Vitamin D Supplementation In The Fight Against Multiple Sclerosis
ASHTON EMBRY
INTRODUCTION
Many different supplements are recommended for people with MS and it
is worthwhile to examine the science and logic behind any given
supplement recommendation. Vitamin D, the sunshine vitamin, is not
often strongly advocated for MS, although small dosages (~200-400 IU)
are usually part of a total vitamin recommendation. I have recently
read a number of papers on the relationship between vitamin D and MS
and the best summary of this topic is by Hayes et al (1997). This
information has convinced me that persons with MS could possibly
significantly benefit from a substantially higher supplementation of
vitamin D than is currently proposed in various self help books (e.g.
Graham, 1989) or suggested by clinicians.
In this essay I will present a brief discussion of vitamin D and
follow that with the scientific evidence which supports the concept
that vitamin D likely plays an important role in controlling
autoimmunity and MS. Such evidence consists of epidemiological data,
animal experiments, immunological analyses, genetics and the results
of small clinical trials which used vitamin D or a metabolite as the
therapeutic agent. When all the data are considered as a whole, it
becomes apparent that adequate supplementation of vitamin D may well
be beneficial and, given the very low cost and safety of such a
therapy, persons with MS might want to make sure they are receiving
sufficient amounts each day.
The key questions of, how much vitamin D is needed, is this amount
safe and how can one best obtain this amount, are also addressed.
Vitamin D is a fat- soluble vitamin and can be toxic in large
dosages. Thus it is very important to examine current data in regards
to vitamin D safety and reasonable sources of the vitamin. In the
final part of the essay, vitamin D intake is examined in an
evolutionary perspective and a summary on how vitamin D fits in the
overall "Paleolithic Prescription" for MS concludes the essay.
VITAMIN D
A detailed discussion of the chemistry of vitamin D is far beyond my
capabilities and the scope of this essay. For those wanting such
information, DeLuca and Zierold (1998) provide a very good overview
of the chemistry of vitamin D and its receptor. A few points are
worth mentioning to help one gain an appreciation of what vitamin D
is, how it is activated in the body, and the role it plays in health
and illness. The primary source of this nutrient is not from diet but
rather from a chemical photolysis reaction in the skin. When UV light
from the sun penetrates the epidermis, it is absorbed by a metabolite
of cholesterol (7-dehyrocholestrol) which is then converted into
vitamin D (calciferol). Notably Vitamin D is biologically inert and
is metabolized in the liver to produce 25(OH)D (calcidiol) which is
the main form of circulating vitamin D. Although this substance is
also inactive, its concentration in the blood provides a good
assessment of a person's vitamin D level and the relationship of
various levels of 25(OH)D to health will be discussed later. The
final step in the vitamin D story is that 25(OH)D is converted to an
active hormone, 1,25(OH)2D (calcitriol), in the kidneys.
The main role of vitamin D, through the actions of its metabolized
hormone, calcitriol, is to regulate the amount of calcium and
phosphorous in circulation. In this way it has a major impact on bone
growth or lack thereof (rickets, osteoporosis) and, when most people
think of vitamin D, they think of it in this context. When calcium
levels are low (usually due to insufficient vitamin D and calcium
intake), the body activates the parathyroid gland, which produces PTH
(parathyroid hormone). This hormone kicks starts vitamin D hormone
production and helps to remove calcium from the bones to be used in
more important functions. Thus a measurement of PTH also provides a
good proxy for vitamin D levels in circulation. When adequate vitamin
D is available there is generally no need for the body to produce PTH
and serum levels of this hormone are negligible.
As will be discussed below, recent research has uncovered more roles
for vitamin D besides calcium regulation. The most relevant of these
functions is as an immune regulator which has obvious implications
for its putative role in MS and other autoimmune diseases.
SCIENTIFIC DATA RELATING VITAMIN D TO MS
Goldberg (1974a, 1974b) first proposed the concept that vitamin D was
an important factor in MS. He marshalled a variety of epidemiological
data to make a case for vitamin D being a factor in the onset and
progression of MS. Goldberg emphasized the conspicuous high
prevalence of MS in areas which receive a relatively low amount of
sunlight. Acheson et al (1960) had earlier documented this
relationship between MS prevalence and sunlight with a very
impressive negative correlation between MS prevalence and hours of
sunshine. Goldberg (1974a) took the next step and postulated that
such a close correspondence between low sunlight and MS was due to
low vitamin D production in the population. Goldberg (1974a) also
showed that within areas of low sunlight (e.g. Norway) differences in
MS prevalence could be explained by dietary factors which affect
vitamin D production. Such factors include the amount of fish eaten
(increases vitamin D) and the amount of grains consumed (reduces
vitamin D levels due to the action of phytates). To explain how
vitamin D levels were related to MS, Goldberg (1974b) proposed that
genetically susceptible individuals may need larger than normal
amounts of vitamin D during myelin formation and that insufficient
vitamin D during childhood might result in defective myelin which
would be susceptible to breakdown in later life. Goldberg's ideas
were completely ignored by medical researchers, although, as will be
discussed later, he was able to organize a small clinical trial to
test his concept.
Goldberg's innovative hypothesis that vitamin D is a key factor in
the development of MS and for explaining the distinctive geographic
variations in MS prevalence is just as attractive today as it was 26
years ago. Science started to catch up with Goldberg in the early 80s
with the recognition that immune cells carry a receptor for the
active hormone of vitamin D (1,25-(OH)2D) and that this hormone
likely regulates immune functions (Bhalla et al, 1983).
This discovery led to ongoing research efforts which continue to
uncover a number of important ways in which vitamin D hormone affects
the immune system. One area of research in this regard was a number
of experimental studies with mice and rats which are genetically
susceptible to animal forms of autoimmune disease such as EAE
(closely resembles MS). These studies showed that injections of
vitamin D hormone could protect against or arrest the animal forms of
MS (Lemire and Archer, 1991; Cantorna et al, 1996), type 1 diabetes
(Mathieu et al, 1994), rheumatoid arthritis (Cantorna et al, 1998a)
and lupus (Lemire et al, 1992). Furthermore, immunological analyses
done in conjunction with these experiments revealed the following
immune-regulating actions for vitamin D hormone:
1) Suppresses antibody production by B cells and the proliferation of
T cells in the thymus (Yang et al, 1993).
2) Upregulates cytokines TGF-beta and IL-4. These proteins, which are
produced by immune cells, act as suppressants of inflammatory T cells
(Cantorna et al, 1998b).
3) Inhibits production of pro-inflammatory cytokines such as IL-1,
IL-2, TNF and IFN gamma (Muller and Bendtzen, 1996) which also
reduces inflamammatory reactions.
4) Interferes with T helper function and inhibits the passive
transfer of cellular immunity by Th in vivo (Thomasset, 1994)
5) Inhibits the production of NO (nitric oxide) by immune cells
(Garrion et al, 1997). NO has been identified as one of the most
destructive products of the immune system and is an important factor
in demyelination.
6) Inhibits the proliferation of activated and memory T cells (Muller
and Bendtzen, 1992). Such cells are the main mediators of the
inflammatory autoimmune reactions of MS.
7) Exerts immunomodulating effects in the CNS by inducing a profound
downregulation of antigen expression by both infiltrating and
resident antigen presenting cells (e.g. macrophages) (Nataf et al,
1996).
In summary, vitamin D hormone has numerous effects on the immune
system and acts within the CNS. All of these effects have the
combined result of significantly reducing inflammatory autoimmune
reactions from occurring and they readily explain why vitamin D
hormone is so effective in suppressing a variety of animal autoimmune
diseases including EAE (animal MS) (Hayes et al, 1997).
On the basis of the impressive immunomodulating effects of vitamin D,
Schwartz (1993) hypothesized that the well established reduction of
MS attacks during pregnancy and their increased occurrence following
pregnancy was due in part or whole to the natural large increases in
production of vitamin D hormone during pregnancy and its rapid
decline afterwards. Such a hypothesis seems very plausible and
hopefully will be followed up.
Genetic data also implicate vitamin D in MS and Fukazawa et al (1999)
demonstrated an association between vitamin D receptor genes and MS.
Vitamin D has been used as a therapeutic agent in only a few small
clinical trials. Notably Goldberg helped to organize a small trial
in the early 80s (Goldberg et al, 1986). Ten subjects took 5000
IU/day of vitamin D along with about 1000mg of Ca and 600mg of Mg for
two years. The subjects acted as their own controls with the
exacerbation rates during the trial compared with the subjects'
historical rates of exacerbation. A notable decline in exacerbation
rate was noted, although the small size of the trial makes the
results equivocal. Despite these results and all the scientific data
showing that vitamin D would be a good therapeutic agent, no
follow-up, better controlled trials have ever been done for vitamin D
and MS.
A small clinical trial for RA and a vitamin D metabolite was recently
done by Andjelkovic et al (1999) over a three-month time period. The
results were positive: "Therapy showed a positive effect on disease
activity in 89% of the patients (45% with complete remission and 45%
with a satisfactory effect). Only two patients (11%) showed no
improvement, but no new symptoms occurred". Another relevant study
was a large-scale investigation of the effects of vitamin D
supplementation in infants and the associated risk of type 1 diabetes
(Eurodiab Study Group, 1999). This study clearly demonstrated that
supplementation with vitamin D was associated with a decreased risk
of type 1 diabetes.
In summary, a variety of data, from epidemiology, animal experiments,
immunological investigations, genetics and small clinical trials
indicates that vitamin D can have a suppressant effect on autoimmune
reactions and help to slow autoimmune disease. Thus its use as a
supplement by persons with MS or other similar autoimmune diseases,
such as rheumatoid arthritis and Crohn's, seems warranted.
SUPPLEMENTATION AND SAFETY
The above scientific data suggest that it is important for persons
with cell-mediated autoimmune diseases, including MS, to have
sufficient intake of vitamin D. In this section the questions of, how
much, where to get it and is it safe, are addressed. The best
reference for the answers to these questions is a recent,
comprehensive review by Vieth (1999) entitled "Vitamin D
Supplementation, 25-hydroxyvitamin D concentrations and Safety". The
answers to the above questions are provided in this excellent paper
and readers wanting more information than provided below are referred
to it.
On the question of how much, Vieth (1999) first notes that humans
evolved having a relatively large intake of vitamin D, with a naked
human in Africa likely getting at least 10000 IU a day. He then
reviews all the literature on intake of vitamin D and resultant
levels of 25(OH)D and PTH. The key here is that when adequate levels
of 25(OH)D (an intermediate metabolite of vitamin D) are circulating
there is no need for the body to produce PTH (parathyroid hormone).
On the basis of all the available data, Vieth (1999) concludes that
it is desirable to have 100-125 nmol/litre of 25(OH)D in circulation.
Furthermore, he notes, that to achieve this amount, an intake of
about 4000 IU of vitamin D a day is required. As described earlier,
the main source of vitamin D is the sun and in hot climates (south of
40 N) such an intake is readily possible if an individual spends a
reasonable time in the sun. However, in colder climates, like those
of Canada, northern USA and northwest Europe, it is almost impossible
to average 4000 IU a day because for at least six months of the year
intake from the sun is negligible at best. Even during the few hot
summer months an individual would have to spend considerable time in
the sun to achieve the required intake.
Thus in areas of low sunlight, supplements provide a reasonable
alternative for vitamin D intake. As Vieth (1999) notes "From what is
known now, there is no practical difference whether vitamin D is
acquired from ultraviolet exposed skin of through diet". Cod liver
oil, fish and vitamin D fortified foods are the usual dietary sources
used to get vitamin D. However these sources usually supply much less
than 1000 IU/day and the fortified foods provide a synthetic form of
vitamin D (D2) which is substantially inferior to the natural vitamin
D3 (Trang et al,1998). Furthermore, because cod liver oil also
contains large amounts of vitamin A, it would not be feasible to get
4000 IU of vitamin D from it because of potential problems with too
much vitamin A. Fortunately there are specific vitamin D3 supplements
which are usually small 1000 IU pills and a bottle of 100 costs less
than $10 ($5 CDN in Calgary). This would seem to be the most
reasonable source of 4000 IU a day.
Vieth (1999) also addresses the safety issue of vitamin D at length.
He shows that the "no observed adverse effect level (NOAEL)" is at
least 10,000 IU/day. The lowest observed adverse effect level (LAOEL)
is 40,000 IU/day. Thus 10,000 IU/day is definitely safe (assuming no
hypersensitivity) and 40,000 IU/day is definitely a problem. It would
be next to impossible for anyone living in a northern area to get too
much vitamin D from sunlight and a 4000 IU supplement. Thus such a
supplementation level is safe for anyone who is not hypersensitive to
vitamin D.
It must be stressed that adequate calcium and magnesium intake must
accompany vitamin D supplementation as discussed by Goldberg et al
(1986). Cantorna et al (1999) recently demonstrated that calcium
levels strongly affect the action of vitamin D for suppressing EAE in
mice. Calcium intake should be in the range of 600-900 mg/day with
magnesium intake being about the same as this
In summary, a daily intake of vitamin D of 4000 IU along with 800 mg
of both calcium and magnesium are required for adequate levels of
metabolized vitamin D products to be maintained in circulation. For
those in low sunlight climates, such a vitamin D intake is most
easily achieved with a daily supplement of 4000 IU of a vitamin D3
product.
VITAMIN D IN A PALEOLITHIC PERSPECTIVE
Eaton and Konner (1985) hypothesized that, with the advent of
agriculture and the subsequent industrial and technological
revolutions, consequent changes in dietary habits and major shifts in
the intake of various nutrients have adversely affected human health.
They suggest that these major changes are in part responsible for a
myriad of "genetic-environmental" diseases including heart disease,
stroke, type 2 diabetes and various forms of cancer. As discussed in
Cordain (1999) and Cordain et al (in press), this concept can be
readily applied to autoimmune diseases. In this context it is useful
to examine changes in vitamin D intake during the two million year
evolution of human beings and how such changes are related to the
rise of MS.
Humans lived in hot climates throughout most of their development and
thus they experienced a relatively large intake of vitamin D from
sunlight. Natural selection would have ensured that the human genome
became very compatible with such an intake, estimated to be in the
range of 10000 IU a day. This would have resulted in circulating
concentrations of 25(OH)D of between 100 and 140 nmol/litre which can
regarded as the optimal level of vitamin D. Such a concentration
supplied all the vitamin D hormone required for a variety of
functions including the maintenance of a strong skeletal structure
and the control of autoimmune reactions induced by foreign antigens
derived mainly from infectious agents. The importance of adequate
vitamin D for human health is underscored by the fact that evolution
produced a very simple and seemingly fail-safe method for its
attainment.
As humans migrated out of Africa into temperate areas, less
sun-derived vitamin D became available and daily intakes likely fell
somewhat. However, because long periods were spent outside hunting
and gathering, most Paleolithic people still obtained sufficient
vitamin D (>4000 IU/day) and readily maintained an adequate serum
concentration of 25(OH)D throughout the year.
With the advent of agriculture about 8000 years ago and the ensuing
population explosion, maintaining adequate levels of vitamin D and
its metabolites started to become a problem for the first time in
human history. Population pressures forced humans to migrate into
even more hostile areas in terms of cold climates and low sunlight.
They also tended to eat less fish and spend much more time out of the
sun. Significantly, two of the main foods of agriculture have an
adverse effect on the action of vitamin D. Grains, which are the
number one food of agriculture, contain phytate or phytic acid which
counters the action of vitamin D (Willis and Fairney, 1972). Cordain
(1999) also discusses the role of grain consumption in vitamin D
deficiency. Goldberg (1974a) raised this point and showed that areas
where grains were grown in Norway tended to have the highest rates of
MS. Notably, the only common grain with a very low phytate content is
rice.
Another food introduced into the human diet by agriculture is milk.
Milk may also have an adverse effect on vitamin D by affecting the
vitamin D receptor on cells. Perez-Maceda et al (1991) demonstrated
that part of the bovine albumin protein of milk is a molecular mimic
of the vitamin D receptor. Thus an immune reaction against that milk
protein can potentially result in an autoimmune reaction against the
vitamin D receptor. This would significantly lower the effectiveness
of vitamin D hormone to bind with a variety of cells (including
immune cells) and carry out its important functions.
Our modern lifestyle has only exacerbated the problem of vitamin D
deficiency and large populations now inhabit low annual sunlight
areas. The consumption of fish is very low in many agricultural areas
where diets are completely dominated by high phytate, gluten grains
and dairy products. A dominance of indoor jobs, fears of skin cancer
and the use of sunscreens have reduced exposure times to sunlight
further such that, even in summer, many people do not get anywhere
near the required vitamin D intake from sunlight. Thus it would
appear that chronic vitamin D deficiency (<100nmol/litre of 25(OH)D)
in large populations which live in low sunlight climates is a
Neolithic problem and is caused by a variety of lifestyles factors
which greatly differ from those of the Paleolithic when adequate
vitamin D was readily obtained.
Notably persons with MS tend to be at the problematic end of the
deficiency spectrum (<50 nmol/litre 25(OH)D). The reasons for this
higher than normal deficiency is likely multifold and includes the
tendency for persons with MS to spend less time outside doing various
laborious or sporting activities, the use of steroidal drugs in
treatment, diets with an abundance of grains and milk and no
encouragement from their doctors or MS societies to take sufficient
vitamin D supplements. A study of 80 persons with MS by Nieves et al
(1994) revealed a mean level of 25(OH)D of only 43 nmol/litre with a
quarter of the subjects " having frank vitamin D deficiency
(<25nmol/l). Not surprisingly the bone mineral density of most of the
subjects was very low. Sadly, this study indicates that many people
with MS likely do not have enough vitamin D intake to maintain their
bones let alone to counter autoimmune reactions. A more recent study
by Cosman et al (1998) supported the findings of Nieves et al (1994).
With both the general Paleolithic perspective and the documented low
levels of vitamin D in persons with MS in mind, it is worth
discussing the role vitamin D plays in the overall development of MS.
First of all it is important to differentiate between autoimmunity
and autoimmune disease. Autoimmunity is the production of immune
cells which are autoaggressive and such a phenonomen has most
probably been present throughout human development. It is well
established that autoaggressive immune cells are produced during
infections (Matzinger, 1998) and the reason for this is that the body
must maintain a vast repertoire of immune cells to ensure protection
against a huge number of pathogens. Thus the common occurrence of
cross-reactive immune cells which react against both foreign and
self-antigens represents an evolved compromise between maximum
protection against foreign invaders and maximum protection against
autoimmunity. Through the actions of the suppressor side of the
immune system, evolution has also ensured that the sporadic
production of autoaggressive immune cells due to random infections
would not go unchecked and result in uncontrolled autoimmunity. Such
runaway autoimmunity is called autoimmune disease. Thus, although
autoimmunity has always been with us, autoimmune disease is likely a
relatively new phenonomen in human development and is due to a
relatively recent loss of control (suppression) of sporadically
produced autoaggresive immune cells by a portion of the population.
The best explanation for the recent rise in autoimmune disease is
that new environmental agents have upset the delicate balance between
the production and suppression of autoaggressive immune cells either
by increasing autoimmune reactions or by hindering the control of
such reactions. When the balance tips towards increased autoimmune
reactions and/or decreased suppression, autoimmunity can progress to
autoimmune disease. The profoundly different dietary regimen, which
began with the adoption of agriculture, is one obvious source of such
new, immune-disruptive agents. The Paleolithic diet was dominated by
fruits, vegetables and lean wild meats which had a low saturated fat
content. The main foods "recently" introduced by agriculture are
grains (i.e. grass seed), dairy products and meat from domesticated
animals which has a very high saturated fat content. As discussed in
detail by Cordain (1999) and Cordain et al (in press), it would
appear that proteins from various foods introduced by the Neolithic
agricultural revolution (e.g. gluten, dairy, legumes) result in
autoimmune reactions mainly by increasing intestinal permeability and
by mimicking infectious and self-antigens. The great increase in the
consumption of saturated fat also contributes to an increase in
inflammatory reactions (Fraser et al, 1999).
Such food-driven autoimmune reactions, although of relatively low
magnitude in comparison with infection-driven autoimmune reactions,
occur almost on a daily basis. They have a significant cumulative
effect and thus recently introduced foods are clearly suitable
candidates for the agents which result in harmless autoimmunity
becoming problematic autoimmune disease in genetically susceptible
persons.
This increase in Neolithic dietary elements that contribute to
autoimmune reactions is matched by a notable decrease during the
Neolithic of nutrients that play a significant role in the
suppression of autoimmune reactions. These suppression-inducing
nutrients include both omega 3 fats (fish oil) (Calder, 1998 ) and
vitamin D (references herein). Thus the newly adopted dietary habits
of agriculture promote autoimmune disease both by increasing
autoimmune reactions and by lessening anti-inflammatory responses.
Not surprisingly, MS and other autoimmune diseases are most common in
areas where the dietary regimen contains a dominance of
pro-inflammatory food types and a paucity of anti-inflammatory
nutrients. The common deficiency of vitamin D is just one of numerous
Neolithic nutritional factors which, in combination with the ever
present infectious agents, result in a variety of autoimmune diseases
in these areas. Consequently, it is just one of a number of factors
which must be reversed if one hopes to successfully combat an
autoimmune disease.
As discussed above, it appears the best method of reversing vitamin
D deficiency is to use a supplement of 4000 IU which will result in
optimal levels of vitamin D metabolites. This in turn should result
in increased suppression of autoimmune reactions precipitated by food
and infectious agents and help to turn the tide against uncontrolled
autoimmunity. It seems only reasonable that a person's best hope of
controlling an autoimmune disease is to reverse as many of the
adverse Neolithic influences, including vitamin D deficiency, as
possible.
SUMMARY
An abundance of scientific evidence indicates that vitamin D
deficiency is associated with MS onset and progression. Such evidence
includes epidemiology which demonstrates that high prevalence rates
of MS closely track areas of low intake of vitamin D. Animal
experiments reveal that vitamin D hormone can suppress a variety of
animal autoimmune diseases including EAE, the animal equivalent of
MS. Furthermore, associated immunological studies have shown that
vitamin D hormone has a number of immunomodulating functions, all of
which contribute to the suppression of inflammatory autoimmune
reactions. Small clinical trials have suggested that vitamin D has
some efficacy in slowing autoimmune disease progression although no
properly controlled trials have been conducted.
Vitamin D can be readily attained from exposure to sunlight and
studies have shown that the optimal intake of vitamin D is about
4000- 6000 IU a day. This results in a circulation concentration of
25(OH)D ( a vitamin D metabolite) of 100-125 nmol/litre and this
level seems to be required for the proper functioning of all vitamin
D-dependent systems. In colder, low sunlight areas such an intake
from the sun is impossible for most of the year and it is important
to use supplements to makeup the shortfall in vitamin D supply.
Currently suggested supplement levels of 200-400 IU are much too low.
A daily supplement of 4000 IU of vitamin D3 seems warranted for
people who do not get a lot of exposure to sunlight throughout the
year. This amount is well below the no observed adverse effect level
which is conservatively placed at 10000 IU/day and thus such
supplementation is safe for anyone who is not hypersensitive to
vitamin D.
Throughout most of the two million years of human development, humans
had a relatively high intake of vitamin D (~5000-10,000 IU/day) from
the sun. Major environmental changes brought on by the agricultural,
industrial and technological revolutions have resulted in large
populations in northern climates experiencing a subclinical and
chronic vitamin D deficiency and this deficiency is more pronounced
in persons with MS. Vitamin D deficiency is just one of a number of
nutrient-related factors which play a role in MS. Notably the dietary
regimens which contain the most pro-inflammatory food types (e.g.
gluten, dairy, saturated fat) and the least anti-inflammatory
nutrients ( vitamin D, omega 3 fats) occur in areas in which MS and
other autoimmune diseases are most common. To combat MS, a person
must change their lifestyle with diet revision being perhaps the most
useful modification. As part of this change, it is important to
ensure that sufficient vitamin D (4000 IU/day) is acquired through
sun exposure and supplements.
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