The etiology, pathophysiology, and clinical manifestations

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1 J Vet Intern Med 000;14: Hypercalcemia in Cats: A Retrospective Study of 71 Cases ( ) Karine C.M. Savary, G. Sylvester Price, and Shelly L. Vaden A retrospective study was conducted to characterize the diseases, clinical findings, and clinicopathologic and ultrasonographic findings associated with hypercalcemia (serum calcium concentration 11 mg/dl) in 71 cats presented to North Carolina State University Veterinary Teaching Hospital. The 3 most common diagnoses were neoplasia (n 1), renal failure (n 18), and urolithiasis (n 11). Primary hyperparathyroidism was diagnosed in 4 cats. Lymphoma and squamous cell carcinoma were the most frequently diagnosed tumors. Calcium oxalate uroliths were diagnosed in 8 of 11 cats with urolithiasis. Cats with neoplasia had a higher serum calcium concentration ( mg/dl) than cats with renal failure or urolithiasis and renal failure ( mg/dl; P.03). Serum phosphorus concentration was higher in cats with renal failure than in cats with neoplasia (P.004). Despite the fact that the majority of cats with uroliths were azotemic, their serum urea nitrogen and creatinine concentrations and urine specific gravity differed from that of cats with renal failure. Additional studies are warranted to determine the underlying disease mechanism in the cats we identified with hypercalcemia and urolithiasis. We also identified a small number of cats with diseases that are not commonly reported with hypercalcemia. Further studies are needed to determine whether an association exists between these diseases and hypercalcemia, as well as to characterize the underlying pathophysiologic mechanism for each disease process. Key words: Calcium; Calcium oxalate urolithiasis; Neoplasia; Primary hyperparathyroidism; Renal failure. The etiology, pathophysiology, and clinical manifestations of hypercalcemia are well described in dogs 1 and humans. In dogs, the most common diseases associated with hypercalcemia are neoplasia and hypoadrenocorticism. 1 The most common tumor in dogs associated with hypercalcemia is lymphoma. 1 In humans, malignancy and primary hyperparathyroidism are responsible for 90% of cases of hypercalcemia. However, in cats, only case reports have been published. 3 6 Based on these reports, the diseases associated with hypercalcemia in cats seem to differ from those in dogs. Hypercalcemia in cats has been described with lymphoproliferative diseases, squamous cell carcinoma, and multiple myeloma. 3 6 Hypercalcemia also has been reported in cats with chronic renal failure 7 and primary hyperparathyroidism. 8 The purpose of this retrospective study was to characterize the diseases and clinicopathologic and ultrasonographic findings associated with hypercalcemia in cats that were presented to North Carolina State University Veterinary Teaching Hospital (NCSU-VTH) between 1991 and Materials and Methods Case Selection and Data Collection The clinical pathology database at NCSU was searched to identify hypercalcemic cats referred to the VTH between January 1991 and December Hypercalcemia was defined as serum calcium concentration 11 mg/dl (normal, mg/dl) upon presentation From the Department of Clinical Sciences, North Carolina State University, College of Veterinary Medicine, Raleigh, NC. Data from this study were presented at the Eighteenth Annual Meeting of the Veterinary Cancer Society in Estes Park, CO, Reprints requests: Karine C.M. Savary, DEDV, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough Street, Raleigh, NC 7606; karine savary@ncsu.edu. Submitted February 1, 1999; Revised March 15, July 8, September 15, 1999; Accepted October 15, Copyright 000 by the American College of Veterinary Internal Medicine /00/ /$3.00/0 to the VTH. One hundred hypercalcemic cats were identified. Cats were excluded if a final diagnosis was not available (n 18), a diagnosis of neoplasia was made previously but no macroscopic or cytologic evidence of malignancy was found when hypercalcemia was observed (n 5), hypercalcemia was spurious (ie, not confirmed on a nd sample) (n ), or hypercalcemia was iatrogenic (ie, associated with administration of hypercalcemic drugs) (n 4). Therefore, 71 cases were included in the study. Data presented from 3 of the cats in this retrospective study were presented previously. 9 Medical records were reviewed for signalment, final diagnosis, clinical signs (anorexia, lethargy, polyuria, polydipsia, vomiting, diarrhea, constipation, pollakiuria, stranguria, hematuria, ataxia, paraparesis), clinicopathologic abnormalities (total serum calcium, serum creatinine, serum urea nitrogen [SUN], and serum phosphorus concentrations); urine specific gravity; presence or absence of anemia; presence or absence of calcium oxalate crystalluria; feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) serologic test results; radiographic and ultrasonographic findings (renal size, shape, and echogenicity; presence of uroliths); and urolith analysis. All laboratory tests, except urolith analysis and intact parathyroid hormone assay, were performed at NCSU College of Veterinary Medicine Clinical Pathology and Virology laboratories. Viral status was assessed using enzyme-linked immunosorbent assay (ELISA) or indirect fluorescent antibody for FeLV antigenemia and ELISA for FIV antibody. Standard diagnostic laboratory assays were used. Established references ranges were used to identify aforementioned clinicopathologic abnormalities. Urolith analysis was performed at the Urinary Stones Analysis Laboratory. a Intact parathyroid hormone (PTH) concentration was determined using a -site immunoradiometric assay. b The assay for intact PTH concentration was validated for cats. This assay measures the intact molecule, not the midregion or the carboxyl terminal fragments, and is similar to an assay previously validated in the cat. 10 The following criteria were used to diagnose the various diseases identified in cats with hypercalcemia. Neoplasia and bone marrow disease were diagnosed by cytologic evaluation of needle aspirates or histopathologic evaluation of biopsy specimens. Renal failure was diagnosed if serum creatinine concentration exceeded 1.8 mg/dl despite normal hydration status, if azotemia persisted after rehydration, or if azotemia was documented for more than weeks. Urine specific gravity was not used as a criterion, because cats with renal failure may maintain their ability to concentrate urine. 11 Urolithiasis was diagnosed if uroliths were identified on abdominal ultrasonography or radiography. Postrenal azotemia was defined by the presence of azotemia (serum creatinine concentration 1.8 mg/dl) associated with obstructive

2 Hypercalcemia in Cats 185 urinary tract disease or urine leakage. Idiopathic lower urinary tract disease was diagnosed if cats had signs of recurrent lower urinary tract inflammation, without another cause identified by urinalysis, urine culture, or abdominal ultrasound. Primary hyperparathyroidism was diagnosed when cats with normal renal function had parathyroid adenoma, adenocarcinoma, or hyperplasia identified histopathologically. Diagnoses of infectious diseases and various nonparathyroid endocrine diseases were made on the basis of physical examination findings and results of standard diagnostic tests for those diseases. Statistical Analysis Data reported are mean standard deviation. The Kruskal Wallis test was used to determine whether the magnitude of hypercalcemia varied as a function of age. 1 This test was used instead of linear regression analysis because serum calcium concentration data were not normally distributed. Fisher s exact test was used to determine whether serum calcium concentration varied as a function of either gender or breed. 13 Fisher s exact test also was used to determine whether gender, breed, frequency of clinical signs, renal size, and presence of anemia and calcium oxalate crystalluria varied as a function of the diseases associated with hypercalcemia. The Kruskal Wallis test was used to determine whether the magnitude of alteration in serum calcium concentration, serum phosphorus concentration, SUN, serum creatinine concentration, and urine specific gravity varied as a function of the diseases identified. Many of the disease groups identified contained fewer than 5 cats, and they were not included in the aforementioned statistical analyses. Statistical significance was considered at P.05. Results Seventy-one cats with hypercalcemia were identified. The mean serum calcium concentration was mg/ dl, and the median was 11.5 mg/dl. The mean age of the affected cats was years (range, 1 19 years); the median was 9 years. The cats included 36 castrated males and 35 spayed females. Fifty-seven cats (80%) were domestic shorthaired or domestic longhaired mixed-breed cats and 14 were purebred (0%). The magnitude of hypercalcemia did not vary as a function of age, gender, or breed. Anorexia and lethargy were the most common clinical signs observed (n 50, 70%). Gastrointestinal signs were observed in 19 cats (vomiting was reported in 13 cats, diarrhea in 3 cats, and constipation in 3 cats). Polyuria or polydipsia was observed in 17 cats (4%). Urinary signs were observed in 16 cats (3%). Neurologic signs were observed in 10 cats (14%). No relationship was found between any clinical signs and the magnitude of hypercalcemia. Neoplasia was diagnosed in 1 cats (Table 1). Two thirds of these cats had either lymphoma (n 7) or squamous cell carcinoma (n 7). Two cats had renal lymphoma. One cat each with generalized, mediastinal, gastrointestinal, laryngeal, and nasal lymphoma was identified. Only 1 of these cats was FeLV-positive. Cats with squamous cell carcinoma had tumors in the mandible (n 5) or the ear canal (n ). Six of these 7 cats had radiographic evidence of bone lysis. Other neoplasms included leukemia (erythroleukemia and aleukemic leukemia, n ), osteosarcoma (n ), fibrosarcoma (n 1), undifferentiated sarcoma (n 1), and bronchogenic carcinoma (n 1). Renal failure was diagnosed in 18 cats (5%). Congenital renal hypoplasia was diagnosed by renal biopsy in 1 cat and pyelonephritis was diagnosed in 3 cats. Table 1. Diagnosis in 71 cats with hypercalcemia. Diagnosis Group Neoplasia Renal failure Urolithiasis Primary hyperparathyroidism Nonparathyroid endocrine disease Liver disease Postrenal azotemia Idiopathic lower urinary tract disease Bone marrow disease Infectious disease Infectious/nonparathyroid endocrine disease n Urolithiasis was diagnosed in 11 cats (15%). Uroliths were located in the kidney (n 1); kidney and ureter (n 3); kidney, ureter, and bladder (n 1); ureter and bladder (n 3); and bladder (n 3). Nine of these cats also were in renal failure. Calcium oxalate uroliths were confirmed in 8 cats that underwent surgery. One half of the cats had recurrent calcium oxalate uroliths and underwent additional surgery. Uroliths were calcium oxalate monohydrate in 3 cats, mixed calcium monohydrate and dihydrate in 3 cats, and calcium oxalate dihydrate in cats. A diet history was available in 9 cats. Four cats were fed an acidifying diet (s/d or c/d diets c ) and 5 cats were fed a nonacidifying diet (k/d diet c ). Urine ph was 5.0 in 5 cats, 6.0 in 4 cats, and 7.0 in cats. Three of 11 cats with uroliths had metabolic acidosis at the time of presentation. A history of vitamin D administration was not obtained in any of these cats. Primary hyperparathyroidism was diagnosed in 4 cats. A palpable neck mass was not reported in the medical record of any of these cats. Ultrasonography of the neck (performed in 1 cat) was within normal limits. Intact PTH concentration, measured in 3 cats, was within the normal range. Parathyroid adenoma and parathyroid hyperplasia were diagnosed in cats each. Both cats with adenomas had an enlarged right external parathyroid gland and a presenting complaint of constipation. Parathyroid hyperplasia of all 4 parathyroid glands was diagnosed in of the 4 cats with primary hyperparathyroidism. One of these cats also had metastatic adrenal carcinoma. Six cats had a nonparathyroid endocrine disease (hyperthyroidism [n ], hypoadrenocorticism [n 1], diabetes mellitus [n 3]). Two of the cats with diabetes mellitus had concomitant infectious diseases (feline infectious peritonitis [n 1] and toxoplasmosis [n 1], Table 1). One cat had severe chronic Actinomyces rhinitis and 1 had pulmonary cryptococcosis. Myelodysplasia was diagnosed in 1 cat and myelofibrosis was diagnosed in another. Three cats had icterus as a result of liver failure. In these cats, hypercalcemia was documented in consecutive blood samples, but subsequently resolved. Two of these cats had hepatic lipidosis and 1 had biliary hyperplasia and fibrosis. Idiopathic lower urinary tract disease was observed in cats. Postrenal azotemia was observed in another cats. Of these cats, 1 had a urethral obstruction from a mixed calcium oxalate monohydrate and dihydrate calculus and bilateral nephroliths and the other had bilateral hydronephro-

3 186 Savary, Price, and Vaden sis due to obstructive ureteroliths and a suspected ureteral tear. The relationship between the diseases identified and clinical signs or laboratory abnormalities was evaluated in the following diagnosis groups: nonazotemic cats with neoplasia (n 15), cats with renal failure (n 18), and azotemic cats with urolithiasis (n 9). Nonazotemic cats with urolithiasis (n ) and cats with other diseases were excluded from this analysis because sample size was too small ( 4 cats per disease group). Cats with neoplasia and concurrent azotemia (n 6) also were excluded from comparative analysis because it could not be determined whether the azotemia in these 6 cats was secondary to hypercalcemia of malignancy, to renal failure independent of hypercalcemia of malignancy, or both diseases. Polyuria, polydipsia, and urinary signs were not observed in cats with neoplasia, whereas polyuria or polydipsia was observed in 9 of 18 cats with renal failure and in 5 of 9 cats with urolithiasis and renal failure (P.01). Urinary signs were observed in 4 of 18 cats with renal failure and in 5 of 9 cats with urolithiasis and renal failure (P.005). Serum calcium concentration varied as a function of the diagnosis group. Cats with neoplasia had higher serum calcium concentrations ( mg/dl; P.03) than did cats with renal failure ( mg/dl) or cats with urolithiasis and renal failure ( mg/dl). Serum phosphorus concentration was higher in cats with renal failure ( mg/dl) than in those with neoplasia ( mg/dl; P.004). No difference was found in serum phosphorus concentration between the renal failure and urolithiasis and renal failure groups. However, serum creatinine and SUN concentrations were significantly higher in cats with renal failure compared to cats with urolithiasis and renal failure (P.05) or cats with neoplasia (P.0001). Urine specific gravity was lower in cats with renal failure ( ) than in those with neoplasia ( , P.01). Interestingly, urine was more concentrated in cats with urolithiasis and renal failure ( ) than in cats with renal failure (P.04). Calcium oxalate crystalluria was more common in cats with urolithiasis and renal failure (3/9) than in cats with renal failure (0/17) or neoplasia (/14, P.03). Kidney size varied as a function of diagnosis group. Small kidneys were more likely to be observed in cats with renal failure (1/15) or in cats with urolithiasis and renal failure (8/9, P.001), compared to nonazotemic cats with neoplasia (0/6). Anemia was found more frequently in cats with renal failure (10/17) or cats with urolithiasis and renal failure (5/9) than in cats with neoplasia (/14; P.04). Discussion The data reported here suggest that neoplasia, renal failure, urolithiasis, and hyperparathyroidism are the most frequent disorders associated with hypercalcemia in cats. The mechanism of hypercalcemia was most likely attributable to neoplasia, renal failure, or hyperparathyroidism in cats with these diseases. However, the mechanism of hypercalcemia in the 11 cats with urolithiasis in which no underlying disease was identified is unknown. The hypercalcemia in these cats is unlikely to have been spurious, because it was confirmed on a nd sample. The hypercalcemia could have been the result of subclinical neoplasia, hyperparathyroidism, or another disease capable of causing hypercalcemia. However, differences in clinical signs, SUN, serum creatinine concentration, and urine specific gravity between azotemic cats with renal failure and azotemic cats with urolithiasis and the difference in the magnitude of hypercalcemia between cats with neoplasia and those with urolithiasis suggest that the mechanism of hypercalcemia in cats with urolithiasis in which no underlying disease was identified differs from that in cats with renal failure or neoplasia. Although the results of this retrospective study characterize the diseases associated with hypercalcemia in cats, our results are limited. The prevalence of hypercalcemia in each of the diseases identified was not determined and serum ionized calcium concentration were not determined. Furthermore, follow-up information was not available to determine if hypercalcemia resolved after clinical management. Therefore, additional studies are warranted to confirm these causes and investigate the mechanisms of hypercalcemia for each disease process. Neoplasia was the most common disease associated with hypercalcemia in cats. Neoplasia also is the most common cause of hypercalcemia in dogs. 1 However, the species differ with respect to tumor types associated with hypercalcemia. In dogs, lymphoma is the most frequent cause of hypercalcemia, 1,14 whereas in cats both lymphoma and squamous cell carcinoma were common causes of hypercalcemia. Although hypercalcemia of malignancy has been reported previously in cats with lymphoproliferative diseases, 3,4 the majority of previously reported cats were positive for FeLV infection. 3,15,16 Only 1 of the 7 cats with lymphoma in the present study was FeLV-positive. The previously reported association of FeLV infection and hypercalcemia may have been attributable to FeLV-induced neoplasia. Additional studies are warranted to determine whether the mechanism of hypercalcemia in cats with lymphoma is attributable to parathyroid hormone-related polypeptide (PTHrP), as reported in dogs. 17,18 Hypercalcemia of malignancy has been reported previously in cats with squamous cell carcinoma 4 but has not been reported in dogs with squamous cell carcinoma. In humans, squamous cell carcinoma of the head and neck is a well-recognized cause of hypercalcemia 19,0 and all 7 cats with squamous cell carcinoma reported here had tumors in the head and neck region. Hypercalcemia in humans with squamous cell carcinoma is humorally mediated by PTHrP. 1 Hypercalcemia in cats with squamous cell carcinoma may be caused by a similar mechanism. Six of 7 cats with squamous cell carcinoma had radiographic evidence of bone lysis and hypercalcemia possibly was a direct result of bone lysis by a local tumor. However, in a previous report of hypercalcemic cats with squamous cell carcinoma, osteolytic lesions were not observed. 5 Osteosarcoma, fibrosarcoma, and bronchogenic carcinoma were identified as possible causes of hypercalcemia of malignancy in the present study, and these neoplasms have not been reported previously to cause hypercalcemia in cats. Multiple myeloma is another tumor that has been re-

4 Hypercalcemia in Cats 187 ported in association with hypercalcemia of malignancy in dogs and cats. 6 Multiple myeloma was not observed as a cause of hypercalcemia in the cats of the present study. Hypercalcemia has been reported previously in 11.5% of cats with chronic renal failure 7 and renal failure was the nd most common disorder observed in the present series of hypercalcemic cats. Although acute renal failure could not conclusively be ruled out, the presence of anemia and small kidney size on ultrasound in the majority of these cats suggests that they were in chronic renal failure. Most dogs with hypercalcemia and chronic renal failure have normal to low serum ionized calcium concentrations. 3 5 Unfortunately, serum ionized calcium concentrations were not available in any of the cats with renal failure in this study. Urolithiasis was observed in 11 of 71 cats with hypercalcemia; 1 cat with postrenal azotemia had calcium oxalate urolithiasis. Uroliths were composed of calcium oxalate in 8 of 11 cats. The association between hypercalcemia and urolithiasis has been described previously 9,6,7 and mild hypercalcemia has been reported to occur in as many as 35% of cats with calcium oxalate uroliths. 8 The cause of these findings is unknown. However, crystals are known to form in urine supersaturated with crystallogenic substances. 9 In the 71 cats reported here, calcium oxalate crystalluria occurred more frequently in cats with calcium oxalate uroliths as compared to cats with neoplasia, renal disease, and other causes of hypercalcemia. This finding suggests that calcium oxalate crystalluria may predispose cats to the development of calcium oxalate urolithiasis. Calcium oxalate crystalluria and urolith formation may be a consequence of persistent hypercalcemia attributable to unrecognized primary hyperparathyroidism, occult neoplasia, or another disease capable of causing hypercalcemia. An acidifying diet also may be a predisposing factor to calcium-containing urolith formation, 30 but the majority of the cats with calcium oxalate uroliths in this report were not fed an acidifying diet and only 3 cats with uroliths had metabolic acidosis. Nine of the 11 cats with calcium oxalate uroliths were in renal failure. The association between hypercalcemia, calcium oxalate uroliths, and chronic renal failure in cats has been reported previously. 9,6 Hypercalcemia observed in cats with urolithiasis possibly is attributable to renal failure. However, in cats with renal failure, SUN and serum creatinine concentrations were significantly higher and the urine was less concentrated compared to cats with urolithiasis and renal failure. These differences suggest that the mechanism or magnitude of renal dysfunction in cats with urolithiasis and renal failure differs from that in cats with renal failure. Calcium-containing uroliths in association with primary hyperparathyroidism has been reported in a cat with a parathyroid adenocarcinoma, 31 in dogs, 3,33 and in humans with primary hyperparathyroidism. 34,35 Therefore, primary hyperparathyroidism possibly is responsible for persistent hypercalcemia observed in these cats with calcium oxalate uroliths. We advocate routine evaluation of serum ionized calcium concentrations in cats with urolithiasis, azotemia, and hypercalcemia. Serum ionized calcium concentration is expected to be low in cats with primary renal failure and high in cats with primary hyperparathyroidism. A study of the urinary calcium excretion in hypercalcemic cats with calcium oxalate urolithiasis to determine if cats with urolithiasis are normocalciuric or hypercalciuric may provide insight on the pathophysiology of this problem. Primary hyperparathyroidism was recognized infrequently in the cats of this study. None of the cats with primary hyperparathyroidism had increased intact PTH concentration, palpable neck masses, or masses detected ultrasonographically. However, a diagnosis of primary hyperparathyroidism cannot be excluded based on normal intact PTH concentration because a normal intact PTH concentration in a hypercalcemic cat is inappropriate. In a previous report, serum PTH was normal in 1 cat with primary hyperparathyroidism and abnormally high in another cat. 8 Normal or high-normal intact PTH concentrations have been reported in humans with primary hyperparathyroidism 34 and in dogs with primary parathyroid hyperplasia, 36 adenoma, 37 or carcinoma. 38 None of the cats in this report with primary hyperparathyroidism had a palpable neck nodule, nor did 3 of 7 cats in a previous report. 8 This finding suggests that parathyroid tumors may escape detection on physical examination in affected cats. Therefore, some of the cats with urolithiasis as well as those with diseases that have not previously been reported to be associated with hypercalcemia may have had primary hyperparathyroidism. However, our observations were made retrospectively and it is possible that the neck region was not thoroughly examined or that results were not properly recorded in the medical record. Ultrasonography also failed to demonstrate a mass in the parathyroid region in 1 affected cat and ultrasonography of the neck was not done in the other cats in this report. The diagnostic utility of ultrasonography of the parathyroid glands in cats has not been evaluated. The observations that neck palpation may not reliably detect parathyroid tumors and serum PTH concentrations are not readily available suggest that additional tests may be warranted in cats with hypercalcemia of unknown origin and in cats with hypercalcemia and calcium oxalate urolithiasis. Routine use of cervical ultrasonography may be helpful. Furthermore, evaluation of thallium-technetium and technecium-sestamibi scans that are used to diagnose primary hyperparathyroidism in dogs 37 and humans 39 may be warranted in cats. In cats with persistent hypercalcemia, recurrent calcium oxalate urolithiasis, and normal intact PTH concentration, consideration of surgical exploration of the neck for parathyroid masses is reasonable. Cryptococcosis has not been reported in association with hypercalcemia in cats. However, other granulomatous diseases such as blastomycosis have been associated with hypercalcemia in dogs. 40 Cryptococcosis is a well-recognized cause of hypercalcemia in humans. 41 The mechanism of hypercalcemia observed in the cat with disseminated cryptococcosis possibly is similar to the mechanism of hypercalcemia in granulomatous diseases of dogs and humans. Hyperthyroidism due to an adenoma has not been reported to cause hypercalcemia in cats. However, in humans with adenomatous hyperthyroidism and hypercalcemia, thyroid hormone may have a direct stimulatory effect on bone resorption. 4 A similar mechanism possibly was responsible for the hypercalcemia observed in the hyperthyroid cats of

5 188 Savary, Price, and Vaden the present study. Alternatively, hypercalcemia in these cats may have been spurious, or secondary to subclinical neoplasia, primary hyperparathyroidism, or renal disease. One of these mechanisms also may be responsible for the hypercalcemia observed in cats with liver failure, diabetes mellitus, FeLV-negative myelodysplasia and myelofibrosis, urinary tract disease, toxoplasmosis, Actinomyces rhinitis, and feline infectious peritonitis. Hypercalcemia in the cats with liver failure was confirmed on consecutive analyses and it resolved when clinical signs of liver failure improved, making spurious hypercalcemia unlikely in theses cats. Our findings suggest that, other than anorexia and lethargy, the relative frequency of clinical signs in hypercalcemic cats differs from that in dogs. 1 Anorexia and lethargy were observed in 88% of hypercalcemic dogs 1 and in 70% of the cats in this series. Polyuria or polydipsia was reported in 68% of hypercalcemic dogs, 1 whereas these signs occurred in only 4% of the cats in this study. Vomiting was observed in 53% of hypercalcemic dogs 1 and in 18% of these cats. Urinary signs were observed in 3% of the cats in this series but have not been reported in dogs. This finding may be attributable to differences in the types of diseases associated with hypercalcemia between these species. In the present study, 15% of the cats had urolithiasis, whereas this disorder has not been noted in hypercalcemic dogs. Muscular signs of weakness and twitching are described in 3% of hypercalcemic dogs, 1 but were not reported in any of these cats. The observed difference in clinical signs between hypercalcemic cats and dogs may be attributable to the fact that different diseases cause hypercalcemia in these species. Furthermore, hypercalcemia is a clinicopathologic abnormality that occurs as the result of various disease processes. Therefore, whether the clinical signs observed are secondary to hypercalcemia or to the primary disease process is unknown. Interestingly, 3 hypercalcemic cats had a presenting complaint of constipation and of these cats had primary hyperparathyroidism. Constipation may have been related to underlying dehydration or to hypercalcemia, as has been reported in humans with primary hyperparathyroidism. 34 In humans, constipation is believed to be related to hypercalcemia-induced reduction in gastrointestinal tract smooth muscle excitability. This retrospective study demonstrates that neoplasia and renal disease are common diagnoses in hypercalcemic cats. Cats with neoplasia have a higher serum total calcium concentration than cats with renal failure or urolithiasis. Serum phosphorus concentration is lower in cats with malignancy than in cats with urinary tract disease. Further studies are warranted to characterize the cause-and-effect relationship between hypercalcemia and the numerous diseases identified in this study. The association between neoplasia, renal failure, and hypercalcemia was expected. Our findings suggest that the tumor types in cats with hypercalcemia differ from those observed in dogs. Our findings also suggest that a diagnosis of primary hyperparathyroidism cannot be excluded by a normal intact PTH concentration. This study also helps confirm the association between hypercalcemia and calcium oxalate urolithiasis in cats. Additional studies are warranted to determine whether calcium oxalate urolith formation is a manifestation of primary hyperparathyroidism or if urolith formation is related to abnormal calcium homeostasis or calcium excretion in hypercalcemic cats. Footnotes a Urinary Stones Analysis Laboratory, Department of Medicine, School of Veterinary Medicine, University of California, Davis, CA b Diagnostic Products Corporation, Michigan State University, Animal Health Diagnostic Laboratory, East Lansing, MI c Hill s Pet Nutrition, Inc, Topeka, KS Acknowledgment We thank Dr Marria Correa for her assistance with data analysis. References 1. Eliott J, Dobson JM, Dunn JK, et al. Hypercalcaemia in the dog: A study of 40 cases. J Small Anim Pract 1991;3: Potts JT. Hyperparathyroidism and other hypercalcemic disorders. Adv Intern Med 1996;41: McMillan FD. Hypercalcemia associated with lymphoid neoplasia in two cats. Feline Pract 1985;15: Dust A, Norris AM, Valli VEO. Cutaneous lymphosarcoma with IgG monoclonal gammopathy, serum hyperviscosity and hypercalcemia in a cat. Can Vet 198;3: Klausner JS, Bell FW, Hayden DW, et al. Hypercalcemia in two cats with squamous cell carcinomas. J Am Vet Med Assoc 1990;196: Sheafor SE, Gamblin RM, Couto CG. 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