Hypercalcemia

Hypercalcemia is not common in any species but is encountered more often in dogs and horses than in cats and cows. Evaluation of a patient with Ca result above or at the top of the reference range should be done with consideration of albumin concentration and evidence of acid-base imbalance. A Ca result near the high limit of the reference range in a hypoalbuminemic animal indicates hypercalcemia and a need to consider causes of hypercalcemia. The deleterious effects of hypercalcemia are more pronounced in an animal with concurrent acidosis and ameliorated somewhat by alkalosis. Hypercalcemia has numerous effects on the body. Renal: In the kidney, calcium has several deleterious effects. 1) Nephrogenic diabetes insipidus: Calcium decreases the renal concentrating ability by inhibiting the response to ADH and reducing medullary tonicity (via decreasing NaCl absorption in the loop of Henle, decreasing the permeability of the collecting ducts to urea and enhancing renal medullary blood flow). This results in polyuria and polydipsia with a low urine specific gravity (< 1.030). 2) Renal tubule damage: This is due to decreased GFR from renal vasoconstriction. This can result in renal ischemia and renal tubular dysfunction. In addition, hypercalcemia can result in mineralization in the kidney. This results in ischemia of the renal tubules and urolithiasis (if severe). Animals with hypercalcemia often present with renal failure. After the cause of the hypercalcemia has been identified and corrected, renal function should be reassessed. 3) Urinary tract infections: Calcium predisposes to urinary tract infections, via unknown mechanisms. All tissues: If the calcium phosphate product is > 60 - 80 mg/dL, soft tissue mineralization can result causing organ dysfunction. Gastrointestinal system: Decreased contractility. Neuromuscular system: Decreased excitability. Cardiovascular system: Increased excitability with arrythmias and ventricular fibrillation. Pathophysiologic mechanisms of hypercalcemia Increased absorption. Increased osteolysis. Decreased renal excretion. Increased protein binding (under these situations, ionized calcium is often normal, but total calcium is elevated). Causes of hypercalcemia Physiologic. Young, growing dogs, especially large breeds, often have Ca slightly higher than the reference range for adult dogs. Primary hyperparathyroidism. This has been reported in both dogs and cats and is due to chief cell neoplasia (adenoma or carcinoma) or hyperplasia. In dogs, it is familial in Keeshonds and inherited in German Shepherd dogs. There is autonomous PTH secretion, with hypercalcemia, hypophosphatemia and isosthenuria. Calcium uroliths may be observed in dogs but not cats. Clinical signs are vomiting, anorexia, polyuria, polydipsia, folding fractures (from osteolysis), muscle weakness. Cats are often not polyuric or polydipsic. Note that phosphate may be normal or even high if the animal has a decreased GFR. Primary hyperparathyroidism is diagnosed by identifying a parathyroid adenoma by surgical exploration and biopsy and/or by measuring high or normal PTH concentration in conjunction with high ionized calcium values. Humoral hypercalcemia of malignancy. Hypercalcemia is a paraneoplastic syndrome in domestic animals and is a great tumor marker. The most common cause of persistent hypercalcemia in dogs and cats is non-parathyroid neoplasms. Lymphoid neoplasms are the most common of the tumors to cause hypercalcemia. The second most common tumor in dogs associated with hypercalcemia is adenocarcinoma of the apocrine glands of the anal sac. Other tumors that are sporadically associated with hypercalcemia are carcinomas originating in various tissues. Primary or metastatic bone tumors occasionally cause hypercalcemia. In horses, hypercalcemia has been seen with lymphoma, ameloblastoma, gastric SCC and an adrenal cortical carcinoma. In most instances, the hypercalcemia is due to elaboration of PTHrP, although other cytokines (IL-6, IL-1) and vitamin D are involved. Hypercalcemia in multiple myeloma is usually due to localized bone lysis from IL-6 secretion by osteoblasts and fibroblasts in the bone marrow stroma. Addison's disease. Up to 28-45% of dogs have high total calcium (with normal ionized calcium) in Addison's disease. The hypercalcemia is thought to be due to enhanced absorption of calcium in the gastrointestinal tract, hemoconcentration, decreased GFR from volume contraction and increased complexing and protein binding of calcium. Replacement therapy with corticosteroids returns the calcium to normal within a few days. Vitamin D toxicity. Until recently, hypervitaminosis D was a rare cause of hypercalcemia. Rodenticides containing cholecalciferol (Rampage, Quintox, and Rat-Be-Gone) are now widely available. Ingestion of these rodenticides produces marked hypercalcemia (Ca of 15 to 20 mg/dl) within 24 hours. Other causes of hypervitaminosis D are excessive dietary supplementation and ingestion of plants whose leaves contain cholecalciferol (Cestrus diurnum or day-blooming jessamine, Solanum malacoxylon, and Trisetum flavescens). In addition, lymphomas can generate vitamin D as can macrophages. Vitamin D is responsible for the hypercalcemia secondary to granulomatous disease (e.g. blastomycosis, histoplasmosis, and coccidioidomycosis) in dogs. Vitamin D toxicosis induces hypercalcemia and hyperphosphatemia. Chronic renal failure. Usually in CRF total calcium is normal or decreased. However, 10-20% of cases (especially in dogs with inherited renal disease), calcium can be elevated. However, ionized calcium is normal or even decreased. The mechanism is unknown, however autonomous PTH secretion with decreased PTH degradation, reduced calcium excretion and increased complexing with anions are hypotheses. Hypercalcemia should be attributed to renal failure only after other causes of hypercalcemia have been considered and ruled out. In dogs and cats, hypercalcemia is much more likely to be the cause of renal failure with signs of azotemia, polyuria/polydipsia, and poorly concentrated urine than the result of renal failure. Note that hypercalcemia is a frequent finding (with decreased phosphate) in horses with chronic renal failure, especially if on a high calcium diet. Miscellaneous causes: osteolytic bone lesions (rare), vitamin A toxicosis, calcium carbonate ingestion, hyperalbuminemia (spurious), hypothermia, hyperthyroidism (increased bone resorption) and idiopathic hypercalcemia in cats with renal failure. Conditions iPTH iCa vitamin D primary hyperPTH Normal or high High Not required renal hyperPTH High Low Not required Hypercalcemia of malignancy Low High Normal or high Vit D intoxication Low High High Measurement of intact parathyroid hormone (iPTH), ionized calcium (ICa), and 25-hydroxyvitamin D can usually discriminate between the various causes of hypercalcemia in dogs. Guidelines for interpretation of these tests in combination is shown are shown in the table at right.

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