5 Steps in the Workup of Dogs with Hypercalcemia

Hypercalcemia in the dog can result from many different causes, as I discussed in my last post on "Top 10 Differentials for Hypercalcemia in the Dog." These include malignancy (lymphosarcoma and apocrine gland carcinoma of the anal sac), hypoadrenocorticism, primary hyperparathyroidism, renal failure, vitamin D toxicosis, and spurious results due to laboratory error or hyperlipidemia (1-3).

In some dogs with hypercalcemia, the primary diagnosis will soon become obvious after analysis of history and findings from physical examination. In other dogs, the underlying cause of the hypercalcemia will still not be known.

Diagnosing the cause of hypercalcemia in dogs can be difficult. Therefore, I recommend a stepwise approach to diagnosis to help elucidate the underlying cause of each patient's hypercalcemia.

Important Initial Steps in Workup of All Hypercalemic Dogs

1. Verify that hypercalcemia exists
The first step in workup is to verify that true hypercalcemia is really present by repeating the total calcium concentration and by directly measuring an ionized calcium (iCa) concentration (4).  Both of these samples should be collected after an overnight fast. Measurement of serum iCa is important to determine whether increase in calcium is clinically significant since the total calcium can sometimes be mildly increased but the ionized calcium remains normal (e.g., renal disease).

2. Complete history and physical exam
Diagnosing the source of ionized hypercalcemia begins with a complete history to rule out vitamin D toxicosis caused by over-supplementation, rodenticide, certain plants, or antipsoriasis creams (1-3).  A complete physical examination may reveal the presence or absence of enlarged lymph nodes, hepatospenomegaly, rectal (anal sac) masses, or skeletal pain. Don't forget to do a thorough rectal examination since some of the anal sac tumors can not be easily visualized.

3. Routine laboratory data and imaging
Even though hypercalcemia associated with Addison's disease is third on my "Top 10 list," such hypercalcemia only develops in dogs with severe hyperkalemia, hyponatremia, and hypocortisolemia (5). Atypical hypoadrenocorticism does not generally lead to ionized hypercalcemia. If Addison's is suspected, basal serum cortisol or the cortisol response to ACTH stimulation should be monitored. The hypercalcemia resolves spontaneously with cortisosteroid therapy for the dog's Addison's disease and does not require specific treatment (5).

In most dogs, most of the differentials on this list can be quickly excluded (based on history, physical exam, and routine laboratory and imaging findings), leaving only primary hyperparathyroidism and occult lymphosarcoma (and other malignancies) to worry about.

4. Measure serum PTH and PTH-rp
Once we reach this point, the next step is to determine whether the hypercalcemia is parathyroid-dependent (parathyroid thyroid hormone (PTH)-secreting tumor causing hypercalcemia) or parathyroid-independent (normal parathyroid glands with appropriately suppressed PTH secretion in response to hypercalcemia).  This is easily done by measuring a serum PTH concentration. Dogs with primary hyperparathyroidism will have mid-normal to high concentrations of PTH, whereas dogs with most other forms of hypercalcemia have low to undetectable PTH concentrations (1-3).

Because hypercalcemia associated with nonparathyroid neoplasia is often caused by the secretion of parathyroid hormone-related protein (PTHrP), determination of serum PTH-rp can be helpful if malignancy is suspected (1,3,6). However, PTHrP concentrations are not always increased in malignancy, so hypercalcemia of malignancy always remains a differential diagnosis in a hypercalcemic dog found to have low serum concentrations of both PTH and PTHrP (1,3).

5. Perform cervical ultrasound
If serum PTH is mid-normal to high, cervical ultrasonography can be used to detect a parathyroid tumor (3,7). For definitive diagnosis primary hyperparathyroidism, histopathological examination of the excised parathyroid tumor is ideal.

Bottom Line

In some dogs with hypercalcemia, the primary diagnosis will soon become obvious after analysis of the patient's history and results of the physical examination. In other dogs, the cause will not be obvious. In these animals, one must look at the information from hematology, serum biochemistry, body cavity imaging, cytology, and histopathology, if necessary. Parathyroid ultrasound, as well as assays for measurement of PTH, and PTH-related protein, may necessary to confirm a diagnosis.

References:

1. Schenck PA, Chew DJ, Nagode LA, et al.  Disorders of calcium: hypercalcemia and hypocalcemia. In: Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, ed. DiBartola SP, 3rd ed., pp. 122–194. Saunders Elsevier, St. Louis, MO, 2006.
2. Schenck PA, Chew DJ. Hypercalcemia: a quick reference. Veterinary Clinics of North America Small Animal Practice 2008;38:449–453.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research 2005; 66:1330–1336.
5. Peterson ME, Fineman JM. Hypercalcemia associated with hypoadrenocorticism in sixteen dogs. Journal of the American Veterinary Medical Association 1982; 181:802-804.
6. Strewler GJ. The physiology of parathyroid hormone-related protein. New England Journal of Medicine 2000;342:177–185.
7. Wisner ER, Nyland TG. Ultrasonography of the thyroid and parathyroid glands. Veterinary Clinics of North America Small Animal Practice 1998;28:973–991.