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
1. dehydration
2. azotemia
3. cardiac arrhythmias
4. severe neurologic dysfunction
5. weakness
