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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.)

Over the past two decades, vitamin D level measurements have become some of the most frequently ordered tests in the laboratory. This increase is due to a growing awareness of widespread vitamin D deficiency and scientific data suggesting the beneficial effects of vitamin D in various diseases. A literature search was carried out in PubMed for cases reporting vitamin D intoxication and overdose. Thirteen articles were included in this review. Intoxication was severe in the reported cases. Patients presented with serum vitamin D concentrations ranging between 150 and 1220 ng/mL and serum calcium concentrations between 11.1 and 23.1 mg/dL. Most of the reported patients showed symptoms of vitamin D toxicity such as vomiting, dehydration, pain, and loss of appetite. The underlying causes included manufacturing errors, overdosing by patients or prescribers, and combinations of these factors. Our literature search highlights the fact that even though vitamin D intoxication is rare, it does occur and therefore patients and prescribers should be more cognizant of the potential dangers of vitamin D overdose. [ABSTRACT FROM AUTHOR]

In patients with tuberculosis, abnormal extrarenal production of 1,25-dihydroxyvitamin D3 by activated macrophages in granulomatous tissues may result in hypercalcaemia. More commonly reported in adults with active pulmonary tuberculosis, this complication may rarely occur in extrapulmonary tuberculosis, and children. The hypercalcaemia may be precipitated by usually recommended vitamin D and calcium supplementation in patients with tuberculosis. We report here an infant with tubercular meningitis who developed hypercalcaemia 12 days after starting routine vitamin D and calcium supplementation. This communication highlights the importance of close monitoring of calcium levels in patients with tuberculosis, especially if started on vitamin D and calcium replacement before antitubercular therapy. [ABSTRACT FROM AUTHOR]

Background: The multiple biological effects of vitamin D and its novel activities on inflammation and redox homeostasis have raised high expectations on its use as a therapeutic agent for multiple fibrogenic conditions. We have assessed the therapeutic effects of 1α,25-Dihydroxyvitamin D 3 , the biologically active form of vitamin D, in the context of lung fibrosis., Methods: We have used representative cellular models for alveolar type II cells and human myofibroblasts. The extension of DNA damage and cellular senescence have been assessed by immunofluorescence, western-blot and senescence-associated β-galactosidase activity. We have also set up a murine model for lung fibrosis by intraperitoneal injections of bleomycin., Results: Vitamin D induces cellular senescence in bleomycin-treated alveolar epithelial type II cells and aggravates the lung pathology induced by bleomycin. These effects are probably due to an alteration of the cellular DNA double-strand breaks repair in bleomycin-treated cells., Conclusions: The detrimental effects of vitamin D in the presence of a DNA damaging agent might preclude its use as an antifibrogenic agent for pulmonary fibrosis characterized by DNA damage occurrence and cellular senescence.

In early 2000's vitamin-D deficiency was shown to be prevalent in several countries including the United States (US). Studies exploring the role of vitamin-D metabolism in diverse disease pathways generated an increased demand for vitamin-D supplementation and an immense public interest in measurement of vitamin-D metabolite levels. In this report, we review the role of vitamin-D metabolism in disease processes, clinical utility of measuring vitamin-D metabolites including 25-hydroxyvitamin-D (25(OH)D), 1,25-dihydroxyvitamin-D and 24,25-dihydroxyvitamin-D and discuss vitamin-D assay methodologies including immunoassays and liquid chromatography mass spectrometry (LC-MS/MS) assays. We also provide examples of vitamin-D toxicity and insight into the trends in serum 25(OH)D levels in the US population based on 10 years of data from on serum 25(OH)D values from ~5,000,000 patients who were tested at the Mayo Medical Laboratories between February 2007-February 2017.

A 67-year-old female was admitted to the hospital with a history of lethargy, memory impairment, confusion, anorexia and gait imbalance for 2 weeks duration. She did not have any history of fall or head injury. She had total hip replacement 1 year back and was on orthopedic follow-up. Magnetic resonance imaging (MRI) on admission revealed no focal abnormalities. Routine biochemistry detected hypercalcemia, and she was treated with I/V fluid, diuretics and glucocorticoids. She was screened thoroughly to exclude occult malignancy. After 7 days of admission, a follow-up orthopedic prescription revealed that she was getting inj. Arachitol 6 lac units every week for last 3 months. On the 9th day of admission, she was detected to have very high serum 25(OH) vitamin D level (254.70 ng/ml). Patient was discharged after 2 weeks after her serum calcium came down to normal range with the advice of no dietary calcium and vitamin D intake. Her 25(OH) vitamin D level remained high for the next 6 months. Now she is completely asymptomatic and her serum 25(OH) D is normal. [ABSTRACT FROM AUTHOR]

Introduction Our dried blood spot vitamin D testing service enables members of the public to assess their vitamin D status. Vitamin D has become popular with the media and the general public. We noticed that our direct access service had a higher rate of high to toxic 25-hydroxyvitamin D levels compared with our GP population and we wanted to know why. Methods Between January 2013 and September 2015 we contacted all direct access users who had 25-hydroxyvitamin D >220 nmol/L measured using LC/MS/MS. We investigated the amount, type and length of supplementation used and whether or not users were medically supervised. Results A total of 372 service users had 25-hydroxyvitamin D concentrations >220 nmol/L. Of 14,806 direct access samples received, 372 (2.5%) were from users with 25-hydroxyvitamin D concentrations ranging from 221 to 1235 nmol/L. Only 0.06% of GP patients had results >220 nmol/L over the same time frame. There were 361 direct access users regularly supplementing, taking between 1000 to 120,000 IU/day. Two users took bolus doses of 300,000 and 900,000 IU. Only 23 users taking supplements (6.4%) were under medical supervision. There were 28 users with levels >500 nmol/L, but only one was under medical supervision. The internet was the main source of supplements (74%). Conclusions The proportion of high to toxic concentrations of vitamin D was higher in direct access users than in the GP population. Many people were taking more than the Institute of Medicine's recommendation of 10,000 IU/day, yet only a few were being medically supervised. Clinicians should be aware that patients may be self-administering very high concentrations of vitamin D, especially when investigating unexplained hypercalcaemia.

Key Points: Hypercalcaemia can occur under various pathological conditions, such as primary hyperparathyroidism, malignancy or granulomatosis, and it induces natriuresis and polyuria in various species via an unknown mechanism. A previous study demonstrated that hypercalcaemia induced by vitamin D in rats increased endothelin (ET)-1 expression in the distal nephron, which suggests the involvement of the ET system in hypercalcaemia-induced effects. In the present study, we demonstrate that, during vitamin D-induced hypercalcaemia, the activation of ET system by increased ET-1 is responsible for natriuresis but not for polyuria. Vitamin D-treated hypercalcaemic mice showed a blunted response to amiloride, suggesting that epithelial sodium channel function is inhibited. We have identified an original pathway that specifically mediates the effects of vitamin D-induced hypercalcaemia on sodium handling in the distal nephron without affecting water handling., Abstract: Acute hypercalcaemia increases urinary sodium and water excretion; however, the underlying molecular mechanism remains unclear. Because vitamin D-induced hypercalcaemia increases the renal expression of endothelin (ET)-1, we hypothesized that ET-1 mediates the effects of hypercalcaemia on renal sodium and water handling. Hypercalcaemia was induced in 8-week-old, parathyroid hormone-supplemented, male mice by oral administration of dihydrotachysterol (DHT) for 3 days. DHT-treated mice became hypercalcaemic and displayed increased urinary water and sodium excretion compared to controls. mRNA levels of ET-1 and the transcription factors CCAAT-enhancer binding protein β and δ were specifically increased in the distal convoluted tubule and downstream segments in DHT-treated mice. To examine the role of the ET system in hypercalcaemia-induced natriuresis and polyuria, mice were treated with the ET-1 receptor antagonist macitentan, with or without DHT. Mice treated with both macitentan and DHT displayed hypercalcaemia and polyuria similar to that in mice treated with DHT alone; however, no increase in urinary sodium excretion was observed. To identify the affected sodium transport mechanism, we assessed the response to various diuretics in control and DHT-treated hypercalcaemic mice. Amiloride, an inhibitor of the epithelial sodium channel (ENaC), increased sodium excretion to a lesser extent in DHT-treated mice compared to control mice. Mice treated with either macitentan+DHT or macitentan alone had a similar response to amiloride. In summary, vitamin D-induced hypercalcaemia increases the renal production of ET-1 and decreases ENaC activity, which is probably responsible for the rise in urinary sodium excretion but not for polyuria., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Vitamin D is a pro-hormone that plays an important role in body calcium regulation. Vitamin D toxicity occurs rarely due to its wide therapeutic index. A 38-year-old Iranian man was admitted to our hospital with a diagnosis of vitamin D toxicity. Laboratory test revealed hypercalcemia and elevated 25-hydroxyvitamin D (25(OH)D) level. Despite the cessation of vitamin D intake and diuretic treatment, he presented four months later with high 25(OH)D level and similar clinical features. Due to the potential release of vitamin D from adipose tissue, serial monitoring of 25(OH)D level is recommended.

To document the biochemical and pathologic features of vitamin D intoxication in lynx and to characterize mineral metabolism in healthy lynx, blood samples were obtained from 40 captive lynx that had been receiving excessive (approximately 30 times the recommended dose) vitamin D3 in the diet, and from 29 healthy free ranging lynx. Tissue samples (kidney, stomach, lung, heart and aorta) were collected from 13 captive lynx that died as a result of renal disease and from 3 controls. Vitamin D intoxication resulted in renal failure in most lynx (n = 28), and widespread extraskeletal calcification was most severe in the kidneys and less prominent in cardiovascular tissues. Blood minerals and calciotropic hormones in healthy lynx were similar to values reported in domestic cats except for calcitriol which was higher in healthy lynx. Changes in mineral metabolism after vitamin D intoxication included hypercalcemia (12.0 ± 0.3 mg/dL), hyperphosphatemia (6.3 ± 0.4 mg/dL), increased plasma calcidiol (381.5 ± 28.2 ng/mL) and decreased plasma parathyroid hormone (1.2 ± 0.7 pg/mL). Hypercalcemia and, particularly, hyperphosphatemia were of lower magnitude that what has been previously reported in the course of vitamin D intoxication in other species. However, extraskeletal calcifications were severe. The data suggest that lynx are sensitive to excessive vitamin D and extreme care should be taken when supplementing this vitamin in captive lynx diets.

Unlabelled: There has been an increased use of vitamin D both by prescription and by the public as a widely available supplement. We evaluated 15 years of single-substance vitamin D exposures to US poison centers., Methods: Retrospective analysis of data from the National Poison Data System (NPDS) to evaluate clinical effects, trends, and outcomes of exposures to vitamin D over the period January 1, 2000 through June 30, 2014. Cases were limited to exposures involving vitamin D as a single substance. Multiple vitamin products that may have included vitamin D were not included in this study., Results: From 2000 through June 30, 2014, there were 25,397 human exposures to vitamin D reported to NPDS. There was a mean of 196 cases per year from 2000 to 2005, followed by a 1600% increase in exposures between 2005 and 2011 to a new annual mean of 4535 exposures per year. The mean and median ages were 23.4 years and 10 years, respectively. There were no fatalities, but five (0.02%) major effect outcomes. Serious medical outcomes (major or moderate outcome) were infrequent, ranging from 2 patients/year to 22 patients/year. Clinical effects were primarily gastrointestinal (0.7-1.5%) and mild neurological effects (0.2-0.4%). There was a decline in the percentage of patients treated in a health care facility and of patients with serious medical outcome., Conclusion: Despite the enormous increase in number of exposures, there was not a significant increase in patients with a serious medical outcome. Rare severe outcomes may occur., (© The Author(s) 2015.)

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.

The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) started an intensive review of commercially available parenteral vitamin and trace element (TE) products in 2009. The chief findings were that adult multi-TE products currently available in the United States (U.S.) provide potentially toxic amounts of manganese, copper, and chromium, and neonatal/pediatric multi-TE products provide potentially toxic amounts of manganese and chromium. The multivitamin products appeared safe and effective; however, a separate parenteral vitamin D product is needed for those patients on standard therapy who continue to be vitamin D depleted and are unresponsive to oral supplements. The review process also extended to parenteral choline and carnitine. Although choline and carnitine are not technically vitamins or trace elements, choline is an essential nutrient in all age groups, and carnitine is an essential nutrient in infants, according to the Food and Nutrition Board of the Institute of Medicine. A parenteral choline product needs to be developed and available. Efforts are currently under way to engage the U.S. Food and Drug Administration (FDA) and the parenteral nutrient industry so A.S.P.E.N.'s recommendations can become a commercial reality., (© 2015 American Society for Parenteral and Enteral Nutrition.)

We investigated the therapeutic effect of Xin Mai Jia (XMJ) on atherosclerosis (AS) in rats. Rat models of AS were established by peritoneally injecting vitamin D, feeding a high-fat diet, and inducing balloon injuries in rats. The stomachs of the rats were irrigated continuously for 10 weeks with XMJ. Blood lipid- and hemorheology-related indices of blood samples were detected. Pathological changes in the right common carotid arterial tissues were also determined. The protein expression levels of endothelial nitric oxide synthase, angio-tensin-1, and endothelin-1 were determined by western blotting. XMJ reduced cholesterol, trigylecride, and low-density lipoprotein levels as well as blood viscosity, sedimentation, and hematocrit. Furthermore, XMJ alleviated vascular endothelial injury and reduced/eliminated atherosclerotic plaques. In contrast, XMJ significantly increased the endothelium-dependent relaxing response of the AS rat models. The western blotting results showed that XMJ upregulated endothelial nitric oxide synthase but downregulated angiotensin-1 and endothelin-1. XMJ prevented the development of AS by regulating blood lipid levels, hemorheology, and vascular function.

The active form of vitamin D3, 1α,25(OH)2D3, plays a major role in maintaining calcium/phosphate homeostasis. In addition, it is a potent antiproliferative and pro-differentiating agent. Unfortunately, it usually causes hypercalcemia in vivo when effective antitumour doses are used. It has therefore been found necessary to synthesise new analogues that retain or even increase the antitumour effects but preclude hypercalcemia. This report presents the synthesis of a novel Gemini vitamin D analogue (UVB1) and its biological evaluation. We demonstrate that this compound has potent antitumoural effects over a wide panel of tumour cell lines while showing lack of hypercalcemic activity and toxicity effects in in vivo assays., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Fifty two steroids and 9 Vitamin D analogs were docked into ten crystallographically-defined DNA dinucleotide sites and two human topoisomerase II ATP binding sites using two computational programs, Autodock and Surflex. It is shown that both steroids and Vitamin D analogs exhibit a propensity for non-covalent intercalative binding to DNA. A higher predicted binding affinity was found, however, for steroids and the ATP binding site of topoisomerase; in fact these drugs exhibited among the highest topo II binding observed in over 1370 docked drugs. These findings along with genotoxicity data from 26 additional steroids not subjected to docking analysis, support a mechanism wherein the long known, but poorly understood, clastogenicity of steroids may be attributable to inhibition of topoisomerase. A "proof of principle" experiment with dexamethasone demonstrated this to be the likely mechanism of clastogenicity of, at least, this steroid. The generality of this proposed mechanism of genotoxicity across the steroids and vitamin-D analogs is discussed.

Retinoids and 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) induce differentiation of myeloid leukemia cells into granulocyte and macrophage lineages, respectively. All-trans retinoic acid (ATRA), which is effective in the treatment of acute promyelocytic leukemia, can induce differentiation of other types of myeloid leukemia cells, and combined treatment with retinoid and 1,25(OH)2D3 effectively enhances the differentiation of leukemia cells into macrophage-like cells. Recent work has classified macrophages into M1 and M2 types. In this study, we investigated the effect of combined treatment with retinoid and 1,25(OH)2D3 on differentiation of myeloid leukemia THP-1 and HL60 cells. 9-cis Retinoic acid (9cRA) plus 1,25(OH)2D3 inhibited proliferation of THP-1 and HL60 cells and increased myeloid differentiation markers including nitroblue tetrazolium reducing activity and expression of CD14 and CD11b. ATRA and the synthetic retinoic acid receptor agonist Am80 exhibited similar effects in combination with 1,25(OH)2D3 but less effectively than 9cRA, while the retinoid X receptor agonist HX630 was not effective. 9cRA plus 1,25(OH)2D3 effectively increased expression of M2 macrophage marker genes, such as CD163, ARG1 and IL10, increased surface CD163 expression, and induced interleukin-10 secretion in myeloid leukemia cells, while 9cRA alone had weaker effects on these phenotypes and 1,25(OH)2D3 was not effective. Taken together, our results demonstrate selective induction of M2 macrophage markers in human myeloid leukemia cells by combined treatment with 9cRA and 1,25(OH)2D3.

Vitamin D (VitD) intoxication, a well-known cause of hypercalcaemia in children, has renal, cardiac and neurological consequences. Iatrogenic or accidental administrations are the most common causes. We present two cases of hypervitaminosis D due to over-the-counter VitD supplement self-medication. A 12-year-old boy was hospitalised for abdominal pain, constipation and vomiting. Routine biochemistry indicated severe hypercalcaemia and renal failure. Plasma 25-OH VitD level was very high and parathyroid hormone was suppressed. Renal ultrasound showed nephrolithiasis. Hydration, diuretics and prednisone induced a progressive reduction of calcium levels. His brother, who was receiving the same treatment, was hospitalised although asymptomatic. Normal serum calcium and renal function were revealed, while 25-OH VitD was high and parathyroid hormone was suppressed. Renal ultrasound was within the normal range. Examination of the VitD content of the over-the-counter supplement revealed a higher amount than declared. VitD administration implies several risks and must be prescribed only when needed and under strict medical control.

Introduction: The aim of the present study was to assess the prevalence of vitamin D deficiency and toxicity, the frequency of 25-hydroxyvitamin D (25[OH]D) testing, and 25(OH)D variations with respect to patient gender, patient age and season in New South Wales, Australia., Methods: A retrospective analysis of pathology records was performed to ascertain patient age, patient gender, sample collection date, plasma or serum 25(OH)D levels, calcium and parathyroid hormone (PTH) levels, and test numbers between 2001 and 2010. Linear regression with Bonferroni correction was used to calculate and compare age-adjusted mean 25(OH)D levels. Relationships of 25(OH)D with PTH and calcium were tested using Spearman's rank correlation., Results: 25(OH)D testing increased by 730% over the ten-year study period. In 2010, many men (33%) and women (40%) were, to some degree, vitamin D deficient (≤ 50 nmol/L). Vitamin D toxicity was rare, with only one instance noted. 25(OH)D levels correlated positively with calcium and negatively with PTH levels. 25(OH)D levels decreased with age. In 2010, 25(OH)D levels were highest in February and lowest in September/October. Cyclical variation was observed for 25(OH)D levels between 2006 and 2010., Conclusion: We found that vitamin D deficiency was prevalent in both men and women, with a higher prevalence in the latter, despite the substantial increased demand for 25(OH)D testing in our population over the decade. Vitamin D deficiency was associated with elevated PTH levels. Vitamin D toxicity was rare and only observed once during our study period. 25(OH)D levels decreased with age and varied with season, with the highest levels observed in late summer and the lowest in early spring.

The high worldwide prevalence of vitamin D deficiency is largely the result of low sunlight exposure with subsequently limited cutaneous vitamin D production. Classic manifestations of vitamin D deficiency are linked to disturbances in bone and mineral metabolism, but the identification of the vitamin D receptor in almost every human cell suggests a broader role of vitamin D for overall and cardiovascular health. The various cardiovascular protective actions of vitamin D such as anti-diabetic and anti-hypertensive effects including renin suppression as well as protection against atherosclerosis and heart diseases are well defined in previous experimental studies. In line with this, large epidemiological studies have highlighted vitamin D deficiency as a marker of cardiovascular risk. However, randomized controlled trials (RCTs) on vitamin D have largely failed to show its beneficial effects on cardiovascular diseases and its conventional risk factors. While most prior vitamin D RCTs were not designed to assess cardiovascular outcomes, some large RCTs have been initiated to evaluate the efficacy of vitamin D supplementation on cardiovascular events in the general population. When considering the history of previous disappointing vitamin RCTs in general populations, more emphasis should be placed on RCTs among severely vitamin D-deficient populations who would most likely benefit from vitamin D treatment. At present, vitamin D deficiency can only be considered a cardiovascular risk marker, as vitamin D supplementation with doses recommended for osteoporosis treatment is neither proven to be beneficial nor harmful in cardiovascular diseases.

The plethora of vitamin D studies over the recent years highlight the pleomorphic effects of vitamin D outside its conventional role in calcium and bone homeostasis. Vitamin D deficiency, though common and known, still faces several challenges among the medical community in terms of proper diagnosis and correction. In this review, the different levels of vitamin D and its clinical implications are highlighted. Recommendations and consensuses for the appropriate dose and duration for each vitamin D status are also emphasized.