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Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit. To model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol, representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in patients with multiple sclerosis. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant experimental autoimmune encephalomyelitis with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger multiple sclerosis disease activity by raising mean levels of T-cell excitatory calcium., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Interest in vitamin D has increased during the past 2 decades, with a corresponding increase in laboratory testing of 25-hydroxyvitamin D [25(OH)D]. The vast majority of specimens tested display normal or deficient levels of 25(OH)D; concentrations rarely fall in the potentially toxic range., Methods: We performed a retrospective investigation of elevated 25(OH)D levels during a 16-year period at the University of Iowa Hospitals and Clinics (UIHC), a 734-bed tertiary-/quaternary-care academic medical center in the midwestern United States. Detailed medical-record review was performed for patients with serum/plasma 25(OH)D concentrations higher than 120 ng per mL., Results: A total of 127,932 serum/plasma 25(OH)D measurements were performed on 73,779 unique patients. Of these patients, 780 (1.05%) had results that exceeded 80 ng per mL and 89 patients (0.12%) had results that exceeded 120 ng per mL. Only 4 patients showed symptoms of vitamin D toxicity. Three of these cases involved inadvertent misdosing of liquid formulations., Conclusions: Symptomatic vitamin D toxicity is uncommon, and elevated levels of 25(OH)D do not strongly correlate with clinical symptoms or total serum/plasma calcium levels. Our study highlights the potential risks of the liquid formulation of vitamin D.

Context: Vitamin D intoxication is characterized by elevated serum 25-hydroxyvitamin D (25(OH)D) and suppressed serum 1,25-dihydroxvitamin D (1,25(OH)2D). We evaluated two adolescents with hypercalcemia due to vitamin D intoxication; both had elevated serum 1,25(OH)2D by Diasorin RIA, but normal serum 1,25(OH)2D concentrations by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Objective: This study aimed to determine the effect of 25(OH)D2 and 25(OH)D3 on 1,25(OH)2D concentration determined using RIA and LC-MS/MS., Methods: Pools of normal serum and an artificial serum matrix were prepared and aliquots were spiked with >99% pure 25(OH)D2 or 25(OH)D3 (50-700 ng/mL). Samples were maintained at 4°C or heated to 56°C, and the concentrations of vitamin D metabolites were measured by LC-MS/MS and Diasorin RIA., Results: Median 1,25(OH)2D increased by 114% with RIA and 21% with LC-MS/MS with addition of 100 ng/mL 25(OH)D3, and 349% (RIA) and 117% (LC-MS/MS) with 700 ng/mL of 25(OH)D3. Each 1-ng/mL increase in 25(OH)D3 increased 1,25(OH)2D by 0.231 pg/mL (RIA) and 0.121 pg/mL (LC-MS/MS). Spiking with 25(OH)D2 led to similar changes. Heat inactivation of serum, and using an artificial serum matrix, were associated with similar effects of 25(OH)D on 1,25(OH)2D assays., Conclusions: Vitamin D intoxication with high serum levels of 25(OH)D2 or 25(OH)D3 can be associated with elevated levels of 1,25(OH)2D due to interference in a commonly used RIA. A similar but attenuated effect also occurs when 1,25(OH)2D is measured using LC-MS/MS but does not seem to be clinically significant. The basis for this effect on the LC-MS/MS assay is presently uncertain.

Vitamin D toxicity also known as hypervitaminosis D was previously believed to be rare. But with an increase in vitamin D supplementation several cases have been reported in literature. Fat soluble vitamins like Vitamin D, due to their ability to accumulate in the body, have a higher potential for toxicity than water soluble vitamins. The main clinical consequence of vitamin D toxicity is hypercalcemia. In this report we describe an adult female patient who developed very high serum Vitamin D levels (746 ng/mL, RI: 20 to 50) as a result of medication error. Inspite of such high serum concentrations the patient was without any clinical symptoms and had normal serum calcium. We critically discuss the mechanism of toxicity and hypothesize the possible molecular/metabolic factors which might have been responsible for this nontoxic presentation. This case study highlights the fact that physicians need to consider the risk of medication errors while prescribing Vitamin D therapy. Clinical trials to study Vitamin D toxicity in humans is not possible ethically. Thus the evidence base regarding the safety profile of Vitamin D supplementation in humans has been build through case reports. This review of the paradoxical clinico-laboratory manifestation of hypervitaminosis D could possibly contribute to existing literature., (Copyright© by the American Society for Clinical Pathology (ASCP).)

We have examined several analogs of 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in an animal model of osteoporosis (ovariectomized rats) to identify a compound with a greater therapeutic range than 1,25-(OH)(2)D(3) for treatment of this bone disease. Here, we report that one analog, Ro-26-9228, had a bone-protecting effect but did not induce hypercalcemia at a wide concentration range. Analysis of biochemical markers and the bone histomorphometry of analog-treated rats suggested that Ro-26-9228 acted by inhibiting bone resorption and increasing the number of differentiated osteoblasts. To determine the basis for the segregation between hypercalcemia and bone-protecting action, we examined gene expression in tissues that regulate calcium homeostasis. We found that 1,25-(OH)(2)D(3) induced 24-hydroxylase mRNA expression in the duodena of ovariectomized rats, but Ro-26-9228 did not. Furthermore, in the duodena of intact animals, 1,25-(OH)(2)D(3) induced a significant increase in calbindin D 9K and plasma membrane calcium pump 1 mRNAs, but Ro-26-9228 had no effect on these mRNAs. On the other hand, the osteoblast-specific gene products osteocalcin and osteopontin were significantly up-regulated in trabecular bone by both the natural hormone and Ro-26-9228. Further investigation of gene-regulatory events in trabecular bone revealed that both 1,25-(OH)(2)D(3) and Ro-26-9228 up-regulated TGF beta1 and beta2 mRNAs. We concluded that the unique properties of Ro-26-9228 include preferential gene regulation in osteoblasts over duodenum and effective induction of growth factors in bone.