Diagnostic Work Up for Dogs with Hypercalcemia of Unknown Origin

My patient is an 8-year old spayed female mixed-Labrador that presented with marked polydipsia and polyuria. Otherwise, she appears to be feeling well; she has a normal appetite, with no weight loss, vomiting, diarrhea, or coughing.

Her initial work-up identified a high total serum calcium of 13.7 mg/dl (reference interval, 8.9-11.4 mg/dl), which was confirmed two days later (repeat calcium, 13.1 mg/dl). The rest of the serum biochemical analysis (including the serum sodium, potassium, urea nitrogen and creatinine) were normal. The results of a complete blood count were normal and a complete urinalysis was also unremarkable, except for a low urine specific gravity (1.010).

Chest and abdominal radiographs were normal.

A complete calcium panel was next performed (1), with the following results:

• Serum ionized calcium (iCa) = 1.63 mmol/L (reference interval, 1.25-1.45)
• Serum parathyroid hormone (PTH) = 1.0 pmol/L (0.5 - 5.8)
• Plasma parathyroid hormone-related polypeptide (PTHrp) = 0.3 pmol/L (<0.5)

How would you recommend that I proceed in the workup of this dog? I'm considering an abdominal ultrasound and bone marrow exam to look for occult lymphoma, and maybe a trial response to asparaginase?

My Response:

In adult dogs with repeatable hypercalcemia, the two most common causes include primary hyperparathyroidism and malignancy (2,3). Most dogs with primary hyperparathyroidism feel good (normal attitude and appetite), whereas those with hypercalcemia of malignancy tend to be clinically ill (4-7).  With the low-normal serum PTH value and measurable (but normal) PTHrp value, neither of those categories can be completely excluded (2,3,8).

With the current assay for PTH employed at DCPAH (1), it's been my observation that a serum PTH value higher than 1 pmol/L is generally consistent with primary hyperparathyroidism and a PTH value lower than 1 is consistent with PTH-independent hypercalcemia (usually neoplasia).  However, remember that PTH is a peptide and is subject to breakdown and degradation during shipping, especially if the plasma sample was not kept frozen or at least cool.  Therefore, sample handling issues (delay in transit or sample warming) can result in falsely-low serum PTH concentration. If there is any doubt about the sample integrity when it arrived in the lab, a new serum sample should be collected to recheck the PTH concentration. After the serum is collected, it should be immediately frozen and shipped by overnight delivery to the lab (with dry ice or freezer pack) to ensure valid results.

Hypercalcemia associated with Addison's disease is also relatively common in dogs and is possible in this case (9). However, the normal serum concentrations of sodium and potassium and the fact that your dog is not showing signs of serious illness make hypoadrenocorticism unlikely.  Most of these hypercalcemic dogs have overt Addison's disease, with moderate to marked hyperkalemia and hyponatremia.  That said, you could certainly run a resting cortisol concentration to help exclude hypoadrenocorticism — the finding of a serum cortisol value above 2.0 µg/dl basically rules out Addison's disease (10).

Rare causes of hypercalcemia also include hypervitaminosis D or A and granulomatous disease, so these must be considered (2,3,11,12). Most of the other differentials can be excluded with routine serum biochemical analysis and history (Table 1).

Table 1: Differential list for hypercalcemia in dogs

Workup for undefined hypercalcemia

There are a number of ways to handle this case. Here is a workup list for you to consider, starting with the easiest and least invasive:

1. Perform thorough rectal exam to rule out an anal sac adenocarcinoma (13-15).
2. Carefully check for lymph node enlargement and aspirate any lymph nodes that you can palpate.
3. Measure a resting cortisol concentration to help exclude hypoadrenocorticism. If the basal cortisol concentration is low, this should be followed up with an ACTH stimulation test to confirm Addison's disease (10).
4. Consider repeating the serum PTH concentration. Since lipemia can effect the results, the dog should be fasted overnight. After blood collection, allow serum to clot at room temperature for 30 to 60 min prior to separation. The serum sample should be immediately frozen and shipped by overnight delivery to the lab (with dry ice or freezer pack) for PTH analysis (1).
5. If the repeat PTH value is above 1.0 pmol/L (in other words, not suppressed) consider having an experienced radiologist perform a cervical ultrasound exam looking for a parathyroid nodule, which would more strongly suggest primary hyperparathyroidism (16).  
6. If the repeat PTH value is suppressed or if the cervical ultrasound fails to detect a parathyroid tumor, then consider a complete abdominal ultrasound examination to screen for possible occult cancer, especially lymphoma.
7. Collect multiple aspirates of the liver and spleen with ultrasound-guidance, even if those organs appear normal on your ultrasound exam. I've had cases in which the ultrasound exam appears normal but the cytology said otherwise.
8. Consider a bone marrow aspirate. However, given the normal hematology results, this is less likely to be diagnostic.
9. Finally, if all of the above fails to yield a definitive diagnosis, then consider monitoring the ionized calcium and PTH concentrations to make sure that the hypercalcemia does not rapidly progress and that the PTH value remains stable.  If the PTH value increases to the mid-normal to high range, that finding would be most consistent with primary hyperparathyroidism; on the other hand, if the value falls further, that would be consistent with PTH-independent hypercalcemia (e.g., malignancy) (2,3).

Bottom Line

If nothing is found on your complete workup, I've learned that close observation and monitoring is sometimes the best route to take.  This includes periodic exams (including lymph node palpation and rectal exams), as well as following the serum iCa concentrations. I've had a few dogs with persistent, but stable, idiopathic hypercalcemia in which a definitive cause for the hypercalcemia was never identified. But the dogs (and eventually the owners) didn't care all that much, since the degree of hypercalcemia remains fairly stable and was not very progressive.

By contrast, in those dogs that have progressive disease and develop severe, worsening hypercalcemia, the underlying cause will eventually be obvious, even if it isn't apparent during the initial workup.

References:

1. Michigan State University, Diagnostic Center for Population and Animal Health (DCPAH).
   4125 Beaumont Road, Lansing, MI 48910-8104. 
2. 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.
3. Skelly BJ. Hyperparathyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:43-55.
4. Jores K, Kessler M. Primary hyperparathyroidism in the dog. Diagnosis, therapy and postoperative management in 19 dogs. Tierarztliche Praxis Ausgabe K, Kleintiere/Heimtiere 2011;39:389-396.
5. Schaefer C, Goldstein RE. Canine primary hyperparathyroidism. Compend Contin Educ Vet 2009;31:382-390.
6. Bergman PJ. Paraneoplastic hypercalcemia. Top Companion Anim Med 2012;27:156-158.
7. Vasilopulos RJ. Humoral hypercalcemia of malignancy: Diagnosis and treatment. Compend Contin Educ Vet 2003;25.
8. Rosol TJ, Nagode LA, Couto CG, et al. Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia. Endocrinology 1992;131:1157-1164.
9. Peterson ME, Feinman JM. Hypercalcemia associated with hypoadrenocorticism in sixteen dogs. J Am Vet Med Assoc 1982;181:802-804.
10.  Lennon EM, Boyle TE, Hutchins RG, et al. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). J Am Vet Med Assoc 2007;231:413-416.
11. Mellanby RJ, Mee AP, Berry JL, et al. Hypercalcaemia in two dogs caused by excessive dietary supplementation of vitamin D. J Small Anim Pract 2005;46:334-338.
12. Dow SW, Legendre AM, Stiff M, et al. Hypercalcemia associated with blastomycosis in dogs. J Am Vet Med Assoc 1986;188:706-709.
13. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995). J Am Vet Med Assoc 2003;223:825-831.
14. Meuten DJ, Capen CC, Kociba GJ, et al. Hypercalcemia of malignancy: Hypercalcemia associated with an adenocarcinoma of the apocrine glands of the anal sac. Am J Pathol 1982;108:366-370.
15. Hause WR, DVM, Stevenson S, DVM, MS, Meuten DJD, et al. Pseudohyperparathyroidism associated with adenocarcinomas of anal sac origin on four dogs. J Am Anim Hosp Assoc 1981;17:373-379.
16. Wisner ER, Penninck D, Biller DS, et al. High-resolution parathyroid sonography. Vet Radiol Ultrasound 1997;38:462-466.