Vitamin D Supplementation in Central Nervous System Demyelinating Disease-Enough Is Enough

Abstract

The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS.

Keywords: T cells; experimental autoimmune encephalomyelitis; hypercalcemia; multiple sclerosis; vitamin D; vitamin D receptor.

Figure 1

Vitamin D metabolism. Vitamin D (cholecalciferol) can be obtained from dietary intake or by synthesis in the skin from 7-dehydroxycholesterol in response to ultraviolet (UV) light. The first step in vitamin D metabolism occurs in the liver, where it is hydroxylated by 25-hydroxylases (CYP2R1, CYP27A1 and CYP3A4) towards 25-hydroxyvitamin D (25(OH)D₃). The second step in vitamin D metabolism takes place mainly in the kidneys, where it is hydroxylated by 1α-hydroxylase (CYP27B1) to the biologically most active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). Both 1,25(OH)₂D₃ and 25(OH)D₃ are immune modulatory upon binding to a vitamin D receptor (VDR) present in the nucleus of almost all immune cells. However, 25(OH)D₃ shows a 100-fold less binding affinity as compared to 1,25(OH)₂D₃. Other functions of 1,25(OH)₂D₃ is the regulation of intestinal calcium and phosphate absorption, calcium mobilization from bone and reabsorption of calcium in the kidney. Secondary hypercalcemia, mediated by high serum vitamin D levels, may lead to a T cell stimulatory effect.