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Hypercalcemia in dogs and cats (Proceedings)
There are 3 important fractions of calcium. This includes ionized calcium (45-50% of total calcium), which is the physiologically active fraction and is maintained within a fairly narrow range; protein-bound calcium (50-55% of total calcium) which is typically bound to albumin and is an inactive form of calcium; and complexed calcium, which in the normal patient accounts for less than 1-2% of total calcium, but can elevate the total calcium without affecting ionized calcium in chronic renal failure due to retention of substances such as citrate and oxalate that form calcium complexes.
There are 3 important fractions of calcium. This includes ionized calcium (45-50% of total calcium), which is the physiologically active fraction and is maintained within a fairly narrow range; protein-bound calcium (50-55% of total calcium) which is typically bound to albumin and is an inactive form of calcium; and complexed calcium, which in the normal patient accounts for less than 1-2% of total calcium, but can elevate the total calcium without affecting ionized calcium in chronic renal failure due to retention of substances such as citrate and oxalate that form calcium complexes. The major defense against fluctuations in ionized calcium is parathyroid hormone (PTH). PTH increases calcium resorption in the kidney, increases phosphorous excretion by the kidney, increases calcium and phosphorous mobilization from bone, and stimulates increased production of 1,25-dihydroxycholecalciferol (vitamin D) which increases calcium and phosphorous absorption from the intestine and increased calciuim and phosphorous mobilization from bone.
The most common clinical sign/presenting complaint for a dog or cat with hypercalcemia is polyuria/polydipsia. It is critically important to remember that the minimum database for a dog or cat with PU/PD includes a complete blood count, serum biochemistry profile, urinalysis, and urine culture (this should be done regardless of the urinalysis results). Although clinical signs may be mild or absent in patients with hypercalcemia, those with hypercalcemia that warrants investigation typically are symptomatic. Other clinical signs of hypercalcemia include GI signs such as anorexia, vomiting, constipation, and pancreatitis (rare); possible stranguria/pollakiuria from stone formation; CNS signs such as mental dullness, obtundation, coma, shivering, twitching, and seizures; and muscle weakness. Most of the clinical signs associated with hypercalcemia can be attributed to depolarization of the cell membranes and loss of excitability of nervous and muscle tissue (smooth and skeletal). Hypercalcemia also inhibits the response of the renal tubules to the effects of ADH.
Although there may be no visible abnormalities, the following are findings that may clue in a diagnosis during the physical examination: lymphadenopathy, which may suggest lymphosarcoma or fungal disease; a mass in the rectal wall (apocrine gland adenocarcinoma); mammary masses (mammary adenocarcinoma); kidney size (chronic renal failure); "rubber jaw" (chronic renal failure); and bradycardia with weak femoral pulses (hypoadrenocorticism).
We assume that a CBC/Chemistry profile/UA have already been performed, otherwise the diagnosis of hypercalcemia would not have been made. Other items on the laboratory work that should be evaluated and that may provide clues to the diagnosis include the following: pancytopenia or bicytopenia which may be suggestive of bone marrow infiltration with leukemia or lymphosarcoma; serum globulin level, which would be markedly elevated with multiple myeloma; and azotemia, which can be seen with chronic renal failure unrelated to hypercalcemia, secondary to renal mineralization from prolonged hypercalcemia, or prerenal from polyuria with depressed fluid intake. Serum phosphorous is usually low or low-normal (rarely >4 mg/dl) as a result of increased PTH or PTH-rp, unless azotemia has developed. The presence of hyperphosphatemia without azotemia is more suggestive of vitamin D toxicosis or other nonparathyroid causes. Hyperkalemia and hyponatremia in combination suggest hypoadrenocorticism
To further characterize the cause of the hypercalcemia and determine the significance of the hypercalcemia, ionized calcium and serum PTH levels are obtained in most cases. PTH is relatively labile and requires that the serum be separated immediately after the clot has formed, frozen immediately, and shipped overnight with 2-3 frozen gel packs. Assays for vitamin D and parathormone-related peptide, which is produced in malignancy, are also available and helpful.
Differentials for hypercalcemia include the following
1. Hypercalcemia of malignancy: it is said that the first 3 differentials for hypercalcemia should be lymphosarcoma, lymphosarcoma, and lymphosarcoma. Malignancy-associated hypercalcemia can be a result of the following mechanism: osteolysis (multiple myeloma, leukemia), PTH-rp production (lymphosarcoma, multiple myeloma, apocrine gland adenocarcinoma, mammary adenocarcinoma). Diagnosis is dependent on appropriate imaging/fine-needle aspirate/biopsy procedures.
2. Primary hyperparathyroidism: typically the result of single adenoma; adenomatous hyperplasia and carcinomas can also occur, but less frequently. Diagnosis is usually confirmed by documenting elevated serum PTH and ionized calcium. A parathyroid nodule can occasionally be detected by ultrasound examination of the neck. The adenoma is rarely ever palpable. Treatment is surgical removal of the parathyroid gland containing the adenoma: careful monitoring of calcium levels post-therapy is necessary to detect post-parathyroidectomy rebound hypocalcemia.
3. Hypervitaminosis D: typically hypercalcemia is present with hyperphosphatemia in vitamin D toxicosis; cholecalciferol rodenticide is a major cause of this disorder; toxicosis usually becomes severe within 48-72 hours; other sources of vitamin D include certain prescription dermatologic ointments for people (these often produce a severe, but transient hypercalcemia that results in renal mineralization), over-supplementation with vitamin D of a patient with hypoparathyroidism, and Cestrum diurnum (day blooming jessamine) toxicosis.
4. Hypoadrenocortisism: serum calcium will be increased in 30-50% of dogs with hypoadrenocorticism (as well as cats); typically correlates well with serum potassium levels; not clinically important, as the other problems of hypoadrenocorticism are more pressing.
5. Chronic renal failure: renal secondary hyperparathyroidism is a well-recognized phenomenon in chronic renal failure; it is important to note that hyperparathyroidism occurs as a result of suppression of ionized calcium from the presence of hyperphosphatemia; the compensatory hyperparathyroidism helps maintain ionized calcium in the low-normal range—these patients never have elevated ionized calcium. Total calcium may be elevated in chronic renal failure (although it usually is not) from the accumulation of complexed calcium but the ionized calcium is not elevated and this hypercalcemia is not physiologically important to the patient.
6. Miscellaneous causes of hypercalcemia include the following: bacterial or fungal osteomyelitis, blastomycosis, histoplasmosis, schistosomiasis, and coccidioidomycosis, sepsis (rare), hypothermia (rare).
7. Laboratory error: the following can falsely elevate serum total calcium: lipemia, hemoconcentration, hemolysis.
Acute medical therapy for hypercalcemia (any cause)
Indications for symptomatic treatment of hypercalemia include the following
3. cardiac arrhythmias
4. severe neurologic dysfunction
The following therapeutic steps are recommended
1. Fluid therapy: the fluid of choice is 0.9% NaCl; saline diuresis promotes calcium diuresis; the rate should replace the deficit plus include 2-3 X maintenance to promote diruresis.
2. Furosemide: maximizes urinary sodium excretion, thus increasing calcium excretion (sodium competes with tubular uptake with calcium, resulting in calcium loss); not typically given until adequate fluid therapy has been established and dehydration is resolved; typically given as 5 mg/kg IV bolus and then 5 mg/kg/hr as constant rate infusion.
3. Glucocorticoids: I do not advocate their use UNLESS a diagnosis has been established. The use of glucocorticoids can make the diagnosis of lymphosarcoma difficult because of lymphocytolysis caused by GCs. GCs decrease bone resorption, decerase intestinal absorption, increase renal excretion. Counteract effects of vitamin D and granulomatous disease. Minimal to no response in patients with solid tumors or primary hyperparathyroidism.
4. Bisphosphonates: etidronate and pamidronate; inhibit osteoclast activity; can be nephrotoxic.
5. Calcitonin: reduces osteoclast activity; salmon calcitonin is commercially available; not routine successful; used primarily for cholecalciferol toxicity; variable reported doses (4.5 U/kg SC q8h, 8 U/kg SC q24h, 5 U/kg SC q12h); development of antibodies may limit long-term use.
6. Miscellaneous: plicamycin (inhibits osteoclast activity), EDTA (complexes ionized calcium), bicarbonate (decreases ionized fraction), dialysis.
Note: Mild hypercalcemia is occasionally seen in cats with calcium oxalate urolithiasis and has been poorly addressed in the literature. We have identified this phenomenon and have seen resolution when cats were fed a diet low in vitamin D. The belief is that some cats may have excessive vitamin D receptors on their intestinal epithelial cells, thus absorbing greater quantities of dietary calcium. The compensatory renal hypercaliuria promotes calcium oxalate formation. Serum PTH is usually very low and ionized calcium high in these cats, supportive of intestinal hyperabsorption. Hill's Prescription diet x/d appears to be an effective diet.