Hypercalcemia in Dogs and Cats: Causes and Diagnosis

Hypercalcemia is a common finding in clinical practice and ranges from an incidental laboratory abnormality to a clinically urgent condition. The first and most important step in interpretation is distinguishing between total hypercalcemia and ionized hypercalcemia. Only ionized calcium reflects the biologically active fraction and determines whether clinically relevant hypercalcemia is truly present.

Total Calcium versus Ionized Calcium

An increased total calcium concentration should always be interpreted critically, as it is influenced by protein binding and hydration status. As a result, a patient may have an elevated total calcium concentration without an actual increase in biologically active calcium.

In practice, this means:

• ↑ total calcium → first confirm whether it persists and assess the clinical context (see below for more details)
• Persistent abnormality → measure ionized calcium (iCa)
• Normal iCa → usually no further investigation required
• ↑ iCa → always investigate further, even in the absence of clinical signs

This distinction is particularly important in cats, where idiopathic hypercalcemia is common and often subclinical.

Causes of Hypercalcemia

The differential diagnoses differ markedly between dogs and cats and this should always be taken into account.

DOG:

In dogs, the primary differentials include:

• Neoplasia (often PTHrP-mediated)
• Hypoadrenocorticism
• Primary hyperparathyroidism
• Kidney disease
• Vitamin D intoxication
• Granulomatous diseases such as fungal infections, parasitic infections, or lymphadenitis

Neoplasia is one of the most important causes, with lymphoma and anal sac adenocarcinoma being classic examples. Addison’s disease remains an important “must not miss” differential, especially when other electrolyte abnormalities such as hyperkalemia and hyponatremia are present.

CAT:

In cats, the list of differentials is somewhat different:

• Idiopathic hypercalcemia (most common)
• Chronic kidney disease
• Neoplasia
• Vitamin D intoxication
• Primary hyperparathyroidism (rare)

Idiopathic hypercalcemia is the most common cause of ionized hypercalcemia in cats. Many cats remain asymptomatic, emphasizing the importance of correct interpretation of laboratory values.

In chronic kidney disease, it is common for total calcium to be elevated while ionized calcium often remains normal. Therefore, measuring iCa in azotemic patients is essential.

Clinical Signs

The clinical presentation depends both on the magnitude and the rate of increase in calcium concentration. Clinical signs are often nonspecific and may overlap with many other diseases.

Typical clinical signs include:

• Lethargy and anorexia
• Vomiting
• Polyuria and polydipsia (especially in dogs)
• Weight loss and muscle weakness

In cats, we also commonly observe:

• Constipation
• Lower urinary tract disease (e.g., secondary to urolithiasis)

In more severe cases, neurologic signs, cardiac arrhythmias, or even coma may occur. At the same time, hypercalcemia, particularly in cats, is frequently detected incidentally.

Diagnostic Approach

A structured approach helps prevent important causes from being overlooked.

Step 1: Confirm the Abnormality

An increased total calcium concentration should ideally be re-evaluated:

• After the animal has been fasted (minimum 12 hours)
• Well hydrated
• Using a blood sample without significant hemolysis

If hypercalcemia persists, ionized calcium should subsequently be measured. Correct sample collection and handling are crucial when measuring ionized calcium, as the value is highly influenced by pH changes. The sample should be collected anaerobically (avoiding air exposure), analyzed rapidly, and preferably processed promptly in a heparinized tube, since CO₂ loss through exposure to air increases pH and can artifactually decrease ionized calcium concentrations.

Step 2: Initial Interpretation

Once iCa is confirmed to be elevated, attention should focus on the most common underlying causes. Several simple parameters can help guide interpretation.

Important interpretation guidelines:

• ↑ Ca + ↓ phosphate → suggestive of PTH- or PTHrP-mediated disease
• ↑ Ca + ↑ phosphate → suggestive of chronic kidney disease, vitamin D intoxication, or osteolysis

Additionally, always evaluate:

• Is azotemia present?
• Are there clinical signs suggestive of neoplasia?
• Are there indications of intoxication?

Step 3: Targeted Further Investigation

Based on the initial findings, further diagnostics should be directed toward a specific diagnosis.

Chronic Kidney Disease

Often associated with increased total calcium, but not necessarily with increased iCa. If iCa is elevated, hypercalcemia should be considered a separate concurrent problem and can in certain cases be the cause of the kidney disease.

Neoplasia

Should be suspected in patients with systemic clinical signs or abnormalities on diagnostic imaging. PTHrP can assist in diagnosis, but a normal value does not exclude malignancy.

Primary Hyperparathyroidism

Characterized by a normal or increased PTH concentration (upper half of the reference interval or higher) in the presence of increased iCa. Phosphate concentrations are often low. Cervical ultrasonography may provide additional information.

Vitamin D Intoxication

A thorough history is crucial. Consider rodenticides, supplements, or toxic plants. Hyperphosphatemia is commonly present.

Idiopathic Hypercalcemia (Cat)

Diagnosed after exclusion of all other causes. Typically characterized by a mild to moderate increase in iCa together with low PTH concentrations.

Step 4: Additional Testing

Depending on the suspected cause:

• Diagnostic imaging (thorax, abdomen)
• Urinalysis (urolithiasis can be present)
• PTH and PTHrP measurements
• Vitamin D metabolites

Interpretation of PTH is particularly important. A non-suppressed PTH concentration in the presence of hypercalcemia indicates a parathyroid-dependent cause, whereas suppressed PTH concentrations are more suggestive of malignancy, vitamin D intoxication, or other non-parathyroid causes.

Practical Considerations

Several points are essential in practice:

• Do not use EDTA for calcium measurements
• Measure iCa correctly: avoid hemolysis and minimize air exposure during sample handling
• Never consider hypercalcemia a diagnosis itself, but rather the consequence of an underlying disease

A systematic approach in which true (ionized) hypercalcemia is first confirmed, followed by targeted exclusion of the most common underlying causes, forms the basis of accurate diagnosis.