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Hypercalcemia is an elevated circulating blood calcium level.

Calcium is a vital intracellular and extracellular ion involved in neuronal activation, muscle contraction, enzymatic reactions, hormone secretion, and bone matrix.

Normal calcium homeostatic mechanisms maintain extracellular calcium concentrations within a narrow normal range of 9 - 11.4 mg/dL.

Extracellular calcium exists in three forms: ionized (the biologically active form), complexed (to plasma buffers), and protein-bound (mainly to albumin). Most commonly, total calcium is measured on serum biochemical analyses and represents the sum of all calcium fractions. Serum-ionized calcium (iCa) concentration is a more accurate measure of hypercalcemia than total serum calcium or corrected serum calcium concentrations[1].

The most common causes of ionized hypercalcemia are neoplasia (termed hypercalcemia of malignancy), followed by renal failure, hyperparathyroidism, and hypoadrenocorticism. Dogs with lymphoma and anal sac adenocarcinoma have higher serum iCa concentrations than those with renal failure, hypoadrenocorticism, and other types of neoplasia. Chronic metabolic acidosis associated with chronic renal disease changes the ionized calcium (i-Ca) fraction, usually increasing its concentration[2].

Hypercalcemia of malignancy manifests as a result of three underlying pathological processes associated with neoplasia:

  • interference with 1 alpha-hydroxylase activity, leading to unregulated conversion of calcidiol to active calcitriol and enhanced intestinal absorption of calcium[3][4]
  • hypersecretion of parathyroid releasing protein (PTHrP), a polypeptide structurally similar to intact parathyroid hormone[5][6]
  • heightened activity of interleukin-1, interleukin-6 and tumor necrosis factor[7]. The production and secretion of these humoral mediators lead to pathologic increases in osteoclastic resorption, often without visible radiographic bone lesions.

A list of causes of ionized hypercalcemia include, in order of importance:

- Lymphoma[8], polyostotic lymphoma[9]
- Thymoma[10]
- Osteosarcoma
- Anal sac adenocarcinoma
- Hepatoid gland carcinoma
- Multiple myeloma[11]
- Hypoadrenocorticism
- Hypoaldosteronism[12]
- Hypothyroidism[13]
- Hyperparathyroidism[14]
- Vitamin D toxicosis
- Waldenström's macroglobulinemia[15]
- Schistosoma japonicum[16]
- Heterobilharzia americana[17]
- Leishmania spp[18]
- Hepatozoon canis[19]
- Pythium insidiosum gastric granuloma[20]
- Blastomyces spp[21]

This can be summarized by the common mnemonic - 'HARD IONS':

A tentative diagnosis of hypercalcemia can be established from blood levels showing a persistent, fasting total calcium >12 mg/dL, but elucidation of underlying disease processes must be investigated to accurately diagnose the cause.

Vitamin D toxicosis is associated with hypercalcemia as well as hyperphosphatemia.

Because the most commonly reported cause of hypercalcemia is lymphoma, evaluation of peripheral lymph nodes with aspiration cytology (even if they are normal on palpation) is warranted in patients with unexplained hypercalcemia[25].

Thoracic radiographs may be indicated to assess the presence of a mediastinal mass (lymphoma, thymoma), metastatic neoplasia, fungal pneumonia, osteopenia, orlytic bone lesions. Abdominal radiographs may have evidence of mass effect, hepatosplenomegaly, bony changes, uroliths, or renal mineralization.

A parathyroid ultrasound is indicated to evaluate size and shape of the parathyroid glands for evidence of primary or secondary hyperparathyroidism.

Treatment is dependent upon underlying cause, but management of hypercalcemia involves aggressive intravenous fluid therapy. To reverse increased calciuresis through an improved glomerular filtration rate, fluids devoid of calcium such as physiologic saline (isotonic saline solution - 0.9% sodium chloride) is recommended.

Other drugs which may assist include loop diuretics such as furosemide, insulin and aminobisphosphonates, chiefly zoledronate and pamidronate[26].

In cases of vitamin D toxicosis, calcitonin also reduces osteoclastic activity and hypercalcemia.


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  3. Rosol TJ et al (1992) Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia. Endocrinology 131:1157-1164
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