Ionized Hypercalcemia in Dogs: A Retrospective Study of 109 Cases (1998–2003)

Background: Serum hypercalcemia in dogs has been reported in association with a variety of diseases. Serum-ionized calcium (iCa) concentration is a more accurate measure of hypercalcemia than total serum calcium or corrected serum calcium concentrations. The severity of hypercalcemia has been utilized to suggest the most likely differential diagnosis for the hypercalcemia.
Hypothesis: Diseases causing ionized hypercalcemia may be different than those that cause increases in total or corrected serum calcium concentrations. The severity of ionized hypercalcemia in specific diseases cannot be used to determine the most likely differential diagnosis for ionized hypercalcemia.
Animals: One-hundred and nine client-owned dogs with a definitive cause for their ionized hypercalcemia evaluated between 1998 and 2003 were included in this study.
Methods: Retrospective, medical records review.
Results: Neoplasia, specifically lymphosarcoma, followed by renal failure, hyperparathyroidism, and hypoadrenocorticism were the most common causes of ionized hypercalcemia. Dogs with lymphoma and anal sac adenocarcinoma have higher serum iCa concentrations than those with renal failure, hypoadrenocorticism, and other types of neoplasia. The magnitude of serum-ionized hypercalcemia did not predict specific disease states.
Conclusions and Clinical Importance: Serum-ionized hypercalcemia was most commonly associated with neoplasia, specifically lymphosarcoma. Although dogs with lymphosarcoma and anal sac adenocarcinoma had higher serum iCa concentrations than dogs with other diseases, the magnitude of the serum iCa concentration could not be used to predict the cause of hypercalcemia. Total serum calcium and corrected calcium concentrations did not accurately reflect the calcium status of the dogs in this study.     

Ultrasonography of the parathyroid glands in dogs--a review

The purpose of the study was to give an overview over the usefulness of ultrasonographic examination of parathyroid glands in dogs. By means of a 10 MHz high-resolution linear transducer it was possible to visualize parathyroid glands in healthy dogs. There was a positive correlation between body weight and size of the parathyroid glands, additionally the likelihood to detect 4 glands increased with an increase in body weight. Dogs with chronic renal failure had significantly larger parathyroid glands than healthy dogs and dogs with acute renal failure. In dogs with hypercalcemia of malignancy either none or parathyroids which were small in relation to body weight were detected. In contrast visualisation of parathyroid masses in dogs with primary hyperparathyroidism was easy due to their increased size and anechoic appearance. In dogs with severe azotemia the ultrasonographic examination of the parathyroid glands is helpful to differentiate between acute and chronic renal failure, in dogs with hypercalcemia to differentiate between hypercalcemia of malignancy and hypercalcemia due to primary hyperparathyroidism.     

Severe hypercalcemia in a dog with a retained fetus and endometritis

A 10-month-old sexually intact female German Shorthaired Pointer examined because of lethargy, episodes of fever, inappetence, and vomiting was found to have severe hypercalcemia. Results of laboratory testing, radiography, and ultrasonography excluded previously recognized causes of hypercalcemia in dogs. Instead, the dog was found to have purulent endometritis and an incompletely resorbed fetus. Treatment with fluids i.v., diuretics, and calcitonin failed to adequately reduce serum calcium concentration, but serum calcium concentration was normal within 4 days after the dog underwent an ovariohysterectomy. Retention of one or more fetuses and endometritis should be included in the differential diagnosis for dogs with hypercalcemia.     

DOHUBLE-PHASE PARATHYROID SCINTIGRAPHY IN DOGS USING TECHNETIUM-99M-SESTAMIBI

The purpose of this study was to evaluate the utility of double-phase parathyroid scintigraphy using 99mTc-sestamibi for detecting and localizing hyperfunctioning parathyroid glands in hypercalcemic dogs. Fifteen hypercalcemic dogs that underwent parathyroid scintigraphy were included in this study: 3 dogs with hypercalcemia of malignancy, and 12 dogs with hyperfunctioning parathyroid tissue (parathyroid adenoma or parathyroid hyperplasia). The presence of parathyroid adenoma or parathyroid hyperplasia was documented by histopathologic examination. In 3 dogs with hypercalcemia of malignancy, parathyroid scintigraphy was negative for hyperfunctioning parathyroid tissue and the scans were classified as true negative. Parathyroid scintigraphy correctly identified the presence and location of hyperfunctioning parathyroid tissue in only 1 of 6 dogs with a parathyroid adenoma. False positive and false negative results occurred in dogs with parathyroid adenomas. Parathyroid scintigraphy failed to detect hyperfunctioning parathyroid tissue in 5 of 6 dogs with parathyroid hyperplasia and were classified as false negative. False positive results were obtained in the remaining dog with parathyroid hyperplasia. Sensitivity of parathyroid scintigraphy for detecting and localizing hyperfunctioning parathyroid tissue was 11%, specificity was 50%, and overall accuracy was 27%. Positive and negative predictive value were 25% and 27%, respectively. Sensitivity for detection of parathyroid adenomas was 25%, and sensitivity for detection of hyperplastic glands was 0 %. Results of this study indicate that double-phase parathyroid scintigraphy does not appear to have acceptable accuracy in detecting hyperfunctioning parathyroid glands in dogs. Due to the poor sensitivity and specificity of the technique in dogs, parathyroid scintigraphy is not recommended for definitive identification of abnormal parathyroid glands as the cause of hypercalcemia in dogs.     

Immunohistochemistry for parathyroid hormone-related protein (PTHrP) in benign and malignant mammary mixed tumors of dogs with and without hypercalcemia

We evaluated the expression of parathyroid hormone-related protein (PTHrP) by immunohistochemistry in eight benign and malignant mammary mixed tumors of dogs with (n = 4) and without (n = 4) hypercalcemia. Positive immunoreactive staining for PTHrP was observed in all four tumors from hypercalcemic dogs. The mammary tumors from 2 of the 4 normocalcemic dogs stained positively for PTHrP, but the numbers of immunoreactive cells and intensity of the immunoreaction were less than in the hypercalcemic dogs. In the other 2 tumors without hypercalcemia, the tissue samples were negative for PTHrP.     

Elevated parathyroid hormone-related protein and hypercalcemia in two dogs with schistosomiasis.

Two adult dogs were evaluated for hypercalcemia. Diagnostic evaluation identified elevated parathyroid hormone-related protein (PTHrP) and presumptive humoral hypercalcemia of malignancy. At necropsy, schistosomiasis was diagnosed. North American schistosomiasis is caused by Heterobilharzia americana. Clinical findings may include dermatitis, coughing, diarrhea, and anorexia. Clinicopathological findings may include hypercalcemia, hyperglobulinemia, hypoalbuminemia, anemia, and eosinophilia. Diagnosis by fecal examination is difficult. Praziquantel or fenbendazole treatment may be curative or palliative. These are the first reported cases of hypercalcemia with elevated PTHrP in animals without diagnosed malignancy. Elevation of PTHrP has not been previously reported in hypercalcemic humans or in animals with granulomatous inflammation.     

ANALYSIS OF FACTORS AFFECTING OUTCOME OF ULTRASOUND‐GUIDED RADIOFREQUENCY HEAT ABLATION FOR TREATMENT OF PRIMARY HYPERPARATHYROIDISM IN DOGS

Radiofrequency (RF) parathyroid ablation is a noninvasive treatment for hyperparathyroidism in dogs. There are no published data assessing factors associated with RF parathyroid ablation success or failure in order to guide patient selection and improve outcome. The purpose of this retrospective analytical study was to determine whether imaging findings, biochemical data, or concurrent diseases were associated with RF heat ablation treatment failure. For inclusion in the study, dogs must have had a clinical diagnosis of primary hyperparathyroidism, undergone cervical ultrasound and RF ablation of abnormal parathyroid tissue, and must have had at least 3 months of follow‐up information available following the date of ultrasound‐guided parathyroid ablation. Dogs were grouped based on those with recurrent or persistent hypercalcemia and those without recurrent or persistent hypercalcemia following therapy. Parathyroid nodule size, thyroid lobe size, nodule location, and presence of concurrent disease were recorded. Recurrence of hypercalcemia occurred in 9/32 dogs that had ablation of abnormal parathyroid tissue (28%) and one patient had persistent hypercalcemia (3%) following parathyroid ablation. Nodule width (P = 0.036), height (P = 0.028), and largest cross‐sectional area (P = 0.023) were larger in dogs that had recurrent or persistent hypercalcemia following ablation. Hypothyroidism was more common in dogs with recurrent disease (P = 0.044). Radiofrequency ablation was successful in 22/32 (69%) dogs. Larger parathyroid nodule size and/or concurrent hypothyroidism were associated with treatment failure in dogs that underwent ultrasound‐guided RF parathyroid nodule ablation.     

Canine anal sac adenocarcinomas: clinical presentation and response to therapy

A retrospective study of 43 dogs with anal sac adenocarcinoma (ASAC) was performed to characterize the clinical presentation and response to treatment. Clinical signs at presentation varied considerably, with signs related either to sublumbar nodal metastasis (tenesmus or constipation) or hypercalcemia (polyuria-polydipsia and anorexia) being the most frequent findings. At the time of presentation, 23 (53%) dogs had hypercalcemia and 34 (79%) had metastases, with the regional lymph nodes (31 dogs, 72%) being the most common site of metastasis. A variety of chemotherapeutic agents were administered, with partial remission (PR) recorded in 4 of 13 (31%) dogs treated with cisplatin and in 1 of 3 (33%) dogs treated with carboplatin. The median survival for all dogs was 6 months (range, 2 days-41 months). There was no statistical association between the presence of hypercalcemia and survival, although the power of the study to detect an increase in survival of 3 months was low (.33). We conclude that platinum chemotherapy has antitumor activity in canine apocrine gland carcinoma and that further study of these agents is warranted.     

Intact Parathyroid Hormone Assay and Total Calcium Concentration in the Diagnosis of Disorders of Calcium Metabolism in Dogs

Serum samples from eight dogs with primary hyperparathyroidism, seven dogs with hypercalcemic lymphosarcoma (hypercalcemia of malignancy), and four dogs with primary hypoparathyroidism were submitted to the Animal Health Diagnostic Laboratory at Michigan State University for intact parathyroid hormone (PTH) assay. When compared with the adjusted total serum calcium concentration, the intact PTH concentration was consistent with the correct diagnosis in all cases. Two dogs with hypercalcemic lymphosarcoma were mildly azotemic. In both of these cases the intact PTH concentration was consistent with hypercalcemia of malignancy despite the presence of azotemia. These data support a significant role for intact serum PTH assay in the differential diagnosis of disorders of calcium metabolism.     

Bone changes in hypercalcemia of malignancy in dogs

Bone was collected for trabecular bone morphometry from 6 dogs with hypercalcemia of malignancy. Five of the dogs had lymphosarcoma and 1 had an anal sac apocrine gland carcinoma with vertebral metastases. Parathyroid gland weights varied around normal, with those for 1 dog being slightly low and those for another dog being moderately increased. As a group, the dogs had decreased bone volume, with increased resorption surfaces and increased numbers of osteoclasts. In 4 dogs, osteoid seams and osteoblasts were limited in extent and this distinguished them from dogs with hyperparathyroidism. Although most dogs had received corticosteroids, chemotherapy, or radiation treatment, the bone changes in these dogs were similar to 1 dog that had not received treatment. Also, the changes could not be related to uremia or renal mineralization that had developed in 2 of the dogs. Two of the dogs had somewhat greater amounts of osteoid-covered surface and slightly widened osteoid seams, ie, findings more like those of hyperparathyroidism. One of these dogs had anal sac apocrine gland carcinoma and the other had lymphosarcoma in which there was invasion of the bone cortex at the sampling site. It was concluded that bone remodeling changes do occur in hypercalcemia of malignancy and that these changes are varied and often are not those of hyperparathyroidism.     

Chemotherapeutic responses in dogs with lymphosarcoma and hypercalcemia

Twelve dogs with lymphosarcoma and hypercalcemia were treated over a period of 36 months. Signs and laboratory findings were referable to hypercalcemia and azotemia. All dogs were staged, classified histologically, and given cytoreductive chemotherapy, using 5 drugs (vincristine sulfate, cytosine arabinoside, cyclophosphamide, L-asparaginase and prednisone). For azotemia, symptomatic therapy (0.9% NaCl solution and furosemide) was given. Seven dogs responded completely, with marked reduction of lymphadenopathy and return of serum calcium concentration to normal. Median duration of remission in this group was 48 days (range, 14 to 93), and median survival time was 112 days (range, 85 to 153). Five nonresponding dogs had less than 50% reduction in measurable tumor mass, although serum calcium concentration returned to normal. The median survival time for this group was 34 days (range, 23 to 68). Two of the nonresponders died from sepsis and another from disseminated intravascular coagulation. Response to therapy did not appear to be influenced by age, breed, sex, initial calcium concentration, degree of azotemia, or histologic classification.     

Evaluation of total and ionized calcium status in dogs with blastomycosis: 38 cases (1997-2006)

OBJECTIVE: To determine blood ionized calcium (iCa) and serum total calcium (tCa) concentrations in dogs with blastomycosis and to evaluate whether serum tCa concentration, albumin-adjusted serum calcium concentration (AdjCa-Alb), and total protein-adjusted serum calcium concentration (AdjCa-TP) accurately predict iCa status. DESIGN: Retrospective case series. ANIMALS: 38 client-owned dogs with a cytologic diagnosis of blastomycosis. PROCEDURES: Dogs were classified as hypocalcemic, normocalcemic, or hypercalcemic on the basis of blood iCa concentration, serum tCa concentration, AdjCa-Alb, and AdjCa-TP; classification on the basis of serum tCa concentration, AdjCa-Alb, and AdjCa-TP was compared with blood iCa concentration. RESULTS: Except for 2 hypercalcemic dogs, all dogs had blood iCa concentrations within the reference interval. Use of serum tCa concentration overestimated hypocalcemia in 57.9% (22/38) of dogs and underestimated hypercalcemia in 1 dog. Use of AdjCa-Alb correctly reclassified all dogs as normocalcemic that were classified as hypocalcemic on the basis of serum tCa concentration, but failed to predict hypercalcemia in 1 dog. Use of AdjCa-TP correctly reclassified all but 2 dogs as normocalcemic that were classified as hypocalcemic on the basis of serum tCa concentration, and failed to predict hypercalcemia in 1 dog. No correlation was found between blood iCa concentration and serum concentrations of tCa, total protein, and albumin; AdjCa-Alb; or AdjCa-TP. CONCLUSIONS AND CLINICAL RELEVANCE: High blood iCa concentration was uncommon in dogs with blastomycosis. Hypoalbuminemia contributed to a low serum tCa concentration despite a blood iCa concentration within reference limits. The use of serum tCa concentration, AdjCa-Alb, and AdjCa-TP may fail to identify a small number of dogs with high blood iCa concentrations.     

Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004)

OBJECTIVE: To evaluate pretreatment clinical and laboratory findings in dogs with naturally occurring primary hyperparathyroidism. DESIGN: Retrospective study. ANIMALS: 210 dogs with primary hyperparathyroidism and 200 randomly selected, age-matched control dogs that did not have primary hyperparathyroidism. PROCEDURE: Medical records for dogs with primary hyperparathyroidism were reviewed for signalment; clinical features; and results of clinicopathologic testing, serum parathyroid hormone assays, and diagnostic imaging. RESULTS: Mean age of the dogs with primary hyperparathyroidism was 11.2 years (range, 6 to 17 years). The most common clinical signs were attributable to urolithiasis or urinary tract infection (ie, straining to urinate, increased frequency of urination, and hematuria). Most dogs (149 [71%]) did not have any observable abnormalities on physical examination. All dogs had hypercalcemia, and most (136 [65%]) had hypophosphatemia. Overall, 200 of the 210 (95%) dogs had BUN and serum creatinine concentrations within or less than the reference range, and serum parathyroid hormone concentration was within reference limits in 135 of 185 (73%) dogs in which it was measured. Urolithiasis was identified in 65 (31 %) dogs, and urinary tract infection was diagnosed in 61 (29%). Mean serum total calcium concentration for the control dogs-was significantly lower than mean concentration for the dogs with primary hyperparathyroidism, but mean BUN and serum creatinine concentrations for the control dogs were both significantly higher than concentrations for the dogs with primary hyperparathyroidism. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that urolithiasis and urinary tract infection may be associated with hypercalcemia in dogs-with primary hyperparathyroidism, but that development of renal insufficiency is uncommon.     

Parathyroid hormone-related protein (PTHrP) produced by dog lymphoma cells

Parathyroid hormone-related protein (PTHrP) was investigated in a canine lymphoma case with hypercalcemia by means of immunoradiomentric assay (IRMA) and molecular analysis. The plasma calcium level of the patient dog was 13.7 mg/dl. The PTHrP concentration examined by IRMA was 6.1 pmol/L in the plasma sample from the dog, but it was undetectable (< 1.1 pmol/L) in plasma samples from 4 lymphoma cases without hypercalcemia or 5 normal dogs. The PTHrP concentration examined in the culture supernatant of the lymphoma cells from this case was 1.3 pmol/L, whereas those of the lymphoma cells from a lymphoma case without hypercalcemia was undetectable. PTHrP mRNA was clearly detected not only in the lymphoma cells from this dog with hypercalcemia but also in lymphoma cells from 4 lymphoma cases without hypercalcemia and 2 canine lymphoma cell lines.     

Hypercalcemia

Elevated serum calcium occurs relatively uncommonly in dogs and rarely in cats. Hypercalcemia can serve as a marker of disease that enables diagnosis but may also contribute to development of lesions and the clinical signs of disease. Specific clinical signs do not necessarily accompany hypercalcemia, and its presence will frequently be unsuspected. Fortuitous hypercalcemia is often discovered after a review of serum biochemical profile results. This article emphasizes malignancy-associated hypercalcemia and the emergence of cholecalciferol rodenticide toxicity as an important cause of hypercalcemia, as well as its treatment.     

Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia

Uncorrected hypercalcemia can cause clinical signs such as polyuria, polydipsia, vomiting, diarrhea, lethargy, and depression and contributes to the development of primary renal failure and soft tissue mineralization. Treatment of hypercalcemia includes diagnosis and treatment of the underlying disease process and some combination of excracellular fluid volume expansion by administration of fluids intravenously and administration of glococorticosteroids, salmon calcitonin, and furosemide. Bisphosphonates such as pamidronate disodium also may be safe and effective in the treatment of hypercalcemia. The purpose of our study was to characterize the efficacy and safety of pamidronate in the treatment of hypercalcemia attritutable to several different disease processes in the dog and cat. Seven dogs and 2 cats were administered pamidronate at a dose of 1.05-2.0 mg/kg IV for a variety of disease processes, including neoplasia (n = 4), calcipotriene toxicity (n = 3), nocardiosis (n = 1), and idiopathic hypercalcemia with chronic renal failure (n = 1). In all the animals, IV pamidronate administration rapidly decreased serum calcium concentrations without evident toxicosis. Two animals received pamidronate several times without obvious toxicosis. On the basis of the findings in our retrospective study, pamidronate may be a safe and effective drug with which to lower both serum total and ionized calcium concentrations in patients with hypercalcemia arising from a wide variety of underlying disease processes.     

Hypercalcemia associated with gastric pythiosis in a dog

A 20-month-old castrated male Labrador Retriever with a 3-month history of anorexia, weight loss, and vomiting was evaluated. Plasma biochemical abnormalities included marked hyperglobulinemia and hypercalcemia. Serum levels of parathyroid hormone, parathyroid hormone-related protein, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were either low or within reference intervals. Gastric wall thickening and abdominal lymphadenomegaly were observed with abdominal ultrasonography. Cytologic evaluation of a sample obtained via fine-needle aspiration of the gastric wall revealed pyogranulomatous inflammation and numerous poorly stained hyphae. Partial gastrectomy was performed, and a diagnosis of gastric pythiosis was made by immunohistochemical staining of infected gastric tissue, as well as by immunoblot serology. This case demonstrates that diagnostic samples for cytologic evaluation can be obtained by fine-needle aspiration of Pythium insidiosum-infected tissues and that a presumptive diagnosis can be made by examination of a Romanowsky-stained smear. Furthermore, pythiosis should be considered as a differential diagnosis for hypercalcemia, especially in young dogs with inflammatory lesions that have a granulomatous component. The mechanism for the hypercalcemia in this dog was not determined; however, calcium concentrations normalized after surgical resection of the gastric lesion.     

Hypercalcemia and high parathyroid hormone-related protein concentration associated with malignant melanoma in a dog

A 12-year-old Cocker Spaniel with an oral malignant melanoma was evaluated for progressive lethargy and anorexia. No metastases were identified during antemortem evaluation, but severe hypercalcemia was evident. Antemortem diagnostic testing failed to identify a cause for the hypercalcemia. No neoplasms other than the melanoma were identified on postmortem examination. Serum parathyroid hormone-related protein concentration was markedly high, and the melanoma had moderate to marked immunostaining for this protein. Paraneoplastic syndromes are rare in dogs with malignant melanoma.     

HIGH-RESOLUTION PARATHYROID SONOGRAPHY

The purpose of this study was to assess the diagnostic utility of parathyroid ultrasonography to differentiate causes of hypercalcemia in dogs. We analyzed qualitative and quantitative ultrasound imaging findings and clinical pathology data from 33 dogs that underwent parathyroid ultrasound examination as part of the diagnostic evaluation for hypercalcemia. Diagnoses of the diseases causing hypercalcemia included parathyroid carcinoma (n = S), parathyroid adenoma (n = 15), parathyroid adenomatous hyperplasia (n = 6), chronic renal insufficiency (n = 3), and hypercalcemia of malignancy (n = 4). All parathyroid lesions were round or oval and hypoechoic compared with surrounding thyroid parenchyma. Adenomatous and adenocarcinomatous glands were 4 mm or larger in longest linear measurement on US examination and were statistically significantly larger than hyperplastic glands. (p < 0.001) Linear measurements of parathyroid glands acquired at the time of ultrasound examination correlated well with direct siz determination after surgical excision. (r²= 0.9, p < 0.0001) Parathyroid lesions <4 mm are highly suspicious for parathyroid adenoma or carcinoma, while US lesions <4 mm most likely represent primary adenomatous hyperplasia or secondary parathyroid hyperplasia. Parathyroid size estimation from ultrasound examination is an accurate predictor of true size.     

Hypercalcemia secondary to cholecalciferol rodenticide toxicosis in two dogs

Hypercalcemia secondary to cholecalciferol rodenticide toxicosis was identified in two dogs. The first dog died shortly after admission. The second dog responded to treatment with sodium chloride solution, prednisolone, furosemide, and calcitonin. Treatment was needed for a longer period than anticipated and the serum calcium concentration did not stabilize for approximately one month. Although not conclusively demonstrated, calcitonin was considered the cause of severe anorexia. This new class of rodenticides has great toxic potential for dogs, and it is recommended that serum calcium concentration be carefully monitored as treatment for hypercalcemia is gradually withdrawn.