[A rare cause of kidney injury: vitamin D3 intoxication]. / A vesekárosodás ritka oka: D3-vitamin-intoxikáció.

The beneficial effects of vitamin D3 treatment are known, and its side effects are documented. In connection with the case presentation, we would like to sum up the dangers of excessive vitamin D supplementation, and to draw attention to the shortcomings experienced in everyday medical practice. We discuss the tests required to create a diagnosis of vitamin D intoxication, the differential diagnosis, and present the possible treatment strategies. A 57-year-old female patient was admitted to hospital in November 2020 due to complaints of nausea, vomiting, diarrhea and general weakness. Upon admission, laboratory tests confirmed new-onset kidney damage (eGFR 38 mL/min/1.73 m2), calcium metabolism was not checked. During non-invasive investigations, urinary sediment results showed leukocyturia and non-nephrotic proteinuria, but no clear underlying cause was found. Nephrology consultation suggested acute tubular injury, kidney biopsy was performed, immune serology and serum protein electrophoresis tests were ordered. Despite conservative treatment, her kidney function deteriorated further (eGFR 32 mL/d/1.73 m2). The patient arrived at our department in December 2020 with histological results in progress. Laboratory tests taken on arrival confirmed severe hypercalcemia (tCa 3.22 mmol/L, iCa 1.74 mmol/L), and kidney function was stable (eGFR 33 mL/p/1.73 m2). Intact parathyroid hormone level was below the normal range (0.54 pmol/L), 25-OH-vitamin D level was extremely high (1106.2 nmol/L). The patient then admitted that in October 2020, she received a course of "megadose" parenteral vitamin D, but she could not recall the exact dosage nor wanted to mention the department administering the treatment. We diagnosed vitamin D intoxication. Intravenous saline, furosemide and calcitonin treatment was started. The result of the treatment: serum calcium level normalized (2.52 mmol/L), and kidney functions improved (eGFR 54 mL/p/1.73 m2). Vitamin D treatment was stopped. The patients' serum tCa and vitamin D levels normalized by February 2021, and her kidney functions improved (tCa 2.54 mmol/L, 25-OH-vitamin D 125.0 ng/mL, eGFR 72 mL/p/1.73 m2). Kidney biopsy confirmed the presence of acute tubular necrosis. Granulomatous diseases and multiple myeloma were excluded. The symptoms of vitamin D intoxication are non-specific and varied, each case presents a differential diagnostic challenge. Orv Hetil. 2023; 164(47): 1871-1876.

[How I treat vitamin D intoxication in a child with cystic fibrosis]. / Comment je traite une intoxication à la vitamine D chez un enfant atteint de mucoviscidose.

At least 80 % of persons with cystic fibrosis are pancreatic insufficient and benefit from daily supplementation with fat-soluble vitamins (ADEK). Magistral formulations offer ideal flexibility for prescriptions tailored to vitamin A, D and E blood levels. However, they expose to human errors, mainly leading to vitamin D intoxication whose clinical features are related to hypercalcaemia. Symptoms are mostly digestive (vomiting, constipation, abdominal pain …) and, less frequently, renal (nycturia …) complaints. When symptoms and/or serum calcium levels ≥ 14 mg/100 ml are present, prompt management is required. Besides interruption of supplementation, rapid intravenous hyperhydration (saline) is essential. Once hydration has been restored, and still under close biological supervision, a loop diuretic (furosemide) may be used but the drug of choice to achieve rapid normalization of blood calcium levels will often be intravenous pamidronate. Normalization of serum vitamin 25(OH)-D levels may take several months but the prognosis is very good. In Belgium, the very late reimbursement of a fixed combination of fat-soluble vitamins (Dekas®) meeting the standards of the pharmaceutical industry is expected to reduce the incidence of these intoxications, at the price, however, of less flexible prescription.

Au moins 80 % des patients atteints de mucoviscidose présentent une insuffisance pancréatique exocrine et bénéficient quotidiennement d'une supplémentation en vitamines liposolubles (ADEK). Une préparation magistrale offre alors une souplesse idéale de prescription. Elle expose cependant à des erreurs humaines, qui mènent surtout à des intoxications à la vitamine D. Les symptômes, souvent surtout digestifs (vomissements, constipation, douleurs abdominales …), voire rénaux (nycturie …), sont liés à l'hypercalcémie. En cas de symptômes et/ou de calcémie ≥ 14 mg/100 ml, une prise en charge immédiate est nécessaire. Outre l'interruption de la supplémentation, elle inclut d'abord une hyperhydratation rapide, par voie intraveineuse (sérum physiologique). Une fois l'hydratation restaurée, et toujours sous contrôles biologiques rapprochés, un diurétique de l'anse (furosémide) peut être utilisé, mais c'est souvent une administration intraveineuse de pamidronate qui permettra la normalisation rapide de la calcémie. Le taux sérique de vitamine 25(OH)-D peut mettre plusieurs mois à se normaliser, mais le pronostic est très bon. Remboursée tardivement en Belgique, une combinaison fixe de vitamines liposolubles (Dekas®), répondant aux normes de l'industrie pharmaceutique, devrait limiter le nombre de ces intoxications au prix, toutefois, d'une moindre souplesse de prescription.

Rare cause of life-threatening hypercalcemia in an infant: a case report. / Cause rare d'hypercalcémie gravissime chez l'enfant : cas clinique

Background: 25-Hydroxyvitamin D 24-hydroxylase (CYP24A1) deficiency is a rare cause of autosomal recessive infantile hypercalcemia due to vitamine D hypersensitivity. Case presentation: We report the case of a 2-year-old boy who presented with severe hypercalcemia-hypercalciuria and a bilateral nephrocalcinosis. Laboratory investigations detected a collapsed parathormone and a highly elevated 1α,25-dihydroxycholecalciferol along with an increased phosphate excretion (hypophosphatemia and hyperphosphaturia). An adapted management with two courses of palmidronic acid and an eviction of vitamin D and calcium allowed to stabilize him. A homozygous p.Leu409Ser pathogenic variant on CYP24A1 gene resulting in a collapsed 25-Hydroxyvitamin D24-hydroxylase activity was found. A normal development is possible with a meticulous clinical, biological and nutritional management and monitoring. Conclusions: Vitamin D hypersensitivity is challenging during childhood, especially due to the need to avoid vitamin D while requiring a close nutritional monitoring to maintain a normal growth. Biomarkers such as vitamin D metabolite ratio and 24,25(OH)2D3 along with ionized calcium and nutritional management can contribute to properly follow patients with vitamin D hypersensitivity.

Contexte: Le déficit en 25-hydroxyvitamine D 24-hydroxylase (CYP24A1) est une cause rare d'hypercalcémie infantile autosomique récessive due à une hypersensibilité à la vitamine D. Présentation du cas: Nous rapportons le cas d'un garçon de 2 ans qui a présenté une hypercalcémie-hypercalciurie sévère et une néphrocalcinose bilatérale. Les examens de laboratoire ont détecté une parathormone effondrée et un 1α,25-dihydroxycholécalciférol très élevé ainsi qu'une excrétion accrue de phosphate (hypophosphatémie et hyperphosphaturie). Une prise en charge adaptée avec deux cures d'acide palmidronique et une éviction de la vitamine D et du calcium a permis de le stabiliser. Un variant pathogène homozygote p.Leu409Ser sur le gène CYP24A1 entraînant un effondrement de l'activité de la 25-hydroxyvitamine D24-hydroxylase a été retrouvé. Un développement normal est possible avec une prise en charge et un suivi clinique, biologique et nutritionnel méticuleux. Conclusions: L'hypersensibilité à la vitamine D est un défi pendant l'enfance, notamment en raison de la nécessité d'éviter la vitamine D tout en exigeant un suivi nutritionnel étroit pour maintenir une croissance normale. Les biomarqueurs tels que le rapport des métabolites de la vitamine D et la 24,25(OH)2D3, ainsi que le calcium ionisé et la gestion nutritionnelle peuvent contribuer à un suivi adéquat des patients souffrant d'hypersensibilité à la vitamine D.

Successful Management of Severe Hypercalcemia with Zoledronic Acid: A Report of Two Pediatric Cases.

Severe hypercalcemia associated with vitamin D intoxication or malignancy in children is a rare and life-threatening condition. There is little published experience with Zoledronic acid in the treatment of pediatric severe hypercalcemia. Here, we present two pediatric cases of severe hypercalcemia, one due to vitamin D intoxication and the second to malignancy, in which Zoledronic acid was used as the first-line bisphosphonate in the treatment. While both cases responded well to a single dose of Zoledronic acid, the second case experienced hypocalcemia requiring calcium treatment after Zoledronic acid infusion. Our report shows that Zoledronic acid may be an effective option in the treatment of severe pediatric hypercalcemia, although patients should be followed closely after infusion due to the risk of hypocalcemia. We provide additional published evidence for the effectiveness of Zoledronic acid in correcting severe pediatric hypercalcemia and hope this will encourage future studies with larger numbers of patients.

LC-MS/MS reduces interference by high levels of 25(OH)D and its metabolites on measured 1,25(OH)2D.

BACKGROUND: High-dose vitamin D supplementation has been recommended as treatment to several conditions; however, potential side effects such as hypercalcemia should be considered, plus the fact that high levels of 25(OH)D may interfere with potential 1,25(OH)2D measurements. Our study compared two methods of measuring 1,25-dihydroxyvitamin D [1,25(OH)2D] in samples with 25-hydroxyvitamin D [25(OH)D] levels above 150 ng/mL (375 nmol/L). METHODS: We studied serum samples referred to 25(OH)D and 1,25(OH)2D quantification. The concentrations of 25(OH)D and 1,25(OH)2D were measured using DiaSorin chemiluminescent assays (CLIA) in 213 samples (CLIA group), whereas in 357 samples 25(OH)D and 1,25(OH)2D were measured by DiaSorin CLIA and liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively (CLIA + MS group). RESULTS: Median concentrations of 25(OH)D and 1,25(OH)2D in the CLIA group were 371 ng/mL (928 nmol/L, range 154-856 ng/mL) and 350 pg/mL (875 pmol/L, range 41-1280 pg/mL), respectively, and correlated significantly (Spearman correlation coefficient rs = 0.8469, P < 0.001). In the CLIA + MS group, the median concentrations of 25(OH)D and 1,25(OH)2D were, respectively, 344 ng/mL (860 nmol/L, range 152-756 ng/mL) and 56 pg/mL (140 pmol/L, range 17-151 pg/mL), and were not correlated (rs = 0.0218, P = 0.6811). No significant difference was found in calcium, creatinine, and PTH serum values between the groups. CONCLUSION: Methods for measuring 1,25(OH)2D in patients with high levels of 25(OH)D may be susceptible to interference by 25(OH)D and its metabolites and should be validated carefully. In such cases, measurement of 1,25(OH)2D using LC-MS/MS is preferred.

RISK OF HYPERCALCEMIA IN ELDERLY PATIENTS WITH HYPERVITAMINOSIS D AND INTOXICATION.

OBJECTIVE: We aimed to determine the risk of hypercalcemia in a geriatric population with very high dose levels of 25-hydroxy-vitamin D (25(OH)D). PATIENTS AND METHOD: This study was designed as a retrospective, cross-sectional two-center study for examining the elderly patients with very high 25(OH)D levels (>88ng/mL) between January 2014 and December 2019. After recruitment, subgroup analyses of the patients were performed based on their calcium and vitamin D levels. RESULTS: A total of 81.101 elderly patients, who had been evaluated for their vitamin D levels, were screened. Of the 458 (0.6%) elderly patients with 25(OH)D>88 ng/mL according to our criteria, 217 patients with complete data were accepted into our study. The median 25(OH)D level was 103.7ng/mL (min-max:88.2-275.9). Most of the elderly patients (86.6%) with very high 25(OH)D levels were normocalcemic. When patients with hypercalcemia were compared with normocalcemic group, no difference was observed in the levels of 25(OH)D, intact parathormone (iPTH), phosphorus, alkaline phosphatase (ALP), and their age. However, the PTH suppression rate was significantly higher in hypercalcemic group (p=0.005). CONCLUSION: The elderly patients with very high 25(OH)D levels would appear to be mostly normocalcemic whereas life-threatening hypercalcemia would also occur. Treatment and follow-up planning should be done according to the clinical guideline recommendations.

Nonuremic Calciphylaxis Associated With Hypercalcemia and Rheumatologic Diseases.

Calcific uremic arteriolopathy, termed calciphylaxis, was previously considered a condition that developed mostly in patients requiring dialysis. It has now been described in kidney transplant patients, in advanced chronic kidney disease (CKD) patients not requiring dialysis, and in individuals with maintained kidney function. We describe an individual with CKD stage 3b with hypercalcemia who presented with features highly specific for calciphylaxis based on results of a skin biopsy. The condition has high morbidity and mortality, and thus prompts immediate cessation of the offending agents or treatment of the cause. The following case and literature review demonstrates a need for a detailed assessment of patients' risks and exposures and expanding the differential diagnosis to include calciphylaxis in nonuremic patients with necrotic ulcers with a plan for early imaging and possible biopsy.

Perinatal outcomes of high-dose vitamin D administration in the last trimester

In recent years, interest in the evaluation of vitamin D levels and the possible outcomes of their deficiency during pregnancy has increased. However, there is no consensus on when to start vitamin D supplementation, its duration, dosage, and the optimum level during pregnancy. The toxicity of vitamin D is as important as its deficiency. From the history of a 5-day-old male baby who was investigated for hypercalcemia, it was learned that the mother took 300,000 IU vitamin D-five ampoules/oral at 30 weeks of gestation every other day. The infant was born prematurely, postpartum bradycardia required positive pressure ventilation, and his hypercalcemia lasted approximately 4 months despite treatment. Maternal excessive and inappropriate use of vitamin D can cause preterm labor and severe hypercalcemia, which is a life-threatening complication in the neonatal period. This case is presented to draw attention to the negative effects of maternal high-dose vitamin D during pregnancy.

Vitamin D intoxication due to misuse: 5-year experience.

INTRODUCTION: Vitamin D intoxication (VDI) is a well-known cause of hypercalcemia in children and leads to serious kidney, heart, and neurological problems. In the treatment of VDI, the goal is to correct hypercalcemia. Our aim was to evaluate the clinical features of patients with VDI, identify the causes of VDI in our region, and help guide precautions and treatment of VDI. MATERIALS AND METHODS: The medical records of patients with VDI presenting between January 2015 and December 2019 were retrospectively analyzed. RESULTS: In total, 38 patients aged 0.3-4 years including 20 males (52.6%) were included in the study. Vomiting (65.8%), loss of appetite (47.4%), and constipation (31.6%) were the most common symptoms. The cause of intoxication was prescribed D3 vials in 23 patients, non-prescribed D3 vials in nine patients, and incorrectly produced fish oil supplement in six patients. Admission serum calcium and 25 (OH) D levels were 3.75±0.5mmol/L and 396±110ng/mL, respectively. A statistically significant correlation was found between the serum calcium levels at the time of diagnosis and the dose of vitamin D received, serum 25 (OH) D, phosphorus, and parathyroid (PTH) levels. Nephrocalcinosis was present in 15 (39.5%) patients. The mean time to achieve normocalcemia was 6.18±2 days. The mean time to achieve normocalcemia in patients treated with pamidronate was 5.94±0.7 days. CONCLUSION: Stoss therapy should not be administered for children of families with problems of adherence to treatment. It should be noted that VDI may develop as a result of improperly produced nutritional supplements. General practitioners and pediatricians must be aware of VDI risks and explain them to parents. Pamidronate is effective for treating VDI in children.

A case report of severe vitamin D intoxication / Schwere Vitamin-D-Intoxikation : Ein Fallbericht.

A CASE REPORT OF SEVERE VITAMIN D INTOXICATION: A 58-year-old woman presented with a symptomatic, hypertensive crisis, acute kidney failure AKIN2 and a severe hypercalcemia. The parathyroid hormone levels were in the lower normal range with highly elevated Vitamin D levels. For more than half a year she was taking 100'000 IU Vitamin D daily. Under volume loading, calcium-low-diet, Denosumab for blocking calcium resorption from bone and Ketoconazol to inhibit activation of Vitamin D a normalization of the calcium levels as well as an improvement of renal function could be observed. Loss-of-function mutations in the genes CYP24A1 and SLC34A1, involved in vitamin D metabolism leading to hypercalcemia could not be found in this patient.

Reference values of 25-hydroxyvitamin D revisited: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC)

ABSTRACT Hypovitaminosis D is a common condition with a negative impact on health. This statement, prepared by experts from the Brazilian Society of Endocrinology and Metabolism and the Brazilian Society of Clinical Pathology/Laboratory Medicine, includes methodological aspects and limitations of the measurement of 25-hydroxyvitamin D [25(OH)D] for identification of vitamin D status, and identifies individuals at increased risk for deficiency of this vitamin in whom 25(OH)D measurement is recommended. For the general population, 25(OH)D levels between 20 and 60 ng/mL are considered normal, while individuals with levels below 20 ng/mL are considered to be vitamin D deficient. This statement identifies potential benefits of maintaining 25(OH)D levels > 30 ng/mL in specific conditions, including patients aged > 65 years or pregnant, those with recurrent falls, fragility fractures, osteoporosis, secondary hyperparathyroidism, chronic kidney disease, or cancer, and individuals using drugs with the potential to affect the vitamin D metabolism. This statement also calls attention to the risk of vitamin D intoxication, a life-threatening condition that occurs at 25(OH)D levels above 100 ng/mL

Can adverse effects of excessive vitamin D supplementation occur without developing hypervitaminosis D?

Vitamin D is a fat-soluble hormone that has endocrine, paracrine and autocrine functions. Consumption of vitamin D-supplemented food & drugs have increased significantly in the last couple of decades due to campaign and awareness programs. Despite such wide use of artificial vitamin D supplements, serum level of 25 hydroxyvitamin D does not always reflect the amount of uptake. In contrast to the safe sunlight exposure, prolonged and disproportionate consumption of vitamin D supplements may lead to vitamin D intoxication, even without developing hypervitaminosis D. One of the reasons why vitamin D supplementation is believed to be safe is, it rarely raises serum vitamin D levels to the toxic range even after repeated intravenous ingestion of extremely high doses of synthetic vitamin D analogs. However, prolonged consumption of vitamin D supplementation may induce hypercalcemia, hypercalciuria and hyperphosphatemia, which are considered to be the initial signs of vitamin D intoxication. It is likely that calcium and phosphorus dysregulation, induced by exogenous vitamin D supplementation, may lead to tissue and organ damages, even without developing hypervitaminosis D. It is needed to be emphasized that, because of tight homeostatic control of calcium and phosphorus, when hypercalcemia and/or hyperphosphatemia is apparent following vitamin D supplementation, the process of tissue and/or organ damage might already have been started.

An unusual case of hypercalcemia in a patient of concomitant hypoparathyroidism and celiac disease.

Milk alkali syndrome has shown resurgence with increase in use of (prescription or non prescription) calcium supplements. Cases of iatrogenic vitamin D intoxication has also increased due to increasing use of high doses of injectable vitamin D formulations by physicians, surgeons, orthopaedicians, gynecologists and other specialties inadvertently. Here, we present an unusual case of a 17-year-old boy who presented with iatrogenic hypercalcemia as a result of combination of milk alkali syndrome with vitamin D intoxication despite being a case of hypoparathyroidism and concomitantly suffering from celiac disease.

Efficacy and safety of pamidronate in children with vitamin D intoxication.

BACKGROUND: Bisphosphonates are used in the treatment of vitamin D intoxication (VDI) after failure of conventional therapy including prednisolone. Safety concerns restrict the use of bisphosphonates from being used as first-line therapy for VDI in children. The aim of this study was to evaluate the efficacy and safety of pamidronate in comparison with prednisolone in children with VDI. METHODS: We reviewed the hospital records of children consecutively diagnosed with VDI at two medical centers in a 15 year period. RESULTS: The subjects consisted of 21 children (age, 0.3-4.2 years) who were treated with prednisolone and/or bisphosphonates. Pamidronate (n = 18) or alendronate (n = 3) was used in six patients after unsuccessful prednisolone treatment, and in 15 patients from baseline. Initial serum calcium and 25-hydroxyvitamin D were 16.1 ± 1.9 mg/dL and 493 ± 219 ng/mL, respectively. The median time to reach normocalcemia in the pamidronate, alendronate and prednisolone groups was 3 days (range, 2-12 days), 4 days (range, 3-6 days) and 17 days (range, 12-26 days), respectively (P = 0.013). The pamidronate group had a fivefold shorter hospital stay than the prednisolone group. Three patients initially treated with prednisolone developed nephrocalcinosis but this did not occur in any patient treated with bisphosphonates from baseline. Apart from transient fever and moderate hypophosphatemia, no side-effect of bisphosphonate treatment was observed. CONCLUSIONS: Pamidronate is efficient and safe for the treatment of VDI in children. Pamidronate use significantly shortens the duration of treatment, and thereby may prevent the development of nephrocalcinosis. Instead of prednisolone, pamidronate should be used together with hydration and furosemide as the first-line therapy for VDI.

Prolonged vitamin D intoxication: presentation, pathogenesis and progress.

Vitamin D toxicity from unactivated vitamin D (calciferol) therapy is currently a rare cause of hypercalcaemia. However, the frequency of this event may increase as high-dose unactivated vitamin D preparations become available. Prolonged vitamin D toxicity can cause reversible hypercalcaemia and partially reversible renal impairment. Parathyroid hormone may not be suppressed with unactivated vitamin D toxicity, especially if renal disease coexists.