The links: Hypercalcemia is one of the most common paraneoplastic syndromes, and cancer is the most common cause of hypercalcemia in
companion animals. Hypercalcemia of malignancy is usually associated with T-cell lymphoma and apocrine gland anal sac adenocarcinoma
in dogs and lymphoma, bronchogenic carcinoma, and squamous cell carcinoma in cats.
The signs: Clinical signs of hypercalcemia include polyuria, polydipsia, lethargy, weakness, nausea, anorexia, vomiting, constipation,
diarrhea, and weight loss.
The tests: The main diagnostic tests include a CBC, a serum chemistry profile, urinalysis, a radiographic or ultrasonographic examination,
a rectal examination (in dogs), and ionized calcium, PTH, and PTHrP measurements.
The treatment: In addition to addressing the primary tumor, supportive treatment consists chiefly of fluid therapy and furosemide, as well
as, in some cases, glucocorticoids and aminobisphosphonates.
Cancer accounts for about 50% of all deaths in companion animals more than 10 years of age.1 Cancer-related morbidity and mortality can result not only from neoplastic invasion of vital organs such as the pulmonary
parenchyma or liver but also from neoplasm-associated alterations in bodily structure or function that occur distant to the
primary tumor and any metastatic lesions. These alterations are classically referred to as paraneoplastic syndromes. Hypercalcemia is a common paraneoplastic syndrome in people and companion animals that frequently contributes to morbidity.2-6 Various tumor-related factors may lead to paraneoplastic hypercalcemia, including the release of humoral peptides, the abnormal
expression of membrane-bound ligands, and dysregulated enzymatic pathways responsible for calcium homeostasis.7-9
The most common cause of hypercalcemia in companion animals is cancer, with about 45% to 65% of hypercalcemic dogs and 10%
to 30% of hypercalcemic cats having underlying neoplasia.7,10-13 The cancers that most frequently lead to paraneoplastic hypercalcemia are T-cell lymphoma and apocrine gland anal sac adenocarcinoma
in dogs and lymphoma, bronchogenic carcinoma, and squamous cell carcinoma in cats.7,10,14 Given the prevalence of cancer in geriatric pets and the morbidity associated with hypercalcemia, this review focuses on
the diagnosis and treatment of paraneoplastic hypercalcemia in dogs and cats.
Calcium homeostasis is a tightly regulated physiologic process whereby the body maintains steady-state concentrations of ionized
calcium, the biologically active fraction of total calcium, in the plasma and extracellular fluid through a dynamic interaction
among key hormones and vitamins and their respective target organs. Three principal soluble mediators balance whole body calcium
concentrations: parathyroid hormone (PTH), calcitonin, and calcitriol (the biologically active form of vitamin D). PTH and
calcitriol are the master regulators of calcium homeostasis, with calcitonin playing a lesser, yet essential role.
These mediators exert their biologic activities on three target organs: the kidneys, intestines, and bone matrix. If serum
calcium concentrations are decreased, the parathyroid glands secrete PTH to act on 1) the distal renal tubules, causing calcium
reabsorption and phosphorus excretion from the kidney; 2) the intestines indirectly through the conversion of calcidiol to
highly active calcitriol in the proximal renal tubules, which will increase intestinal absorption of calcium and phosphate;
and 3) the bones, either by stimulating the activity of existing bone cells (early effect) or by increasing the number of
osteoclasts and their bone resorption activities (late effect) via PTH's effect on osteoblasts.
Conversely, if serum calcium concentrations are elevated, PTH secretion is down-regulated, leading to 1) a net calcium loss
through the distal tubules, 2) a reduction in intestinal calcium absorption, and 3) diminished osteoclastic bone resorption.
Both PTH and calcitriol promote calcium retention within the body, while calcitonin reduces calcium mobilization from the
skeleton chiefly by inhibiting osteoclastic bone resorption.9,15 While PTH has a positive feedback effect on calcitriol synthesis, the main negative feedback mechanisms on calcitriol production
are calcitriol itself, as well as hypercalcemia and high phosphorus concentrations.16 Calcitriol also provides a negative feedback effect on PTH secretion.