Why we should offer routine vitamin D supplementation in pregnancy and childhood to prevent multiple sclerosis

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Summary

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that runs a chronic course and disables young people. The disease is more prevalent in the geographic areas that are farthest from the equator. No form of treatment is known to be effective in preventing MS or its disabling complications. A number of epidemiological studies have shown a protective effect of exposure to sunlight during early life and a recent longitudinal study confirmed that vitamin D supplementation reduced life-time prevalence of MS in women. Very little is known regarding the role of vitamin D on the developing brain but experimental data suggest that cerebral white matter is vitamin D responsive and oligodendrocytes in the brain and spinal cord and express vitamin D receptors. It is possible that differentiation and axonal adhesion of oligodendrocytes are influenced by vitamin D level during brain development and a relative lack of vitamin D may increase oligodendroglial apoptosis. The age effect of migration on susceptibility to develop MS could be explained by a role of vitamin D on brain development. In areas of high MS prevalence, dietary supplementation of vitamin D in early life may reduce the incidence of MS. In addition, like folic acid, vitamin D supplementation should also be routinely recommended in pregnancy. Prevention of MS by modifying an important environmental factor (sunlight exposure and vitamin D level) offers a practical and cost-effective way to reduce the burden of the disease in the future generations.

Introduction

The cause and the exact pathogenesis of multiple sclerosis (MS) are unknown [1]. The pathological hallmark of MS is confluent and multi-focal demyelination in association with progressive neuronal loss. In the past, most researchers assumed an autoimmune mechanism of demyelination in MS driven by T-lymphocytes sensitised to one or more target epitopes in the myelin protein [2], [3]. However, it is acknowledged even by the ardent followers of autoimmunity that there exists no reproducible and specific immunological marker for MS [3]. Experimental allergic encephalomyelitis (EAE) is an animal model of demyelination induced by artificial T-cell sensitisation to myelin basic protein. Clinically and pathologically, EAE bears only superficial resemblance to MS and most treatments that work in EAE are not considered to be safe or effective in the human trials of MS [1]. Morbidity and occasional mortality from immunological treatments in MS are of significant concern, especially because these treatments do not prevent the disease or its progression over the years. Pathological findings in newly forming acute demyelinating lesions may be characterised by virtual absence of lymphocytes or myelin phagocytes that bear no resemblance with the histology of EAE [4]. There is a growing controversy at present whether the primary disease process in MS is autoimmune [5], [6].

One of the most valid criticisms of the autoimmune mechanism and the EAE model in MS is that these assumptions cannot explain either the geographic distribution or the effect of early life migration on the prevalence of MS. Exposure to sunlight during early life is considered to have a protective effect on the disease [7]. Seasonal fluctuations in the vitamin D level have been associated with MS relapses [8], [9] and a prospective longitudinal study in women recently found that dietary vitamin D supplementation significantly reduced the incidence of MS [10]. Here, I suggest that vitamin D supplementation in pregnancy and early life may prevent the symptomatic manifestation of MS later in life. Vitamin D supplementation in pregnant women should be considered as a public health policy similar to maternal folic acid supplementation that is currently recommended to prevent neural tube defects.

The present review is based on our reading of the existing medical texts and a search of the PubMed and Medline for articles combining (a) multiple sclerosis and vitamin D; (b) season of birth and multiple sclerosis; (c) migration and multiple sclerosis; (d) vitamin D and population; and (e) myelin and/or oligodendrocytes and vitamin D and/vitamin D receptor published by March 2004. Only articles in English were considered and where appropriate, original articles cited in the published reference lists were traced.

Section snippets

Physiology of vitamin D

Vitamin D (Fig. 1) is a steroid hormone in structure and function. The dietary form of vitamin D is an essential nutrient only if humans are not sufficiently exposed to sunlight. With adequate exposure to solar ultraviolet B radiation, vitamin D is synthesised in the skin and no dietary supplement is needed. The biologically active form of vitamin D requires successive hydroxylations in the liver and kidneys before it enters the circulation. Active vitamin D, i.e., 1,25 dihydroxyvitamin D3, is

Dietary requirement of vitamin D

It is not a current recommendation, at least in the United Kingdom, that vitamin D supplementation should be routinely offered either during pregnancy or childhood unless there are concerns about nutritional deficiency or malabsorption. It is generally accepted that simple vitamin D deficiency can be prevented by dietary supplementation of 400 units (800 units in Asians and in the elderly) every day [14]. In England, a daily requirement of 100 units was considered adequate in the adults on the

Vitamin D levels in population

Longitudinal evaluation of vitamin D status in healthy subjects suggest that there are marked seasonal and gender differences in the vitamin D levels [19], [20]. The Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) in the United States surveyed 18,875 young adults and adolescents and measured serum vitamin D levels. Vitamin D insufficiency was common in all groups of adolescents and adults in the winter/lower latitude subpopulation even though the studied subjects

Season of birth and life time risk of multiple sclerosis

In 1950s, it was observed among the US veterans that the average annual hours of sunshine and the winter daily solar radiation at places of births strongly and inversely correlated with the life-time incidence of MS [25]. Subsequent studies in Australia in 1962 [26] and among immigrants in Israel in 1967 [27] also confirmed these findings. In 1991, a retrospective study from Denmark observed that the season of births of people who were later diagnosed with MS differed significantly from that of

Maternal contribution to the risk of MS

There is a substantially higher risk of MS in children born to parents with MS [34]. Part of this risk is certainly genetic but it seems that the risk may also be modified by environmental factors. This is because if the risk was purely genetic, then a similar proportion of children born to either of the affected parents (mother or father) would develop MS provided there were no other significant difference among these children with respect to the environmental risk factors after birth (e.g.

Seasonal incidence of MS and vitamin D levels

Changes in the brain lesion volumes as detected by the gadolinium enhanced MRI are related to the seasonal fluctuations in the vitamin D levels, with the low levels preceding high lesion activity and high levels associated with low activity [8], [9]. A large, population based prospective study in Stockholm, Sweden, observed a seasonal pattern of monosymptomatic optic neuritis, with highest incidence (31%) during spring and the lowest incidence (17%) during winter (p = 0.007; C.I. 1.13–3.01) [36].

Epidemiology of MS: relationship with solar exposure and early life migration

Several aspects of MS epidemiology may suggest a significant contribution of environment during the early life (childhood and adolescence) on the later-life risk of the disease. MS is uncommon in the topics and increases with distance from the equator in both hemispheres. A very important feature of the natural history of MS is that residency in a favourable geographic area (low disease prevalence) sometime before the age of 15 years can reduce the risk in individuals with higher genetic

Vitamin D and MS

The suggestion that vitamin D may have a protective effect on MS is not new. It has been previously hypothesised that early life vitamin D deficiency may be a risk factor for various neurological and psychiatric diseases including MS [45] and that vitamin D is a natural inhibitor of MS [46]. A number of studies have also revealed that individuals with MS have insufficient vitamin D levels and there is higher prevalence of reduced bone mass [47], fracture history [48] and dental caries [49], [50]

Is the protection against MS offered by solar radiation or by vitamin D (a product of solar radiation)?

Those who favour an immunopathogenic hypothesis of MS have proposed that the observed latitudinal variations in MS and the protective effect of solar exposure is related to the direct “immunosuppressive” effect of ultraviolet radiation [54], [55]. It is difficult to accept this explanation given that protection against the disease is not paralleled by the expected side effects of solar radiation (skin cancer) in healthy population living at an area of high MS prevalence. Also, population based

Conclusions

Early life sunlight exposure and dietary vitamin D supplementation diminish the risk of MS. Despite the convincing epidemiological data on the protective effect of sunlight exposure during pregnancy and childhood and the effect of vitamin D supplementation in adults, we do not clearly know how vitamin D may prevent MS because there has not been enough research in this area. However, low vitamin D appears to be an important modifiable external risk factor for MS. Reduced maternal vitamin D

Acknowledgement

I am very grateful to Professor Peter O Behan (Senior Research Fellow, University of Glasgow) for his helpful suggestions. AC is supported by the David and Frederick Barclay Foundation.

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