cholecalciferol and Nephrocalcinosis

Public concern over vitamin D deficiency has led to widespread use of over the counter (OTC) vitamin D (-D3 or -D2) supplements, containing up to 10,000 IU/unit dose (400 IU=10μg). Overzealous use of such supplements can cause hypercalcemia due to vitamin D toxicity. Infants are particularly vulnerable to toxicity associated with vitamin D overdose. OTC supplements are not subject to stringent quality control regulations from FDA and high degree of variability in vitamin D content in OTC pills has been demonstrated. Other etiologies of vitamin D induced hypercalcemia include hyperparathyroidism, granulomatous malignancies like sarcoidosis and mutations in the CYP24A1 gene. The differential diagnosis of hypercalcemia should include iatrogenic and genetic etiologies. C24-hydroxylation and C3-epimerization are two important biochemical pathways via which 25-hydroxyvitamin D3 (25(OH)D3) is converted to its metabolites, 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) or its C3 epimer, 3-epi-25-OH-D3 respectively. Mutations in the CYP24A1 gene cause reduced serum 24,25(OH)2D3 to 25(OH)D3 ratio (<0.02), elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D3), hypercalcemia, hypercalciuria and nephrolithiasis. Studies in infants have shown that 3-epi-25(OH)D3 can contribute 9-61.1% of the total 25(OH)D3. Therefore, measurements of parathyroid hormone (PTH) and vitamin D metabolites 25(OH)D3, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3 are useful to investigate whether the underlying cause of vitamin D toxicity is iatrogenic versus genetic. Here we report a case of vitamin D3 associated toxicity in a 4-month-old female who was exclusively breast-fed and received an oral liquid vitamin D3 supplement at a dose significantly higher than recommended on the label. The vitamin D3 content of the supplement was threefold higher (6000 IU of D/drop) than listed on the label (2000 IU). Due to overdosing and higher vitamin D3 content, the infant received ∼50,000 IU/day for two months resulting in severe hypercalcemia, hypercalciuria and nephrocalcinosis. We also review the relevant literature on vitamin D3 toxicity in this report.

Topics: Cholecalciferol; Dietary Supplements; Female; Humans; Hypercalcemia; Hypercalciuria; Iatrogenic Disease; Infant; Nephrocalcinosis; Vitamins

Nephrocalcinosis is used to describe renal parenchymal calcification. Causes of nephrocalcinosis include persistent hypercalcemia, hypercalciuria, acid-base disorders, hyperoxaluria and urinary stasis. Patients with nephrocalcinosis initially present no symptom. However, advanced nephrocalcinosis is irreversible and causes impaired renal function. Therefore, careful observation for the presence and progression of nephrocalcinosis is necessary for patients who have risk factors for this disorder.

Topics: Acid-Base Imbalance; Calcium; Cholecalciferol; Humans; Hypercalcemia; Hyperoxaluria; Hyperparathyroidism; Nephrocalcinosis; Risk Factors; Urinary Retention

Topics: Calcium; Calcium Metabolism Disorders; Cholecalciferol; Cushing Syndrome; Diagnosis, Differential; Fanconi Syndrome; Fractures, Bone; Glomerular Filtration Rate; Humans; Hypercalcemia; Hyperparathyroidism; Hyperthyroidism; Kidney Calculi; Nephrocalcinosis; Osteitis Deformans; Osteoporosis; Parathyroid Hormone; Sarcoidosis

The pivotal role of vitamin D (vit D) in skeletal health is well known. Neonatal vit D storage at birth is dependent on maternal levels, and newborns receive 50-70% of their mother's 25-hydroxyvitamin D [25(OH)D]. Deficiency of vit D can lead to prematurity bone disease, with an incidence of up to 55% in infants weighing < 1000 g. The aim of this study is to assess the effectiveness of monitored supplementation of vit D in a population of preterm infants.. Preterm infants born at 24-32 weeks of gestation will be recruited within the first 7 days of life. Depending on the type of feeding, and after reaching partial enteral feeding or at 7 days of life, vit D supplementation will consist of 500 IU and an additional 150-300 IU/kg included in human milk fortifiers (if fed exclusively with breast milk) or 190 IU/kg in milk formulas. Subjects will be randomised to either monitored (with an option of dose modification based on 25(OH)D levels as per protocol) or standard therapy up to 52 weeks of post-conceptional age (PCA). The primary outcome measure will be the number of neonates with deficiency or excess levels of 25(OH)D at 40  ±2 weeks of PCA. Additional 25(OH)D levels will be measured at birth, at 4 and 8 weeks of age, and/or at 35 and 52  ±2 weeks of PCA. Secondary objectives will include the incidence of osteopenia, nephrocalcinosis and nephrolithiasis. Serum parameters of calcium phosphorus metabolism will also be measured.. Despite multiple years of research and numerous publications, there is still a lack of consensus in regard to how much vit D infants should receive and how long they should receive it. Because 80% of calcium and phosphorus placental transfer occurs between 24 and 40 weeks of gestation, preterm infants are especially prone to adverse effects of vit D insufficiency. However, both inadequate and excessive amounts of vit D may be unsafe and lead to serious health issues. The results of our study may shed new light on these concerns and contribute to optimising vit D supplementation.. ClinicalTrials.gov, NCT03087149 . Registered on 15 March 2017.

Topics: Biomarkers; Bone Diseases, Metabolic; Cholecalciferol; Clinical Protocols; Dietary Supplements; Gestational Age; Humans; Incidence; Infant; Infant, Newborn; Infant, Premature; Nephrocalcinosis; Nephrolithiasis; Poland; Premature Birth; Research Design; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency

Activating mutations of the calcium-sensing receptor (CaR) can cause isolated hypoparathyroidism. Treatment of hypocalcemia in these patients remains to be optimized, because the use of 1-hydroxylated vitamin D3 derivatives can cause hypercalciuria and nephrocalcinosis. We identified activating CaR mutations in 8 (42%) of 19 unrelated probands with isolated hypoparathyroidism. The severity of hypocalcemic symptoms at diagnosis was independent of age, mutation type, or mode of inheritance but was related to the degree of hypocalcemia; serum Ca was 1.97 +/- 0.08, 1.82 +/- 0.14, and 1.54 +/- 0.22 mmol/liter, respectively, in asymptomatic (n = 7), mildly symptomatic (n = 8), and severely symptomatic patients (n = 6). Hypocalcemia segregated with the CaR mutation, but no phenotype-genotype relationships were identified. Fourteen patients received regular 1-hydroxylated vitamin D3 treatment (mean duration, 7.2 +/- 4.9 yr). Nine had hypercalciuric episodes, which were associated with nephrocalcinosis in eight cases. Serum Ca during treatment predicted hypercalciuria and nephrocalcinosis poorly, because either or both of the latter could develop in hypocalcemic patients. Thus, mutational analysis of the CaR gene should be considered early in the work-up of isolated hypoparathyroidism. Treatment options should be weighed carefully in patients with serum Ca below 1.95 mmol/liter. The risk of nephrocalcinosis during treatment can be minimized by carefully monitoring urinary Ca excretion.

Topics: Aging; Amino Acid Substitution; Calcium; Cholecalciferol; DNA Mutational Analysis; Female; Humans; Hypocalcemia; Hypoparathyroidism; Male; Middle Aged; Nephrocalcinosis; Parathyroid Hormone; Pedigree; Receptors, Calcium-Sensing; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome

Vitamin D supplements are readily available as over-the-counter preparations. However, although rare, cases of vitamin D overdose still occur and are associated with nephrocalcinosis and life-threatening hypercalcemia. Errors in manufacturing of nutritional supplements may be a cause of vitamin D intoxication in children. This study aimed to identify factors associated with vitamin D overdose-related nephrocalcinosis in children due to manufacturing errors in supplements.. This retrospective study reviewed medical charts of pediatric patients with non-registered supplement-related vitamin D overdose at a tertiary referral hospital between 2006 and 2011. Clinical and laboratory characteristics of patients with or without nephrocalcinosis were evaluated. Receiver operating characteristics curve and area under the receiver operating characteristics curve were used to determine the most predictive value of each characteristic.. Children with smaller BSAs were more vulnerable to high-dose vitamin D

Topics: Child; Child, Preschool; Cholecalciferol; Humans; Hypercalcemia; Infant; Male; Nephrocalcinosis; Retrospective Studies; Vitamin D; Vitamins

Topics: Biopsy; Cholecalciferol; Dietary Supplements; Glucocorticoids; Humans; Male; Nephrocalcinosis; Renal Dialysis; Renal Insufficiency; Tomography, X-Ray Computed; Treatment Outcome; Weight Lifting; Young Adult

Topics: Child; Chloride Channels; Cholecalciferol; Genetic Linkage; Humans; Male; Mutation; Nephrocalcinosis; Nuclear Family; X Chromosome

Adrenal medullary hyperplasia and pheochromocytomas are induced in rats by a variety of non-genotoxic agents, and we have hypothesized that these agents induce lesions indirectly by stimulating chromaffin cell proliferation. Vitamin D3, which has not been previously associated with adrenal medullary proliferative lesions, is the most potent in vivo stimulus to chromaffin cell proliferation yet identified. The present investigation utilized the vitamin D3 model to prospectively test the relationship between mitogenicity and focal proliferative lesions in the adrenal medulla and to determine early events in the pathogenesis of these lesions. Charles River Crl:CD BR rats were treated with 0; 5000; 10,000; or 20,000 IU/kg/day of vitamin D3 in corn oil (5 ml/kg) by oral intubation. Rats were killed after 4, 8, 12, or 26 weeks of treatment, following a final week of labeling with bromodeoxyuridine (BrdU) using a mini-pump. Adrenal sections were double-stained for BrdU and phenylethanolamine-N-methyl transferase (PNMT) to discriminate epinephrine (E) from norepinephrine (NE) cells or for vesicular acetylcholine transporter (VAchT) to identify cholinergic nerve endings. Vitamin D3 caused a 4-5-fold increase in BrdU labeling at week 4, diminishing to a 2-fold increase by week 26. An initial preponderance of labeled E cells gave way to a preponderance of labeled NE cells. By week 26, 17/19 (89%) animals receiving the 2 highest doses of vitamin D3 had focal adrenal medullary proliferative lesions, in contrast to an absence of lesions in control rats. The lesions encompassed a spectrum including BrdU-labeled "hot spots" not readily visible on H and E sections, hyperplastic nodules, and pheochromocytomas. Lesions were usually multicentric, bilateral, and peripheral in location, and almost all were PNMT-negative. The lesions were not cholinergically innervated, suggesting autonomous proliferation. Hot spots, hyperplastic nodules, and pheochromocytomas appear to represent a continuum rather than separate entities. Their development might involve selective responses of chromaffin cell subsets to mitogenic signals, influenced by both innervation and corticomedullary interactions. A number of non-genotoxic compounds that induce pheochromocytomas in rats are known to affect calcium homeostasis. The results of this study provide further evidence to support the hypothesis that altered calcium homeostasis is indirectly involved in the pathogenesis of pheochromocytomas, via eff

Topics: Administration, Oral; Adrenal Gland Neoplasms; Adrenal Medulla; Animals; Body Weight; Bromodeoxyuridine; Carcinogenicity Tests; Carrier Proteins; Cholecalciferol; Cholinergic Fibers; Epinephrine; Hyperplasia; Kidney; Male; Membrane Transport Proteins; Nephrocalcinosis; Norepinephrine; Organ Size; Pheochromocytoma; Rats; Rats, Sprague-Dawley; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins

Idiopathic hypercalciuria (IH) associated with nephrocalcinosis was found in three of six siblings. After the three affected children were maintained on a low-calcium diet, they demonstrated increasing hypercalciuria, parathyroid hormone, and vitamin D3 levels. An oral calcium loading test was not necessary to diagnose renal IH. During treatment with hydrochlorothiazide, the calcium excretion was normalized. These patients are remarkable because nephrocalcinosis is generally regarded as a rare complication of renal IH. Moreover, the fact that three of six siblings are affected raises the question of whether the renal form of IH is genetically distinct from other forms of IH.

Topics: Adolescent; Calcium; Calcium, Dietary; Child; Child, Preschool; Cholecalciferol; Female; Humans; Metal Metabolism, Inborn Errors; Nephrocalcinosis; Parathyroid Hormone; Ultrasonography; Water-Electrolyte Balance

Vitamin D is required for the normal development of teeth and bones. When there is excess vitamin D, systemic and dental changes may occur. This is a case report of a girl who experienced hypercalcemia secondary to excess vitamin D derived from the consumption of milk that was incorrectly fortified. The changes in the permanent dentition to date are enamel hypoplasia and focal pulp calcification. These changes correspond to the timing of the toxemia caused by hypervitaminosis D.

Topics: Animals; Bone Development; Child; Cholecalciferol; Dental Enamel Hypoplasia; Dental Pulp Calcification; Female; Food, Fortified; Humans; Hypercalcemia; Milk; Nephrocalcinosis; Odontogenesis; Tooth Calcification; Tooth Discoloration

We conducted two safety studies of 25-hydroxycholecalciferol [25(OH)D3] in poultry broilers at levels ranging from 1 to 200 times those commonly used for cholecalciferol (vitamin D3) supplementation in the industry. In the first experiment, 1-d-old male and female broiler chickens were fed commercial diets containing either vitamin D3 or 25(OH)D3 at concentrations of 69, 207, and 690 micrograms of 25(OH)D3/kg of feed. The second experiment compared effects of 25(OH)D3 and vitamin D3 on performance and survival of broilers at levels ranging from 1 to 200 times the basal level of 69 micrograms/kg feed. When 25(OH)D3 was fed in equal amounts (wt/wt) to vitamin D3, there was an increase in body weight and a decrease (improvement) in adjusted feed efficiency in both experiments, but the changes were significant only in the first experiment. In the first experiment, serum 25(OH)D3 concentrations increased from 13.3 +/- 4.3 to 42.5 +/- 18 ng/mL in birds fed vitamin D3 or 25(OH)D3, respectively, and rose to 246 +/- 38 ng/mL in birds fed the highest level of 25(OH)D3. Tissue 25(OH)D3 concentrations were much lower than serum concentrations and were highly correlated to the latter, regardless of dietary treatment. In Experiment 2, there was some evidence of renal calcification in birds fed 25(OH)D3 at 10 times the basal level, whereas dietary levels of vitamin D3 of 50 times the basal level were required to show some evidence of renal calcification. On the basis of both renal calcification and body weight, the present studies would suggest that 25(OH)D3 is 5 to 10 times more toxic than vitamin D3.

Topics: Animals; Body Weight; Calcifediol; Chickens; Cholecalciferol; Consumer Product Safety; Female; Food, Fortified; Male; Mortality; Nephrocalcinosis; Tissue Distribution

The established prophylaxis for vitamin D-deficient rickets today is 400 IU vitamin D3 given daily during the first year of life. With this regimen, vitamin D intoxication is a rare event. Nevertheless, we have recently seen 4 infants with vitamin D intoxication after a so called "stoss" prophylaxis, i.e. twice 300,000 units (7.5 mg) vitamin D3 orally within 4 weeks. One patient presented with failure to thrive due to marked hypercalcemia (3.9 mmol/l) and nephrocalcinosis, 2 patients showed medullary nephrocalcinosis on ultrasonography and one patient had gross hematuria and spontaneous passage of a calculus. Three patients had massive hypercalciuria (calcium/creatinine ratio 1.8-4.8 mol/mol, normal less than 1). The 25 (OH) vitamin D3 plasma levels, measured only in 2 patients, were strikingly increased (270 and 158 nmol/l, respectively, normal 25-80). Urinary calcium excretion slowly decreased to normal values on a low calcium diet and high fluid intake. Nephrocalcinosis, however, persisted in 2 patients and showed a slight progression ultrasonographically in one patient. The short time interval between vitamin D administration and onset of symptoms and the subsequent clinical course provide strong evidence that hypercalciuria and nephrocalcinosis were due to vitamin D "stoss" prophylaxis in all four cases. In conclusion, there is no indication for vitamin D "stoss" prophylaxis for vitamin D-deficient rickets in infants. Vitamin D intoxication still has to be considered as a possible cause of hypercalciuria.

Topics: Calcifediol; Calcium; Cholecalciferol; Female; Humans; Infant; Male; Nephrocalcinosis; Ultrasonography

Administration of high doses of vitamin D3 (2,600 IU/100 ml of drinking water) to adult rats, for one month, significantly altered renal function (P less than 0.01) and enhanced renal accumulation of oxalate (71.44 x 18.82 micrograms/g of tissue in treated rats vs 38.87 +/- 11.96 micrograms/g in untreated rats; P less than 0.001), phosphate (1.388 +/- 188 micrograms/g in treated rats vs 870 +/- 171 micrograms/g in untreated rats; P less than 0.01) and calcium (477 +/- 107 micrograms/g in treated rats vs 326 +/- 104 micrograms/g in untreated rats; P less than 0.01). Urinary analyses of principal promotors and inhibitors of lithogenesis revealed high calcium excretion (1,576 +/- 0.419 mg/24 hr in treated rats vs 0.969 +/- 0.214 mg/24 hr in untreated rats; p less than 0.01) and decreased magnesium excretion (0.330 +/- 0.135 mg/24 hr in treated rats vs 0.910 +/- 0.168 mg/24 hr in untreated rats; p less than 0.001). Microscopic calcium deposits were found in the medulla, especially in renal papilla. These results suggested that vitamin D3, when administered at high doses for a long time, may induce nephrocalcinosis and alter renal function.

Topics: Animals; Calcium; Cholecalciferol; Creatinine; Kidney; Kidney Calculi; Male; Nephrocalcinosis; Oxalates; Oxalic Acid; Phosphates; Rats; Rats, Inbred Strains; Uric Acid

Twenty-four children with vitamin D intoxication and a follow-up of one to thirteen years old (means: four years and seven months) are reviewed. Over-dosage was prescribed by medical order in 66.6% of patients and by the mother herself in 16.6%. Intensity of clinical symptoms (renal, neurologic, digestive) were related with daily dose administered whilst final secuelae depends on duration of overdosage. Hipercalcemia was easily corrected by association of low calcium diet, corticoesteroids and/or furosemide in least than a month in 81% of cases. Two patients died during the acute fase and 22.7% remain with permanent damage (five in chronic renal failure, one in haemodialysis and three with low IC).

Topics: Bone Diseases, Metabolic; Calcinosis; Calcium; Child; Child, Preschool; Cholecalciferol; Female; Humans; Hypertension; Infant; Male; Nephrocalcinosis

Vitamin D intoxication was induced in chicks by treatment with large amounts of radioactive cholecalciferol (vitamin D3) either by s.c. injections or by stomach tube. Hypercalcemia and nephrocalcinosis were present, confirming toxicity. The distribution of cholecalciferol and its metabolites in the tissues of the intoxicated birds was compared with that in birds that were treated with physiological amounts of radioactive cholecalciferol. Treatment with pharmacological doses resulted in marked elevation of cholecalciferol and its metabolites in all tissues examined, including elevation of 1 alpha,25-dihydroxycholecalciferol in the intestine. The predominant form of cholecalciferol in these birds was found to be the unchanged vitamin, whereas in birds treated with physiological doses 25-hydroxycholecalciferol was the predominant metabolite. The route of vitamin administration was found to be of importance only when pharmacological doses were given: generally, higher levels were noted when administered via s.c. injections than via stomach tube, except in the arteries. It is suggested that in vitamin D intoxication, the factor responsible for the pathological changes in soft tissues is cholecalciferol itself. High levels of 1 alpha,25-dihydroxycholecalciferol may be responsible for the hypercalcemia.

Topics: Animals; Bone and Bones; Chickens; Cholecalciferol; Hypercalcemia; Injections; Intestines; Intubation; Kidney; Liver; Male; Nephrocalcinosis; Vitamin D

Acute massive vitamin D overdosage occurred in a family after eating food cooked in a nut oil containing 5 million units of vitamin D3/ml. The plasma vitamin D was 55 and 60 i.u./ml in the father and mother respectively, and 9.6 i.u./ml in their 11-month-old infant (normal range, 0--1.6 i.u/ml). All the family presented with symptoms of hypercalcaemia and the infant responded quickly to prednisone. After steroids had failed to control the hypercalcaemia in the parents, neutral phosphate was successful, although necessary for 9 months. Before phosphate therapy it was shown that both parents were in strongly negative calcium balance, indicating that the vitamin D was mobilizing calcium from bone. Eleven years later all 3 patients are well but a renal biopsy in one of them shows persistent nephrocalcinosis.

Topics: Acute Disease; Adult; Cholecalciferol; Female; Humans; Hypercalcemia; Infant; Male; Nephrocalcinosis; Nuts; Oils; Phosphates; Prednisone

Topics: Administration, Oral; Animals; Bone Diseases; Cholecalciferol; Diet; Ergocalciferols; Gout; Haplorhini; Hypercalcemia; Kidney; Macaca; Nephrocalcinosis; Uric Acid; Vitamin A Deficiency

Topics: Animals; Calciphylaxis; Cholecalciferol; Dihydrotachysterol; Ergocalciferols; Female; Heart; Hypercalcemia; Kidney; Male; Nephrocalcinosis; Pregnancy; Pregnancy, Animal; Rats; Reserpine

Topics: Animals; Aortic Diseases; Calcinosis; Calcium Phosphates; Cholecalciferol; Crystallization; Female; Hypercalcemia; Nephrocalcinosis; Organophosphonates; Rats

Topics: Alloxan; Calcinosis; Cholecalciferol; Dihydrotachysterol; Ergocalciferols; Islands; Islets of Langerhans; Kidney Diseases; Kidney Tubules; Nephrocalcinosis; Pancreas; Pathology; Rats; Research