Vitamin D Supplementation in Multiple Sclerosis


Brief introduction

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. [Peterlik 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 (TGF-b) [Mahon 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 RRMS. [Goldberg 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 activity. [Wang 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. [Dann SM, 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. 2006 Apr;117(4):836-41.] 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.' [Braff 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 (1-2): 93-101.]

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) [Vieth 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.' [Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.]

High dose Vitamin D will be of particular importance to those receiving doxycycline or minocycline, both of which can cause photosensitivity reactions. It is important to take the D3 form.

[Note: Disordered calcium metabolism is frequent in sarcoid, a non-caseating granulomatous condition. Hypercalcaemia may be found in 20% of patients with sarcoid, while hypercalciuria may be even more common, and is of major clinical importance.
[reviewed by Adams JS, et al., Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest. 1983 Nov; 72(5): 1856-60.] Sarcoid granulomas abound in macrophages; the sarcoid macrophage has been found to to synthesize 1,25(OH)2D3 from its precursor 25(OH)D3, thus by-passing the strict regulation by parathyroid hormone. The excess circulating 1,25(OH)2D3 produced extrarenally causes increased intestinal absorption of calcium, enhanced bone resorption, and resultant hypercalciuria with or without hypercalcaemia. Other diseases with granulomatous features may also involve disordered calcium metabolism, albeit less severe; these include a subset of persons with active Crohn's disease [Abreu MT, Kantorovich V, Vasiliauskas EA. et al., Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut. 2004 Aug;53(8):1129-36.]

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page uploaded 7th February 2006; revised 4th March 2006