Interaction of serum calcium with serum phosphorus important with hypercalcemia

Q Will you provide a brief review as to causes and management of hypercalcemia in older dogs and cats?

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.

Serum ionized calcium concentration

Total serum calcium and serum ionized calcium values are higher in dogs than in cats. In clinically healthy dogs and cats, serum ionized calcium concentration is typically proportional to the level of total serum calcium concentration. The serum ionized calcium concentration is usually 50-60 percent of total serum calcium concentration.

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.

Vitamin D toxicosis can result from oversupplementation with vitamin D3, ingestion of plants containing calcitriol glycosides, cholecalciferol rodenticide exposure and calcipotriol (Dovonex, United States and Canada; Daivonex, Europe human anti-psoriatic cream). Nonmalignant skeletal lesions include osteomyelitis (bacterial/fungal), 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 percent of hypercalcemic dogs are also azotemic. Azotemia is uncommon only in dogs with hyperparathyroidism. In hypercalcemic cats, renal failure is most commonly associated with hypercalcemia, occurring in 38 percent of cats with hypercalcemia. Neoplasia is the second most common cause of hypercalcemia, with 33 percent diagnosed with lymphosarcoma, 33 percent with squamous cell carcinoma, and the remaining diagnosed with leukemia, osteosarcoma, fibrosarcoma, undifferentiated sarcoma and bronchogenic carcinoma. Calcium oxalate urolithiasis is noted in about 15 percent of all cats with hypercalcemia.

In cats, the frequency of hypercalcemia without obvious explanation is increasing in clinical practice. Total serum calcium concentration is increased, often without obvious clinical signs, for months to more than one year. Serum ionized calcium concentration is increased, sometimes out of proportion to the degree of increase in total serum calcium concentration. Nephrocalcinosis may be observed on abdominal radiographs or renal ultrasonography, but renal function based on BUN and serum creatinine concentrations initially is normal.

Chronic renal failure eventually develops in most of these cats. Challenge with prednisone therapy results in long-term decreases in serum ionized and total serum calcium concentrations in some cats.

Treatment

Whether to institute aggressive treatment directed against hypercalcemia depends largely on the severity of presenting 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.

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 always the definitive treatment for hypercalcemia. Complete excision of isolated tumors 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.

Parenteral fluids, furosemide, glucocorticosteroids or combinations of these treatments will effectively reduce serum calcium concentrations in most animals with hypercalcemia. Normal saline solution (0.9% NaCl) is the preferred fluid solution for correction of intravascular volume deficit and for further mild volume expansion. Potassium supplementation is often necessary to maintain normal serum potassium concentration during extended periods of fluid treatment.

Furosemide follows rehydration and fluid volume expansion and is importance for treatment of persistent hypercalcemia. Furosemide (5 mg/kg initial intravenous bolus dose followed by 5 mg/kg per hour 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 significantly reduce the magnitude of persistent hypercalcemia in animals with lymphosarcoma, multiple myeloma, hypoadrenocorticism, hypervitaminosis D, or granulomatous disease, but glucocorticosteroids have little effect on other causes of hypercalcemia.

Several therapeutic modalities concomitantly are often needed in these cases. Diphosphonates assist in lowering serum calcium concentration. Etidronate disodium (Didronel; 5-15 mg/kg daily to twice daily) is a first-generation compound that is not well-absorbed orally but still is useful. Pamidronate disodium (Aredia; 1.3 mg/kg in 150 ml 0.9% saline solution in a two-hour intravenous infusion and can be repeated in one to three weeks) and risedronate (Actonel) are new-generation bisphosphonates that may be more effective than etidronate disodium. Calcitonin is an antidote for cholecalciferol rat poison but may be useful in other cases in which bone resorption is the primary cause of hypercalcemia.

Calcitonin treatment is expensive, effects may be short-lived as in hours, and the magnitude of its effect is unpredictable. Mithramycin (25 mcg/kg intravenous in 5% dextrose and water solution over two to four hours every two to four weeks) 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 concentration in hypercalcemia caused by the action of excess vitamin D metabolites.