infections, smoking, etc.), the vitamin D status remains apparently normal and hypovitaminosis D per se is not required in order to trigger the disease. Thirdly, hypovitaminosis D may seem banal since it is not specific to multiple sclerosis and may be found, when looked for, in all kinds of pathologies as well as in most sections of the general population. This last point may explain why 25(OH)D serum levels in patients with multiple sclerosis are not very different from those of controls in some studies. However, patients with multiple sclerosis could radically differ from normal subjects in that, in addition to hypovitaminosis D, they have multiple other risk factors that normal subjects do not have (e.g. genetic disposition and past infections), all these factors likely interacting together to trigger the disease (see above and Fig. 1). It should be noted, moreover, that in order to suspect a possible role of hypovitaminosis D in the pathogenesis of a given affection, there must also be a rationale and various studies involving vitamin D upstream in the same pathology, such as those that already exist in multiple sclerosis (see the preceding chapters of this paper and Fig. 1) but not, at least for the time being, in other neurological pathologies. In summary, our vitamin D hypothesis in multiple sclerosis could explain (i) the existence of a few multiple sclerosis cases with apparently normal vitamin D status, other environmental and genetic risk factors then likely being determinant for them; and (ii) the fact that both patients with multiple sclerosis and normal subjects often have a similar low vitamin D status, since all the risk factors—including hypovitaminosis D, other environmental factors and particular genetics—may interact together in patients with multiple sclerosis, but probably not in normal subjects, finally triggering the disease.

Relation to Clinical Stages

In multiple sclerosis, hypovitaminosis D is observed throughout the course of the disease, including at the moment of the first relapses or even in a clinically isolated syndrome, in which a majority of patients are already in a state of insufficiency (Soilu-Hänninen et al., 2005; Hanwell et al., 2009; Hiremath et al., 2009; Pierrot-Deseilligny, 2009; Mowry et al., 2010; Fig. 5). Moreover, vitamin D status cannot be predicted for a given patient since a severe deficiency may be observed in people who are young, not yet disabled and apparently in good general health. It should also be emphasized that many relatively young ambulatory patients already have both marked osteoporosis and a chronic vitamin D insufficiency (Marrie et al., 2009; Sioka et al., 2009; Steffensen et al., 2010). Therefore, in an optimal preventive perspective, it appears important to determine the vitamin D status of all patients, regardless of their appearance and the stage of the disease. This systematic measurement could also be extended to subjects with a radiologically isolated syndrome, siblings of patients with multiple sclerosis and even young adults who have had late infectious mononucleosis, i.e. categories of subjects in whom the risk of multiple sclerosis is potentially higher than in the general population. However, it is also true that the more advanced the disease, the greater the vitamin D insufficiency. Thus, the serum level of patients with a secondary progressive form of multiple sclerosis is generally very low, around 40 nmol/l (Nieves et al., 1994; Ozgocmen et al., 2005; Smolders et al., 2008b; Fig. 5), whereas parathyroid hormone serum levels may be high (Nieves et al., 1994). From a pathogenic point of view, three different but associated factors may contribute to worsening an initial hypovitaminosis D in the course of multiple sclerosis: (i) sensitivity to heat (Uthoff symptom), including to sun, which increases symptoms when the external or internal temperature increases, may lead patients to avoid sunshine as early as the beginning of the disease; (ii) a little later in the disease, disability may limit the amount of time patients spend outdoors and consequently their exposure to the sun; and (iii) lastly, with age, the synthesis of vitamin D is less efficient, which also constitutes an aggravating factor. Therefore, in advanced forms of multiple sclerosis, hypovitaminosis D could partly be the consequence of sensitivity to heat (Simmons et al., 2004), disability (Van der Mei et al., 2007a) and age, independently of being one of the possible mechanisms worsening the neurological status. Accordingly, whatever the various factors contributing to the hypovitaminosis D observed in multiple sclerosis, the lack of vitamin D is widespread in this affection and should therefore be systematically detected, with a view to simple supplementation for patients in a state of insufficiency to improve their general health (Myrh, 2009; Pierrot-Deseilligny, 2009). The distinct question of an additional, specifically neurological curative effect of vitamin D in multiple sclerosis will not be resolved until the results of reliable therapeutic trials become available, i.e. in several years time. Be that as it may, it should be noted that this question of a possible neurological curative effect of vitamin D in multiple sclerosis may be only partly linked to that of a role of hypovitaminosis D as a risk factor before the start of the disease.

Figure 5.

Serum levels of 25(OH)D in a Paris cohort of patients with multiple sclerosis. A total of 325 consecutive outpatients with a relapsing-remitting form (RR, n = 202), secondary-progressive form (SP, n = 91) of multiple sclerosis or a clinically isolated syndrome (CIS, n = 32) were referred to Salpêtrière hospital between 1 June 2008 and 31 May 2009, most of the patients with multiple sclerosis being treated with immunomodulator or immunosuppressive therapies, but none being supplemented with vitamin D at the time of titration: 222 female and 103 male; mean age: 41 years in relapsing-remitting form, 51 years in secondary progressive form and 36 years in clinically isolated syndrome; mean Expanded Disability Status Scale: 3.1 in relapsing-remitting, 5.6 in secondary progressive and 0.9 in clinically isolated syndrome; mean duration of disease: 6.9 years in relapsing-remitting, 14.6 years in secondary progressive and 0.4 year in clinically isolated syndrome; mean serum level of vitamin D: 50 nmol/l in relapsing-remitting, 39 nmol/l in secondary progressive and 45 nmol/l in clinically isolated syndrome. The sex ratio and the proportion of serum samples collected during the two half-years (i.e. June–November and December–May) were analogous in the three groups of patients. The results of serum levels of vitamin D were divided into quantiles of 25 nmol/l and the percentage of patients in each quantile is shown. Note that the international norm for 25(OH)D serum level commonly accepted at present is over 75 nmol/l and that most patients in the three forms of multiple sclerosis were in a state of insufficiency ( < 75 nmol/l), very few reaching the currently recommended level of 100 nmol/l.

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