Introduction

Although relatively uncommon, hypercalcaemia is diagnosed with increasing frequency in practice because of the ease with which both total and ionised calcium can now be measured. When recognised, the clinician is often faced with the dilemma of separating the clinical signs induced by the hypercalcaemia itself versus those caused by the underlying disorder. A second dilemma is instituting treatment for hypercalcaemia to minimise potential complications whilst avoiding those that could adversely affect the diagnostic work-up. Fortunately, clinically significant hypercalcaemia has a relatively well defined set of differential diagnoses and a wide array of diagnostic tests are now available that offer an opportunity to confirm a diagnosis with greater ease than previously. In addition, therapies are now available that are capable of effectively managing the hypercalcaemia without interfering with any subsequent diagnostic tests.

Tests of Calcium Homeostasis

In evaluating calcium homeostasis both calcium and phosphate should be measured simultaneously. Total calcium is usually measured as part of a routine clinicopathological panel and consists of protein-bound (mainly albumin) calcium (40%), ionised calcium (iCa) (50%) and calcium that is complexed (10%) with other anions such as phosphate, citrate, bicarbonate or lactate. The iCa fraction is considered to be biologically active and is the component that regulates PTH (parathyroid hormone) secretion. Serum phosphorus consists of inorganic phosphate, phospholipids and phosphate esters. An increase in either calcium or phosphate causes a reciprocal decrease in the other. Soft tissue calcification is most severe when the calcium phosphate product exceeds 5.0.

Total calcium concentrations tend to be higher in younger animals and are obviously influenced by circulating albumin concentrations. Measurement of ionised calcium gives a much clearer indication of actual calcium status since it is not influenced by the protein-bound or complexed fractions. Caution is advised with measurement of ionised calcium as it is influenced by pH (higher concentrations as pH decreases) and should be analysed relatively rapidly.

Valid specific, two-site intact PTH immunoradiometric assays are now commercially available. Serum PTH concentrations should be evaluated relative to the total or, preferably, ionised calcium concentration. Serum or EDTA plasma can be used, but since PTH is relatively labile it should be appropriately handled to prevent erroneously low results.

Parathyroid hormone-related protein is associated with certain malignancies. Some laboratories now offer this assay but it should not be used as a replacement for thorough investigation for neoplasia.

Assays for vitamin D are becoming increasingly available but their usefulness in small animal medicine remains unclear unless vitamin D toxicosis requires confirmation.

Effects of Hypercalcaemia

The clinical signs associated specifically with hypercalcaemia are often mild, insidious and non-specific and commonly relate to the renal, gastrointestinal or neuromuscular systems. More severe clinical signs are usually associated with the underlying disease, the development of renal failure or in some cases, severe hypercalcaemia:

 Gastrointestinal features include anorexia, vomiting, constipation and, rarely, pancreatitis.

 Renal features include polyuria/polydipsia and occasionally signs related to recurrent urinary tract infections or calculi.

 Neuromuscular features include listlessness, weakness, muscle wastage and, rarely, stiff gait, shivering, obtundation, coma.

Polyuria and polydipsia are common in dogs. Anorexia and lethargy predominate in cats. A cervical nodule may be palpable in cats with hyperparathyroidism.

Causes of Hypercalcaemia

In dogs, hypercalcaemia is most often associated with malignancy, hypoadrenocorticism and renal disease with lower prevalences of hyperparathyroidism and vitamin D toxicosis (Table 1). In cats, neoplasia, renal failure and idiopathic hypercalcaemia appear to be most common. Other infrequent causes of hypercalcaemia include the diuretic phase of acute renal failure, a small percentage of cases of nutritional hyperparathyroidism, disseminated osteomyelitis, granulomatous disease and severe hypothermia.

Hypercalcaemia of Malignancy

Malignancy-associated (paraneoplastic) hypercalcaemia is the most common cause of hypercalcaemia in dogs. Whilst the presence of neoplasia is often apparent on physical examination, isolated hypercalcaemia should always prompt thorough investigations for occult neoplasia. The hypercalcaemia may be intermittent, but if severe can result in renal failure, encephalopathy, coma and death. Generally more clinical signs are apparent in dogs with hypercalcaemia of malignancy because of the co-existence of the hypercalcaemia and neoplasia.

Hypercalcaemia may result from local factors that stimulate osteoclastic resorption (e.g., multiple myeloma), or tumour tissue, situated at a site distant from bone may produce parathyroid hormone-related protein (PTHrP) (e.g., lymphosarcoma, anal gland adenocarcinoma). Destruction of bone from metastatic lesions may also play a role in some tumours.

Hypoadrenocorticism

Approximately 20% of dogs with hypoadrenocorticism have hypercalcaemia. The mechanism is obscure but may relate to hypocortisolaemia and reduced renal output. Ionised calcium concentrations may be normal or elevated. The hypercalcaemia is usually only mild to moderate and phosphate concentrations also tend to be increased.

Chronic Renal Failure

10 to 20% of dogs have mild to moderate hypercalcaemia although normal or low calcium is more common. Associated ionised calcium concentrations are either normal or low. Serum phosphate concentrations are elevated. Diagnostically, these animals pose a challenge as further investigations are required to determine if they have chronic renal failure or renal failure induced by hypercalcaemia. Ionised calcium concentrations help differentiate the two.

Hyperparathyroidism

In dogs, a single benign parathyroid gland adenoma is the most common cause of primary hyperparathyroidism. Parathyroid adenocarcinoma and parathyroid hyperplasia are less common. There is a familial predisposition in Keeshonds. It is rare in cats.

Idiopathic Hypercalcaemia of Cats

A hypercalcaemic syndrome of cats of unknown aetiology has emerged in recent years. Many cats have concurrent evidence of a lower urinary tract disorder.

Vitamin D Toxicosis

Vitamin D toxicity may result from overzealous dietary supplementation, overdosage of vitamin D in the treatment of hypoparathyroidism or intoxication with cholecalciferol containing rodenticides and human topical psoriatic treatments. It is associated with moderate to severe hypercalcaemia with hyperphosphataemia and, therefore, diffuse soft tissue calcification.

Treatment

Surgical removal of the tumour is the optimum treatment for primary hyperparathyroidism. The dog/cat must be monitored for hypocalcaemia.

Symptomatic therapy for hypercalcaemia is indicated when dehydration, azotaemia, cardiac arrhythmia, severe neurological dysfunction or weakness exists or when the hypercalcaemia is severe (> 4 mmol/l). Several methods have been suggested to control acute or severe hypercalcaemia. Correction of fluid deficits, saline diuresis and diuretic therapy with furosemide are the most commonly used methods. Glucocorticoid therapy should be avoided. Glucocorticoids are rapidly beneficial in malignancy-associated hypercalcaemia and such a response helps to support a diagnosis. However, confirmation of occult neoplasia and its successful treatment becomes more difficult in dogs that have received glucocorticoids.

Fluid Therapy

Rehydration is an important step in treating hypercalcaemic dogs as dehydration worsens pre-existing hypercalcaemia. Correction of fluid deficits does not normalise serum calcium concentrations. Rehydration with mild volume expansion eliminates the effects of dehydration and promotes calciuresis. Normal saline given at two to three times maintenance over the dehydration deficit is usually effective. The patient should be monitored for signs of overhydration and potassium may require supplementation.

Diuretic Therapy

The use of furosemide together with saline diuresis ensures maximal renal excretion of calcium. Volume expansion must precede diuretic administration. One protocol suggests a 5 mg/kg IV bolus followed by a 5 mg/kg/hour infusion or 2-4 mg/kg every 8-12 hours.

Bisphosphonates

Fluid therapy is usually successful and other treatments rarely necessary. However, if more long-term control of hypercalcaemia is required (e.g., whilst awaiting other results) alternative therapies must be instituted. These include bisphosphonate infusions (pamidronate, clodronate), calcitonin, plicamycin, EDTA, bicarbonate and dialysis. Salmon calcitonin (Calsynar®) is administered subcutaneously at a dose of 4-8 iu/kg BID to TID but its effects are short-lived and multiple treatments are required. Sodium bicarbonate as a slow intravenous bolus (1 mmol/kg every 10-15 minutes for four treatments) has a minimal effect on circulating calcium concentration. Plicamycin (25 μg/kg slowly intravenously over 4-6 hours once/twice-weekly) is a potent inhibitor of osteoclastic bone resorption but is associated with numerous adverse reactions including thrombocytopenia and hepatic/renal failure. The bisphosphonates are osteoclastic inhibitors widely used in human medicine. At a dose of 1.3 (1.0-2.0) mg/kg in 150 ml 0.9 % saline infused intravenously over 3-4 hours (pamidronate, Aredia®) or 20-25 mg/kg intravenously in 500 ml saline over four hours (clodronate), calcium concentrations can be suppressed within 48 hours for up to several weeks.

Table 1. Abnormalities of calcium homeostasis in certain disorders.

References

1.  Brennan SF, O'Donovan J, Mooney CT (2006) Changes in ionised calcium under three storage conditions. Journal of Small Animal Practice 47, 383-386.

2.  Feldman EC, Hoar B, Pollard R, Nelson RW (2005) Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). Journal of the American Veterinary Medical Association 227, 756-761.

3.  Hostutler RA, Chew DJ, Jaeger JQ, Klein S, Henderson D, DiBartola S (2005) Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia. Journal of Veterinary Internal Medicine 19, 29-33.

4.  Mellanby RJ, Craig R, Evans M, Herrtage ME (2006) Plasma concentrations of parathyroid hormone-related protein in dogs with potential disorders of calcium metabolism. The Veterinary Record 159, 833-838.

5.  Midkiff AM, Chew DJ, Randolph JF, Center SA, DiBartola SP (2000) Idiopathic hypercalcaemia in cats. Journal of Veterinary Internal Medicine 14, 619-626.