INTRODUCTION

When a serum sample is submitted to the laboratory, typically the total serum calcium concentration is what is reported. Total calcium includes ionized calcium, complexed calcium, and protein-bound calcium. In most laboratories, hypercalcemia is documented when serum total calcium concentration is > 12.0 mg/dL in dogs. The exact value when hypercalcemia exists must be determined for each laboratory. Serum total calcium and serum ionized calcium values are lower in cats than in dogs. In our laboratory, hypercalcemia in dogs is defined when the total serum calcium is greater than 11.6 mg/dL and the ionized calcium concentration is greater than 6.0 mg/dL.

In clinically normal animals, serum ionized calcium is typically proportional to the level of serum total calcium (ionized calcium is usually 50–60% of total calcium). However, in diseased animals, serum ionized calcium is NOT proportional to total serum calcium, and cannot be predicted from total serum calcium. Ionized calcium is often much lower than predicted in patients with renal failure, regardless of their serum total calcium level (low, normal, or high). Patients with hypoalbuminemia and “corrected” serum total calcium values may still have decreased levels of ionized calcium. Patients with moderate to severe metabolic acidosis undergo increases in their ionized calcium fraction due to shifting of calcium from protein-bound stores of calcium. For these reasons, measurement of serum ionized calcium concentration is recommended in all patients with renal failure or hypercalcemia. Since ionized serum calcium concentration is affected by exposure to oxygen and pH, serum samples should be collected and handled anaerobically before analysis. Serum ionized calcium concentration does not change in samples stored up to 72 hours at room temperature, or at 4°C when samples are collected and stored anaerobically. When delay in measurement of serum samples is necessary (as in sending samples to an outside laboratory), anaerobic collection with cold storage up to 72 hours will result in the most accurate assessment of serum ionized calcium.

CLINICAL SIGNS OF HYPERCALCEMIA

Small increases in ionized serum calcium concentration above normal can have adverse physiologic consequences, whereas conditions increasing total serum calcium without an increase in ionized calcium do not exhibit deleterious effects. Thus, measurement of ionized serum calcium concentration is of utmost importance. The degree of interaction with serum phosphorus is important, as those with a total serum calcium times phosphorus concentration product greater than 70 are most likely to have severe tissue changes associated with mineralization. Hypercalcemia can be toxic to all body tissues, but major deleterious effects are on the kidneys, nervous system, and cardiovascular system. Most animals with total serum calcium greater than 15.0 mg/dL will show systemic signs, and those with serum calcium concentrations greater than 18.0 mg/dL are severely ill. Polydipsia, polyuria, and anorexia are the most common clinical signs attributed to hypercalcemia, though depression, weakness, vomiting, and constipation can also occur. Uncommonly, cardiac arrhythmias, seizures, and muscle twitching are observed. Severe hypercalcemia that has developed rapidly (hypervitaminosis D) can result in death.

DIFFERENTIAL DIAGNOSES OF HYPERCALCEMIA

Diseases result in hypercalcemia by causing increased bone resorption of calcium, decreased renal excretion of calcium, increased GI absorption of calcium, increased serum binding of calcium to proteins/complexes, or a combination of these processes. The causes of hypercalcemia noted in referral hospitals may not reflect the same frequency of diagnosis encountered in primary care facilities. Observations from a primary care biochemistry laboratory indicate that renal failure is most commonly associated with hypercalcemia in the dog.

Hypercalcemia can be transient and inconsequential (common), persistent and inconsequential (occasionally), or persistent and pathologic. The differential diagnoses for persistent pathologic hypercalcemia are heavily biased toward malignancy. Nonpathologic conditions associated with hypercalcemia include non-fasting (minimal increase), physiologic growth of young animals, laboratory error, and spurious as a result of lipemia or detergent contamination of the sample/tube. Transient/inconsequential causes associated with hypercalcemia include hemoconcentration, hyperproteinemia, hypoadrenocorticism, and severe environmental hypothermia. Diseases result in pathologic, persistent hypercalcemia by causing increased bone resorption, decreased renal excretion of calcium, increased GI absorption of calcium, increased serum binding of calcium to proteins/complexes, or combinations of these processes. HARDIONS is an eponym technique used to remind us of several categories of disease that may result in hypercalcemia: H = Hyperparathyroidism (primary and tertiary), HHM (humoral hypercalcemia of malignancy); A = Addison’s Disease; R = Renal Disease; D = Vitamin D toxicosis (includes granulomatous disease); I = Idiopathic (mostly cats); O = Osteolytic (osteomyelitis, immobilization), N = Neoplasia (HHM and local osteolytic hypercalcemia); S = Spurious.

Malignancies typically associated with hypercalcemia include lymphoma, anal sac apocrine gland adenocarcinoma, thymoma, and carcinomas of the lung, pancreas, skin, nasal cavity, thyroid, mammary gland, and adrenal medulla. Other hematologic malignancies associated with hypercalcemia include multiple myeloma, lymphoma, myeloproliferative disease, and leukemia. Granulomatous diseases resulting in hypercalcemia include blastomycosis and other fungal diseases, dermatitis, panniculitis, and injection site granuloma. Vitamin D toxicosis can result from oversupplementation with vitamin D3, ingestion of plants containing calcitriol glycosides, cholecalciferol rodenticide exposure, and calcipotriol (Dovonex anti-psoriatic cream). Nonmalignant skeletal lesions include osteomyelitis (bacterial/mycotic), hypertrophic osteodystrophy (HOD), and disuse osteoporosis (immobilization). Other causes of hypercalcemia may include excessive use of intestinal phosphate binders, excessive calcium supplementation (calcium carbonate), hypervitaminosis A, milk-alkali syndrome, thiazide diuretics, acromegaly, thyrotoxicosis, postrenal transplantation, and aluminum exposure.

In hypercalcemic dogs, neoplasia is the most common underlying diagnosis, followed by hypoadrenocorticism, primary hyperparathyroidism, and chronic renal failure. Approximately 70% of hypercalcemic dogs are also azotemic, with azotemia uncommon only in dogs with hyperparathyroidism.

Frequency of Disease Associated with Hypercalcemia

TREATMENT OF HYPERCALCEMIA

The urgency to institute aggressive treatment directly against hypercalcemia depends largely on the severity of clinical signs, regardless of the specific level of hypercalcemia. The trend in magnitude of hypercalcemia plays a role in this decision, as rapidly rising hypercalcemia justifies more aggressive intervention. Unfortunately, there is no absolute serum calcium concentration that can be used as a guideline for the decision to treat aggressively.

Removal of the underlying cause is the definitive treatment for hypercalcemia, but this is not always immediately possible. Many animals with pathologic hypercalcemia will have an associated malignancy that is quickly diagnosed, but not readily treated. Complete excision of isolated neoplasms will abolish hypercalcemia, and in animals with disseminated metastases, multicentric neoplasia, or nonresectable primary malignancy, tumor burden and hypercalcemia may be decreased by appropriate chemotherapy, radiation therapy, and immunotherapy. Supportive therapy is often necessary to decrease serum calcium concentration to less toxic levels. Unfortunately, there is no single treatment protocol consistently effective for all causes of hypercalcemia, and thus regimens must be tailored for each patient.

Parenteral fluids, furosemide, sodium bicarbonate, glucocorticosteroids, or combinations of these treatments will effectively reduce serum calcium concentrations in most animals with hypercalcemia. The first goal of fluid therapy is to correct dehydration, because hemoconcentration contributes to increased serum ionized calcium concentration. Physiologic saline (0.9% NaCl) is the solution of choice for correction of intravascular volume deficit, and for further mild volume expansion. Potassium supplementation is often necessary to maintain normal serum potassium during extended periods of fluid treatment.

Furosemide (Lasix^®) follows rehydration and fluid volume expansion in importance for treatment of persistent hypercalcemia. Furosemide (5 mg/kg IV initial bolus dose followed by 5 mg/kg/hr infusion) can be helpful in acutely decreasing serum calcium concentration by a maximum of about 3 mg/dL. Less aggressive regimens of furosemide administration may be effective in combination with other treatments, or for chronic management of hypercalcemia.

Glucocorticosteroids can contribute significantly in reducing the magnitude of persistent hypercalcemia in patients with lymphosarcoma (cytolysis), multiple myeloma, hypoadrenocorticism, hypervitaminosis D, or granulomatous disease, but they have little effect on other causes of hypercalcemia. Steroids exert their effect mainly by reducing bone resorption, decreasing intestinal calcium absorption, and increasing renal calcium excretion. Steroids should be withheld if a definitive diagnosis has not been established.

Recently, chemical ablation of the parathyroid gland has been reported as an effective means of reducing serum calcium concentrations in dogs with primary hyperparathyroidism. Guided by ultrasound, ethanol is injected into the parathyroid mass. Both total and ionized calcium concentrations return to normal within 24 hours in most dogs. Transient hypocalcemia may develop, and may require treatment.

Several modalities of therapy concomitantly are often necessary. Diphosphonates are osteoclast “poisons” that assist in lowering serum calcium. Etidronate (Didronel–EHDP) is a first generation compound that is not well absorbed orally, but can still be useful. Pamidronate and risedronate are new-generation bisphosphonates that are better absorbed, but have not been widely used in veterinary medicine. Calcitonin is an antidote for cholecalciferol rat poison, but may be useful in other cases in which bone resorption is a major cause of hypercalcemia. Calcitonin treatment is expensive, effects may be short-lived (hours), and the magnitude of its effect is unpredictable. Infusions of sodium bicarbonate may be given during hypercalcemic crisis (cardiac arrhythmia, severe depression, acute renal failure) that have not responded to other treatments. Mithramycin has also been shown to decrease serum calcium levels for several days, though extreme caution must be used to properly infuse low doses over several hours to reduce renal and hepatic toxicities. Low calcium diets are only helpful in substantially lowering serum calcium in hypercalcemia caused by the action of excess vitamin D metabolites.

Treatment of Hypercalcemia