High-Dose Vitamin D-Mediated Hypercalcemia as a Potential Risk Factor in Central Nervous System Demyelinating Disease

Abstract

The exact cause of multiple sclerosis (MS) is unknown; however, it is considered to be an inflammatory disease of the central nervous system (CNS) triggered by a combination of both environmental and genetic factors. Vitamin D deficiency is also discussed as a possible disease-promoting factor in MS, as low vitamin D status is associated with increased formation of CNS lesions, elevated number of relapses and accelerated disease progression. However, it remains unclear whether this association is causal and related and most importantly, whether vitamin D supplementation in MS is of direct therapeutic benefit. Recently, we could show that in a murine model of MS, administration of a moderate vitamin D dose was of clinical benefit, while excessive vitamin D supplementation had a negative effect on disease severity. Of note, disease exacerbation was associated with high-dose vitamin D caused secondary hypercalcemia. Mechanistically dissecting this outcome, we found that hypercalcemia independent of vitamin D similarly triggered activation of disease-perpetuating T cells. These findings caution that vitamin D should be supplemented in a controlled and moderate manner in patients with MS and concomitantly highlight calcium as a novel potential MS risk factor by itself. In this review, we will summarize the current evidence from animal and clinical studies aiming to assess whether vitamin D may be of benefit in patients with MS. Furthermore, we will discuss any possible secondary effects of vitamin D with a particular focus on the role of calcium on immune cells and in the pathogenesis of CNS demyelinating disease.

Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D

“…Actually, some authors have raised the possibility that VitD excess could trigger inflammation through T-cell stimulation via hypercalcemia. In this sense, serum calcium levels and body weight loss have been frequently employed to indicate VitD toxicity [ 72 , 73 ]. In healthy individuals, exogenous VitD toxicity is generally associated with the continuous use of high VitD doses [ 74 ].…”

100 YEARS OF VITAMIN D: Supraphysiological doses of vitamin D changes brainwave activity patterns in rats

“…In addition, among the clinical manifestations, changes in the level of consciousness are one of the most common symptoms of vitamin D in high-doses associated hypercalcemia, especially when serum levels are greater than 13 mg/dL. In this case, the individual usually progresses to lethargy, mental confusion with probable outcomes to the state of coma or seizures ( 40 , 41 ). There are numerous reports of encephalopathy/coma in hypercalcemic patients and this is closely related to a delta–theta activity pattern ( 42 ).…”

Association of Total Calcium With Serum Uric Acid Levels Among United States Adolescents Aged 12–19 Years: A Cross-Sectional Study

“…However, CA concentration is positively correlated with inflammation. Some studies showed that hypercalcemia is linked with inflammatory diseases (27,28). Some crucial inflammatory cytokines, such as IL-6, IL-1β, can upregulate the CA-sensing receptor, which can control blood CA homeostasis and is a promoter and responder of inflammation (24,29).…”