18 Jan 2016
Stephanie Lalor
Job Title
Figure 2. A radiograph of ureteroliths. Image: Sally Birch/Willows Veterinary Centre and Referral Centre.
Calcium is very tightly regulated within the body. As 99% of calcium is stored in bones, this acts as a reservoir enabling the release of calcium when the extracellular fluid calcium levels decrease1.
Parathyroid hormone (PTH), vitamin D and calcitonin are actively involved in the regulation of serum calcium concentrations.
PTH largely controls the minute-to-minute regulation of calcium and is secreted by the chief cells of the parathyroid glands. It has a short half-life of three to five minutes2.
PTH is secreted in response to decreased serum concentrations of calcium and raises these by encouraging increased calcium absorption from the bone, and increased calcitriol formation and decreased calcium excretion by the kidneys.
Calcitriol also encourages increased serum calcium concentrations by rising the internal absorption of calcium, decreasing renal calcium excretion and enhancing the ability of PTH to cause bone reabsorption.
Calcium exists in three forms within the serum: ionised, protein bound and complexed2. Investigations are only required if ionised calcium is persistently high.
Heparinised whole blood is used for assessment of calcium via in-house machines. Ethylenediaminetetraacetic acid (EDTA) plasma cannot be used, as a falsely low calcium concentration will be obtained due to chelation of the calcium by EDTA.
Ionised calcium concentrations need to be assessed at physiological pH, as an acidic pH will increase the ionised calcium concentration. The sample should be processed anaerobically because this will result in artificially decreased ionised calcium due to the resultant increase in pH.
There are many causes for hypercalcaemia in cats. Non-pathological causes, which do not require further investigation, include:
Transient increases in calcium can be seen with:
Persistent and pathological causes of hypercalcaemia (using HARDIONS acronym):
Clinical signs of hypercalcaemia include:
Investigations of hypercalcaemia:
In cats, the most common cause of a persistent ionised hypercalcaemia is idiopathic hypercalcaemia. This is a diagnosis of exclusion. The hypercalcaemia may be detected during routine screening. In one study, 46% showed no clinical signs3.
As it is a diagnosis of exclusion, other causes of hypercalcaemia need to be ruled out by performing the aforementioned investigations. Hormonal testing in these cases usually reveals a low normal PTH concentration, with PTHrP below the limit of detection.
Although some cats with idiopathic hypercalcaemia may be asymptomatic, treatment is advised as chronic hypercalcaemia can cause a wide variety of problems, such as uroliths, gastrointestinal signs and renal dysfunction.
Usually, the first step is to consider transitioning to a high fibre diet, as this should decrease the gastrointestinal absorption of calcium. Urinary diets to prevent calcium oxalate urolithiasis can also be considered as they contain a reduced amount of calcium and result in a neutral urinary pH that decreases the risk of calcium oxalate urolith formation.
If dietary therapy alone does not work, the next step is to consider treatment with glucocorticoids, such as prednisolone. Glucocorticoids will decrease intestinal absorption of calcium, renal tubular reabsorption of calcium and decrease skeletal mobilisation of calcium. The starting dose of oral prednisolone is 5mg PO q24hr per cat and can be increased as required to attain normocalcaemia.
If steroid therapy is ineffective or contraindicated, for example, the patient concurrently has diabetes mellitus, then bisphosphonates can be considered. These work by reducing the activity and number of osteoclasts and, therefore, decreasing calcium mobilisation from the bone.
Pamidronate can be administered intravenously, or oral medication with alendronate once a week can be considered. Ionised calcium should be remeasured prior to each dosing. Bisphosphonates can cause nephrotoxicity, so cats with pre-existing renal disease, or who are dehydrated, should not be treated with these agents.
In addition, alendronate can lead to oesophagitis and, therefore, it should be given with at least 10ml of water. A recent study of 12 cats has shown alendronate at a dose of 5mg/cat to 20mg/cat (median dose of 10mg/cat q1w) orally q1w was well tolerated and resulted in decreased ionised calcium concentrations over a six month period5.
Malignancy-associated hypercalcaemia is seen in approximately a third of feline hypercalcaemia cases, compared to two-thirds of canine cases6. In cats, this is most commonly noted in associated lymphoma or squamous cell carcinoma, although it has been seen with other neoplastic conditions; for example, multiple myeloma.
Cats with neoplasia have been found to have a higher serum calcium concentration than cats with renal failure or urolithiasis, however, there is significant overlap noted7.
Certain neoplasms secrete PTHrP and, therefore, result in hypercalcaemia.
Neoplasia can also result in hypercalcaemia by mechanisms independent of PTHrP. If a tumour invades the bone, such as squamous cell carcinoma or multiple myeloma, then osteolysis occurs, which can release calcium and result in hypercalcaemia.
Unlike idiopathic hypercalcaemia, where cats are generally still well, cats with underlying neoplasia are often systemically ill. Hormonal testing in these cases will reveal a low PTH and, possibly, a high PTHrP. Malignancy-associated hypercalcaemia can occur independent of PTHrP and a low PTHrP does not rule out underlying neoplasia.
Treatment of the underlying neoplasia usually results in normalisation of the calcium concentration. For severe elevations of calcium, additional supportive therapy – for example, fluid therapy with or without bisphosphonates – may be required. The fluid therapy is 0.9% saline, as it contains no calcium and will promote renal calcium excretion.
Prednisolone should not be used prior to thorough investigations as this may mask an underlying neoplasia, hampering effective diagnostics.
Total calcium may be elevated in chronic kidney disease; however, the ionised calcium is usually low or normal and only rarely elevated. The severity of hypercalcaemia has been shown to correlate with the severity of renal disease8.
As hypercalcaemia can result in renal disease, it poses a dilemma when a patient presents with both. In general, hypercalcaemia in patients with chronic kidney disease is usually mild. In renal disease, production of calcitriol is reduced, which results in secondary hyperparathyroidism.
Calcium-containing phosphate binders and aluminium-based phosphate binders have not been shown to result in feline hypercalcaemia, although it is a possibility2.
Vitamin D toxicity is uncommonly noted in cats, but has been seen in diets with excessive vitamin D concentration or following ingestion of products containing vitamin D, such as rodenticides12.
In cases of hypercalcaemia due to hypervitaminosis D, PTH concentrations are expected to be low due to negative feedback and increased vitamin D metabolites.
Primary hyperparathyroidism has been very rarely reported in feline medicine. It may be possible to palate the enlarged parathyroid gland on physical examination (approximately 57% of cases)13.
PTH is high or high normal in cats with this condition. In a hypercalcaemic cat, PTH secretion should be suppressed, so a PTH in the higher end of the reference range is abnormal and consistent with this condition. Surgical therapy is the treatment of choice.
As the hypercalcaemia will have resulted in atrophy of the remaining parathyroid glands, a postoperative hypoparathyroidism can occur and the patient must be closely monitored for hypocalcaemia and treated appropriately with calcium supplementation and calcitriol, which is tapered over time.
Stephanie Lalor
Job Title