Diagnostic investigation for ionised hypercalcaemia may be prompted by total hypercalcaemia on a biochemical profile, urolithiasis, neoplasia, constipation, or undiagnosed non-specific signs, even when total serum calcium (tCa) is normal. Ionized hypercalcaemia has deleterious long-term consequences and should be managed even in asymptomatic patients.

Differential Diagnoses for Hypercalcaemia in the Cat

Idiopathic Hypercalcaemia (IHC)

Idiopathic hypercalcaemia (IHC) is the most common cause of ionized hypercalcaemia in cats. Cats of any age can be affected. Long-haired cats are over-represented. IHC is characterised by mild to moderate hypercalcaemia, normophosphataemia, and an appropriate parathyroid response (i.e., ↓PTH). Clinical signs vary with the degree of hypercalcaemia but around 50% of cats are asymptomatic. The diagnosis is made by excluding other causes.

Chronic Kidney Disease (CKD)

Chronic kidney disease (CKD) is a common cause of total hypercalcaemia. In renal azotaemia, the complexed calcium fraction is usually increased while the ionized fraction is normal. In the azotaemic patient with elevated tCa, measurement of iCa is indicated. If iCa is normal then no further investigation of the hypercalcaemia is required. However, if iCa is elevated in an azotaemic patient, ionized hypercalcaemia may be contributing to the renal dysfunction. Further investigation of hypercalcaemia is indicated. Phosphate-binder use should be reviewed as long-term use of aluminum-based phosphate-binders can cause toxicity which resembles idiopathic hypercalcaemia. Resolution may take months after medication withdrawal. Calcium, particularly carbonate-based binders, should be withdrawn as should calcitriol therapy. A rare differential in the setting of ionized hypercalcaemia and azotaemia is tertiary hyperparathyroidism, where the set-point of the parathyroid glands is increased in advanced CKD (↑iCa ↑PTH).

Humoral Hypercalcaemia of Malignancy (HHM)

Humoral hypercalcaemia of malignancy (HHM) results when tumour-derived parathyroid hormone-related peptide (PTHrP) or other mediators mimick the action of PTH. HHM is less common in cats than dogs. Feline HHM is reported in head, neck, and bronchopulmonary carcinomas, lymphoma, osteosarcoma, fibrosarcoma, and multiple myeloma.

Primary Hyperparathyroidism

Primary hyperparathyroidism is rare in cats. Most cases are over 8 years of age. Adenomas are most common, but hyperplasia and carcinoma are reported. Involvement of more than one gland is unusual. Cervical masses are palpable in 50% of cases. A high or normal PTH in the face of ionized hypercalcaemia is consistent with autonomous secretion from the parathyroid gland. Low or normal serum phosphate is expected in primary hyperparathyroidism and HHM. Ultrasound may assist in detecting parathyroid lesions. Surgical patients undergoing parathyroidectomy should be monitored closely for postoperative hypocalcaemia because of feedback atrophy of the remaining glands.

Hypervitaminosis D

Sources of vitamin D intoxication include dietary, rodenticide ingestion, certain houseplants (Cestrum diurnum), calcitriol supplementation, and ingestion of analogues (e.g., calcipotriene). Commercial assays measure 25-OH cholecalciferol (calcidiol). Calcitirol assays are less widely available. Vitamin D analogues may not be detected by these assays. PTH and PTHrP are low or undetectable in hypervitaminosis D. If cholecalciferol or ergocalciferol have been ingested, calcidiol levels will be elevated for weeks because of lipid storage. Calitriol levels are normal or occasionally increased. In calcitriol toxicity, calcidiol levels will be normal. Calcitriol may be increased or, because it has a short half-life in circulation, levels may be normal.

Granulomatous Disease

Activated macrophages can convert calcidiol to calcitriol. Hypercalcaemia has been reported in occasional cases of nocardial, mycobacterial, cryptococcocal, blastomycosis, histoplasmosis, and actinomycetal infection.

Hypoadrenocorticism

Hypoadrenocorticism is a rare endocrinopathy of cats and <10% of cases have hypercalcaemia.

Signs associated with Hypercalcaemia

Clinical signs may relate to the hypercalcaemia itself and any underlying disease. Signs associated with ionized hypercalcaemia range from inapparent to severe depending on the rate and the magnitude of iCa elevation. Lethargy, anorexia, and vomiting are most common followed by polyuria/polydipsia (PUPD), lower urinary tract signs (e.g., stranguria, haematuria, pollakiuria, periuria from urinary tract infection, inflammation, or obstruction), weight loss, weakness, and tremors. Constipation has been associated with hypercalcaemia in cats. Severe ionized hypercalcaemia can cause obtundation, arrhythmias, seizures, and death.

Tips for Diagnostic Investigation of the Hypercalcaemic Cat

↑tCa is confirmed by repeat testing on a fasted, non-haemolysed sample in a well-hydrated patient. Information from the history and physical examination helps to rank the differentials. CKD and neoplasia should be ruled out early on in the investigation.

Where ↑tCa is persistent then iCa should be measured concurrently. Where tCa is elevated and iCa is normal, no further investigation is necessary. If iCa is elevated consider the following;

• The age and signalment of the cat primary hyperparathyroidism is a rare disease of older cats. Long-haired cats are overrepresented for idiopathic hypercalcaemia.
• Potential for vitamin D toxicity review diet history, access to rodenticides, medications, houseplants.
• Review physical examination findings for evidence of neoplasia, cervical lesions, bone pain.
• Is there physical or laboratory evidence of renal disease? This is the most common cause of ↑tCa.
• What is the phosphate level? Phosphate is typically low in PTH and PTHrP-mediated hypercalcaemia. Elevated phosphate occurs with renal disease, vitamin D intoxication, and osteolysis.
• Imaging may show evidence of neoplasia, urolithiasis, or bony lesions (multiple myeloma, other neoplasia, osteomyelitis). Cervical ultrasonography can help to rule in primary hyperparathyroidism.
• PTH, PTHrP, and vitamin D testing. Assays have been validated for feline PTH (measured as the intact molecule, iPTH, or PTH 1–84) and PTHrP. Vitamin D metabolites do not differ between species. An inappropriate PTH level (elevated or top half of reference range) in the face of concurrent ↑iCa indicates a parathyroid-dependent process. Whether this results from primary or teritary hyperparathyroidism can be concluded from the rest of the clinical data. Where PTH is appropriately low (bottom half of reference range or undetectable) in the face of concurrent ↑iCa, then all other diagnoses should be considered. Where PTHrP is elevated then malignancy becomes the major differential. Where PTHrP is normal or subnormal malignancy cannot be ruled out.
• Idiopathic hypercalcaemia is diagnosed by ruling out all other causes.

Practicalities of Laboratory Investigation

• EDTA (ethylenediaminetetraacetic acid) chelates calcium so should not be used for samples for calcium measurement.
• For tCa, serum or heparinised plasma collected after a 12 hour fast is recommended.
• Adjustment of tCa to TP or albumin is not recommended in cats.
• iCa can be measured in-house or submitted to a commercial laboratory.
• For iCa assay, anaerobic collection, the use of dry heparinised syringes, and storage at 4°C (if not processed immediately) reduce errors.
• The availability of PTH and PTHrP should be investigated locally. These tests are currently available at www.dcpah.msu.edu. Sample handling requirements as per website should be followed carefully.

Treatment for Idiopathic Hypercalcaemia

The long-term consequences of hypercalcaemia include renal damage, urolithiasis, and soft tissue calcification. Diet change may be helpful and should be individualized. If the iCa elevation is minimal, phosphate is not elevated, and diet change has not been effective, then regular monitoring may be all that is required. Glucocorticoids reduce intestinal calcium absorption and bone resorption and may increase calciuresis. The use of frusemide or glucocorticoids long-term is not recommended.

Bisphosphonates

Bisphosphonates inhibit bone resorption by promoting osteoclast apoptosis at sites of active bone turnover. Oral alendronate is effective for treatment of idiopathic hypercalcaemia but dosing precautions are necessary and the risks associated with long-term alendronate therapy are not yet fully understood.^1,2 Food substantially reduces the bioavailability of oral alendronate. Medication must be accompanied by a water swallow because alendronate has the potential to cause drug-induced oesophageal disease (resulting in oesophagitis that may progress to oesophageal stricture formation). We use a starting dose of 10 mg per cat once weekly PO given on an outpatient basis. Medication is administered following a 12 hour fast, with a 5 ml water swallow, and the cat is fed 2 hours later. Once iCa is controlled, the dosing interval is progressively increased to determine the minimum effective dose. Medication-free periods should be considered in the long-term. In humans and dogs, long-term bisphosphonates can cause osteonecrosis of the jaw.³ Patella fractures and cortical bone thickening in a cat on long-term alendronate therapy are reported.⁴

References

1.  Whitney JL, Barrs VRD, Wilkinson MR, Briscoe KA, Beatty JA. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. J Feline Med Surg. 2011;13(2):129–134.

2.  Hardy BT, Galvao JFD, Green TA, et al. Treatment of ionized hypercalcemia in 12 cats (2006–2008) using PO-administered alendronate. J Vet Intern Med. 2015;29(1):200–206.

3.  Burr DB, Allen MR. Mandibular necrosis in beagle dogs treated with bisphosphonates. Orthod Craniofac Res. 2009;12(3):221–228.

4.  Council N, Dyce J, Drost WT, de Brito Galvao JF, Rosol TJ, Chew DJ. Bilateral patellar fractures and increased cortical bone thickness associated with long-term oral alendronate treatment in a cat. JFMS Open Rep. 2017;3(2):2055116917727137.