Introduction

When a serum sample is submitted to the laboratory, typically it is the total serum calcium concentration that 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 > 11.0 mg/dL in cats. 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 cats is defined when the total serum calcium is greater than 10.1 mg/dL and the ionized calcium concentration is greater than 5.5 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 hr 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 hr 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.

The most common clinical signs associated with hypercalcemia in cats are anorexia and lethargy (88%), followed by GI signs, polyuria/polydipsia, urinary, and neurologic signs. Vomiting and polyuria/polydipsia are reported much less commonly in cats with hypercalcemia, as compared to dogs. The magnitude of hypercalcemia is not related to the clinical signs.

Differential Diagnosis of Hypercalcemia

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 in cats include lymphoma and a variety of carcinomas. It is not necessary for a cat to be FeLV positive to develop lymphoma and hypercalcemia. Granulomatous diseases are uncommon causes of hypercalcmeia in cats. Vitamin D toxicosis can result from over-supplementation with vitamin D3, ingestion of plants containing calcitriol glycosides, cholecalciferol rodenticide exposure, and Calcipotriol (Dovonex anti-psoriatic cream). Cats receiving calcium carbonate at higher doses as a form of intestinal phosphate binder sporadically develop hypercalcemia. Idiopathic hypercalcemia is an important differential diagnosis in cats; it is very uncommon in dogs.

In a retrospective study of 71 cats, mean serum calcium concentration for all groups of hypercalcemic cats was 12.2 ± 1.6 mg/dL (median 11.5). Serum calcium concentration was highest in cats with neoplasia (13.5 ± 2.5 mg/dL) compared to cats with renal failure alone (11.5 ± 0.4), or urolithiasis and renal failure (11.5 ± 0.5).

In hypercalcemic cats, renal failure is most commonly associated with hypercalcemia, occurring in 38% of cats with hypercalcemia. Approximately one-third of hypercalcemic cats diagnosed with renal failure also have urolithiasis. Calcium oxalate urolithiasis is noted in about 15% of all cats with hypercalcemia. Neoplasia (without renal involvement) is diagnosed in approximately 21% of hypercalcemic cats. Approximately one-third of the neoplasias are lymphosarcomas, and one-third are squamous cell carcinomas. The remaining tumors can include leukemias, multiple myeloma, osteosarcoma, fibrosarcoma, undifferentiated sarcoma, and bronchogenic carcinoma. Primary hyperparathyroidism accounts for about 5.6% of hypercalcemic cats, and non-parathyroid endocrine disease affects approximately 5.6% of cats with hypercalcemia. Infectious disease possibly associated with granulomatous inflammation also accounts for about 5.6% of cases. In addition, hypercalcemia may be associated with cholecalciferol rodenticide toxicosis (vitamin D toxicosis), hypoadrenocorticism, and liver disease.

Frequency of Associated Condition with Hypercalcemia in Cats (Savary et al., 2000)

Idiopathic Hypercalcemia of Cats

Though hypercalcemia is less common in cats than in dogs, recognition of an important new syndrome in cats has emerged since 1992. In cats, the frequency of hypercalcemia without obvious explanation is increasing. We have observed several young to middle-aged cats with mild to moderate hypercalcemia with no definable etiology following standard diagnostics. Serum total calcium is increased for months to more than one year, often without obvious clinical signs. Ionized calcium is increased, sometimes out of proportion to the degree of increase in total serum calcium. Nephrocalcinosis may be observed on radiographs or renal ultrasonography, but renal function based on BUN and serum creatinine is usually normal initially. Chronic renal failure eventually develops in some of these cats, and urinary calculi develop in a few of these cases. These cats have no evidence for malignancy based on thoracic and skeletal radiography, abdominal sonography, bone marrow evaluation, and in some instances, full necropsy. Serology for FeIV and FIV has been negative, and T4 values have been normal. PTH levels have been normal or low, PTHrP has not been detectable, and 25-(OH)-vitamin D levels have been within normal limits. Calcitriol levels are usually normal. Venous blood gas analysis has not revealed any major acid-base disturbance (chronic acidosis could have explained chronic ionized hypercalcemia). Exploration of the cervical region has failed to reveal evidence for primary hyperparathyroidism; subtotal parathyroidectomy has failed to result in resolution of hypercalcemia in those cases in which this was performed. A change to a high fiber diet was recommended for most of these cats, in the hope that dietary calcium would be less available for intestinal absorption, but this did not change serum calcium levels in any cats. Challenge with prednisone therapy results in long-term decreases in ionized and total serum calcium in some cats.

Idiopathic Hypercalcemia in 20 Cats (Midkiff et al., 2000)

Calcium Oxalate Urolithiasis

Veterinary urologists from the University of Minnesota Urolithiasis Center have noted that approximately one-third of calcium oxalate urolith-forming cats in their series have associated hypercalcemia. Some of these hypercalcemic cats decreased their serum calcium concentration following a diet change to one with increased fiber. A report from the University of Georgia has also noted what appears to be idiopathic hypercalcemia in five calcium oxalate stone-forming cats. Complete calcium-regulatory hormone profiles were not been published from these cats. The hypercalcemia in cats of this study resolved after discontinuation of urinary acidifying therapy or a dietary change, or both.

It is not clear if the pathophysiology of idiopathic hypercalcemia in oxalate stone-forming cats is the same as for those cats that do not form stones. It is quite possible that both represent different phases of the same disease process. Future studies are needed that include full analysis of calcium regulatory hormones including calcitriol and ionized calcium measurements. Detailed diet history needs to be collected and assessed for a possible role of diet. It is likely that studies of calcium balance that include dietary intake, intestinal absorption, fecal excretion, bone resorption, and urinary excretion will be needed to at least discover the mechanism of the hypercalcemia. Markers of increased bone turnover that appear in urine may prove useful to help determine if bone resorption contributes to this form of hypercalcemia. Measurement of vitamin A metabolites and aluminum should also be performed in an attempt to examine some of the more unusual possibilities for the development of hypercalcemia. Alkali treatment as a challenge to assess the effects of chronic dietary acidification should be considered to see if the hypercalcemia resolves. Bisphosphonate treatment could also be considered to see if hypercalcemia resolves.

Vitamin D in Cats

The effects of excessive vitamin D intake (more than three times the maximum AAFCO allowance) on growth and renal function in breeding queens and kittens have been investigated, finding that cats are extremely resistant to the toxic effects of excessive vitamin D intake. Mild hypercalcemia did occur in kittens eating a high vitamin D, high calcium diet (34,000 IU vitamin D/kg diet, 2.3% calcium, 0.4% magnesium). Hypercalcemia did not occur in kittens that were fed a high vitamin D, low magnesium diet (34,000 IU vitamin D/kg diet, 0.7% calcium, 0.2% magnesium), or a control diet (4800 IU vitamin D/kg diet, 0.7% calcium, 0.4% magnesium). These results suggest that mild hypercalcemia may occur in growing kittens fed a diet that is high in vitamin D and calcium.

Selected Reading

1.  McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases. J Am Anim Hosp Assoc 1999; 35(4): 297-301.

2.  Midkiff AM, Chew DJ, Randolph JF, Center SA, DiBartola SP. Idiopathic hypercalcemia in cats. J Vet Intern Med 2000; 14: 619-626.

3.  Savary KCM, Price S, Vaden SL. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000; 14: 184-189.