Vitamin D Supplementation in Multiple Sclerosis
Vitamin D has long been known to be involved in the regulation of body levels of calcium and phosphorus, and in the mineralization of bone. In recent years it has become clear that Vitamin D receptors are present in numerous cell types. Evidently it has wide-ranging effects in a number of systems. Vitamin D3, or cholecalciferol, is generated in the skin by the action of sunlight on a precursor; it is also taken in the diet. Unsupplemented dietary sources are probably inadequate. Of itself, D3 has little biological activity, but, in a two-stage process, it is firstly hydroxylated in the liver to 25(OH)D3 which is alpha-hydroxylated, in a reaction tightly controlled by parathyroid hormone to 1,25(OH)2D3. This molecule has the greatest biological activity.
Vitamin D and Multiple Sclerosis.
It has long been known that
MS has a geographical distribution. This is more complex than
is usually stated [Kurtzke
JF. A reassessment of the distribution of multiple sclerosis.
Acta Neurol Scand. 1975 Feb;51(2):137-57] implying a multifactorial background. The incidence
is lower in those who have a diet high in fish oils [Esparza ML, Sasaki
S, Kesteloot H. Nutrition, latitude, and multiple sclerosis mortality:
an ecologic study. Am J Epidemiol. 1995 Oct 1;142(7):733-7.] In general, though, the incidence
of MS accords with the amount of sunlight received which in turn
accords with latitude and other factors such as cultural dictates.
Vitamin D deficiency is common in MS. [Nieves J, et al., High prevalence
of vitamin D deficiency and reduced bone mass in multiple sclerosis.
Neurology. 1994 Sep;44(9):1687-92.]
These authors found the bone mass density (BMD) of the lumbar
spine and femoral neck was 1 to 2 SDs lower in women with MS
against controls. BMD was lower in patients with more severe
disease. The mean 25-hydroxycholecalciferol level of the sample
population (43 nmol/l) was in the insufficient range, and 12
patients (23%) had frank vitamin D deficiency (< 25 nmol/l).
BMD and age-related BMD at all skeletal sites measured were lowest
when 25-hydroxycholecalciferol levels were deficient. Parathyroid
hormone (PTH) was frankly elevated in 13% of patients. PTH levels
were negatively correlated with 25-hydroxycholecalciferol levels
and with BMD.The authors comment: 'Vitamin D deficiency in the
female MS patient might be safely and inexpensively corrected
by the routine use of vitamin D supplements.' Peterlik and Cross
have written an excellent review of the results of hypovitaminosis
D in chronic disease: the paper is informative and well-referenced.
M, Cross HS. Vitamin D and calcium deficits predispose for multiple
chronic diseases. Eur J Clin Invest. 2005 May; 35 (5): 290-304.
Review.] These authors
comment: 'In addition to skeletal disorders, calcium and vitamin
D deficits increase the risk of malignancies, particularly of
colon, breast and prostate gland, of chronic inflammatory and
autoimmune diseases (e.g. insulin-dependent diabetes mellitus,
inflammatory bowel disease, multiple sclerosis), as well as of
metabolic disorders (metabolic syndrome, hypertension).' In a
key study on vitamin D supplementation and the development of
MS Munger and colleagues [Munger KL, et al., Vitamin D intake and incidence
of multiple sclerosis. Neurology. 2004 Jan 13;62(1):60-5] found that intake of vitamin D from
supplements was inversely associated with risk of MS; the relative
risk comparing women with an intake of 400 IU/day or more with
women with no supplemental vitamin D intake was 0.59 (95% CI
= 0.38 to 0.91; p for trend = 0.006). Supplementation with Vitamin
D in MS was followed by elevation of Transforming Growth Factor-beta
BD et al., Cytokine profile in patients with multiple sclerosis
following vitamin D supplementation. J Neuroimmunol. 2003 Jan;134(1-2):128-32.] TGF-b is a large family (with perhaps
as many as 100 members) of broadly anti-inflammatory signalling
proteins which, though incompletely understood, promote wound
healing, inhibit macrophage and lymphocyte proliferation. Interestingly,
in a small prospective study, supplementation of the diet with
Omega 3 fish oils (which is rich in 25(OH)D) in people with MS
brought about moderate benefit. [Weinstock-Guttman B, et al., Low fat
dietary intervention with omega-3 fatty acid supplementation
in multiple sclerosis patients. Prostaglandins Leukot Essent
Fatty Acids. 2005 Nov;73(5):397-404.] Supplementation with Vitamin D, calcium and magnesium
has resulted in a decrease of relapse rate in young people with
P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse
rate through dietary supplementation with calcium, magnesium
and vitamin D. Med Hypotheses. 1986 Oct;21(2):193-200] though this was a small study.
Vitamin D, antibacterial peptides (cathelicidins) and immunomodulation.
In 2004 Wang and colleagues
published a study showing that 1,25(OH)2D3 directly induces specific
antimicrobial gene expression and activity leading to the production
of cathelicidins, small peptides which have marked antimicrobial
TT, Nestel FP, Bourdeau V, et al., Cutting edge: 1,25-dihydroxyvitamin
D3 is a direct inducer of antimicrobial peptide gene expression.
J Immunol. 2004 Sep 1;173(5):2909-12] Cathelicidins have a very broad spectrum of activity,
and promote wound healing and re-epthelialization of breaks in
the skin: they are absent in chronic (non-healing) ulcers. [Heilborn JD, Nilsson
MF, Kratz G, et al., The cathelicidin anti-microbial peptide
LL-37 is involved in re-epithelialization of human skin wounds
and is lacking in chronic ulcer epithelium. J Invest Dermatol.
2003 Mar; 120 (3): 379-89.]
Cathelicidins have activity against intracellular bacteria; this
has been demonstrated in Mycobacterium tuberculosis [Liu PT, Stenger S,
Li H, Wenzel L. et al., Toll-like receptor triggering of a vitamin
D-mediated human antimicrobial response. Science. 2006 Mar 24;311(5768):1770-3]
Cathelicidins are active
in the innate defence system of the gut, lining the mucosa and
preventing attachment by epithelial-adherent bacterial pathogens.
Eckmann L. Innate immune defenses in the intestinal tract. Curr
Opin Gastroenterol. 2007 Mar;23(2):115-20.] Cathelicidins are active in vitro against Herpes
Simplex Virus and cathelicidin deficiency has been found in persons
with eczema herpeticum. [Howell MD, Wollenberg A, Gallo RL. et al., Cathelicidin
deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol.
The study of cathelicidins and their potential is clearly just
beginning. note that 'cathelicidin peptides have properties of
both natural antibiotics and host stimulatory molecules. The
rapid increase in cathelicidin at epithelial interfaces exposed
to injury or infection can provide a simultaneous barrier to
microbial proliferation and an additional alarm to the host.'
MH, Hawkins MA, Di Nardo A. et al., Structure-function relationships
among human cathelicidin peptides: dissociation of antimicrobial
properties from host immunostimulatory activities. J Immunol.
2005 Apr 1;174(7):4271-8.]
The actions of vitamin D on the immune system are reviewed in
this paper [van
Etten E, Mathieu C. Related Articles, Immunoregulation by 1,25-dihydroxyvitamin
D3: basic concepts. J Steroid Biochem Mol Biol. 2005 Oct; 97
Supplementation: what dose?
Supplementation with D3 seems,
on this evidence, reasonable and even advisable. What would be
a reasonable and advisable daily dose? The safe upper limit of
supplementation in adults is officially declared to be 50 micrograms
(2,000 iu.) Vieth and colleagues state that 100 micrograms (4000
iu.) may be safely given (and, in older persons may be necessary)
R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3
intake exceeding the lowest observed adverse effect level. Am
J Clin Nutr. 2001 Feb; 73(2): 288-94.] The authors support their statement with convincing
evidence. This paper is recommended reading. Hathcock and colleagues,
in a very recent and thorough study, make the comment: 'Collectively,
the absence of toxicity in trials conducted in healthy adults
that used vitamin D dose > or = 250 microg/d (10,000 IU vitamin
D3) supports the confident selection of this value as the UL.'
JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D.
Am J Clin Nutr. 2007 Jan;85(1):6-18.]
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