Ionized calcium-to-phosphorus ratio predicts neoplasia in azotemic dogs: a retrospective study of 105 cases.

OBJECTIVE: To evaluate dogs with total hypercalcemia, azotemia, and normal serum phosphorus concentrations to determine whether a calcium-to-phosphorus ratio (Ca:P) or ionized Ca:P (iCa:P) could be utilized to predict underlying neoplasia. ANIMALS: 105 dogs were included in the study. Thirty-seven percent (n = 39) had known neoplasia, and 63% (66) had no evidence of neoplasia. PROCEDURES: A retrospective medical records search was performed. An observational cutoff of 2.5 for Ca:P and 0.33 for iCa:P was used for determining sensitivity and specificity between the neoplasia and nonneoplasia groups. RESULTS: Total hypercalcemia was higher in dogs with neoplasia compared to nonneoplastic cases of hypercalcemia. Ca:P of 2.5 had an 80% sensitivity and 46% specificity for predicting neoplasia. iCa:P of 0.33 had a 92% sensitivity and 77% specificity for predicting neoplasia in azotemic dogs. CLINICAL RELEVANCE: The sensitivity and specificity of Ca:P was low, making it an unreliable tool to predict neoplasia in this specific study population. However, iCa:P may have some usefulness in determining presence of neoplasia in patients with high calcium, azotemia, and normal phosphorus.

The effect of attenuating dietary phosphate restriction on blood ionized calcium concentrations in cats with chronic kidney disease and ionized hypercalcemia.

BACKGROUND: Hypercalcemia is commonly observed in cats with azotemic chronic kidney disease (CKD). Dietary phosphate restriction is considered standard of care but may contribute to the development of hypercalcemia. The optimal dietary management strategy for these cats is unclear. OBJECTIVES: To describe the effect of feeding a moderately phosphate-restricted diet (MP; 1.5 g/Mcal phosphorus; Ca : P ratio, 1.3) to cats with concurrent azotemic CKD and ionized hypercalcemia. ANIMALS: Client-owned cats with ionized hypercalcemia (ionized calcium [iCa] concentration >1.4 mmol/L) at diagnosis of CKD (n = 11; baseline hypercalcemics) or after CKD diagnosis while eating a phosphate-restricted clinical renal diet (0.8 g/Mcal phosphorus; Ca : P ratio, 1.9; n = 10; RD hypercalcemics). METHODS: Changes in variables over time, after starting MP at visit 1, were assessed using linear mixed model analysis within each group of cats. Data are reporte as median [25th, 75th percentiles]. RESULTS: At visit 1, iCa was 1.47 [1.42, 1.55] mmol/L for baseline hypercalcemics and 1.53 [1.5, 1.67] mmol/L for RD hypercalcemics. Blood iCa decreased (P < .001) when RD hypercalcemics were fed MP, with iCa <1.4 mmol/L in 8/10 cats after 2.2 [1.8, 3.7] months. Plasma phosphate concentrations did not change. In contrast, the baseline hypercalcemic group overall showed no change in iCa but a decrease in plasma phosphate concentration during 8.8 [5.5, 10.6] months on the MP diet, although 4/11 individual cats achieved iCa <1.4 mmol/L by 3.4 [1.0, 6.2] months. CONCLUSIONS AND CLINICAL IMPORTANCE: Attenuation of dietary phosphate restriction could result in normalization of iCa in cats that develop hypercalcemia while eating a clinical renal diet.

Development of a Multivariate Predictive Model to Estimate Ionized Calcium Concentration from Serum Biochemical Profile Results in Dogs.

BACKGROUND: Ionized calcium concentration is the gold standard to assess calcium status in dogs, but measurement is not always available. OBJECTIVES: (1) To predict ionized calcium concentration from biochemical results and compare the diagnostic performance of predicted ionized calcium concentration (piCa) to those of total calcium concentration (tCa) and 2 corrected tCa formulas; and (2) to study the relationship between biochemical results and variation of measured ionized calcium concentration (miCa). ANIMALS: A total of 1,719 dogs with both miCa and biochemical profile results available. METHODS: Cross-sectional study. Using 1,200 dogs, piCa was determined using a multivariate adaptive regression splines model. Its accuracy and performance were tested on the remaining 519 dogs. RESULTS: The final model included creatinine, albumin, tCa, phosphorus, sodium, potassium, chloride, alkaline phosphatase, triglycerides, and age, with tCa, albumin, and chloride having the highest impact on miCa variation. Measured ionized calcium concentration was better correlated with piCa than with tCa and corrected tCa and had higher overall diagnostic accuracy to diagnose hypocalcemia and hypercalcemia, but not significantly for hypercalcemia. For hypercalcemia, piCa was as sensitive (64%) but more specific (99.6%) than tCa and corrected tCa. For hypocalcemia, piCa was more sensitive (21.8%) and as specific (98.4%) as tCa. Positive and negative predictive values of piCa were high for both hypercalcemia (90% and 98%, respectively) and hypocalcemia (70.8% and 87.7%, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Predicted ionized calcium concentration can be obtained from readily available biochemical and patient results and seems more useful than tCa and corrected tCa to assess calcium disorders in dogs when miCa is unavailable. Validation on external data, however, is warranted.

[Diagnostic approach and management of hypercalcaemia in dogs exemplary of primary hyperparathyroidism]. / Diagnostische Aufarbeitung und Management der Hyperkalzämie des Hundes am Beispiel des primären Hyperparathyreoidismus.

Hypercalcaemia can be caused by many different diseases. This article summarizes the causes, pathophysiologic mechanisms and diagnostic procedures as well as treatment recommendations. The main focus is on hypercalcaemia in primary hyperparathyroidism (PH), complemented by a case report. An elevated total calcium level should generally be investigated and verified by measurement of ionized calcium concentration. The further diagnostic approach depends on the phosphate level. Tumour screening, measurement of parathormone and parathromone-related protein and sonography of parathyroid glands may be necessary. If the calcium-phosphate-product exceeds 60 mg/dl, there is a risk of tissue mineralisation and a rapid treatment of hypercalcaemia is required. For acute therapy, sodium chloride infusion, furosemide and glucocorticoids can be used. Glucocorticoids should only be given after strict indication and after a definite diagnosis. For long-term management, bisphosphates, particularly alendronate, are increasingly used successfully. Causal therapy of PH can be performed by parathyreoidectomy, heat ablation or ethanol ablation. Thereafter, particularly in cases of severe preoperative hypercalcaemia, hypocalcaemia can occur. Treatment is performed using vitamin D3 (calcitriol), which may also be given preoperatively in cases of severe hypercalcaemia. A concomitant oral calcium supplementation using calcium carbonate as medication of choice is contentious. Due to a potential relapse after successful excision of the affected parathyroid gland in PH, the serum calcium level should be monitored periodically.

Hypercalcemia in a Dog with Chronic Ingestion of Maxacalcitol Ointment.

A miniature dachshund male with severe azotemia of unknown cause was referred. Serum biochemistry revealed severe azotemia and hypercalcemia, but serum intact parathormone and parathormone-related protein were normal. Although the owner reported that the dog had never ingested any drugs or supplements, it was revealed that the owner's son used antipsoriatic ointment, maxacalcitol, which contained an active vitamin D3 analogue, daily and the dog often ate the son's dander and licked his skin, especially after he applied the maxacalcitol ointment. After the dog was insulated from the maxacalcitol ointment and the son as much as possible, the hypercalcemia and azotemia improved gradually and had mostly resolved at 3 mo. The dog has been generally free of clinical signs without any treatment for over 2 yr.

Hypercalcemia: Pathophysiology, Clinical Signs, and Emergent Treatment.

Hypercalcemia is uncommonly encountered in veterinary patients. When it does occur, the effects can be severe, resulting in significant morbidity and mortality if not recognized and addressed in a timely manner. Causes of hypercalcemia are varied and include pituitary-dependent and pituitary-independent causes. A diagnosis of hypercalcemia should be made based on documentation of ionized hypercalcemia. The mainstay of emergency treatment usually involves aggressive IV fluid diuresis, the use of diuretics, and, often, glucocorticoids. The use of bisphosphonates has become increasingly more common in veterinary medicine.

Blood calcium dynamics after prophylactic treatment of subclinical hypocalcemia with oral or intravenous calcium.

Total serum Ca dynamics and urine pH levels were evaluated after prophylactic treatment of subclinical hypocalcemia after parturition in 33 multiparous Jersey × Holstein crossbreed cows. Cows were blocked according to their calcemic status at the time of treatment [normocalcemic (8.0-9.9 mg/dL; n = 15) or hypocalcemic (5.0-7.9 mg/dL; n = 18)] and randomly assigned to 1 of 3 treatments: control [no Ca supplementation (n = 11)]; intravenous Ca [Ca-IV (n = 11), 500 mL of 23% calcium gluconate (10.7 g of Ca and 17.5 g of boric acid as a solubilizing agent; Durvet, Blue Springs, MO)]; or oral Ca [Ca-Oral (n = 11), 1 oral bolus (Bovikalc bolus, Boehringer Ingelheim, St. Joseph, MO) containing CaCl2 and CaSO4 (43 g of Ca) 2 times 12h apart]. Total serum Ca levels were evaluated at 0, 1, 2, 4, 8, 12, 16, 20, 24, 36, and 48 h, and urine pH was evaluated at 0, 1, 12, 24, 36, and 4 8h after treatment initiation. Total serum Ca levels were higher for Ca-IV than for control and Ca-Oral cows at 1, 2, and 4h after treatment initiation, but lower than Ca-Oral cows at 20, 24, and 36 h and lower than control cows at 36 and 48 h. At 1h after treatment initiation, when serum Ca levels for Ca-IV cows peaked (11.4 mg/dL), a greater proportion of Ca-IV (n = 8) cows had total serum Ca levels >10mg/dL than control (n = 0) and Ca-Oral (n = 1) cows. At 24h after treatment initiation, when Ca-IV cows reached the total serum Ca nadir (6.4 mg/dL), a greater proportion of Ca-IV (n = 10) cows had serum Ca levels <8 mg/dL than control (n = 5) and Ca-Oral (n = 2) cows. Treatment, time, and treatment × time interaction were significant for urine pH. Mean urine pH was lower for Ca-Oral cows (6.69) than for control (7.52) and Ca-IV (7.19) cows. Urine pH levels at 1h after treatment were lower for Ca-IV cows compared with both control and Ca-Oral cows, a finding likely associated with the iatrogenic administration of boric acid added as a solubilizing agent of the intravenous Ca solution used. At 12, 24, and 36 h, urine pH levels were lower for Ca-Oral cows compared with both control and Ca-IV cows. This was expected because the oral Ca supplementation used (Bovikalc) is designed as an acidifying agent. Wide fluctuations in blood Ca were observed after prophylactic intravenous Ca supplementation. The implications for milk production and animal health, if any, of these transient changes in total serum Ca have yet to be evaluated.

Endocrine causes of calcium disorders.

Endocrine diseases that may cause hypercalcemia and hypocalcemia include hyperparathyroidism, hypoparathyroidism, thyroid disorders, hyperadrenocorticism, hypoadrenocorticism, and less commonly pheochromocytoma and multiple endocrine neoplasias. The differential diagnosis of hypercalcemia may include malignancy (lymphoma, anal sac carcinoma, and squamous cell carcinoma), hyperparathyroidism, vitamin D intoxication, chronic renal disease, hypoadrenocorticism, granulomatous disorders, osteolysis, or spurious causes. Hypocalcemia may be caused by puerperal tetany, pancreatitis, intestinal malabsorption, ethlyene glycol intoxication, acute renal failure, hypopararthyroidism, hypovitaminosis D, hypomagnesemia, and low albumin. This article focuses on the endocrine causes of calcium imbalance and provides diagnostic and therapeutic guidelines for identifying the cause of hypercalcemia and hypocalcemia in veterinary patients.

Paraneoplastic hypercalcemia in a dog with thyroid carcinoma.

This case report describes a dog with thyroid carcinoma and paraneoplastic hypercalcemia. Following thyroidectomy the dog became hypocalcemic and required supplementation with calcitriol and calcium carbonate. During the following 2 years, attempts to reduce the supplementation resulted in hypocalcemia. The dog died from renal failure with no evidence of thyroid carcinoma.

Hypercalcémie paranéoplasique chez un chien atteint d'un carcinome thyroïdien. Ce rapport de cas décrit un chien atteint d'un carcinome thyroïdien et d'hypercalcémie paranéoplasique. Après une thyroïdectomie, le chien est devenu hypocalcémique et a nécessité une supplémentation au calcitriol et au carbonate de calcium. Durant les deux années suivantes, des tentatives de réduction de la supplémentation ont provoqué l'hypocalcémie. Le chien est mort d'insuffisance rénale sans signe de carcinome thyroïdien.(Traduit par Isabelle Vallières).

Therapeutic approach to electrolyte emergencies.

Hypokalemia, hyperkalemia, hyponatremia, hypernatremia, hypocalcemia, and hypercalcemia are commonly seen in emergency medicine. Severe abnormalities in any of these electrolytes can cause potentially life-threatening consequences to the patient. It is essential that the clinician understand and correct (if possible) the underlying cause of each disorder and recognize the importance of the rates of correction, especially with serum sodium disorders. The recommended doses in this article might have to be adjusted to the individual patient, and these modifications must be adjusted again to the pathophysiology of the primary underlying disorder.

Hypercalcaemia in two dogs caused by excessive dietary supplementation of vitamin D.

A three-year-old Border collie was presented with a two-week history of lethargy, stiff gait, polydipsia and polyuria. Biochemical analysis revealed hypercalcaemia. Serum concentrations of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) were markedly elevated and parathyroid hormone was undetectable. Subsequent analysis of the dog's diet revealed that the food contained excessive amounts of vitamin D. The hypercalcaemia resolved following treatment with bisphosphonates and dietary change. Hypervitaminosis D was diagnosed in a second unrelated dog, which had been fed the same brand of dog food as case 1. The dog was also hypercalcaemic and had markedly elevated serum concentrations of 25(OH)D and 1,25(OH)2D. Hypervitaminosis D in dogs has been reported to occur secondarily to ingestion of either rodenticides containing cholecalciferol or antipsoriatic ointments that contain vitamin D analogues. Hypervitaminosis D has also been reported following the treatment of hypoparathyroidism. To the authors' knowledge, this is the first report of hypervitaminosis D in dogs following the accidental over supplementation of a commercial diet with vitamin D. While the benefits of adequate dietary vitamin D are well established in dogs, the potential deleterious effects of over supplementation of vitamin D should also be acknowledged.

Parathyroid gland function in the uremic rabbit.

Rabbits with renal failure have been reported to be hypercalcemic and to have decreased parathyroid hormone (PTH) concentrations. Thus, it would seem that uremic rabbits are resistant to secondary hyperparathyroidism (HPT). The work reported here was designed to investigate parathyroid gland function in uremic rabbits and the effect of diets with different calcium (Ca) and phosphorus (P) content. The relationship between PTH and ionized calcium (Ca2+), parathyroid gland size and parathyroid cell cycle were studied in three groups of rabbits: Group I, rabbits with normal renal function on a standard diet (Ca = 1.2%, P = 0.6%); Group II, partially nephrectomized rabbits on a standard diet; and Group III, partially nephrectomized rabbits on a low Ca (0.6%)-high P (1.2%) diet. Group I rabbits had baseline Ca2+ = 1.71 +/- 0.05 mmol/l and PTH = 26.9 +/- 3.2 pg/ml. During hypo- and hypercalcemic stimulation PTH reached maximal values (PTHmax) of 94.4 +/- 5.5 pg/ml and minimal concentrations (PTHmin) of 3.2 +/- 0.2 pg/ml. Rabbits from Group II were hypercalcemic (baseline Ca2+ = 2.03 +/- 0.06 mmol/l) and had very low PTH levels (1.7 +/- 0.5 pg/ml); however, they reached a PTHmax that was similar to Group I, 92 +/- 8.7 pg/ml. Group III rabbits were hypocalcemic (baseline Ca2+ = 1.22 +/- 0.08 mmol/l) and had very high basal PTH levels (739 +/- 155 pg/ml). Their PTHmax and PTHmin were 801 +/- 169.4 pg/ml and 102.2 +/- 22.2 pg/ml, respectively. Both parathyroid gland size and parathyroid cell proliferation were increased in Group III. In conclusion, our results show that the Ca and P content of the diet markedly influence PTH secretion in the uremic rabbit and that when placed on a low Ca-high P diet uremic rabbits develop secondary HPT.

Responses of the ultimobranchial gland to vitamin D3 treatment in freshwater mud eel, Amphipnous cuchia, kept in different calcium environments.

Freshwater mud eel, Amphipnous cuchia, were injected intraperitoneally daily with 100 ng of vitamin D3/100 g body weight and maintained in media containing either no calcium or different calcium concentrations. The eels were killed after 1, 3, 5, 10 and 15 days following the treatment and their serum calcium levels were measured. The ultimobranchial glands were fixed and processed using the routine paraffin method for histological studies. The results of the present study indicate that vitamin D3 can induce hypercalcaemia in eels kept in different calcium environments. Also, the ultimobranchial glands became hyperactive following vitamin D3 treatment. It is concluded that in mud eels, the gland has a calcium-regulating function.

Hypercalcemia due to latrogenic secondary hypoadrenocorticism and diabetes mellitus in a cat.

A 9-year-old, spayed female domestic shorthair cat presented for polyphagia, polydipsia, and polyuria following chronic methylprednisolone acetate therapy for pruritus. Initial diagnostics were consistent with uncomplicated diabetes mellitus. Serum calcium was within reference range. Within 12 hours the cat developed depression, anorexia, vomiting, and severe dehydration. Laboratory analysis indicated marked hypercalcemia as measured by both ionized and total calcium concentration. No underlying neoplastic or inflammatory process was identified. An adrenocorticotropic hormone stimulation test was indicative of adrenocortical insufficiency. The hypercalcemia resolved with glucocorticoid supplementation and correction of the dehydration. The diabetes mellitus and adrenal insufficiency both resolved within 9 weeks.

Idiopathic hypercalcemia in cats.

Unexplained hypercalcemia has been increasingly recognized in cats since 1990. In some instances, hypercalcemia has been associated with calcium oxalate urolithiasis, and some affected cats have been fed acidifying diets. We studied the laboratory findings, clinical course, and treatment of 20 cats with idiopathic hypercalcemia. Eight (40%) of the cats were longhaired and all 14 cats for which adequate dietary history was available had been fed acidifying diets. Clinical signs included vomiting (6 cats), weight loss (4 cats), dysuria (4 cats), anorexia (3 cats), and inappropriate urinations (3 cats). Hypercalcemia was mild to moderate in severity. and serum parathyroid hormone concentrations were normal or low. Serum concentrations of phosphorus, parathyroid hormone-related peptide, 25-hydroxycholecalciferol, and calcitriol were within the reference range in most cats. Diseases commonly associated with hypercalcemia (eg, neoplasia, primary hyperparathyroidism) were not identified despite thorough medical evaluations and long-term clinical follow-up. Azotemia either did not develop (10 cats) or developed after the onset of hypercalcemia (3 cats), suggesting that renal failure was not the cause of hypercalcemia in affected cats. Seven of 20 cats (35%) had urolithiasis, and in 2 cats uroliths were composed of calcium oxalate. Subtotal parathyroidectomy in 2 cats and dietary modification in 11 cats did not result in resolution of hypercalcemia. Treatment with prednisone resulted in complete resolution of hypercalcemia in 4 cats.

The postmortem diagnosis of cholecalciferol toxicosis: a novel approach and differentiation from ethylene glycol toxicosis.

The objectives of this study were to develop a novel approach to postmortem diagnosis of cholecalciferol (CCF) toxicosis in dogs using kidney, bile, and urine samples, and to differentiate CCF from ethylene glycol (EG) toxicosis. To achieve these objectives, specimens collected from 2 previous laboratory studies in which dogs were given a single oral toxic dose of CCF (8.0 mg/kg) were used. For EG toxicosis, historical data from the previous 13 years (1985-1998) were reviewed and confirmed cases of EG toxicosis were selected. The historical data were used to compare trace mineral concentrations, specifically of calcium and phosphorus to differentiate between intoxications caused by CCF from that caused by EG in dogs. Kidneys, bile, and urine from dogs that died of CCF toxicosis were analyzed for 25 monohydroxy vitamin D3 (25(OH)D3) and 1,25 dihydroxy vitamin D3 (1,25(OH)2D3) and compared to known control unexposed dogs. Results of this study show that biliary and renal 25(OH)D3 concentrations and renal calcium to phosphorus ratio are of diagnostic value in dogs exposed to toxic concentrations of CCF. The renal calcium to phosphorus ratio was <0.1 in normal dogs, 0.4-0.9 in dogs that died of CCF toxicosis, and >2.5 in dogs that died of EG toxicosis.

Pathophysiology of calcium, phosphorus, and magnesium metabolism in animals.

The goal of this article is to summarize key features of calcium, phosphorus, and magnesium pathophysiology and highlight some of the recent scientific accomplishments in these fields. The area of calcium physiology has been especially active due to the discovery of a new calcium-regulating hormone, parathyroid hormone-related protein, cloning of the parathyroid hormone receptor and identification of a cell membrane receptor for ionized calcium. Advances have also been made in understanding the role of phosphorus and the active form of vitamin D, 1,25-dihydroxyvitamin D in the pathogenesis of secondary hyperparathyroidism in patients with chronic renal failure. The role of magnesium in many pathologic processes, including cardiac disease, is gaining a heightened appreciation due to its function in many metabolic processes and the development of techniques to measure ionized magnesium concentrations.

Vitamin D3 intoxication in naked mole-rats (Heterocephalus glaber) leads to hypercalcaemia and increased calcium deposition in teeth with evidence of abnormal skin calcification.

Naked mole-rats have no access to obvious sources of vitamin D and therefore have an impoverished vitamin D status. In an investigation into the effects of vitamin D supplementation, inadvertently supraphysiological doses of 130,000 times the normal dose of vitamin D were administered. Within 5 days animals appeared lethargic, with reduced food intake. All but one of the seven animals were killed and blood was collected. Plasma vitamin D metabolites 25(OH)D and 1,25(OH)2D and calcium were determined. Both vitamin D metabolite concentrations exceeded the upper limits of sensitivity of the assays (> 100 ng/ml 25(OH)D and > 210 pg/ml 1,25(OH)2D). Active calcium uptake in the intestine was evident along with concomitant increases in calcium concentration in plasma, bone, and teeth. The remaining animal survived, but showed scab-like formations in the skin around the lower jaw and along the nipple line. X-ray analyses revealed calcium deposition in these cornified regions, although there was no evidence of metastatic calcification in other tissues. Deposition of excess calcium in skin that is regularly sloughed off and in teeth that are continuously worn down and replaced may reduce the vitamin D-induced hypercalcaemia and thus alleviate the effects of vitamin D intoxication.