Ultraviolet B (UVB) radiation and vitamin D are important risk reduction factors for multiple sclerosis; viral infections are an important risk factor; dietary fat is a minor risk factor
William B. Grant, Ph.D., SUNARC (www.sunarc.org)
Abstract
A review of the literature shows that a number of environmental factors are involved in the etiology of multiple sclerosis (MS). One finding that has been known since the early 20th century is that there is a latitudinal dependence of MS prevalence, with MS prevalence increasing very strongly with increasing latitude. This has been linked primarily to solar UVB through the production of vitamin D, and, to a lesser extent, increased consumption of dietary fat with latitude. In addition, viral infections have been found associated with development of MS. The mechanisms whereby vitamin D reduces the risk of MS are now fairly well understood. Both dietary changes and UVB/vitamin D therapy appear to be useful in treating MS. It is estimated that if all Americans had the UVB/vitamin D status of those living in southern U.S. states, the numbers of those with MS in the U.S. would be 200,000, rather than 400,000.
Ultraviolet B (UVB) radiation, vitamin D and multiple sclerosis
The latitudinal variation in prevalence of MS has been known since shortly after World War I [Davenport, 1922; Kurtzke et al., 1979; Wallin et al., 2003]. Figure 1 shows the latitudinal dependence in the U.S. for veterans of World War II and the Korean Conflict. The adjusted r2 for this distribution is 0.72, which is quite high for a single-factor ecologic analysis. This means that 72% of the variation can be explained by latitude, leaving 28% to be explained by other factors. An ecologic study in Australia found an r2 of 0.83 between solar ultraviolet radiation (UVR) irradiance and prevalence of MS [van der Mei et al., 2001], giving strong support to the U.S. findings. Based on the variation of MS with latitude in the U.S., it is estimated that half of the 400,000 people with MS would not have MS if all Americans had the UVB/vitamin D status as those living in the southern states.
A population based case-control study was conducted in Tasmania, latitudes 41-43 degrees S. 136 cases with multiple sclerosis and 272 controls randomly drawn from the community and matched on sex and year of birth. Higher sun exposure when aged 6-15 years (average 2-3 hours or more a day in summer during weekends and holidays) was associated with a decreased risk of multiple sclerosis (adjusted odds ratio 0.31, 95% confidence interval 0.16 to 0.59). Higher exposure in winter seemed more important than higher exposure in summer. Greater actinic damage was also independently associated with a decreased risk of multiple sclerosis (0.32, 0.11 to 0.88 for grades 4-6 disease). A dose-response relation was observed between multiple sclerosis and decreasing sun exposure when aged 6-15 years and with actinic damage [van der Mei et al., 2003].
Figure 1. Multiple sclerosis prevalence rate by state for U.S. WWII and Korean Veterans [Kurtzke et al., 1979; Wallin et al., 2003] vs. latitude.
Incident UVB and vitamin D status were proposed to explain this geographic variation in 1974 [Goldberg et al., 1974a,b], in 1986 [Goldberg et al., 1986], and again in 1997 [Hayes et al., 1997]. A recent study found a strong inverse association between non-melanoma skin cancer (NMSC), a measure of total exposure to solar UVR, and MS, with the risk of MS being about half of that of the general population for those who develop NMSC [Goldacre et al., 2004]. One study reported that seasonal variations in MS lesions are correlated with serum 25-hydroxyvitamin D (25(OH)D), being half in summer what they are in winter [Embry et al., 2000], which is related to disease progression, rather than onset. Animal studies support the role of vitamin D in reducing the risk of MS [Cantorna et al., 1996; Meehan and DeLuca, 1997]. One study found significant inverse associations between intake of vitamin D and MS incidence [Munger et al., 2004]. Furthermore, immunological analyses done in conjunction with these experiments identified 8 immune-regulating actions for vitamin D hormone [Cantorna, 2000; Deluca and Cantorna, 2001; Embry, 2004].
The mechanisms whereby vitamin D reduces the risks of developing MS as well as the progression of MS are well known [Cantorna et al., 1996; Meehan and DeLuca, 1997; Cantorna, 2000; Deluca and Cantorna, 2001; Embry, 2004; VanAmerongen et al., 2004].
It should be mentioned that the amount of vitamin D required to reduce the risk of developing MS or having it progress is very likely around 1000 I.U. per day to as high as 4000 I.U. per day [Embry, 2004], which is higher than the value usually stated for maintaining general health. However, men taking the high values are at increased risk for prostate cancer, since the minimal risk for prostate cancer is associated with population mean values of 25(OH)D [Tuohimaa et al., 2004; Grant, 2004]. For both MS and prostate cancer, the important thing seems to be to maintain adequate 25(OH)D levels during winter or other times if lifestyle reduces the opportunities for exposure to solar UVB radiation. Thus, those taking higher doses of vitamin D are strongly advised to have their serum 25(OH)D levels checked.
These observational studies of MS incidence and progression coupled with the identification of a large number of mechanisms that could explain the link appear to be compelling. The making of the link between UVB, vitamin D status, and MS should be considered a classic in the history of epidemiologic studies.
Viral infections
However, vitamin D is not the only factor to consider in the etiology of MS. Kurtzke [1993] summarized the evidence for a viral infection as the cause of MS as follows: "The worldwide distribution of multiple sclerosis (MS) can be described within three zones of frequency: high, medium, and low. The disease has a predilection for white races and for women. Migration studies show that changing residence changes MS risk. Studies of persons moving from high- to low-risk areas indicate that in the high-risk areas, MS is acquired by about age 15. Moves from low- to high-risk areas suggest that susceptibility is limited to persons between about ages 11 and 45. MS on the Faroe Islands has occurred as four successive epidemics beginning in 1943. The disease appears to have been introduced by British troops who occupied the islands for 5 years from 1940, and it has remained geographically localized within the Faroes for half a century. What was introduced must have been an infection, called the primary MS affection (PMSA), that was spread to and from successive cohorts of Faroese. In this concept, PMSA is a single widespread systemic infectious disease (perhaps asymptomatic) that only seldom leads to clinical neurologic MS. PMSA is also characterized by a need for prolonged exposure, limited age of susceptibility, and prolonged incubation. I believe that clinical MS is the rare late outcome of a specific, but unknown, infectious disease of adolescence and young adulthood and that this infection could well be caused by a thus-far-unidentified (retro)virus." See, also, Kurtzke and Heltberg [2001].
A stronger case for infections as a risk factor for MS is found in a study of infection with Epstein-Barr virus (EBV). Such infection has been associated with an increased risk of multiple sclerosis (MS), but the temporal relationship remains unclear [Levin et al., 2003]. A nested case-control study was conducted among more than 3 million US military personnel with blood samples collected between 1988 and 2000 and stored in the Department of Defense Serum Repository. The risk of MS increased monotonically with these antibody titers; relative risk (RR) in persons in the highest category of EBV viral capsid antigen (VCA) (> or =2560) compared with those in the lowest (< or =160) was 19.7 (95% confidence interval [CI], 2.2-174; P for trend =.004). For EBNA complex titers, the RR for those in the highest category (> or =1280) was 33.9 (95% CI, 4.1-283; P for trend <.001) vs those in the lowest category (< or =40) [Levin et al., 2003]. These results suggest a relationship between EBV infection and development of MS.
Vitamin D has been strongly linked as playing an important role in supporting the immune system in reducing the risk of disease [Griffin et al., 2003] and multiple sclerosis in particular [Cantorna, 2000; DeLuca and Cantorna, 2001; Embry, 2004]. Thus, it appears likely that viral infections can lead to an immune response, which, in some individuals, can lead to an autoimmune response, such as MS. The Faroe Islands, being at a high latitude, would get little protection from vitamin D produced by sunlight, so would most likely have to rely on fish for their source of vitamin D [Jablonski and Chaplin, 2000].
Diet and multiple sclerosis
Roy Swank noted a correlation between dietary fat and incidence of MS [Swank, 1950], and in 1949 began a low-fat dietary treatment program for MS [Swank, 1953]. His summary of his long-running study is as follows: Between 1949 and 1984, 150 patients with multiple sclerosis consumed low-fat diets. Fat, oil, and protein intakes; disability; and deaths were determined. With a daily fat consumption less than 20.1 g/day (av 17 g/day), 31% died, and average deterioration was slight. A daily intake greater than 20 g/day (av 25 or 41 g/day) was attended by serious disability and the deaths of 79 and 81%, respectively. Oil intake bore an indirect relationship to fat consumption. Minimally disabled patients who followed diet recommendations deteriorated little if at all, and only 5% failed to survive the 34 yr of the study, whereas 80% who failed to follow diet recommendations did not survive the study period. The moderately disabled and severely disabled patients who followed diet recommendations carefully did far better than those who failed to follow the diet. In general, women tended to do better than men. Those patients treated early did better than those in whom treatment was delayed. High sensitivity to fats suggests that saturated animal fats are directly involved in the genesis of MS [Swank, 1991].
An epidemiologic study has been performed on the relation between the mortality rates from MS for the period 1983-1989 obtained for 36 countries, dietary fat, and latitude. By stepwise multiple regression analysis, saturated fatty acids, animal fat, animal minus fish fat, and latitude correlated independently and positively with multiple sclerosis mortality (p < 0.01-0.001 for fat consumption, and p < 0.05-0.01 for latitude). The ratio of polyunsaturated fatty acids to saturated fatty acids (P/S ratio) and the ratio of unsaturated fatty acids (monounsaturated and polyunsaturated fatty acids) to saturated fatty acids (U/S ratio) correlated independently and negatively with MS mortality (p < 0.05-0.001). These findings support the hypothesis linking dietary fat intake and latitude to MS mortality [Esparza et al., 1995].
A study of dietary factors and presence of MS was conducted in Canada. The relation between nutritional factors and MS was studied among 197 incident cases and 202 frequency-matched controls in metropolitan Montreal during 1992-1995. Among the findings was that he odds ratio (OR) per 897 kcal increase in total energy was 2.03 (95% CI: 1.13-3.67) and 1.99 (95% CI: 1.12-3.54) per 33 g of animal fat intake above the baseline; a higher intake of fruit juices was inversely associated with risk (OR= 0.82; 95% CI: 0.74-0.92). A protective effect was also observed with cereal/breads intake for all cases combined (OR = 0.62; 95% CI: 0.40-0.97) and for fish among women only; pork/hot dogs (OR = 1.24; 95% CI: 1.02-1.51) and sweets/candy (OR = 1.29; 95% CI: 1.07-1.55) were positively associated with risk [Ghadirian et al., 1998].
On the other hand, an investigation of the role of various types of dietary fat and subsequent risk of MS in the Nurses’ Health Study found very limited multivariate risk ratios, thus, no support for dietary fat playing an important role in the etiology of MS [Zhang, 2000]. However, the Nurses’ Health Study has often missed links between dietary fat and chronic disease, such as breast cancer, finally confirming it recently [Cho et al., 2003] even though ecologic studies find strong links [Grant, 2002]. The reason for this difficulty seems to be that since American nurses generally eat the standard American diet, there is too little variation in the dietary factors to readily identify such dietary links. However, in the ecologic approach, countries with vastly different values for dietary factors are used [Grant, 2003].
Omega-3 (n-3) fatty acids have been found to reduce the symptoms of MS and other autoimmune diseases, especially the inflammation [Nordvik et al., 2000; Simopoulos, 2003]. Since these experiments are generally conducted with fish oil rather than vegetable oil, and since fish oil contains vitamin D, it could be that the effects are due to the vitamin D instead of or in addition to the effect of n-3 oils on prostaglandin production of the type that reduce inflammation.
A study as part of the Nurses’ Health Study concluded that he findings do not support hypotheses relating higher intakes of dietary carotenoids, vitamin C, and vitamin E to reduced risk of MS in women [Zhang et al., 2001].
Summary and conclusion
From the evidence presented here, it appears that viral infections can be considered an important risk factor for MS, and that dietary fat is also a minor risk factor. More importantly, the evidence is very strong that UVB radiation and vitamin D are very strong risk reduction factors. Thus, these results add to the information supporting the role of vitamin D in reducing the risk of chronic disease.
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