Richard W. Nelson, DVM, DACVIM
Hypercalcemia is present when the serum calcium concentration is greater than 3 mmol/L (12 mg/dl) or the serum ionized calcium concentration is greater than 1.45 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 (serum calcium < 3.25 mmol/L or 13 mg/dl) and hypercalcemia is discovered only after a serum biochemistry panel is performed, often for unrelated reasons. Clinical signs are usually mild with serum calcium concentrations less than 3.5 mmol/L or 14 mg/dl, are readily apparent with serum calcium greater than 3.75 mmol/L or 15 mg/dl, and become potentially life threatening (i.e., cardiac arrhythmias) when serum calcium exceeds 4.5 to 5 mmol/L or 18 to 20 mg/dl. The most common clinical signs are polyuria, polydipsia, lethargy, inappetence, and weakness. Calcium oxalate and calcium phosphate urolithiasis commonly occur in dogs and cats with chronic hypercalcemia and may cause clinical signs suggestive of lower urinary tract disease.
The differential diagnoses for hypercalcemia are relatively short in dogs and cats. In the dog, humoral hypercalcemia of malignancy (HHM; 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.
Hypercalcemia should always be reconfirmed 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 usually 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 kidney function is normal, hypervitaminosis D or bone osteolysis from metastatic or primary bone neoplasia are the primary differentials.
Determining whether kidney failure is primary or secondary to hypercalcemia caused by another disorder, when hyperphosphatemia and hypercalcemia coexist with azotemia, can be difficult. 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 are 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. Increased serum ionized calcium, normal to increased serum PTH, and nondetectable PTHrP concentrations are diagnostic of primary hyperparathyroidism.
Primary hyperparathyroidism is a disorder resulting from excessive, relatively uncontrolled secretion of parathyroid hormone (PTH) by one or more abnormal parathyroid glands. Functional parathyroid adenoma is the most common histologic finding. Primary hyperparathyroidism typically occurs in older dogs. The mean age at the time of diagnosis is 11 years (range, 6 to 17 years). There is no sex-related predilection. Any breed of dog can be affected although a genetic predisposition exists in the Keeshond.
The diagnosis of primary hyperparathyroidism is based on a combination of clinical signs, findings on physical examination, and results of routine blood and urine tests, diagnostic imaging, and serum PTH concentrations. Obvious abnormalities are not identified on physical examination, which is an important diagnostic finding when differentiating between primary hyperparathyroidism and HHM. The parathyroid mass is not palpable during the physical examination in dogs, but may be palpable in cats and must be differentiated from a thyroid nodule. If a mass is palpated in the neck of a dog with hypercalcemia, thyroid gland carcinoma, squamous cell carcinoma, lymphoma and, least likely, parathyroid gland carcinoma should be considered.
Kidney failure is not a common concurrent finding in dogs with primary hyperparathyroidism. Urine specific gravity is usually not helpful when assessing kidney function in dogs with hypercalcemia because of calcium's interference with the actions of vasopressin on renal tubular cells. Urine specific gravities between 1.002 and 1.012 are common. In our 210 dogs with primary hyperparathyroidism, 24% had urine specific gravity less than 1.008, 36% had urine specific gravity between 1.008 and 1.012, and only 3% had urine specific gravity greater than 1.030. Cystic calculi are the only abnormality identified on diagnostic imaging of the thorax and abdomen in dogs with primary hyperparathyroidism. Uroliths are typically composed of calcium phosphate, calcium oxalate, or mixtures of the two salts. Urinary tract infections may occur secondary to the presence of cystic calculi.
Cervical ultrasound has become a routine part of our diagnostic evaluation of persistent hypercalcemia, especially when the initial diagnostic evaluation of the dog supports primary hyperparathyroidism, i.e., the dog with mild to absent clinical signs, normal physical examination, and unremarkable results of routine blood tests, urine tests, and diagnostic imaging of the thorax and abdomen, except for hypercalcemia, hypophosphatemia, urinary tract infection, and cystic calculi. One or more enlarged parathyroid glands should be identified with cervical ultrasound in dogs with primary hyperparathyroidism. The parathyroid glands of healthy dogs are typically 3 mm or less in maximum width when visualized ultrasonographically. In 130 of our dogs with primary hyperparathyroidism, a solitary parathyroid mass was identified in 89% and two parathyroid masses were identified in 10% of dogs. The median maximum width of the 142 parathyroid masses imaged in 129 dogs was 6 mm (range, 3 to 23 mm); 60% were 4 to 6 mm and 24% were 7 to 10 mm in maximum width.
Measurement of baseline serum PTH concentration is used to establish the diagnosis of primary hyperparathyroidism. Serum PTH test results should always be interpreted in conjunction with serum calcium or serum ionized calcium measured from the same blood sample. If the parathyroid gland is functioning normally, the serum PTH concentration should be below the reference range or undetectable in the face of hypercalcemia because of the inhibitory effects of an increased serum calcium concentration on parathyroid gland function. Dogs with non-parathyroid-induced hypercalcemia should have low to undetectable serum PTH concentrations. Serum PTH concentration within or above the reference range is inappropriate in the face of hypercalcemia and indicative of an autonomously functioning parathyroid gland.