Table 1

A To provide the answer to this important question I referred to the following article: Chew DJ, Nagode LA, Schenck PA: Disorders of hypercalcemia. Proc 19th Annual Forum ACVIM 19:670-672, 2001. An abbreviated summary of this article follows.

Total serum calcium concentration as reported in the serum chemistry profile is a total of the ionized calcium, complexed calcium and protein-bound calcium concentrations. Hypercalcemia is often reported when total serum calcium concentration is greater than 12.2 mg/dl in dogs and greater than 11.4 mg/dl in cats in most in-hospital or reference laboratories. The precise reference value when hypercalcemia exists should be determined only by each in-hospital or reference laboratory.

In diseased dogs and cats, serum ionized calcium concentration is not proportional to total serum calcium concentration and cannot be predicted from total serum calcium concentration. Ionized calcium concentration is often much lower than predicted in dogs and cats with renal failure, regardless if their total serum calcium concentration is low, normal or high.

Animals with hypoalbuminemia and corrected total serum calcium values may still have decreased levels of serum ionized calcium concentration. Animals with moderate to severe metabolic acidosis experience increases in their ionized calcium fraction because of a shift of calcium from protein-bound stores. For these reasons, measurement of serum ionized calcium concentration is recommended in all animals with renal failure or hypercalcemia.

Small increases in serum ionized calcium concentration above the normal range can have adverse physiologic consequences, whereas conditions increasing total serum calcium concentration without an increase in serum ionized calcium concentration do not exhibit deleterious effects.

Because serum ionized calcium concentration is affected by exposure to oxygen and pH, serum samples should be collected and handled anaerobically before analysis is done. When serum samples are collected and stored anaerobically, serum ionized calcium concentration does not change in samples stored up to 72 hours at room temperature or at 4° C. When delay in measurement of serum samples is done - as in sending samples to an outside reference laboratory, anaerobic collection with cold storage up to 72 hours will result in accurate assessment of serum ionized calcium concentration.

Calculated serum calcium-phosphorus product The interaction of serum calcium with serum phosphorus is important. Those animals with a calculated serum calcium-phosphorus product greater than 70 when total serum calcium concentration is multiplied with serum phosphorus concentration are most likely to have severe tissue changes associated with mineralization. Increased total serum calcium concentrations can be toxic to all body tissues, but foremost deleterious effects are to the kidneys, nervous system and cardiovascular system.

Most animals with total serum calcium concentration greater than 14.0 mg/dl will show some systemic signs, and those with serum calcium concentrations greater than 16.0 mg/dl are usually severely ill. Polydipsia, polyuria and anorexia are the most common signs attributed to hypercalcemia, although depression, weakness, vomiting and constipation may also occur. Uncommonly, cardiac arrhythmias, seizures, and muscle twitching are observed. Severe hypercalcemia that has developed rapidly can result in death.

Differential diagnoses The differential diagnoses for persistent hypercalcemia are heavily biased toward malignancy. Other conditions associated with hypercalcemia may 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 or container.

Causes associated with transient hypercalcemia include hemoconcentration, hyperproteinemia, hypoadrenocorticism and severe environmental hypothermia.

HARDIONS is an eponym technique used by Dr. Dennis Chew of The Ohio State University to remind us of several categories of disease that may result in hypercalcemia:

H = Hyperparathyroidism and HHM (humoral hypercalcemia of malignancy);
A = Addison's disease;
R = Renal disease;
D = Vitamin D toxicosis (includes granulomatous disease such as blastomycosis);
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.