Richard W. Nelson, DVM, Diplomate ACVIM
Hypercalcemia is present when the serum calcium concentration is greater than 12 mg/dl or the serum ionized calcium concentration is greater than 1.4 mmol/L. Although all tissues can be affected by hypercalcemia, the neuromuscular, gastrointestinal, renal and cardiac systems are the most important clinically. Clinical signs are often absent with mild increases in serum calcium concentration and hypercalcemia is discovered only after a serum biochemistry panel is performed, often for unrelated reasons. When clinical signs do develop, they initially tend to be nonspecific and insidious in onset. The most common clinical signs are polyuria, polydipsia, lethargy, inappetence, and weakness. The severity of clinical signs depends, in part, on the severity, rate of onset, and duration of the hypercalcemia. Clinical signs become more severe as the magnitude of the hypercalcemia increases, regardless of the rate of onset or duration. Clinical signs are usually mild with serum calcium concentrations less than 14 mg/dl, are readily apparent with serum calcium greater than 15 mg/dl, and become potentially life-threatening (i.e., cardiac arrhythmias) when serum calcium exceeds 18 to 20 mg/dl.
Persistent hypercalcemia usually results from increased calcium resorption from bone or kidney or increased calcium absorption from the gastrointestinal tract. Humoral hypercalcemia of malignancy (HHM) is the most common cause of hypercalcemia and occurs when the tumor produces substances that promote osteoclastic activity and renal calcium reabsorption. These substances include parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrP), 1,25-dihydroxyvitamin D, cytokines such as interleukine-1 and tumor necrosis factor, prostaglandins, and humoral factors that stimulate renal 1-alpha-hydroxylase. Less commonly, hypercalcemia develops from impaired loss of calcium from the serum (e.g., reduced glomerular filtration) or reduced plasma volume (e.g., dehydration).
The differential diagnoses for hypercalcemia is relatively short in dogs and cats (Table 1). In the dog, humoral hypercalcemia of malignancy (especially lymphoma), hypoadrenocorticism, chronic renal failure, hypervitaminosis D, and primary hyperparathyroidism are the most common diagnoses. In the cat, hypercalcemia of malignancy (especially lymphoma and squamous cell carcinoma), chronic renal failure, primary hyperparathyroidism, and idiopathic hypercalcemia are the most common diagnoses. Calcium oxalate urolithiasis and consumption of acidifying diets are commonly identified in cats with hypercalcemia but their role, if any, in causing hypercalcemia is unknown.
Hypercalcemia should always be reconfirmed, preferably from a nonlipemic blood sample obtained from the dog or cat following a 12 hour fast, before embarking on an extensive diagnostic evaluation. Results of a CBC, serum biochemistry panel, and urinalysis, in conjunction with the history and physical examination findings, often provide clues to the diagnosis. Special attention should be paid to the serum electrolytes and renal parameters. Hypoadrenocorticism-induced hypercalcemia occurs in conjunction with mineralocorticoid deficiency; hyponatremia, hyperkalemia, and prerenal azotemia should be present. The serum phosphorus concentration is in the lower half of the normal range or low with HHM and primary hyperparathyroidism. If the serum phosphorus concentration is increased and renal function is normal, hypervitaminosis D or bone osteolysis from metastatic or primary bone neoplasia are the primary differentials.
Determining whether renal failure is primary or secondary to hypercalcemia caused by another disorder when hyperphosphatemia and hypercalcemia coexist with azotemia can be difficult. Chronic and, less commonly, acute renal failure can cause hypercalcemia. Proposed mechanisms for the hypercalcemia include increased protein-bound and complexed calcium fractions of total serum calcium, decreased glomerular filtration rate, increased PTH-mediated bone resorption, and autonomous secretion of PTH caused by parathyroid gland chief cell hyperplasia or an alteration of the set point for PTH secretion. Alternatively, disorders that cause persistent hypercalcemia with concurrent high normal to increased serum phosphate concentration can cause progressive mineralization of the kidney and eventual renal failure. Measurement of serum ionized calcium concentration may help identify dogs and cats with renal failure-induced hypercalcemia; serum ionized calcium concentrations are typically normal or decreased in renal failure and increased in hypercalcemia caused by other disorders.
Hypercalcemia of malignancy and primary hyperparathyroidism are the primary differentials when hypercalcemia and normal to low serum phosphorus concentrations are identified. The most common malignancy is lymphoma. A careful review of the history and physical examination findings may provide clues to the diagnosis. Systemic signs of illness suggest hypercalcemia of malignancy. Dogs and cats with primary hyperparathyroidism are usually healthy and clinical signs are mild. The appendicular skeleton, peripheral lymph nodes, abdominal cavity and rectum should be carefully palpated for masses, lymphadenopathy, hepatomegaly, splenomegaly, or pain on digital palpation of the long bones. Diagnostic tests that are helpful in identifying the underlying malignancy include thoracic and abdominal radiographs, abdominal ultrasound, cytologic evaluation of aspirates of the liver, spleen, lymph nodes, and bone marrow, determination of serum ionized calcium, PTH and PTHrP concentrations, and cervical ultrasound.
Sternal and hilar lymphadenopathy is common with lymphoma-induced hypercalcemia and can be readily identified with thoracic radiographs. Radiographs of the thorax and abdomen can also be used to evaluate bones; discrete lytic lesions in the vertebrae or long bones suggest multiple myeloma. Hyperproteinemia, proteinuria, and plasma cell infiltration in the bone marrow suggest multiple myeloma. Cytologic evaluation of peripheral lymph node, bone marrow, and splenic aspirates can be helpful in identifying lymphoma; involvement of the peripheral lymph nodes or spleen by lymphoma can be present without causing their enlargement. Ideally the largest lymph node should be evaluated. Normal lymph node, bone marrow, and splenic aspirates do not rule out lymphoma.
Measurement of serum ionized calcium, PTH and PTHrP from the same blood sample is helpful in differentiating primary hyperparathyroidism from HHM. Excessive secretion of biologically active PTHrP plays a central role in the pathogenesis of hypercalcemia in most forms of HHM. Increased serum ionized calcium concentration, detectable serum PTHrP concentration, and nondetectable serum PTH concentration is diagnostic for HHM. Lymphoma is the most common cause for detectable PTHrP concentrations but other tumors, including apocrine gland adenocarcinoma and various carcinomas (e.g., mammary gland, squamous cell, bronchogenic) can also cause hypercalcemia by this mechanism. In contrast, increased serum ionized calcium, normal to increased serum PTH, and nondetectable PTHrP concentrations are diagnostic of primary hyperparathyroidism. Ultrasonographic examination of the thyroparathyroid complex may reveal enlargement of one or more parathyroid glands. Most parathyroid adenomas measure 4 to 8 mm in diameter, although an occasional parathyroid adenoma will exceed 1 cm. In contrast, the parathyroid glands will be small or undetectable with hypercalcemia of malignancy.
Evaluation of the change in serum calcium concentration following L-asparaginase administration should be considered for the patient with hypercalcemia of undetermined etiology to rule out occult lymphoma. For the L-asparaginase trial, 20,000 IU/m2 IV of the drug is administered and the serum calcium concentration measured prior to and every 12 hours after administration, for as long as 72 hours. A decline in serum calcium, usually into the normal range, is strongly suggestive of occult lymphoma. Hypersensitivity reactions are the most common adverse effect associated with L-asparaginase administration; pretreatment with an antihistamine is recommended.
Idiopathic hypercalcemia is an increasingly common diagnosis in young to middle-aged cats. Hypercalcemia is usually mild (less than 13 mg/dl) and asymptomatic. Serum phosphorus concentration and renal parameters are normal. The etiology is unknown. Results of a complete diagnostic evaluation as described above are unremarkable. Serum PTH concentrations are in the normal range or low; primary hyperparathyroidism has not been confirmed in any of these cats. Nephrocalcinosis and urolithiasis may develop, presumably secondary to increased urinary calcium excretion. Effective treatment has not been identified. Serum calcium concentrations have decreased in some cats following a dietary change to a high fiber diet or after initiating prednisone treatment but response is unpredictable.
Table 1. Causes of Hypercalcemia in Dogs and Cats
Hypercalcemia of Malignancy
Apocrine gland adenocarcinoma
Carcinoma (squamous cell, mammary, bronchogenic, prostate thyroid, nasal cavity)
Hematologic malignancies (bone marrow osteolysis)
Myeloproliferative disease (rare)
Metastatic or primary bone neoplasia
Chronic and Acute Renal Failure
Hypervitaminosis D: Iatrogenic, Plants, Rodenticides
Idiopathic Hypercalcemia of Cats
Skeletal Lesions: Osteomyelitis, Hypertrophic osteodystrophy
Iatrogenic Disorders: Excess calcium or oral phosphate binders
Factitious: Lipemia, postprandial, young dog (< 6 months)