Both high and low plasma levels of 25-hydroxy vitamin D increase blood pressure in a normal rat model.

The lower threshold plasma 25-hydroxy vitamin D (25(OH)D) level for optimal cardiovascular health is unclear, whereas the toxicity threshold is less clear. The aim of this study was to examine the cardiovascular-vitamin D dose-response curve in a normal rat model. Doses of cholecalciferol ranged from deficiency to toxic levels (equivalent to human doses of 0, 0·015, 0·25 and 3·75mg/d) for 4 weeks, and then cardiovascular health was examined using blood pressure telemetry and high-resolution ultrasound in normal male rats (n 16/group, 64 rats total). After 1 month, only the 0·25mg/d group had plasma 25(OH)D that was within current recommended range (100-125 nmol/l), and all groups failed to change plasma Ca or phosphate. Systolic blood pressure increased significantly (10-15 mmHg) in the rat groups with plasma 25(OH)D levels at both 30 and 561 nmol/l (groups fed 0 and 3·75mg/d) compared with the group fed the equivalent to 0·015mg/d (43 nmol/l 25(OH)D). Although not significant, the group fed the equivalent to 0·25mg/d (108 nmol/l 25(OH)D) also showed a 10 mmHg increase in systolic blood pressure. Carotid artery diameter was significantly smaller and wall thickness was larger, leading to higher peak carotid systolic blood velocity in these two groups. Despite these vascular changes, cardiac function did not differ among treatment groups. The key finding in this study is that arterial stiffness and systolic blood pressure both showed a U-shaped dose-response for vitamin D, with lowest values (best cardiovascular health) observed when plasma 25(OH)D levels were 43 nmol/l in normal male rats.

Pharmacokinetics and safety issues of an accidental overdose of 2,000,000 IU of vitamin D3 in two nursing home patients: a case report.

BACKGROUND: Administration of intermittent high doses of vitamin D3 is increasingly used as a strategy for rapid normalization of low 25-hydroxyvitamin D (25(OH)D) blood concentrations in patients with vitamin D deficiency. Here, we describe the pharmacokinetics of an accidental single oral overdose of 2,000,000 IU of vitamin D3 in two elderly nursing home patients and discuss safety issues. CASE PRESENTATION: Two patients, a Caucasian 90-year old man and a 95-year old woman, were monitored from 1 h up to 3 months after intake for clinical as well as biochemical signs of vitamin D intoxication. Blood vitamin D3 concentrations showed a prompt increase with the highest peak area already hours after the dose, followed by a rapid decrease to undetectable levels after day 14. Peak blood 25(OH)D3 concentrations were observed 8 days after intake (527 and 422 nmol/L, respectively (ref: 50-200 nmol/L)). Remarkably, plasma calcium levels increased only slightly up to 2.68 and 2.73 mmol/L, respectively (ref: 2.20-2.65 mmol/L) between 1 and 14 days after intake, whereas phosphate and creatinine levels remained within the reference range. No adverse clinical symptoms were noted. CONCLUSION: A single massive oral dose of 2,000,000 IU of vitamin D3 does not cause clinically apparent toxicity requiring hospitalization, with only slightly elevated plasma calcium levels in the first 2 weeks. Toxicity in the long term cannot be excluded as annual doses of 500,000 IU of vitamin D3 for several years have shown an increase in the risk of fractures. This means that plasma calcium levels may not be a sensitive measure of vitamin D toxicity in the long term in the case of a single high overdose. To prevent a similar error in the future, the use of multiple-dose bottles need to be replaced by smaller single-unit dose formulations.

Hypervitaminosis-D, an uncommon reality!

Vitamin D deficiency is highly prevalent in India. This has set off a trend among medical practitioners to prescribe vitamin D supplements empirically. Whilst this approach is generally safe, in predisposed individuals it may lead to hypervitaminosis D. Here we present a case where empirical use of high dose vitamin D supplementation had serious consequences highlighting the need to use vitamin D therapy judiciously and to remain vigilant for side-effects in high-risk individuals.

Cholecalciferol.

The primary source of exposure to cholecalciferol in dogs and cats is ingestion of rodenticide baits with vitamin D3 as the active ingredient. Other sources of this toxin are human medications and rarely, contaminated pet food. Although the reported lethal dose 50% for cholecalciferol is 88 mg/kg, deaths have been seen with an individual exposure of 2 mc g/kg in dogs. Clinical signs are induced by profound hypercalcemia affecting multiple body systems. Clinical presentations may include anorexia, depression, muscle weakness, vomiting, polyuria, polydipsia, dehydration, abdominal pain, hematemesis, melena, and bradycardia. Tissue mineralization may develop if calcium × phosphorous product is greater than 60. Serum testing for hypercalcemia, hyperphosphatemia, and decreased serum parathyroid hormone are confirmatory. Initial treatment relies upon decontamination with emesis induction followed by administration of pulse-dose activated charcoal designed to interfere with the extensive enterohepatic recirculation of toxin. Medical management is designed to decrease serum calcium levels by use of intravenous fluid diuresis with administration of furosemide and prednisolone. Biphosphate pamidronate is used to inhibit calcium release from the bone. Phosphate binders aid in decreasing phosphate availability to interact with calcium. The prognosis is better if treatment is instituted early before development of hypercalcemia and hyperphosphatemia enables tissue mineralization to progress.

Common rodenticide toxicoses in small animals.

This article focuses on the 3 most commonly used rodenticide types: anticoagulants, bromethalin, and cholecalciferol. It is important to verify the active ingredient in any rodenticide exposure. Many animal owners may use the term "D-con" to refer to any rodenticide regardless of the actual brand name or type of rodenticide. The EPA released their final ruling on rodenticide risk mitigation measures in 2008 and all the products on the market had to be compliant by June 2011, changing to consumer products containing either first-generation anticoagulants or nonanticoagulants including bromethalin and cholecalciferol. These regulations are likely to cause an increase in the number of bromethalin and cholecalciferol cases.

Aspectos toxicológico, clínico-patológico e ultraestrutural das intoxicações iatrogênica e experimental por vitamina D em coelhos / Toxicological, clinic-pathological and ultrastructural aspects of iatrogenic and experimental poisoning by vitamin D in rabbits

São descritos aspectos toxicológicos, clínico-patológicos e ultraestruturais de coelhos intoxicados iatrogênica e experimentalmente por vitamina D por via subcutânea. Clinicamente, os animais evidenciaram sinais de insuficiência cardiovascular como ascite e edema pulmonar, hiporexia, anorexia, diarréia mucosa, emagrecimento e apatia. As clássicas alterações de mineralização e, por vezes, osseificação, do sistema cardiovascular, bem como as alterações de rins, pulmões, estômago, entre outros órgãos, foram reproduzidas com administrações subcutâneas de solução oleosa de colecalciferol (vitamina D3 não-ativada).

Toxicological, clinic-pathological and ultrastructural aspects of iatrogenic and experimental subcutaneous poisoning in rabbits by vitamin D are described. Clinically the animals showed signs of cardiovascular insufficiency, as ascite and lung edema, hyporexia, anorexia, mucous diarrhoea, loss of weight and apathy. The classical alterations of minera-lization and, occasionally, ossification of the cardiovascular system, as well the lesions of kidneys, lungs, stomach, among other organs, were reproduced by the subcutaneous administration of an oily solution of cholecalciferol (non-activated vitamin D3).

Myocardial necrosis due to vitamin D3 overdose -- scanning electron microscopic observations.

Our studies were carried out on the hearts of virgin female Wistar rats treated with 100,000 i.u. of vitamin D3 (calciol) per os for 3 consecutive days. Multifocal cardionecrosis was established macroscopically in 70% of the vitamin D-treated rats on the 7th day of the experiment when the rats were in the acute phase of intoxication. Using a scanning electron microscopy (SEM), we received three-dimensional information about the structural changes to the rat myocardium damaged by high doses of vitamin D3. The images of necrotic hearts revealed significant disruption of the structural integrity of the myocardium linked to fragmentation of the cardiac muscle bundles and a visible disruption of the extracellular matrix (ECM) components. In healthy hearts, the structural integrity of the myocardium and the dense network of the extracellular matrix were well preserved. In parallel, the effect of an increasing concentration of free Ca2+ on the total proteolytic activity of the heart muscle homogenate of the healthy and necrotic rats was investigated at neutral pH. These data showed that following vitamin D3 intoxication, the proteolytic processes in the rat hearts occurred in Ca2+ overload or saturation. On the basis of our morphological and biochemical results we can suggest that calcium-activated neutral proteinases may have contributed to the structural alteration of the extracellular matrix components and were in this way involved in vitamin D-induced cardionecrosis.

Hyena disease (premature physeal closure) in calves due to overdose of vitamins A, D3, E.

Holstein suckling calves on a farm manifested severe emaciation, generalized alopecia, dome-like cranial deformation, and high mortality (Case 1). Metaphyseal growth plates of the femur were achondroplastic; segmented, partially resorped, and replaced with immature bony trabeculae containing degenerated chondrocytes. The skull was thin and partially replaced with connective tissue. Diffuse and severe fatty degeneration was observed in the hepatic stellate (Ito') cells. After 6 mo, surviving calves manifested unthrifty with short and irregular hindquarters (Case 2). The metaphyseal growth plates were poorly formed, irregular, partially disappeared centrally, and often sealed with thin bony trabeculae. The cartilage matrix was not homogeneous but was finely fibrous, and chondrocytes were flat and degenerated. The bone lesion was diagnosed as chondrodysplasia due to premature physeal closure. These calves had been administered excessive amounts of vitamins A, D3 and E, and blood chemistry of acute case showed hypervitaminosis A and E. Case I demonstrated acute disease, while Case 2 demonstrated chronic sequelae. Hypervitaminosis A was the suspected cause.

24-Hydroxylase: potential key regulator in hypervitaminosis D3 in growing dogs.

A group of growing dogs supplemented with cholecalciferol (vitamin D(3); HVitD) was studied vs. a control group (CVitD; 54,000 vs. 470 IU vitamin D(3)/kg diet, respectively) from 3 to 21 wk of age. There were no differences in plasma levels of P(i) and growth-regulating hormones between groups and no signs of vitamin D(3) intoxication in HVitD. For the duration of the study in HVitD vs. CVitD, plasma 25-hydroxycholecalciferol levels increased 30- to 75-fold; plasma 24,25-dihydroxycholecalciferol levels increased 12- to 16-fold and were accompanied by increased renal 24-hydroxylase gene expression, indicating increased renal 24-hydroxylase activity. Although the synthesis of 1,25-dihydroxycholecalciferol [1,25(OH)(2)D(3)] was increased in HVitD vs. CVitD (demonstrated by [(3)H]1,25(OH)(2)D(3) and increased renal 1alpha-hydroxylase gene expression), plasma 1,25(OH)(2)D(3) levels decreased by 40% as a result of the even more increased metabolic clearance of 1,25(OH)(2)D(3) (demonstrated by [(3)H]1,25(OH)(2)D(3) and increased gene expression of intestinal and renal 24-hydroxylase). A shift of the Ca set point for parathyroid hormone to the left indicated increased sensitivity of the chief cells. Effective counterbalance was provided by hypoparathyroidism, hypercalcitoninism, and the key regulator 24-hydroxylase, preventing the development of vitamin D(3) toxicosis.

[Vitamin D3 poisoning--case report]. / Vitamin D3-Intoxikation--Fallbericht.

Over 650 pigs died within a couple hours in a fattening unit with approximately 3,000 fattening spaces. The pigs showed vomiting, dyspnea, kyphosis, sunken flanks, diarrhea, and polyuria. Another striking symptom of the pigs, besides the apathy, was the aphonia, due to the calcification of the vocal cords. An acute vitamin D3-intoxication was found to be the cause. The pathologic findings, especially the histologic detection of calcification processes of the soft tissues, lead to the suspect of an intoxication with a vitamin D-like substance. Between 39,000 and 196,000 IU/kg of vitamin D3 have been detected in a ready-to-use food mix. 8.8 million IU/kg of crystaline vitamin D3 were found in an open whey bag. An explanation how vitamin D came into the bag could not be clarified to this point.

Enhanced production of calcitriol, and hypercalcaemia in a patient with sarcoidosis provoked by daily intake of calciol.

A case of sarcoidosis is described which presented with hypercalcaemia and renal insufficiency. Initially, a calciol intoxication was diagnosed, because a high daily intake was suspected. However, vitamin D3 metabolites in the blood revealed normal concentrations of calcidiol, but extremely high concentrations of calcitriol. These features rejected the first diagnosis and pointed to high endogenous calcitriol production, which may take place in granulomatous diseases. This is caused by an increased 1-alpha-hydroxylation reaction in activated macrophages. Eventually, muscle biopsy revealed non-caseating granulomas, confirming the diagnosis of sarcoidosis.

The effect of toxic doses of cholecalciferol (vitamin D3) on the serum zinc levels in rats.

Zinc is a trace element important to bone mineralization as well as, in general, nutrition. It is known that cholecalciferol (vitamin D3) affects bone metabolism. In this study, toxic doses of vitamin D3 were injected subcutaneously (25 micrograms/d) to rats for 5 wk. It caused a significant increase in serum zinc levels (p < 0.02). On the other hand, no significant increase was detected in the other groups. Excessive amounts of vitamin D3 caused bone breakdown and increased the levels of zinc in blood.

[Effect of vitamin D over-dosage on the tooth and bone development of rabbits].

The paper investigated the changes of rabbit's tooth and jaw tissues by vitamin-D poisoning experiment. The results showed the dentin, periodontium, jaw bone and long bone of rabbit were all changed. X-ray showed subperiosteum absorbation and periosteum reaction. The mineral content of the rabbit's epiphysis and long bone diaphysis in experiment group were lower than that of control group. The histopathological findings were irregular hyperplasia of dentin, arrange disturbance of periodontal fibers, absorbation of the alveolar bone and mal-ossification of long bones. The above changes were more significant during 30-45 days of rabbit poisoning, after 60 days of poisoning the above signs were gradually released.

[Vitamin D poisoning in infants: a preventable cause of hypercalciuria and nephrocalcinosis]. / Vitamin-D-Intoxikation beim Säugling: eine vermeidbare Ursache von Hypercalciurie und Nephrocalcinose.

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.

Cholecalciferol rodenticide intoxication in a cat.

A 4-month-old 2.5-kg sexually intact female domestic shorthair cat was referred to the teaching hospital because of suspected cholecalciferol intoxication after ingestion of a cholecalciferol-containing rodenticide. At referral, the cat was hypercalcemic, hyperkalemic, and acidotic. Despite management of hypercalcemia and preservation of renal function with physiologic saline solution, furosemide, dopamine, and calcitonin, the cat died, apparently as a result of extensive pulmonary mineralization.

Elevated 25-hydroxy and normal 1,25-dihydroxy cholecalciferol serum concentrations in a successfully-treated case of vitamin D3 toxicosis in a dog.

A 4-y old, 27 kg spayed female German Shepherd dog was observed to ingest one 1-oz package of a rodenticide containing cholecalciferol. An initial serum calcium concentration of 15.7 mg/dl was successfully reduced to normal during 10 d using calcitonin and prednisolone. During that time, the serum 25-hydroxy and 1,25-dihydroxy cholecalciferol concentrations ranged from 637 to 315 ng/ml (normal 32 +/- 6 ng/ml) and 64 to 29 pg/ml (normal 34 +/- 19 pg/ml), respectively. Serum mid-molecule parathyroid hormone concentrations (76 to 97 pcmol/L) were within the normal range (85-140 pcmol/L). These data indicate that hypercalcemia seen in dogs following field exposures to cholecalciferol-containing rodenticides may be associated with elevated 25-hydroxy rather than 1,25-dihydroxy cholecalciferol. Consequently, serum 25-hydroxy cholecalciferol concentrations may be the most conclusive method for diagnosing hypervitaminosis D3 toxicosis in the live dog.