Hypercalcemia in Dogs and Cats
Hypercalcemia can be toxic to all body tissues, but major deleterious effects occur in the kidneys, nervous system, and cardiovascular system. The development of clinical signs from hypercalcemia depends on the magnitude of the calcium increase, how quickly it develops, and its duration. Serum total calcium concentrations of ≤15 mg/dL may not be associated with systemic signs, but serum concentrations of >18 mg/dL are often associated with severe, life-threatening signs. Polydipsia and polyuria are the most common signs of hypercalcemia and result from an impaired ability to concentrate urine and a direct stimulation of the thirst center. Anorexia, vomiting, and constipation can also develop as a result of decreased excitability of GI smooth muscle. Decreased neuromuscular excitability may lead to signs of generalized weakness, depression, muscle twitching, and seizures.
There are many potential causes of hypercalcemia (see Causes of Hypercalcemia in Dogs and Cats). In hypercalcemic dogs, neoplasia (lymphosarcoma) is the most common cause, followed by hypoadrenocorticism, primary hyperparathyroidism, and chronic renal failure. Other causes of hypercalcemia in dogs, in an approximate incidence order as seen in practice, include vitamin D toxicosis, apocrine gland carcinoma of the anal sac, multiple myeloma, carcinomas (lung, mammary, nasal, pancreas, thymus, thyroid, vaginal, and testicular), and finally, certain granulomatous diseases (blastomycosis, histoplasmosis, schistosomiasis). Approximately 70% of hypercalcemic dogs are also azotemic. However, azotemia is uncommon in dogs with hyperparathyroidism.
Causes of Hypercalcemia in Dogs and Cats
In cats, idiopathic hypercalcemia appears to be the most frequent cause of a high total calcium concentration, followed by renal failure and malignancy. Ionized hypercalcemia in conjunction with chronic renal failure is more common in cats than dogs. The most common tumor types associated with hypercalcemia of malignancy in cats are lymphoma and squamous cell carcinoma. Primary hyperparathyroidism occurs in cats but not as frequently as in dogs. Rarely, hypercalcemia is seen in cats with hyperthyroidism.
Malignancy is the most common cause of persistent hypercalcemia in dogs and is a common cause in cats. In hypercalcemia of malignancy, the hypercalcemia primarily results from increased osteoclastic bone resorption, but increased renal tubular resorption and increased intestinal absorption may also play a role. Factors that may be produced by tumors and result in humoral hypercalcemia of malignancy include PTH, PTH-related protein (PTHrP), transforming growth factor, 1,25-dihydroxyvitamin D, prostaglandin E2, osteoclast-activating factor, and other cytokines (interleukin-1, interleukin-2, and γ-interferon). Although many tumors have been associated with hypercalcemia in people, malignancy-associated hypercalcemia in dogs has been most commonly linked to lymphoma, adenocarcinoma of the apocrine glands of the anal sac, and multiple myeloma. Other tumors (thymoma, squamous cell carcinoma, nasal carcinoma, hemangiosarcoma, and undifferentiated adenocarcinoma) have also been associated with hypercalcemia in dogs. In cats, humoral hypercalcemia of malignancy occurs less frequently than in dogs but has been reported with squamous cell carcinoma, multiple myeloma, and lymphoproliferative diseases.
The most common tumor associated with hypercalcemia in dogs, lymphoma is also one of the tumors associated with hypercalcemia in cats. The pathogenesis of the hypercalcemia may involve two general mechanisms. One is local elaboration of an osteolytic factor that induces resorption of bone and mobilization of calcium when the bone marrow is infiltrated by tumor cells. The other, probably more important, is humoral hypercalcemia in which neoplastic cells produce a humoral factor that acts at a distance from the tumor. As evidence for secretion of a humoral substance by tumor cells, increased bone resorption, phosphaturia, and urinary excretion of cyclic adenosine monophosphate (cAMP) have been documented in dogs with lymphoma. Serum concentrations of both PTH and 1,25-dihydroxyvitamin D are generally low in these dogs, but PTHrP has been detected in dogs with lymphoma (see Characteristic Laboratory Abnormalities Associated with Common Causes of Hypercalcemia).
Of dogs with lymphoma, 10%–40% have concurrent hypercalcemia, and a large number of these cases also have the mediastinal form of lymphoma. Although detectable lymphadenopathy is usually present, hypercalcemia may be the first abnormality noted. A thorough physical examination, together with thoracic and abdominal radiographs, abdominal ultrasonography, multiple lymph node aspirates or biopsies, and multiple bone marrow aspirates may be necessary to make the diagnosis. Treatment with glucocorticoids (eg, prednisone) lowers serum calcium concentrations; however, steroids are lympholytic and make identification of lymphoma difficult.
Although remission rates in dogs with lymphoma and hypercalcemia are not statistically different from those without hypercalcemia, survival times are considerably less, indicating that hypercalcemic lymphomas have a poorer prognosis. (Also see Canine Lymphoma and see Feline Leukemia Virus and Related Diseases.)
This tumor usually occurs in older dogs of either sex, with hypercalcemia developing in ~90% of cases. Humoral mechanisms are most likely responsible for the hypercalcemia, because a PTH-like protein has been identified from tumor tissue in dogs. This tumor is usually malignant and has metastasized to regional lymph nodes by the time of diagnosis. Surgical resection is associated with reduction of serum calcium. Failure to remove all of the tumor or recurrence of the tumor usually results in recurrence of hypercalcemia. Despite surgical excision, radiation, and various chemotherapy protocols, the tumor usually recurs within a few months, and prognosis is poor.
This malignancy in dogs and cats has been associated with hypercalcemia in 10%–15% of cases. The pathogenesis of the hypercalcemia is most likely multifactorial. Myeloma cells are known to produce osteoclast-activating factor in people, which may partially account for the hypercalcemia. The presence of extensive bony lysis may also contribute to the increased serum calcium. Although serum protein concentration is usually increased in multiple myeloma, increased protein binding of calcium rarely accounts for the hypercalcemia. Treatment of multiple myeloma with chemotherapy has been associated with longterm survival, but the presence of associated hypercalcemia, light chain proteinuria, and extensive bony lesions is associated with a shorter survival time.
Primary hyperparathyroidism results from excessive secretion of PTH by one or more abnormal (usually neoplastic) parathyroid glands. It is relatively rare in dogs and cats. Persistent hypercalcemia is characteristic. Solitary adenoma of the external or internal parathyroid gland is the most common cause of primary hyperparathyroidism, whereas parathyroid carcinoma has been infrequently reported. Hyperplasia of one or all four parathyroid glands has been described but is very rare.
Hypercalcemia, normal to low serum phosphorus, and low urine specific gravity are the most consistent findings. Azotemia commonly develops as a consequence of moderate to severe hypercalcemia. In hypercalcemic animals that still have relatively normal renal function (normal serum creatinine and urea nitrogen concentrations), determination of serum PTH is helpful in diagnosis. The finding of high-normal to high serum PTH concentrations in hypercalcemic animals with normal renal function is consistent with primary hyperparathyroidism, whereas the finding of low PTH concentrations is consistent with hypercalcemia of malignancy. Ultrasonography of the parathyroid glands is a useful diagnostic technique but requires an ultrasound unit with a high frequency transducer in the 7.5- to 10-MHz range to achieve the necessary resolution. Normal parathyroid glands are not always visualized on ultrasonographic examination, but enlarged parathyroid glands appear as rounded hypoechoic or anechoic structures associated with the thyroid gland. Finding a solitary parathyroid gland in a hypercalcemic animal supports a diagnosis of primary hyperparathyroidism, whereas finding multiple enlarged parathyroid glands is compatible with secondary hyperparathyroidism. Ultrasound cannot distinguish a parathyroid adenoma from an adenocarcinoma. Exploratory surgery of the cervical region is a diagnostic alternative if no other cause of hypercalcemia can be determined.
The most cost-effective and expedient approach to management is surgical exploration of the neck and removal of the abnormal parathyroid tissue. Percutaneous ultrasound-guided chemical (ethanol) or heat ablation of the parathyroid has been used and may be a feasible alternative to surgery in some cases. Attempts to lower the serum calcium concentration with IV fluids (saline) and furosemide before surgery or ablation may be beneficial (see Treatment of Hypercalcemia). No medical treatment exists for primary hyperparathyroidism, although treatment for hypercalcemia can be done if surgery is declined.
Mild hypercalcemia (≤15 mg/dL) has been reported in as many as 30% of dogs with hypoadrenocorticism (Addison disease). Multiple factors may result in the hypercalcemia, including increased calcium citrate (complexed calcium), hemoconcentration (relative increase), increased renal resorption of calcium, and increased affinity of serum proteins for calcium. Although total serum calcium concentrations may be increased, the ionized fraction usually is normal. The hypercalcemia resolves quickly with successful treatment for hypoadrenocorticism.
In cats, chronic renal failure (usually associated with chronic interstitial nephritis) appears to be the most common cause of hypercalcemia. The pathogenesis of the hypercalcemia is not known, but the ionized calcium concentrations remain normal. In dogs, renal failure caused by familial renal disease is more often associated with hypercalcemia than are other forms of chronic renal failure. Hypercalcemia may also be present in acute renal failure during the polyuric phase, but this is rare.
A syndrome in young to middle-aged cats, first described in the early 1990s, involves hypercalcemia that occurs without obvious explanation. It has been suggested that the feeding of acidifying, magnesium-restricted diets predisposes cats to idiopathic hypercalcemia. Another plausible hypothesis is that excessive dietary vitamin D content in some cat foods may contribute to this condition. Total serum calcium is increased for months to years, often without obvious clinical signs in the early stages. Ionized calcium is increased, sometimes out of proportion to the increase in total serum calcium. Longhaired cats may be over-represented; most are not azotemic at initial diagnosis but may later develop azotemia. PTH levels are either low or remain within the reference range, PTHrP is not detectable, and 25-hydroxyvitamin D and calcitriol levels are within normal limits.
Intensive treatment for idiopathic hypercalcemia is rarely indicated, because hypercalcemia has developed gradually and is relatively longstanding, and dramatic clinical signs are usually absent. Most cats can be treated as outpatients with dietary change either alone or in combination with drug therapy.
Diet modification is recommended as a first-line treatment. If an acidifying diet is being fed, it should be discontinued. A number of different diets have been recommended, including high-fiber diets, kidney diets, or diets developed to prevent calcium oxalate urolithiasis. Others recommend feeding canned diets with a composition similar to what cats would eat in the wild (ie, 40%–60% of calories as protein, 30%–50% fat, and <15% carbohydrates). No matter what type of diet is chosen, it is best to feed a wet-only diet to promote urinary dilution and lessen the chance of calcium oxalate stone formation. Administration of prednisone results in longterm decreases in ionized and total calcium concentrations in some cats.
If normocalcemia has not been restored after a dietary feeding trial of 6–8 wk, treatment with glucocorticosteroids or bisphosphonates should be considered. Prednisone is given orally at 5 mg/cat/day for 1 mo before reevaluation. If the serum ionized calcium concentration is normal, this dose is continued for several months. If the ionized calcium value is still increased, the dosage is gradually increased to 10–20 mg/cat/day as needed to restore normocalcemia. Alternatively, treatment with the bisphosphonate alendronate can be instituted, starting at 10 mg orally once weekly; the dosage can be increased to 20–30 mg per week, as needed. It is extremely important to administer alendronate after a 12-hour fast, because food significantly reduces drug absorption; the fast should also be continued for at least 2 hr after alendronate administration. Erosive esophagitis is a known adverse effect of oral bisphosphonates in human patients. Although the risk of development of esophagitis in cats is unknown, the owner can give 5–6 mL of water to the cat with a dosing syringe immediately after administration of the alendronate; a small amount of butter applied to the cat’s lips may increase licking and salivation and promote the transit of the pill to the stomach. The longterm safety and efficacy of oral bisphosphonates in cats are currently unknown, but alendronate appears to be relatively safe for use in cats.
Hypercalcemia resulting from tumor invasion or metastasis to bone develops very rarely in animals. Primary bone tumors (eg, osteosarcoma) and neoplastic cells within the bone marrow (eg, multiple myeloma) may occasionally produce hypercalcemia. The mechanisms whereby bony neoplasia may produce hypercalcemia include mechanical destruction by the infiltrating cells (as occurs with metastatic tumors and osteosarcoma) and local production of osteoclast-activating factor (as occurs with multiple myeloma). Bacterial and mycotic osteomyelitis can also occasionally produce hypercalcemia. The hypercalcemia may result from direct bone lysis or may be mediated by bone-resorbing factors (eg, prostaglandins, osteoclast-activating factor).
Vitamin D toxicity refers to the effects of excessive intake of bioactive metabolites of vitamin D. Toxicity caused by ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) can occur from excessive dietary supplementation (most common in young growing dogs) for treatment of primary hypoparathyroidism. Both of these forms of vitamin D have a slow onset of action and prolonged duration, making correct dosing difficult. Treatment is directed at discontinuing the supplement or decreasing the dose of vitamin D. Toxicity caused by calcitriol (1,25-dihydroxyvitamin D), the most active form of vitamin D, most commonly occurs after treatment of primary hypoparathyroidism. Calcitriol is also the active ingredient in some rodenticides, but these products are no longer widely available in the USA.
In dogs, a newly emerging cause of vitamin D toxicity is ingestion of the calcitriol analogue, calcipotriene (also called tacalcitol), which is a topical preparation used to treat psoriasis in people. Calcipotriene toxicity in dogs can result in severe metastatic calcification in the GI tract, kidney, and other tissues; the condition is commonly fatal.
Hypercalcemia associated with granulomatous disease arises from an alteration of endogenous vitamin D metabolism. Macrophages activated in response to granulomatous inflammation can develop the capability to convert vitamin D precursors to the active form of vitamin D (ie, calcitriol) in an unregulated manner. A similar alteration of vitamin D metabolism in people may explain hypercalcemia in non-Hodgkin lymphoma, Hodgkin lymphoma, and lymphomatoid granulomatosis.
In companion animals, hypercalcemia related to granulomatous disease has been reported in disseminated histoplasmosis, blastomycosis, coccidiomycosis, tuberculosis, and schistosomiasis. Animals with hypercalcemia related to granulomatous disease are expected to have high serum concentrations of ionized calcium and low values for PTH. Serum calcium concentrations return to normal with treatment (ie, antifungal drugs and surgical removal).
The first step in investigating hypercalcemia is to exclude the possibility of spurious test results. Ideally, a fasting sample should be resubmitted, because sample conditions (lipemia or hemolysis) can artifactually increase total serum calcium values reported by colorimetric analyzers.
If the hypercalcemia is repeatable, ionized calcium should be measured, because it is a better reflection of the biologically active form of calcium. Total or adjusted total calcium are not reliable measurements of calcium status.
In some animals with persistent ionized hypercalcemia, identification of the cause will be obvious after analysis of history (vitamin D exposure, drugs, ingestion of houseplants) and physical examination findings (masses, organomegaly, cancer, or granulomatous disease). In other animals, the cause will not be obvious, and hematology, serum biochemistry, body cavity imaging, cytology, and histopathology may be required. In many animals, use of specialized assays, including measurement of PTH, PTHrP, and/or vitamin D is necessary to confirm a diagnosis.
If lymphadenopathy is present, a lymph node aspirate or biopsy should be performed to check for lymphosarcoma. If a tumor of the anal sac is found, surgical removal should be attempted. Any other neoplasm should be treated by surgical removal, chemotherapy, or radiation therapy. Problems may arise when hypercalcemia is complicated by renal failure, or when primary hyperparathyroidism or occult malignancy is suspected. In these cases, the cause of hypercalcemia may not be obvious, and additional steps must be taken to differentiate primary hyperparathyroidism from occult tumors causing hypercalcemia.
Because the ionized calcium fraction is the biologically active form and the component that regulates production of PTH, measurement of the ionized calcium concentration is the first step in evaluation of calcium abnormalities. If ionized calcium is normal, even if total calcium is increased, no further diagnostics are warranted. If ionized calcium is increased, then PTH and PTHrP determinations should be considered if there are no obvious causes of the hypercalcemia.
In many cases of hyper- or hypocalcemia, the total calcium and ionized calcium concentrations are highly correlated (see Characteristic Laboratory Abnormalities Associated with Common Causes of Hypercalcemia). However, in some instances the concentration of total calcium does not reflect the status of ionized calcium. In dogs with renal failure, total calcium is high, but ionized calcium is normal or surprisingly low. In this situation, the total calcium increase seems to reflect increased amounts of calcium complexed to anions, an effect that would not be identified in albumin-adjusted calcium concentrations.
Ionized calcium is measured in serum or heparinized plasma by an instrument using a calcium-specific electrode. Serum ionized calcium may be falsely high when collected in serum separator tubes. There is simultaneous measurement of pH, which affects the binding of calcium to protein in an inverse manner. An increase in pH is accompanied by a decrease in ionized calcium. Serum samples collected and handled in anaerobic conditions provide the best results with ionized calcium assays. Samples collected in EDTA tubes are unsuitable, because EDTA binds available ionized calcium.
Assay of PTH is the next step in evaluation of calcium abnormalities, once hypercalcemia has been confirmed by measurement of the ionized calcium concentration. Evaluation of PTH can reveal whether the parathyroid glands are responding appropriately to the change in calcium concentration or whether inappropriate production of PTH is the cause of the disorder. If calcium metabolism is normal, small increases of ionized calcium inhibit secretion of PTH and small decreases of ionized calcium prompt release of PTH.
Serum or plasma PTH determinations are very useful in evaluation of hypercalcemic dogs and cats. Animals with primary hyperparathyroidism should have mid-normal to high concentrations of PTH, whereas those with most other forms of hypercalcemia have low PTH concentrations (see Characteristic Laboratory Abnormalities Associated with Common Causes of Hypercalcemia).
Hypercalcemia associated with nonparathyroid neoplasia is often caused by production of a humoral factor, PTHrP, that has parathyroid hormone–like bioactivity. Since its discovery in the 1980s, PTHrP has been found to be associated with a variety of tumors that cause hypercalcemia of malignancy in people.
Assay of PTHrP can be used to confirm hypercalcemia of malignancy (see Characteristic Laboratory Abnormalities Associated with Common Causes of Hypercalcemia). There is a relatively high prevalence of positive results in dogs with apocrine gland adenocarcinoma of the anal sac, lymphoma, or other miscellaneous tumors. However, humoral hypercalcemia of malignancy always remains a differential diagnosis in a hypercalcemic dog with a low PTH and a normal or negative PTHrP. In cats, high PTHrP is also consistent with humoral hypercalcemia of malignancy, especially in cats with carcinoma.
Because metabolites of vitamin D are chemically identical in all species, radioimmunoassays developed for use in people are satisfactory for measurement in animals. Calcidiol (25-hydroxyvitamin D) concentration is a good indicator of vitamin D ingestion and can be used to diagnose hypervitaminosis D.
Vitamin D metabolites resulting from the ingestion of cholecalciferol present in rodenticides can be measured with the calcidiol assay. Toxicity from ingestion of cholecalciferol or ergocalciferol would be detected by an increase of calcidiol that may persist for weeks after exposure. Assay of calcidiol also may be used to confirm toxicity from ingestion of rodenticides that contain vitamin D3 as the active ingredient.
Calcipotriene, the vitamin D analogue found in antipsoriasis creams, is not measured with the assay for calcidiol but would be detected in the assay for calcitriol. Unfortunately, the calcitriol assay is not widely available for clinical use.
See Characteristic Laboratory Abnormalities Associated with Common Causes of Hypercalcemia for a summary of the anticipated PTH, ionized calcium, and PTHrP values in the various disorders causing hypercalcemia. Generally, the PTH level is normal to high with primary, secondary, or tertiary hyperparathyroidism. The PTH level is low with other causes of hypercalcemia (eg, hypervitaminosis D, malignancy associated, renal failure, hypoadrenocorticism).
Characteristic Laboratory Abnormalities Associated with Common Causes of Hypercalcemia
A mild degree of hypercalcemia may not be immediately dangerous; there is time to establish a definitive diagnosis before starting treatment. In animals with severe clinical signs associated with hypercalcemia, diagnostic and therapeutic efforts may proceed concurrently. No single treatment protocol is consistently effective for all causes of hypercalcemia; each animal must be approached individually, and the cause of the hypercalcemia must be determined. The definitive treatment of hypercalcemia is treating or removing the underlying cause. Unfortunately, the cause may not be apparent, and supportive measures must be taken to decrease the serum calcium concentration. The goal of all supportive treatment is to enhance urinary excretion of calcium and to prevent calcium resorption from bone.
Loop diuretics such as furosemide (2–4 mg/kg, bid-tid) increase calcium excretion by the kidneys; however, higher dosages may be needed. If dehydration is present, fluid therapy should be instituted first because volume contraction and further hemoconcentration may worsen the hypercalcemia. Thiazide diuretics are contraindicated in hypercalcemia, because these agents decrease calcium excretion by the kidneys and worsen the hypercalcemia.
Glucocorticoids such as prednisone (1–2 mg/kg, bid) or dexamethasone (0.1–0.2 mg, bid) provide a second tier of treatment for hypercalcemic cases that do not respond adequately to IV fluids and furosemide. They reduce bone resorption of calcium, reduce intestinal calcium absorption, increase renal calcium excretion, and are cytotoxic to malignant lymphocytes, leading to substantial reduction in serum calcium concentration in animals with hypercalcemia secondary to lymphoma, myeloma, hypervitaminosis D, granulomatous disease, and hypoadrencorticism. However, use of glucocorticoids may make definitive diagnosis of the underlying cause of the hypercalcemia difficult. This is especially true with lymphosarcoma, because steroids are lymphocytolytic and may alter lymph node architecture and patterns of lymphocyte infiltration in bone marrow.
The third tier of treatment is to add a bisphosphonate, mithramycin, or calcitonin for more longterm control of hypercalcemia. Bisphosphonates assist in lowering serum calcium by reducing the number and action of osteoclasts. Pamidronate is the most commonly used parenteral drug; the recommended dosage in dogs is 1–2 mg/kg, IV, mixed in 0.9% saline given throughout 2 hr. In cats, alendronate is the most common oral preparation used to control idiopathic hypercalcemia. Adequate hydration is essential when treating with bisphosphonates, because these drugs may cause nephrotoxicity, especially at higher doses. The drug can be repeated in 3–4 wk if needed.
Mithramycin, an inhibitor of RNA synthesis in osteoclasts, is an effective treatment for hypercalcemia; the dosage is 25 mcg/kg, IV, given throughout 4–6 hr. A single dose is usually successful in normalizing the serum calcium concentration; effects last from a few days to several weeks. Adverse effects may include thrombocytopenia, nephrotoxicity, and hepatotoxicity but are unlikely after a single dose. However, this drug must be used with extreme caution.
Calcitonin inhibits bone resorption by inhibiting the activity and formation of bone osteoclasts. The dose of calcitonin is 4–8 U/kg, SC, bid-tid. Calcitonin is the most rapidly acting hypocalcemia agent, causing serum calcium to decrease within a few hours after administration. Its effect is rather transient, however, and the maximal reduction in calcium is not as great as that seen with bisphosphonates or mithramycin.
Calcimimetics, a new class of drugs, are calcium-sensing receptor agonists. The mostly commonly used drug of this class is cinacalcet. By interacting with the calcium-sensing receptors in the parathyroid glands, these drugs reduce the secretion of PTH and can effectively suppress circulating PTH in all forms of hyperparathyroidism. They have become a major therapy for secondary hyperparathyroidism associated with renal failure as well as for treatment of primary hyperparathyroidism.