Got milk? The clinical approach to hypercalcemia (Proceedings)


Got milk? The clinical approach to hypercalcemia (Proceedings)

Apr 01, 2010

Small animal patients presenting with a primary complaint of hypercalcemia can often be a diagnostic challenge. Typically, the clinical signs are insidious and nonspecific. A thorough work-up, sometimes necessitating repetition in diagnostic steps may be required to determine the etiology of the hypercalcemia. Treatment should be directed toward resolution of the underlying disease.

Calcium is an important electrolyte in the body and performs two main functions: maintenance of tooth and bone structure and as an important intracellular second messenger. In the latter role, Ca2+ controls many cellular processes including muscle contraction, nerve function, blood coagulation, enzyme activity, cell secretion, and cell adhesion. There is a large concentration gradient of Ca2+ between the extracellular fluid and cell cytoplasm; this favors Ca2+ entry into the cell to activate signal transduction processes. Serum calcium exists in three forms: 50% is ionized (physiologically-active form), 45% is protein bound (primarily albumin and to a lesser extent globulin), and 5% is complexed to anions (citrate, bicarbonate, phosphate, or lactate). The skeletal structure holds a huge reserve of calcium, containing >99% of calcium, mostly in the mineral phase.

Serum ionized calcium is regulated within a narrow range that is controlled by two principal hormones: parathyroid hormone (PTH) and the active form of vitamin D, calcitriol. PTH, synthesized by the chief cells of the parathyroid gland, acts on the bone to increase resorption and calcium mobilization. It also works on the kidney to increase calcium reabsorption and decrease phosphorous reabsorption, and to increase the formation of calcitriol. The net result of PTH secretion is to increase calcium and decrease phosphorous in the serum. Vitamin D is formed from cholesterol precursors in the skin by the action of sunlight. The active form, calcitriol, is formed in the kidney. Vitamin D works primarily on the intestine to increase calcium and phosphorous absorption. The net effect of vitamin D is to increase plasma calcium and phosphorous. Calcitonin is used pharmacologically for treatment of hypercalcemia, although its exact physiologic role is under debate. It is regulated by GI hormones and is probably important in controlling postprandial hypercalcemia. It also appears to be important in calcium regulation in immature animals. It probably is a minor player in the day-to-day regulation of plasma calcium.

Causes of hypercalcemia

The most common cause of hypercalcemia in dogs and cats is malignancy. The neoplastic diseases reported to cause hypercalcemia include lymphoma, anal sac apocrine cell adenocarcinoma, multiple myeloma, mammary carcinoma, thymoma, oral melanoma hepatoblastoma, chronic lymphocytic leukemia, and nasal carcinoma, with lymphoma being the most common. Hypercalcemia seen with malignant disease probably results primarily from enhanced osteoclastic bone resorption mediated by factors systemically released by neoplastic cells. One such factor has been has been identified in the dog as parathyroid hormone related protein (PTHrP) which is identical to PTH at the N-terminal region and can bind with equal affinity to PTH receptors. By activating PTH receptors, PTHrP causes hypercalcemia by a similar mechanism as that of an excess of PTH. Osteolysis from primary bone tumors are a rare cause of hypercalcemia.

Other common disorders associated with hypercalcemia are hypoadrenocorticism chronic renal failure, and urolithiasis in cats. Although in these retrospective studies, a significant number of Addisonian animals were reported to be hypercalcemic, the pathogenesis of the hypercalcemia is unknown. Dogs and cats with chronic renal failure demonstrate hypercalcemia uncommonly, and it is thought that decreased renal calcium excretion and PTH-mediated osteoclastic activity from renal secondary hyperparathyroidism may be responsible. In the cat, idiopathic hypercalcemia of mild to moderate severity has been described. In some cases it has been associated with calcium oxalate urolithiasis and has resolved with discontinuation of an urinary acidification diet. The pathogenesis of hypercalcemia with this condition is unknown.

Rarer etiologies of hypercalcemia in the dog and cat include primary hyperparathyroidism and hypervitaminosis D. Primary hyperparathyroidism may result from parathyroid hyperplasia, adenoma or adenocarcinoma, which are all rare in small animals. Hypervitaminosis D, most commonly results from vitamin D-containing rodenticides or medications, but may be seen with over supplementation with vitamin D, especially in small dogs being given human vitamins. Infectious and inflammatory disorders such as blastomycosis, coccidioidomycosis, feline granulomatous disease, endometritis, and schistosomiasis rarely are reported to cause hypercalcemia in dogs and cats. A recent report also details hypercalcemia following renal transplantation in the cat.

Clinical signs

How does one recognize a hypercalcemic patient? The clinical presentation of hypercalcemia can range from the animal with no clinical abnormalities in which hypercalcemia was found on a routine chemistry to a severly weak or even comatose one. Usually, the clinical signs of hypercalcemia are insidious and so mild that many owners fail to recognize that there is anything wrong with their pet. The most common clinical sign of hypercalcemia is polyuria/polydipsia (PU/PD). This is a direct effect of hypercalcemia on the concentrating ability of the kidney; however, hypercalcemia can also cause acute or chronic renal failure, also resulting in PU/PD. Hypercalcemic animals may also present with signs of lower urinary tract disease since they are predisposed to urinary tract infections and the formation of calcium uroliths. Other less commonly recognized clinical signs include: muscle weakness/atrophy, depression, anorexia, vomiting, constipation, bone pain, pathological fractures, and cardiac arrhythmias. Signs related to specific tumors may also be present.

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