Joao Felipe De Brito Galvao,     Downers Grove, Illinois

Dennis J. Chew,     Columbus, Ohio

Patricia A. Schenck,     Lansing, Michigan

Differential Diagnosis

Hypercalcemia is typically noted on an initial analysis of tCa and is often a seemingly fortuitous discovery when a blood sample is taken for other reasons (e.g., wellness examinations, preanesthesia screening, evaluation of urolithiasis, evaluation of gastrointestinal signs). When an increase in serum tCa is noted, an iCa measurement should be obtained to determine if the increase in tCa is accompanied by an increase in the ionized component, which is biologically active. Serum iCa concentration needs to be measured because the prediction of iCa status from tCa measurement is not accurate, especially in cats with concomitant chronic kidney disease (CKD). Hypercalcemia is detected more commonly when iCa is used as the screening analyte compared with measurement of serum tCa.

Hypercalcemia may be parathyroid-independent or parathyroid-dependent (primary hyperparathyroidism). In parathyroid-independent hypercalcemia, the elevation of iCa results in suppression of parathyroid hormone (PTH) production. In cats with IHC, PTH values are usually undetectable to within the lower half of the normal reference range (see later).

There are many potential causes of hypercalcemia in the cat (Box 55-1). A list of differential diagnoses ensures that all possibilities for the development of hypercalcemia have been considered. However, such a list does not indicate the frequency of the diagnoses. The most common diagnoses in cats with persistent elevations in iCa are IHC and malignancy. CKD is estimated to be accompanied by elevations in serum tCa in about 10% to 15% of cases. iCa was increased in about 30% of cats with CKD in one series compared with about 10% of dogs with CKD. In some cases the cause of hypercalcemia is obvious on analysis of history and physical examination. In others the cause may not be evident, and further workup, including hematology, serum biochemistry, body cavity imaging, cytology, and histopathology, is necessary. In some cases, measurement of the calciotropic hormones 25(OH) vitamin D₃ and 1,25(OH)2 vitamin D₃ (i.e., calcitriol) may be needed to secure the diagnosis. A diagnosis of IHC is made when all other causes of hypercalcemia are excluded. Although IHC is the most frequent diagnosis in cats with hypercalcemia, it is an exceedingly uncommon finding in dogs following adequate diagnostic workup (see Web Chapter 11).

The magnitude of elevation of serum tCa cannot be used to make a diagnosis of the underlying cause since there is considerable overlap in the degree of hypercalcemia in cats with IHC or other conditions. Most cats with IHC present with mild increases in tCa and iCa concentrations (11 to 12 mg/dl [2.75 to 3.00 mmol/L] and 6 to 6.5 mg/dl [1.5 to 1.6 mmol/L], respectively), whereas some cats may have tCa and iCa concentrations greater than 15 to 20 mg/dl (3.75 to 5 mmol/L) and 8 to 11 mg/dl (2 to 2.7 mmol/L), respectively.

The possibility of malignancy as the cause of hypercalcemia in both dogs and cats is always a concern, but malignancy-associated hypercalcemia (MAH), which includes both humoral hypercalcemia of malignancy and local osteolytic hypercalcemia, is much less common in cats than in dogs (it is the number one cause of pathological hypercalcemia in dogs). Based on serum tCa, MAH ranks behind IHC and CKD in frequency in cats. Patients with MAH are usually “sick,” as it takes a reasonably large tumor burden to synthesize the compounds (especially parathyroid-related peptide [PTHrP]) that result in hypercalcemia. Thus it is unlikely for a cat that feels well to have MAH, especially if the hypercalcemia persists for a long period without the cat showing more clinical signs. The less sick the cat is in the face of persistent hypercalcemia, the more likely the diagnosis will be IHC or primary hyperparathyroidism.

Cats have a higher frequency of PTH-independent hypercalcemia than do dogs. In cats with parathyroid-independent hypercalcemia, the next step in the diagnostic evaluation is to rule out MAH, which requires imaging of the thorax and abdomen. Full imaging with thoracic and abdominal radiographs along with abdominal ultrasound is the gold standard in the diagnosis of IHC. Chest radiographs are useful, especially to rule out mediastinal lymphoma that may be associated with hypercalcemia. However, unlike in dogs, hypercalcemia from mediastinal lymphoma rarely occurs in cats. Abdominal radiographs are most useful to rule out nephroliths and ureteroliths that may be associated with hypercalcemia, which may lead to postrenal azotemia. Cats should have an empty colon to enable interpretation of radiographs over the areas of interest. Ultrasound may also be used if available. Treatment recommendations and prognosis may change with the presence of stones. Furthermore, it is strongly recommended to treat hypercalcemia in cats considered to be stone formers, thus decreasing the likelihood of future stone formation.

Many clients are unable to afford the gold standard diagnostic evalution. Lack of clinical signs in conjunction with low PTH and ionized hypercalcemia significantly increases suspicion of IHC. In these cases, it may be appropriate to presumptively diagnose IHC.

Clinical Presentation

Cats with IHC may have persistent elevations in iCa for months without apparent clinical signs, and no relationship has been noted between the magnitude of elevation and occurrence of clinical signs. In a review of 427 cats with IHC diagnosed at an endocrinology referral laboratory, the mean age at presentation was 9.8 years old (range 0.5 to 20 years old), and long-haired cats were overrepresented (27% of cases). Both genders were equally represented. Almost half of the cats had no clinical signs (46%), 18% had mild weight loss, 6% had inflammatory bowel disease, 5% had chronic constipation, 4% presented with vomiting, and 1% were anorectic. Uroliths were reported in 15% of cats with IHC, and calcium oxalate stones were specifically present in 10% of cases (Schenk, 2004).

Serum iCa is increased in cats with IHC, and the PTH concentration is typically in the lower half of the reference range; many affected cats have PTH concentration in the lower quartile of the reference range. Concentrations of both ionized magnesium and 25-hydroxyvitamin D are within the reference range in most cats. Calcitriol concentration is normal to low in most cats, although this has not been measured in a large number of cats. Some cats with IHC develop CKD secondary to persistent hypercalcemia, and cats with CKD may develop IHC over time. Measuring a PTH level is key to determining if the hypercalcemia is from CKD or idiopathic. If PTH is low and azotemia is present, the cat either has IHC and CKD or hypercalcemia from IHC that has led to CKD. If PTH is elevated and hypercalcemia is present, but azotemia is not severe, tertiary renal hyperparathyroidism is considered unlikely. Therefore such a cat likely has IHC and CKD. However, if azotemia is severe (i.e., creatinine >5 mg/dl), PTH is elevated, and hypercalcemia is present, IHC cannot be definitively diagnosed. A few cats may have both CKD and IHC on initial presentation. Serum phosphorus is usually in the normal range in cats with IHC unless it is increased as a result of concurrent CKD. Urine specific gravity is typically greater than 1.030, and it appears that many cats with hypercalcemia can still maximally concentrate their urine if they do not have concurrent CKD.