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.

Top Endocrine Publications of 2013: Canine & Feline Parathyroid & Calcium Disorders

In my third compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the parathyroid gland, including the clinical problems of hypercalcemia and hypocalcemia.

Listed below are 21 research papers written in 2013 that deal with a variety of topics and issues related to calcium, parathyroid or vitamin D metabolism.

These range from the interactions of calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 in the pathogenesis of chronic kidney disease (1) to a number of reports of dogs with hypercalcemia of malignancy (2,4,5,7,16); from a review of hypocalcemia associated with critical illness (3) to a case of reversible myocardial failure associated with primary hypoparathyroidism in a cat (6); from a study of preoperative factors that help predict iatrogenic hypoparathyroidism following parathyroid surgery (8) to reviews of the emergency management of common metabolic abnormalities, including hypocalcemia, in cats that present with collapse (9,10); and from a study of the forms of dietary potassium in the prevention of calcium oxalate urolith formation in cats (11) to the effect of bone meal on urinary calcium and oxalate excretion in cats (12).

Other papers include a review of cholecalciferol (vitamin D3) intoxication leading to hypercalcemia (13) to changes in serum concentrations of calcium, phosphorus, magnesium, parathyroid hormone, calcidiol and calcitriol in growing cats (14) to a study of the plasma calcitonin response associated with hypocalcemia in cats (15); from a study of the vitamin D status in dogs with non-neoplastic and neoplastic esophageal nodules resulting from the nematode spirocercosis (17) to a case report of hypercalcemia secondary to Addison's disease in a cat (18); and finally, from a report of 3 cats with severe hypercalcemia secondary to vitamin D intoxication caused by ingestion of commercial cat foods (19) to a case report of a Persian cat that developed hypercalcemia secondary to intra-abdominal fungal pseudomycetoma (i.e., dermatophyte penetration into the abdominal cavity) (21) .

References:

1. de Brito Galvao JF, Nagode LA, Schenck PA, et al. Calcitriol, calcidiol, parathyroid hormone, and fibroblast growth factor-23 interactions in chronic kidney disease. J Vet Emerg Crit Care (San Antonio) 2013;23:134-162. 
2. Geigy C, Riond B, Bley CR, et al. Multiple myeloma in a dog with multiple concurrent infectious diseases and persistent polyclonal gammopathy. Vet Clin Pathol 2013;42:47-54. 
3. Holowaychuk MK. Hypocalcemia of critical illness in dogs and cats. Vet Clin North Am Small Anim Pract 2013;43:1299-1317, vi-vii. 
4. Javanbakht J, Tavassoli A, Sabbagh A, et al. Evaluation of an anal sac adenocarcinoma tumor in a Spitz dog. Asian Pac J Trop Biomed 2013;3:74-78. 
5. Javanbakht J, Tavassoli A, Sasani F, et al. An overall assessment of circumanal gland adenoma in a terrier mix breed dog. Asian Pac J Trop Biomed 2013;3:580-583. 
6. Lie AR, Macdonald KA. Reversible myocardial failure in a cat with primary hypoparathyroidism. J Feline Med Surg 2013;15:932-940. 
7. Merrick CH, Schleis SE, Smith AN, et al. Hypercalcemia of malignancy associated with renal cell carcinoma in a dog. J Am Anim Hosp Assoc 2013;49:385-388. 
8. Milovancev M, Schmiedt CW. Preoperative factors associated with postoperative hypocalcemia in dogs with primary hyperparathyroidism that underwent parathyroidectomy: 62 cases (2004-2009). J Am Vet Med Assoc 2013;242:507-515. 
9. Murphy K, Hibbert A. The flat cat: 1. a logical and practical approach to management of this challenging presentation. J Feline Med Surg 2013;15:175-188. 
10. Murphy K, Hibbert A. The flat cat: 2. the emergency database and management of common metabolic abnormalities. J Feline Med Surg 2013;15:189-199. 
11. Passlack N, Brenten T, Neumann K, et al. Effects of potassium chloride and potassium bicarbonate in the diet on urinary pH and mineral excretion of adult cats. Br J Nutr 2013:1-13. 
12. Passlack N, Zentek J. Urinary calcium and oxalate excretion in healthy adult cats are not affected by increasing dietary levels of bone meal in a canned diet. PLoS One 2013;8:e70530. 
13. Peterson ME, Fluegeman K. Cholecalciferol. Topics in companion animal medicine 2013;28:24-27. 
14. Pineda C, Aguilera-Tejero E, Guerrero F, et al. Mineral metabolism in growing cats: changes in the values of blood parameters with age. J Feline Med Surg 2013;15:866-871. 
15. Pineda C, Aguilera-Tejero E, Raya AI, et al. Assessment of calcitonin response to experimentally induced hypercalcemia in cats. Am J Vet Res 2013;74:1514-1521. 
16. Robat CS, Cesario L, Gaeta R, et al. Clinical features, treatment options, and outcome in dogs with thymoma: 116 cases (1999-2010). J Am Vet Med Assoc 2013;243:1448-1454. 
17. Rosa CT, Schoeman JP, Berry JL, et al. Hypovitaminosis D in dogs with spirocercosis. J Vet Intern Med 2013;27:1159-1164. 
18. Sicken J, Neiger R. Addisonian crisis and severe acidosis in a cat: a case of feline hypoadrenocorticism. J Feline Med Surg 2013;15:941-944. 
19. Wehner A, Katzenberger J, Groth A, et al. Vitamin D intoxication caused by ingestion of commercial cat food in three kittens. J Feline Med Surg 2013;15:730-736. 
20. Williams TL, Elliott J, Berry J, et al. Investigation of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats. J Small Anim Pract 2013;54:367-373. 
21. Zafrany A, Ben-Oz J, Segev G, et al. Successful treatment of an intra-pelvic fungal pseudomycetoma causing constipation and hypercalcaemia in a Persian cat. J Feline Med Surg 2013. 

Surgical Thyroidectomy: A Useful Treatment Option for Dogs with Thyroid Carcinoma?

Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994–2010)

Joanne L. Tuohy, Deanna R. Worley, and Stephen J. Withrow

Journal of the American Veterinary Medical Association 2012;241:95–103

Tumors of the thyroid gland are the most common endocrine neoplasm of the dog. Thyroid carcinomas, while responsible for approximately 50–70% of all thyroid tumors diagnosed at postmortem examination, account for up to 90% of thyroid tumors detected during life (1-3). Therefore, all thyroid masses detected upon physical examination must be presumed to malignant until proven otherwise.

In dogs suffering from thyroid carcinoma, the likelihood for metastasis is high, with up to 38% of dogs having gross metastatic disease at the time of initial evaluation (4,5). The most common site for metastasis is the lungs, with other sites being the regional lymph nodes, jugular veins, and heart (1-3). Tumor size appears to be predictive of metastasis; in 1 study, dogs with tumor volumes < 21 cubic cm had a significantly lower risk of metastasis (2). The finding of vascular invasion by neoplastic cells is also suggestive of potential metastasis (5). Bilateral thyroid tumors are typically larger than unilateral tumors. In accord with that, one study reported that bilateral tumors were 16 times more likely to metastasize than unilateral thyroid tumors (6).

Treatment options for canine thyroid carcinoma include surgical resection, external radiation therapy, radioiodine therapy, and chemotherapy (7). The choice of treatment for a particular dog with a thyroid gland tumor depends on tumor size, vascularity, and invasiveness; whether the tumor is fixed or mobile upon palpation; and most importantly, whether gross metastatic disease is present (7-10). External beam radiation and radioiodine treatment are indicated for dogs deemed to have nonresectable tumors, such as fixed, deeply invasive, or bilateral tumors (3,6,7,11-14). Metastatic disease can be potentially treated with radioiodine or chemotherapy (7,15-18). Surgical thyroidectomy can be considered in thyroid tumors that are not large or invasive, with no evidence of metastasis (8-10).

To date, however, there are no published guidelines for surgical management of dogs with freely movable thyroid gland tumors. The purpose of the study reported by Tuohy et al (10) was to evaluate the outcome of resection of simultaneous discrete bilateral mobile thyroid gland carcinomas in dogs.  The hypothesis of this study was that dogs with bilateral, mobile thyroid gland carcinoma would be amenable to a single bilateral thyroidectomy procedure, even when parathyroid glandular tissue was not preserved and hypoparathyroidism would be likely. A second hypothesis of this study was that bilateral tumor development does not always necessitate a need for adjuvant chemotherapy in order to obtain prolonged survival.

Objective of this study—To evaluate the outcome of resection of simultaneous discrete bilateral mobile thyroid gland carcinomas in dogs.

Design— Retrospective case series.

Animals— 15 dogs with resected simultaneous discrete bilateral mobile thyroid gland carcinomas. The dogs ranged in age from 7.6 to 11.9 years, with 10 breeds affected.  Seven of the dogs were females, and 8 were castrated males.

Procedures— Medical records (from 1994-2010) were searched for dogs with the appropriate diagnosis and treatment. Information collected included signalment, clinical signs, diagnostic test results, tumor mobility (mobile tumor identified by movement ≥ 1 cm in all planes during palpation), complications, adjuvant treatments, and outcome.

Results— Prior to surgery, serum thyroxine (T4) concentrations were assessed in 10 of the 15 dogs. Four dogs had low serum T4 concentrations (<1.0 μg/dL), and 2 dogs had high serum T4 concentrations (7.4 and 4.5 μg/dL); these dogs had no associated clinical signs. Four dogs were euthyroid (2.0 and 1.6 μg/dL). None of the dogs were treated with supplemental L-T4 prior to thyroidectomy.

Preoperatively, 6 dogs underwent ultrasound examination of the cervical region, 2 had thyroid scintigraphy, and 3 had computed tomographic (CT) scans.

Mobile, discrete, bilateral thyroid gland carcinomas were removed in all dogs. Among the 15 dogs, complete parathyroidectomies were necessary in 9; parathyroid tissue was reimplanted in 4 and preserved in 2. Complications included hemorrhage and laryngeal nerve trauma, but without serious consequences. Thirteen dogs received calcitriol with or without supplemental calcium after surgery.

In the immediate postoperative period, hypocalcemia developed and was corrected in 11 dogs. At the last study followup, 7 dogs continued to receive calcitriol with or without supplemental calcium, and 8 dogs required long-term thyroid hormone treatment.

Serum total T4 concentrations, as assessed at the end of the immediate postoperative period, were low in 4 dogs, within reference range in 4 dogs, and slightly high in 2 dogs. Serum total T4 concentrations in 5 dogs were not determined. Eleven dogs received thyroid hormone treatment (ie, L-T4) whereas 3 dogs did not.

Six dogs received adjuvant chemotherapy. Local tumor recurrence or de novo distant metastasis was not detected at each dog’s last follow-up examination. Median survival time was 38.3 months. Three dogs were lost to follow-up, 8 survived (4.3 to 77 months after surgery), and 4 died of unrelated causes.

Thyroid hormone replacement therapy had a significant effect on overall survival time; median survival time was 38.3 months among  the 11 dogs that received L-T4 and 17.5 months among 3 dogs that did not receive L-T4 (Figure 1). Otherwise, there were no significant effects of chemotherapy or administration of supplemental calcitriol or calcium among the dogs.

Figure 1: Survival curve for dogs that were given L-T4 supplementation (dashed line; n = 11) and dogs that were not given L-T4 following surgery (solid line; 4)

Conclusions and Clinical Relevance— In dogs with thyroid gland carcinomas undergoing bilateral thyroid lobectomies, a successful outcome can be expected, even when parathyroid gland tissue cannot be preserved. The role of adjuvant chemotherapy in treatment outcome was not clearly defined.

My Bottom Line

This study by Tuohy et al (19) suggests that surgical resection is a viable treatment option for dogs with bilateral mobile thyroid gland carcinoma and that a good prognosis can be expected. Thyroid tumor mobility was the most important criterion for determining feasibility of successful resection in these dogs. The size of these tumors did not impact resection or patient survival, nor was preservation of parathyroid gland tissue critical.

Should adjunct chemotherapy or radiotherapy be given to dogs with thyroid carcinoma?
Vascular or lymphatic invasion (or both) by tumor cells was commonly detected during histologic examination of excised thyroid carcinomas (i.e., in 9 of the 15 dogs). This finding suggests that these affected dogs could benefit from adjuvant chemotherapy or external radiotherapy because such invasive tumors likely have a higher risk of metastasis.

None of the dogs in this study received adjuvant external radiotherapy or radioiodine therapy, so neither of these treatments could be evaluated. However, 6 dogs did undergo adjuvant chemotherapy (doxorubicin only or with carboplatin), but their survival time did not differ from the other dogs that did not receive any chemotherapy. This finding highlights the need for more definitive studies on the role of adjuvant chemotherapy in the treatment of thyroid gland carcinoma in dogs.

Postoperative thyroid hormone treatment for dogs with thyroid carcinoma?
After bilateral thyroidectomy, one would expect serum T4 and T3 levels to decrease into the subnormal  range within 1 to 2 days after surgery. If normal or high T4 values are found in the postoperative period (as reported in 6 dogs of this report), functional thyroid metastasis should be suspected and other follow-up tests of thyroid function (e.g., serum thyroid panel, thyroid uptake and scintigraphy) performed. Why 6 of the dogs of this study had normal to slightly high serum T4s in the "immediate" postoperative period is unclear since no additional follow-up information was reported. It is certainly possible — and even likely— that repeat thyroid testing done at a later date would have revealed low serum T4 values.

In human patients, administration of large doses of thyroid hormone is commonly used as an adjunct treatment after surgery, with the goal of inducing mild hyperthyroidism and completely suppressing circulating TSH to low or undetectable levels (20-22). Circulating TSH can serve as a growth factor to stimulate growth of residual tumor cells; therefore, suppression of TSH may prevent or slow the regrowth of carcinoma tissue in patients with residual neoplastic disease.

In this study, it was interesting that thyroid hormone supplementation appeared to improve survival time in the 11 dogs treated (see Figure 1). Unfortunately, it is not known if TSH suppression was achieved in these dogs since the dose(s) of L-T4 given to these dogs was not provided, and follow-up post-pill serum thyroid hormone or TSH values were not reported. However, two things are very clear— it can be difficult to produce iatrogenic hyperthyroidism in dogs with L-T4 supplementation and that high doses would be needed to completely suppress TSH secretion (23,24).

In the end, it's really impossible to know if the L-T4 therapy really had any true suppressive effect on thyroid carcinoma regrowth or on the dog's survival.  That all said, it remains an interesting observation, and high-dose thyroid hormone suppressive therapy certainly deserves to be investigated as an adjuvant  treatment for dogs with thyroid carcinoma.

References

1. Brodey RS, Kelly DF. Thyroid neoplasms in the dog. A clinicopathologic study of fifty-seven cases. Cancer 1968;22:406-416. 
2. Leav I, Schiller AL, Rijnberk A, et al. Adenomas and carcinomas of the canine and feline thyroid. Am J Pathol 1976;83:61-122.  
3. Barber LG. Thyroid tumors in dogs and cats. Vet Clin North Am Small Anim Pract 2007;37:755-773. 
4. Birchard SJ, Roesel OF. Neoplasia of the thyroid gland in the dog—a retrospective study of 16 cases. J Am Anim Hosp Assoc 1981;17:369–372. 
5. Harari J, Patterson JS, Rosenthal RC. Clinical and pathologic features of thyroid tumors in 26 dogs. J Am Vet Med Assoc 1986;188:1160-1164.  
6. Theon AP, Marks SL, Feldman ES, et al. Prognostic factors and patterns of treatment failure in dogs with unresectable differentiated thyroid carcinomas treated with megavoltage irradiation. J Am Vet Med Assoc 2000;216:1775-1779.  
7. Peterson ME: Hyperthyroidism and thyroid tumor in dogs. In: Melian C, Perez Alenza MD, Peterson ME, Diaz M, Kooistra H (eds): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Multimedica, Barcelona, Spain, 2008, pp 113-125. 
8. Klein MK, Powers BE, Withrow SJ, et al. Treatment of thyroid carcinoma in dogs by surgical resection alone: 20 cases (1981-1989). J Am Vet Med Assoc 1995;206:1007-1009. 
9. Liptak JM. Canine thyroid carcinoma. Clin Tech Small Anim Pract 2007;22:75-81. 
10. Radlinsky MG. Thyroid surgery in dogs and cats. Vet Clin North Am Small Anim Pract 2007;37:789-798, viii.  
11. Pack L, Roberts RE, Dawson SD, et al. Definitive radiation therapy for infiltrative thyroid carcinoma in dogs. Vet Rad Ultrasound 2001;42:471-474. 
12. Brearley MJ, Hayes AM, Murphy S. Hypofractionated radiation therapy for invasive thyroid carcinoma in dogs: a retrospective analysis of survival. J Small Anim Pract 1999;40:206-210. 
13. Brearley MJ. Radiation therapy for unresectable thyroid carcinomas. J Am Vet Med Assoc  2000;217:466-467. 
14. Mayer MN, MacDonald VS. External beam radiation therapy for thyroid cancer in the dog. The Can Vet J 2007;48:761-763.  
15. Worth AJ, Zuber RM, Hocking M. Radioiodide (131-I) therapy for the treatment of canine thyroid carcinoma. Aust Vet J 2005;83:208-214. 
16. Turrel JM, McEntee MC, Burke BP, et al. Sodium iodide I 131 treatment of dogs with nonresectable thyroid tumors: 39 cases (1990-2003). J Am Vet Med Assoc 2006;229:542-548. h 
17. Fineman LS, Hamilton TA, de Gortari A, et al. Cisplatin chemotherapy for treatment of thyroid carcinoma in dogs: 13 cases. J Am Anim Hosp Assoc 1998;34:109-112. 
18. Jeglum KA, Whereat A, Young K. Chemotherapy of canine thyroid carcinoma. Compend Contin Educ Pract Vet 1983;5:5:96–98. 
19. Tuohy JL, Worley DR, Withrow SJ. Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). J Am Vet Med Assoc 2012;241:95-103. 
20. Clark OH. TSH suppression in the management of thyroid nodules and thyroid cancer. World J Surg 1981;5:39-47. 
21. Deasy J, Prichard RS, Evoy D, et al. The role of thyrotropin suppression in patients with differentiated thyroid carcinoma. Ir Med J 2010;103:202-205. 
22. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid 2010;20:135-146. 
23. Piatnek DA, Olson RE. Experimental hyperthyroidism in dogs and effect of salivariectomy. Am J Physiol 1961;201:723-728. 
24. Kaptein EM, Hays MT, Ferguson DC. Thyroid hormone metabolism. A comparative evaluation. Vet Clin North Am Small Anim Pract 1994;24:431-466. 

Intraoperative Parathyroid Hormone Monitoring in Dogs with Hyperparathyroidism

Intraoperative Parathyroid Hormone Concentration to Confirm Removal of Hypersecretory Parathyroid Tissue and Time to Postoperative Normocalcaemia in Nine Dogs with Primary Hyperparathyroidism

K.J. Graham, M. Wilkinson, J. Culvenor, N.K. Dhand, and R.K. Churcher

Australian Veterinary Journal 2012;90:203-209.

Primary hyperparathyroidism is a relatively uncommon disease in dogs but must always be considered as a differential cause of hypercalcemia, particularly in an older, relatively asymptomatic dog with no evidence for malignancy (1-5). In primary hyperparathyroidism, parathyroid gland function is autonomous and nonresponsive to inhibition.  In approximately 90% of dogs, single parathyroid adenomas are responsible, but two adenomas, hyperplastic nodules or, rarely, carcinomas have been reported (2,6)

In human patients suffering from primary hyperparathyroidism, intraoperative parathyroid hormone (PTH) measurement is a highly sensitive and specific tool for determining successful removal of autonomously functioning parathyroid tissue (7-10). In this procedure, PTH is measured just prior to parathyroidectomy and at least 10 minutes after parathyroid tumor removal.  Since PTH has a plasma half life of less than 5 minutes (11), removal of a parathyroid tumor leads to a rapid fall in circulating PTH concentrations within minutes. The criterion for a positive test result varies between studies, but is generally accepted that > 50% decrease in PTH values indicates successful parathyroid tumor removal (7-10). A recent prospective veterinary study of 12 dogs demonstrated a greater than 50% reduction in parathyroidectomy PTH in all dogs, confirming correct removal of the hypersecretory gland (12).

The aims of this study by Graham et al (13) were to determine if serum PTH concentrations would decrease after successful parathyroidectomy and whether manipulation or dissection of the target gland would cause a transient increase in PTH, given its rapid half-life.

Objective of Study — To determine whether the intraoperative parathyroid hormone concentration (PTH) during parathyroidectomy can be used to indicate a cure in dogs with primary hyperparathyroidism. A secondary objective was to determine the time taken for the postoperative serum calcium concentration to normalize.

Design — Retrospective study (2005–2010) from a private referral hospital in Sydney, New South Wales, Australia.

Procedure — Nine client-owned dogs underwent surgical parathyroidectomy for naturally occurring primary hyperparathyroidism. The first PTH sample was taken immediately after induction of anesthesia and prior to manipulation of parathyroid tissue.  A second sample was collected as the abnormal parathyroid gland was being manipulated or excised in 6 dogs. A final PTH sample was taken 20–30 minutes after completion of parathyroidectomy in all dogs.

The concentration of ionized calcium (iCa) was measured at various time points postoperatively until it normalized, then stabilized or decreased below reference ranges. Statistical analysis compared the mean pre-, intra- and post-parathyroidectomy PTH concentration and the average rate of decline of iCa concentration postoperative.

Assays—Blood for PTH measurement was collected from the jugular vein and placed into plain tubes on ice for 30 minutes, centrifuged at 2500g and the serum transferred to a plain tube for storage at 4°C until assay. The serum specimens were assayed for PTH within 2 hours of collection, and results were available by the afternoon of surgery.

Intact serum PTH was assayed using an in-house, quick chemiluminescent enzyme immunometric assay, which is a modification of the Immulite PTH assay (Immulite Turbo: Siemens Medical Solutions Diagnostics).

Results – Serum PTH concentrations fell significantly when measured before and shortly after parathyroidectomy from mean pre-PTH value of 168.51 pg/mL to mean post-parathyroidectomy value of 29.20 pg/mL (Fig. 1). Intraoperative manipulation of the parathyroid tumor resulted in a significant increase in the mean PTH value to 279.78 pg/mL (Fig. 1). The average rate of decline of iCa concentration to within the reference range (1.12-1.40 mmol/L) occurred after 24 hours postoperatively.

Figure 1: Mean PTH concentration before surgery, at time of manipulation of the parathyroid tumor, and 20 min after parathyroidectomy.

Conclusions – Intraoperative measurements of PTH can be used clinically to determine cure of primary hyperparathyroidism. Parathyroid hormone increases significantly during parathyroid gland manipulation. Plasma iCa concentration returns to within the reference range on average 24 hours after successful parathyroidectomy. Not all dogs require vitamin D or calcium supplementation postoperatively.

My Bottom Line:

In this study (13), the investigators were able to document that use of intraoperative PTH in dogs undergoing parathyroidectomy for primary hyperparathyroidism can be a very powerful technique to determine successful surgical removal of the parathyroid tumor and predict outcome. Following parathyroid tumor removal, serum PTH fell dramatically when remeasured at 20-30 minutes postoperatively (see Figure 1). This agrees with another study performed in dogs in which serum PTH fell by >50% when rechecked 30-45 minutes after excision of the diseased parathyroid gland (12).

The finding that PTH concentrations can rise dramatically after manipulation of the abnormal parathyroid tissue highlights the importance of waiting at least 20 minutes to collect the final PTH sample after adenoma removal. This interval ensures that circulating PTH has had enough time to fall to it nadir level before collection.  If collected too soon, the PTH may still be too high, leading one to believe that the surgery was not successful.

Is intraoperative PTH testing practical?
The cost and availability of PTH assays is a major limiting factor for use of intra-operative PTH testing in dogs. Very few veterinary practices, even large speciality hospitals, will have access for the dedicated lab equipment needed to perform these assays. A nearby human facility was used in this case series reported by Graham (13), whereas the only other veterinary case series (12) performed quick parathyroid testing with a in-house, dedicated machine.

And that brings up the biggest down-side to this method —is it feasible to have the results of PTH testing back during the surgical procedure so that we know that all of the involved parathyroid tissue has been removed hyperfunctioning gland prior to closing?  If the PTH samples must be sent out to an outside lab for analysis, that typically will take a few days to receive the PTH results. Such a delay overrides or negates almost all of the advantages of this diagnostic technique.

Remember, as shown in this present study (13), we can judge the success of the operation on the basis of serial serum ionized calcium concentrations, which normalize by 24 hours after successful surgery. We do not need a serum PTH measurement to tell us that operation for hyperparathyroidism has been successful, at least not in most dogs with this disease.

References:

1. Berger B, Feldman EC. Primary hyperparathyroidism in dogs: 21 cases (1976-1986). J Am Vet Med Assoc 1987;191:350-356. 
2. Feldman EC, Hoar B, Pollard R, et al. Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). J Am Vet Med Assoc 2005;227:756-761. 
3. Gear RN, Neiger R, Skelly BJ, et al. Primary hyperparathyroidism in 29 dogs: diagnosis, treatment, outcome and associated renal failure. J Small Anim Pract 2005;46:10-16.  
4. 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.
5. 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.
6. Sawyer ES, Northrup NC, Schmiedt CW, et al. Outcome of 19 dogs with parathyroid carcinoma after surgical excision. Vet Comp Oncol 2012;10:57-64. 
7. Irvin GL, 3rd, Solorzano CC, Carneiro DM. Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World J Surg 2004;28:1287-1292. 
8. Sharma J, Milas M, Berber E, et al. Value of intraoperative parathyroid hormone monitoring. Ann Surg Oncol 2008;15:493-498. 
9. Richards ML, Thompson GB, Farley DR, et al. An optimal algorithm for intraoperative parathyroid hormone monitoring. Arch Surg 2011;146:280-285. 
10. Carneiro-Pla D. Contemporary and practical uses of intraoperative parathyroid hormone monitoring. Endocr Pract 2011;17 Suppl 1:44-53. 
11. Bieglmayer C, Prager G, Niederle B. Kinetic analyses of parathyroid hormone clearance as measured by three rapid immunoassays during parathyroidectomy. Clin Chem 2002;48:1731-1738.
12. Ham K, Greenfield CL, Barger A, et al. Validation of a rapid parathyroid hormone assay and intraoperative measurement of parathyroid hormone in dogs with benign naturally occurring primary hyperparathyroidism. Vet Surg 2009;38:122-132.  
13. Graham KJ, Wilkinson M, Culvenor J, et al. Intraoperative parathyroid hormone concentration to confirm removal of hypersecretory parathyroid tissue and time to postoperative normocalcaemia in nine dogs with primary hyperparathyroidism. Aust Vet J 2012;90:203-209. 

Top Endocrine Publications of 2012: Canine & Feline Parathyroid & Calcium Disorders

In my third compilation of the canine and feline endocrine publications of 2012, I’m moving on to disorders of the parathyroid gland, including the clinical problems of hypercalcemia and hypocalcemia.

Listed below are 22 research papers written in 2012 that deal with a variety of topics and issues related to calcium, parathyroid or vitamin D metabolism.

These range from iatrogenic hypoparathyroidism following parathyroid or thyroid surgery (1,20,21) to dietary hypocalcemia in growing dogs (2,14); from paraneoplastic hypercalcemia (3) to puerperal tetany (eclampsia) and hypocalcemia associated with whelping (6); and from dietary and animal-related factors associated with urinary calcium and calcium oxalate stones (7,8) to circulating PTH concentrations in cats with secondary hyperparathyroidism due to renal disease (9).

Other papers discuss the use of intraoperative PTH measurements during parathyroidectomy to help predict cure in dogs with primary hyperparathyroidism (10) to characterization of a mutation that causes vitamin D-dependent rickets in cats (11); from a study of hypovitaminosis D in dogs with endotoxemia (12) to the effect of prednisolone therapy on calcium and vitamin D metabolism in dogs (16,17); from studies of the outcome of dogs with thyroid or parathyroid carcinoma treated with surgical excision (20,21) to an evaluation of calcium and phosphate homeostasis in hyperthyroid cats with chronic kidney disease.

References:

1. Arbaugh M, Smeak D, Monnet E. Evaluation of preoperative serum concentrations of ionized calcium and parathyroid hormone as predictors of hypocalcemia following parathyroidectomy in dogs with primary hyperparathyroidism: 17 cases (2001-2009). J Am Vet Med Assoc 2012;241:233-236. 
2. Becker N, Kienzle E, Dobenecker B. Calcium deficiency: a problem in growing and adult dogs: two case reports. Tierarztl Prax Ausg K Kleintiere Heimtiere 2012;40:135-139. 
3. Bergman PJ. Paraneoplastic hypercalcemia. Top Companion Anim Med 2012;27:156-158. 
4. Brockley LK, Heading KL, Jardine JE, et al. Polyostotic lymphoma with multiple pathological fractures in a six-month-old cat. J Feline Med Surg 2012;14:285-291. 
5. Corbee RJ, Tryfonidou MA, Meij BP, et al. Vitamin D status before and after hypophysectomy in dogs with pituitary-dependent hypercortisolism. Domest Anim Endocrinol 2012;42:43-49. 
6. Davidson AP. Reproductive causes of hypocalcemia. Top Companion Anim Med 2012;27:165-166. 
7. Dijcker JC, Hagen-Plantinga EA, Everts H, et al. Dietary and animal-related factors associated with the rate of urinary oxalate and calcium excretion in dogs and cats. Vet Rec 2012;171:46. 
8. Dijcker JC, Kummeling A, Hagen-Plantinga EA, et al. Urinary oxalate and calcium excretion by dogs and cats diagnosed with calcium oxalate urolithiasis. Vet Rec 2012;171:646. 
9. Finch NC, Syme HM, Elliott J. Parathyroid hormone concentration in geriatric cats with various degrees of renal function. J Am Vet Med Assoc 2012;241:1326-1335. 
10. Graham KJ, Wilkinson M, Culvenor J, et al. Intraoperative parathyroid hormone concentration to confirm removal of hypersecretory parathyroid tissue and time to postoperative normocalcaemia in nine dogs with primary hyperparathyroidism. Aust Vet J 2012;90:203-209. 
11. Grahn RA, Ellis MR, Grahn JC, et al. A novel CYP27B1 mutation causes a feline vitamin D-dependent rickets type IA. J Feline Med Surg 2012;14:587-590. 
12. Holowaychuk MK, Birkenheuer AJ, Li J, et al. Hypocalcemia and hypovitaminosis D in dogs with induced endotoxemia. J Vet Intern Med 2012;26:244-251. 
13. Hong HH, Chou TA, Yang JC, et al. The potential effects of cholecalciferol on bone regeneration in dogs. Clin Oral Implants Res 2012;23:1187-1192. 
14. Hutchinson D, Freeman LM, McCarthy R, et al. Seizures and severe nutrient deficiencies in a puppy fed a homemade diet. J Am Vet Med Assoc 2012;241:477-483. 
15. Kovalik M, Mellanby RJ, Evans H, et al. Ciclosporin therapy is associated with minimal changes in calcium metabolism in dogs with atopic dermatitis. Vet Dermatol 2012;23:481-491. 
16. Kovalik M, Thoday KL, Berry J, et al. Prednisolone therapy for atopic dermatitis is less effective in dogs with lower pretreatment serum 25-hydroxyvitamin D concentrations. Vet Dermatol 2012;23:125-130, e127-128.
17. Kovalik M, Thoday KL, Evans H, et al. Short-term prednisolone therapy has minimal impact on calcium metabolism in dogs with atopic dermatitis. Vet J 2012;193:439-442. 
18. Nunamaker EA, Sherman JG. Oral administration of lanthanum dioxycarbonate does not alter bone morphology of normal cats. J Vet Pharmacol Ther 2012;35:193-197. 
19. Pineda C, Aguilera-Tejero E, Raya AI, et al. Feline parathyroid hormone: validation of hormonal assays and dynamics of secretion. Domest Anim Endocrinol 2012;42:256-264. 
20. Sawyer ES, Northrup NC, Schmiedt CW, et al. Outcome of 19 dogs with parathyroid carcinoma after surgical excision. Vet Comp Oncol 2012;10:57-64. 
21. Tuohy JL, Worley DR, Withrow SJ. Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). J Am Vet Med Assoc 2012;241:95-103. 
22. Williams TL, Elliott J, Syme HM. Calcium and phosphate homeostasis in hyperthyroid cats - associations with development of azotaemia and survival time. J Small Anim Pract 2012;53:561-571. 

Nutritional Management of Idiopathic Hypercalcemia in Cats

Over the last 15 years, idiopathic hypercalcemia has emerged to become the most common cause of hypercalcemia in cats (1-8). Although the underlying cause of this syndrome remains unclear, it is very likely that the cats' diet may be involved, especially the feeding of acidifying, magnesium-restricted diets designed to minimize struvite crystalluria and urolithiasis (9,10). For more information, see my last post on What's Causing Idiopathic Hypercalcemia in Cats?

Before the introduction of high-carbohydrate, magnesium-restricted acidifying diets by the pet food industry, cats did not develop idiopathic hypercalcemia — at least it was never reported until 1999, (1) and I certainly did not see a cat until the mid-1990s.

Nutritional Therapy

I generally start with diet modification as a first-line treatment. If an acidifying diet is being fed, it should be discontinued. However, it may not always be clear that the cat food being fed is an acidifying diet — one should always closely examine the ingredient list to look for the presence of an added urinary acidifier, such as dl-methionine, phosphoric acid, and ammonium chloride.

Although feline urine is normally mildly acidic, feeding cats commercial diets containing high amounts of carbohydrate (e.g., starch and fiber) will result in an alkaline urine pH (11,12). Therefore, many commercial cat food diets contain added acidifiers in order to “counteract” the alkalizing effects of the high carbohydrate diet, even when it is not promoted as a urinary tract diet.

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 for calcium oxalate stones (13). To this end, we have a variety of different types of cat food diets that have been proposed to help lower calcium in cats with idiopathic hypercalcemia (3-8).

Diets Recommended in the Literature

High-fiber diets
High fiber diets (e.g., Purina OM Overweight Management, Iams Intestinal Plus Low-Residue, Hill’s w/d) will restore normocalcemia in some cats with idiopathic hypercalcemia and calcium oxalate urolithiasis (1,5). The effects of fiber on intestinal absorption are complex and depend on the type and amount of fiber, as well as the interactions with other nutrients in the diet. However, these “high fiber diets” are usually supplemented with extra calcium; therefore, calcium content does not explain why these diets are occasionally helpful in treating idiopathic hypercalcemia. Again, changing from an acidifying diet to any diet that is less acidifying (such as high fiber) would be expected to be beneficial.

Another option, of course, would be to feed a lower calcium diet and add fiber to the diet (e.g., psyllium for a mixed-fiber source or guar gum for an all-soluble source) (8). However, because high-fiber diets tend to be lower in protein, cats with idiopathic hypercalcemia chronically fed these diets can loose lean muscle mass to become muscle wasted (14,15). This is especially true if the cat’s appetite is poor, a sign present in some cats with this syndrome (1-8).

Overall, I do not find high-fiber diets to be helpful in the vast majority of cats with idiopathic hypercalcemia and no longer recommend these diets.

Renal diets
Prescription kidney diets (e.g., Purina NF Kidney Function, Royal Canin Renal LP Modified, Iams Renal Plus, Hill’s k/d) also may result in normocalcemia in some cats with idiopathic hypercalcemia (5,6). Although these renal diets appear less acidifying than most maintenance or high-fiber diets, many renal diets still contain added dl-methionine. Most renal diets are low in calcium, so its decreased consumption should lead to a decrease in the amount of calcium absorbed (4).

Remember, however, that renal diets are also restricted in phosphorus, which may lead to increased calcitriol (active vitamin D) synthesis by the kidney; the action of this increased serum calcitriol could offset the advantage of the decreased calcium absorption in cats with idiopathic hypercalcemia (5,16).

Overall, because these diets are lower in protein, renal diets are not my first choice — with time, cats with idiopathic hypercalcemia can become muscle wasted on these diets (14,15).

Diets for calcium oxalate urolithiasis
Canned diets developed to prevent calcium oxalate urolithiasis (e.g., Royal Canin Urinary SO, Purina UR Urinary St/Ox, Iams Urinary-O Plus Moderate pH/O, Hill’s c/d) may be beneficial in the treatment of cats with idiopathic hypercalcemia (5,6). These diets are restricted in calcium and tend to be less acidifying, resulting in a neutral urine pH in most cats. However, some still contain dl-methionine, which should definitely be avoided. Some of these diets are also restricted in oxalic acid, which may help prevent the calcium oxalate stones that develop in 10-15% of cats with idiopathic hypercalcemia.

However, I do not find any of these “calcium oxalate” diets to be very helpful in normalizing the high ionized calcium concentrations found in cats with idiopathic hypercalcemia. Therefore, I cannot strongly recommend these diets, especially if no calcium oxalate stones are present.

Diets That I Recommend

Canned commercial diets with a "natural" macronutrient composition
Feeding commercial canned diets with a composition similar to what cats would eat in the wild—i.e., 40-60% protein, 30-50% fat, and <15% carbohydrates (17-20)— will also be beneficial in lowering serum calcium concentrations in some cats, particularly those with mild forms of idiopathic hypercalcemia.

One can use the online “Protein/Fat/Carbs Chart” found at www.catinfo.org to select a canned cat food that will provide a nutritional composition similar to what cats would ingest in small prey (e.g., small rodents, birds, and insects). Although this diet composition will result in an acidic urine pH (normal for cats), a high-protein diet is preferable over added acidifiers for prevention of struvite crystal formation in cats (12,21) and is not associated with the same degree of metabolic acidosis.

In addition to the macronutrient composition, one should ensure that the canned food selected does not have any added acidifiers (e.g., dl-methionine, phosphoric acid, or ammonium chloride) and is not a magnesium-restricted diet. A diet with a relatively low vitamin D content (< 5 μg [< 200 IU]/1000 kcal) is recommended. Although feeding a low-calcium diet may be ideal, none of the available commercial cat foods are calcium-restricted.

Home-prepared diet restricted in both calcium and vitamin D
For more control over the exact macronutrient, mineral, and vitamin D content of the cats’ diet, feeding a specially formulated, home-prepared diet is recommended. Some cats, especially those with mild ionized hypercalcemia, will show a good response to a diet restricted in both calcium and Vitamin D (22). Such diets must be specially formulated, since none of the commercial cat food diets could be low in either calcium or vitamin D content and still meet AAFCO guidelines to be a “complete and balanced” diet (23).

Again, I recommend formulating this diet to have a macronutritional composition similar to what cats would eat in the wild (i.e., 40-60% protein, 30-50% fat, and < 10% carbohydrates). Products containing high concentrations of vitamin D, such as organ meats and fish oil, should be avoided (22). Calcium content should be kept restricted to 600 mg per 1000 kcal of diet (in contrast, the minimal adult maintenance requirement set by AAFCO is 1500 mg per 1000 kcal) (23). Magnesium should not be restricted, and acidifiers should never be added.

Ideally, this home-prepared diet is formulated under the guidance of a veterinary nutritionist to ensure that it is nutritionally adequate for the cat. If no response is detected after a month or two on this restricted calcium diet, alternative medical therapies (e.g., glucocorticoids, alendronate) should be considered.

My Bottom Line

In cats with idiopathic hypercalcemia, clinical signs and the associated degree of ionized hypercalcemia are usually mild, at least at diagnosis. In general, the severity of hypercalcemia in these cats tends to be slowly progressive.

Therefore, as the first step in management of these cats, I recommend changing their diet to a canned food that has a macronutrient composition closer to a cat’s carnivorous diet in the wild — in other words, high protein, moderate fat, very low carbs, not magnesium-restricted, and no added acidifiers (17-20). Remember that, at least as far as we know, cats eating this way for many hundreds of years did not develop idiopathic hypercalcemia, so I'm hoping that Mother Nature knows best when it comes down to what these cats should be fed.

One should monitor ionized calcium concentrations at 4 and 8 weeks during this initial dietary change. If hypercalcemia persists, the diet can be switched to a home-prepared, formulated calcium- and vitamin D-restricted diet (22). Again, I would still maintain a macronutrient composition that mimics a cat’s natural diet.

If nutritional management fails to normalized ionized calcium concentrations or hypercalcemia is severe, drug therapy with glucocorticoids (e.g., daily oral prednisolone) or bisphosphonates (e.g., weekly oral alendronate) can be initiated (5-8,24). However, both of these drugs can produce adverse side effects (i.e., diabetes mellitus and esophagitis, respectively), so I prefer to withhold drug therapy until absolutely needed (8,25).

Once drug therapy has been instituted, I would still maintain the feeding a low-carb, high-protein canned diet to these cats. The higher protein intake will help maintain lean body mass, whereas the lower carbohydrates may help mitigate the diabetic effects of the high doses of prednisolone that may be needed to control hypercalcemia.

But in some cats, we'll be lucky, and the hypercalcemia will resolve after a change in the cat's diet to one with a nutrient composition closer to the food they were designed to eat. And in a few of those cats, the ionized calcium concentrations will remain normal for months to years, without the need for drug therapy.

References

1. McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases. J Am Anim Hosp Assoc 1999;35:297-301.
2. Midkiff AM, Chew DJ, Randolph JF, et al. Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14: 619–626.
3. Savary KC, Price GS, Vaden S. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000; 14:184-189.
4. Schenck PA and Chew DJ: Idiopathic hypercalcemia in cats. Waltham Focus 2005; 15: 20-24.
5. Chew DJ, Schenck PA. Idiopathic feline hypercalcemia In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Philadelphia: Saunders Elsivier, 2009; 236-241.
6. de Brito Galvao JF, Schenck PA, Chew DJ. Hypercalcemia: Diagnosis and treatment options in dogs and cats. Veterinary Focus 2011;21:27-34.
7. 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.
8. Baral RM. Disorders of calcium metabolism In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012; 625-642.
9. Ching SV, Fettman MJ, Hamar DW, et al. The effect of chronic dietary acidification using ammonium chloride on acid-base and mineral metabolism in the adult cat. J Nutr 1989;119: 902-915.
10. Fettman MJ, Coble JM, Hamar DW, et al. Effect of dietary phosphoric acid supplementation on acid-base balance and mineral and bone metabolism in adult cats. Am J Vet Res 1992;53:2125-2135.
11. Funaba M, Uchiyama A, Takahashi K, et al. Evaluation of effects of dietary carbohydrate on formation of struvite crystals in urine and macromineral balance in clinically normal cats. Am J Vet Res 2004;65:138-142.
12. Funaba M, Yamate T, Hashida Y, et al. Effects of a high-protein diet versus dietary supplementation with ammonium chloride on struvite crystal formation in urine of clinically normal cats. Am J Vet Res 2003;64:1059-1064.
13. Buckley CM, Hawthorne A, Colyer A, et al. Effect of dietary water intake on urinary output, specific gravity and relative supersaturation for calcium oxalate and struvite in the cat. Brit J Nutr 2011;106 Suppl 1:S128-130.
14. Wolfe RR. Sarcopenia of aging: Implications of the age-related loss of lean body mass. Proceedings of the Nestlé Purina Companion Animal Nutrition Summit: Focus on Gerontology. St. Louis, MO. 2010, pp. 12-17.
15. Little SE. Evaluation of the senior cat with weight loss In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;1176-1181.
16. Chew DJ, DiBartola SP, Schenck PA. In: Canine and Feline Nephrology and Urology. Second Ed. St. Louis: Elsevier Saunders, 2011.
17. MacDonald ML, Rogers QR, Morris JG. Nutrition of the domestic cat, a mammalian carnivore. Annu Rev Nutr 1984;4:521-562.
18. Zoran DL. The carnivore connection to nutrition in cats. J Am Vet Med Assoc 2002;221:1559-1567.
19. Zoran DL. The unique nutritional needs of the cat In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed: Saunders Elsevier, 2010;652-659.
20. Eisert R. Hypercarnivory and the brain: protein requirements of cats reconsidered. J Comp Physiol B 2011;181:1-17.
21. Funaba M, Hashimoto M, Yamanaka C, et al. Effects of a high-protein diet on mineral metabolism and struvite activity product in clinically normal cats. Am J Vet Res 1996;57:1726-1732.
22. Fascetti AJ, Delaney SJ. Nutritional management of endocrine disease. In: Fascetti AJ, Delaney SJ, eds. Applied Veterinary Clinical Nutrition. West Sussex: Wiley-Blackwell; 2012:289-300.
23. AAFCO (Association of American Feed Control Officials). Official Publication, 2012.
24. Whitney JL, Barrs VR, Wilkinson MR, et al. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. J Fel Med Surg 2011;13:129-134.
25. Lowe AD, Graves TK, Campbell KL, et al. Apilot study comparing the diabetogenic effects of dexamethasone andprednisolone in cats. J Am Anim Hosp Assoc 2009;45:215-224.

What's Causing Idiopathic Hypercalcemia in Cats?

Over the last two decades, a syndrome of idiopathic hypercalcemia in cats has emerged and appears to be increasing in frequency (1-6). The term "idiopathic hypercalcemia" refers to a high serum ionized calcium concentration of unknown cause, even after extensive medical evaluation has been undertaken to rule out other known causes of hypercalcemia, such as primary hyperparathyroidism and neoplasia (7,8).

Multiple factors have been considered in relation to the underlying cause of idiopathic hypercalcemia. It is still unclear if increased intestinal calcium absorption, increased bone resorption, or decreased renal calcium excretion (or some combination thereof) is the key factor leading to the development of the ionized hypercalcemia in this syndrome.

Despite the fact that the underlying cause of idiopathic hypercalcemia remains elusive, this has clearly become the most common type of hypercalcemia in cats.

Is the Cat's Diet Responsible?

It has been suggested that the diet fed may predispose cats to development of idiopathic hypercalcemia, as well as formation of calcium oxalate calculi found in 10-15% of cats with this syndrome (8,9).

Acidifying diets
Many believe that feeding of acidifying, magnesium-restricted diets predisposes cats to idiopathic hypercalcemia (4,8). In support of this hypothesis is the fact that both calcium oxalate stones and hypercalcemia first became prevalent in the 1990's, shortly after the introduction of feline acidifying diets designed for prevention of struvite crystals (1-3). In addition, 3 of 5 cats in one series (1) and all 14 cats for which diet history was available in another report (2) had been fed acidifying diets designed to minimize struvite crystalluria and urolithiasis.

When fed to normal cats, such acidifying diets may lead to a state of mild systemic acidosis (10), which, in turn, promotes increased calcium resorption from bone and can produce a state of negative calcium balance. The calcium salts present in bone represent the largest store of alkaline base in the body and, therefore, act as a buffer in states of metabolic acidosis (11). Therefore, when human subjects are fed a diet that produces a net acid load, excessive calcium salt may be released from bone, resulting in increased urinary calcium excretion (11-13). In agreement with these human studies, the induction of metabolic acidosis in cats fed an acidifying diet may result in both mild ionized hypercalcemia and hypercalciuria (10).

Excessive Vitamin D
Another plausible hypothesis is that excessive dietary vitamin D content in some cat foods may contribute to this syndrome (5). Cats have a low requirement for vitamin D (1.4 μg [56 IU] cholecalciferol per 100 kcal diet) (14), at least when fed a diet with adequate concentrations (and a correct ratio) of calcium and phosphorus.

The vitamin D levels in commercial cat diets are not listed on the label and are not always included on product guides or company websites. However, if the label states that a cat diet is “complete and balanced,” the vitamin D levels must be between 3.1-62.5 μg [125-2,500 IU] per 1000 kcal to comply with AAFCO guidelines (15). Therefore, the amounts of vitamin D added to commercial cat foods could range from 2- to 50-fold higher than the minimal requirement recommended by the NRC (14). Most commercial cat foods likely contain relatively high amounts of vitamin D, which could result in hypervitaminosis D in some cats and contribute to ionized hypercalcemia in at least some of them (14,16).

The finding of “normal” serum concentrations of 25-hydroxyvitamin D and calcitriol in most cats with idiopathic hypercalcemia goes against this hypothesis that excessive dietary vitamin D levels in the diet contributes to this syndrome (2,9).  However, it is important to realize that reference range limits for 25-hydroxyvitamin D and calcitriol have all been established in clinically normal cats fed standard diets which again may be rather heavily supplemented with vitamin D.

Bottom Line

In almost all cats with idiopathic hypercalcemia, clinical signs are usually relatively mild, at least at diagnosis. In general, the severity of hypercalcemia in these cats tends to be slowly progressive. Therefore, most cats can be treated as outpatients with either dietary therapy, alone or in combination with drug therapy— i.e., glucocorticoids or bisphosphonates (4-8,17).

I generally start with diet modification as a first-line treatment. In my next post, I'll review the 5 dietary options that have been proposed for this syndrome and give you my recommendations about how to best manage these cats with dietary therapy.

References:

1. McClain HM, Barsanti JA, Bartges JW. Hypercalcemia and calcium oxalate urolithiasis in cats: a report of five cases. J Am Anim Hosp Assoc 1999;35:297-301.
2. Midkiff AM, Chew DJ, Randolph JF, et al: Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14: 619–626.
3. Savary KC, Price GS, Vaden S. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000;14:184-189.
4. Schenck PA and Chew DJ: Idiopathic hypercalcemia in cats. Waltham Focus 2005; 15:20–24.
5. Chew DJ, Schenck PA. Idiopathic feline hypercalcemia In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Philadelphia: Saunders Elsivier, 2009;236-241.
6. de Brito Galvao JF, Schenck PA, Chew DJ. Hypercalcemia: Diagnosis and treatment options in dogs and cats. Veterinary Focus 2011;21:27-34. 
7. 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.
8. Baral RM. Disorders of calcium metabolism In: Little SE, ed. The Cat: Clinical Medicine and Management. St. Louis: Elsevier Saunders, 2012;625-642.
9. Schenck PA, Chew DJ, Refsal K, et al: Calcium metabolic hormones in feline idiopathic hypercalcemia (abstract). J Vet Intern Med 2004;18:442.
10. Ching SV, Fettman MJ, Hamar DW, et al. The effect of chronic dietary acidification using ammonium chloride on acid-base and mineral metabolism in the adult cat. J Nutr 1989;119:902-915.
11. Arnett TR. Extracellular pH regulates bone cell function. J Nutr 2008;138:415S-418S. 
12. Jajoo R, Song L, Rasmussen H, et al. Dietary acid-base balance, bone resorption, and calcium excretion. J Am College Nutr 2006;25:224-230.
13. Vormann J, Remer T. Dietary, metabolic, physiologic, and disease-related aspects of acid-base balance. J Nutr 2008;138:413S-414S. 
14. National Research Council. Vitamins. In: Nutrient Requirements of Dogs and Cats. Washington, DC: National Academies Press. 2006:193-245.
15. AAFCO. (Association of American Feed Control Officials). Official Publication, 2007.
16. Morita T, Awakura T, Shimada A, et al. Vitamin D toxicosis in cats: natural outbreak and experimental study. J Vet Med Sci 1995;57:831-837.
17. Whitney JL, Barrs VR, Wilkinson MR, et al. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. J Feline Med Surg 2011;13:129-134.

Treating Idiopathic Hypercalcemia in Cats with Alendronate

Use of Bisphosphonates to Treat Severe Idiopathic Hypercalcaemia in a Young Ragdoll Cat

J.L. Whitney, V.R.D. Barrs, M.R. Wilkinson, K.A. Briscoe, and J.A. Beatty

Journal of Feline Medicine and Surgery 2011;13:129-134.

Within the past 20 years, idiopathic hypercalcemia has emerged to become the most common type of hypercalcemia in cats (1-3). This condition is now widespread in the United States and has also been reported in many other parts of the world. Cats with idiopathic hypercalcemia range in age from very young to geriatric, and longhaired cats are over-represented (1-5). The diagnosis is based on the laboratory findings (high serum total and ionized calcium concentrations with low to low-normal PTH values) after exclusion of other less common causes of hypercalcemia (especially malignancies) (3-6).

Because the pathogenesis for idiopathic hypercalcemia remains unknown, treatment for this condition can be difficult. Response to dietary changes have produced mixed results, and most cats eventually require medical management, such as prednisolone, to control the hypercalcemia (4,7,8). When neither dietary modification nor treatment with prednisolone are successful in lowering the high circulating calcium concentrations, treatment with an oral bisphosphonate (i.e., alendronate; Fosamax) has been suggested as another option (4,7,8).

Despite the fact that protocols for alendronate have been published in numerous proceedings and book chapters (5,7,8), no case studies of cats with idiopathic hypercalcemia had been reported in a refereed scientific journal until this present report.

In this case report by Whitney et al. (9), the authors describe a cat with well-documented idiopathic hypercalcemia. This cat failed to respond completely to prednisolone but responded well to long-term treatment using alendronate, with resolution of all clinical and biochemical signs of hypercalcemia.

Case report
A 3-year-old Ragdoll cat was examined for investigation of polyuria, polydipsia, vomiting, weight loss, and hypercalcemia. Physical examination was unremarkable (body weight, 3.19 kg). Serum biochemical abnormalities included hypercalcemia (total calcium, 3.8 mmol/L [15.2 mg/dl]; reference range, 1.75-2.6 mmol/L) and hypophosphatemia (1.8 mmol/L; reference range, 2.1-2.8 mmol/L).

Repeat analysis confirmed total (3.74 mmol/L [15 mg/dl]) and ionized (1.8 mmol/L; reference range, 1.2-1.32 mmol/L) hypercalcemia. Urine specific gravity was 1.040 with normal concentrations of urea nitrogen and creatinine. On microscopic examination of the urine, occasional calcium oxalate crystals were identified.

Thoracic radiographs and abdominal ultrasound examination were unremarkable. Parathyroid glands could not be identified on cervical ultrasound examination. Serum intact parathyroid hormone (iPTH) was low, consistent with a parathyroid-independent process (iPTH < 12 pg/ml; reference range, 22-122 pg/ml). Idiopathic hypercalcemia was diagnosed and the cat was discharged on prednisolone (5 mg once daily, PO).

On day 14, the cat was reported to be lethargic and had lost weight (down to 3.06 kg). Persistent total hypercalcemia (3.7 mmol/L [14.8 mg/dl]) and ionized hypercalcemia (1.73 mmol/L) were detected. The frequency of prednisolone therapy was increased to 5 mg, BID. At one month, the owners reported ongoing lethargy and the cat had become anorectic. Serum total hypercalcemia (3.94 mmol/L [15.8 mg/dl]) and ionized hypercalcemia (1.87 mmol/L) persisted so the cat was switched to oral alendronate (Fosamax) 5 mg once weekly, PO.

At recheck, 1 month later, the cat was bright and eating well. No abnormalities were found on physical examination and she had gained weight. Total hypercalcemia was identified (3.85 mmol/L [15.4 mg/dl]). The dose of alendronate was increased to 10 mg once weekly, PO. One month later, the frequency of administration was subsequently increased to 10 mg every 3 days because of persistent hypercalcemia.

At assessment 5 months after initial presentation, the cat was bright with a good appetite and had gained 1.1 kg. No abnormalities were detected on physical examination, serum biochemistry or urinalysis. The serum total calcium (2.6 mmol/L [10.4 mg/dl]) and ionized calcium (1.6 mmol/L) were normal. The dose frequency of alendronate has been gradually reduced. At the time of writing, 18 months after initiating bisphosphonates, the cat is clinically and biochemically normal. The current dose of alendronate is 10 mg administered once weekly.

Bottom Line

This is the first reported case of the use of oral bisphosphonate, alendronate, in the successful long-term management of idiopathic hypercalcemia in a cat (9).

Pharmacology of the bisphosphonates

The bisphosphonates are a group of drugs that inhibit bone resorption and are the standard therapy for malignant humoral hypercalcemia in human patients (10). They act by inhibiting osteoclast apoptosis and sites of active bone turnover (11,12). When given by intravenous infusion, these drugs (e.g., pamidronate) have also been used in dogs for the treatment of primary and secondary bone cancer, cholecalciferol intoxication, and humoral hypercalcemia of malignancy (13-17).

There is a single reported case of the treatment of a cat with concurrent idiopathic hypercalcemia and chronic kidney disease with IV pamidronate (16). However, intravenous treatment with bisphosphonates is almost never needed in cats with idiopathic hypercalcemia, since the hypercalcemia is chronic and the cats are usually not in an acute crisis. Use of an oral bisphosphonates such as alendronate is preferred.

Dosing of alendronate in cats
The dosing regime in this cat (10 mg of alendronate once weekly without food) is similar to what others have reported for cats. If no decrease in serum calcium occurs after 1 month of therapy, the weekly dose can be gradually increased as high as 30 mg per week (5,7,8).

Food substantially reduces the bioavailability and absorption of oral alendronate, so it is recommended that it be administered on an empty stomach (generally after at least a 12-hour fast) (5,7,8). The oral bioavailability of alendronate in the fasted state is about 0.7% in humans, and less than 2% in all species studied (11,12).

Potential side effects of alendronate
Care must be taken when dosing cats with oral alendronate. In human patients oral alendronate administration has been associated with esophagitis and esophageal stricture in up to 15% of patients (18-22).  It is important to ensure that the medication does not stick in the esophagus, which could potentially lead to esophagitis. To minimize this risk, owners should immediately administer 5-6 ml of water orally to their cat after dosing to enhance the passage of the alendronate tablet into the stomach (5,7,8).

Effectiveness of alendronate
Overall, it appears that alendronate treatment is relative safe and effective for cats with idiopathic hypercalcemia, but further studies are needed. Oral bisphosphonates will likely replace prednisolone as the second choice for treatment of this disorder in cats.

Dietary therapy for idiopathic hypercalcemia?
However, I also believe that we need to reexamine the use of dietary therapy in these cats, since it is very likely that diet may play a role in the pathogenesis of idiopathic hypercalcemia. In my next post, I’ll discuss the role of diet, why high-fiber diets generally fail to lower calcium in these cats, and what diets may actually help some cats with mild hypercalcemia restore normocalcemia without the use of potentially toxic drugs.

References:

1. Savary KC, Price GS, Vaden SL. Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997). J Vet Intern Med 2000;14:184-189. 
2. Midkiff AM, Chew DJ, Randolph JF, et al. Idiopathic hypercalcemia in cats. J Vet Intern Med 2000;14:619-626. 
3. Schenck PA and Chew DJ: Idiopathic hypercalcemia in cats. Waltham Focus 2005; 15: 20-24.
4. Chew DJ, Schenck PA. Idiopathic feline hypercalcemia In: Bonagura JD,Twedt DC, eds. Kirk’s Current Veterinary Therapy XIV. St Louis: Sanders Elsevier, 2009; 236-241.
5. de Brito Galvao JF, Schenck PA, Chew DJ. Hypercalcemia: Diagnosis and treatment options in dogs and cats. Veterinary Focus 2011;21:27-34. 
6. Schenck PA, Chew DJ, Refsal K, et al: Calcium metabolic hormones in feline idiopathic hypercalcemia (abstract). J Vet Intern Med 2004;18:442.
7. Chew DJ, Schenck PA. Idiopathic hypercalcemia—what do I do? Proceeding of the North American Veterinary Conference 2007; 732-734.
8. 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.
9. Whitney JL, Barrs VR, Wilkinson MR, et al. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. J Feline Med Surg 2011;13:129-134. 
10. Gnant M. Adjuvant bisphosphonates: a new standard of care? Curr Opin Oncol 2012; 24:635-642. 
11. Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18:75-85. 
12. Lin JH, Russell G, Gertz B. Pharmacokinetics of alendronate: an overview. Int J Clin Pract Suppl 1999;101:18-26. 
13. Rumbeiha WK, Fitzgerald SD, Kruger JM, et al. Use of pamidronate disodium to reduce cholecalciferol-induced toxicosis in dogs. Am J Vet Res 2000;61:9-13. 
14. Milner RJ, Farese J, Henry CJ, et al. Bisphosphonates and cancer. J Vet Intern Med 2004;18:597-604. 
15. Fan TM, de Lorimier LP, Charney SC, et al. Evaluation of intravenous pamidronate administration in 33 cancer-bearing dogs with primary or secondary bone involvement. J Vet Intern Med 2005;19:74-80. 
16. Hostutler RA, Chew DJ, Jaeger JQ, et al. Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia. J Vet Intern Med 2005;19:29-33. 
17. Fan TM. The role of bisphosphonates in the management of patients that have cancer. Vet Clin North Am Small Anim Pract 2007;37:1091-1110.
18. Lilley LL, Guanci R. Avoiding alendronate-related esophageal irritation. Am J Nurs 1997;97:12-14. 
19. Chase JL. Lowering the risk of esophagitis from alendronate therapy. Am J Health Syst Pharm 1998;55:892-893. 
20. Peter CP, Handt LK, Smith SM. Esophageal irritation due to alendronate sodium tablets: possible mechanisms. Dig Dis Sci 1998;43:1998-2002. 
21. Ribeiro A, DeVault KR, Wolfe JT, 3rd, et al. Alendronate-associated esophagitis: endoscopic and pathologic features. Gastrointest Endosc 1998;47:525-528. 
22. Abraham SC, Cruz-Correa M, Lee LA, et al. Alendronate-associated esophageal injury: pathologic and endoscopic features. Mod Pathol 1999;12:1152-1157. 

Hypercalcemia in Canine Hypothyroidism

Hypercalcemia in a Dog with Primary Hypothyroidism

R. G. Lobettia

Journal of the South African Veterinary Association 2011;82: 242–243

Hypercalcemia is a relatively common problem in dogs, with the most common cause being malignancy-associated hypercalcemia (i.e., resulting from lymphoma, anal gland adenocarcinoma, multiple myeloma, or various other carcinomas). Other common causes include primary hyperparathyroidism, hypoadrenocorticism (Addison’s disease) chronic renal failure, and vitamin D toxicosis (1-3).

Hypothyroidism is not generally considered in the differential diagnosis or hypercalcemia in dogs. However, hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5), and, if left untreated, these hypothyroid dogs may continue to show slightly high serum calcium concentrations during adulthood (4).

In this case report (6), Lobetti describes a middle-aged dog with primary hypothyroidism that also developed symptomatic hypercalcemia. After instituting thyroid replacement therapy, both the hypercalcemia and associated clinical signs of polyuria resolved. This is the first report of this association between adult-onset hypothyroidism and symptomatic hypercalcemia in dogs.

Case Report
A 7-year old female beagle was examined because of polyuria and polydipsia, poor appetite, and weight gain. Physical examination revealed that the dog was slightly obese, with bradycardia (80 bpm). Routine blood work revealed marked hypercalcemia (3.27 mmol/L [13.1 mg/dl]; reference range, 2–3 mmol/L). A tentative diagnosis of hypothyroidism was made on the basis of a low serum T4 concentration (<6 nmol/L; reference range, 18–45 nmol/l) together with a high serum TSH value (1.05 ng/ml; reference range, 0.02–0.8 ng/ml).  

The dog was referred for further workup. On repeat serum biochemistry analysis, abnormalities included hypercholesterolemia (13.5 mmol/L [521 mg/dl]; reference range, 3–6 mmol/L) and hypercalcemia (3.44 mmol/ L [13.8 mg/dl]). Results of a complete blood count and urinalysis revealed no abnormalities.

An abdominal ultrasound examination, survey thoracic radiographs, and fine needle aspirate cytology of the spleen, liver and peripheral lymph nodes were all normal. Therefore, hypercalcemia of malignancy was considered unlikely.

A plasma parathyroid hormone (PTH) was low (7 pg/ml; reference range, 15–25 pg/ml). In addition, ultrasonography of the parathyroid glands was normal, making primary hyperparathyroidism unlikely.

The dog was treated with L-thyroxine (300 μg, twice a day). On follow up assessment 2 weeks later, the dog was more active and the bradycardia had resolved, but the polyuria and polydipsia were still present. A repeat serum calcium concentration remained high at 3.46 mmol/L (13.8 mg/dl). Supplementation with L-T4 was continued at 300 μg twice a day.

On recheck 9 weeks later, the dog was active and had lost weight, but now the polyuria and polydipsia had resolved. The serum concentrations of both calcium (2.97 mmol/ L [11.88 mg/dl]), and total T4 (25.5 nmol/L) has normalized.

Fifteen months after the initial diagnosis, the dog’s body weight was stable and her activity normal; no polyuria and polydipsia were reported. Serum concentrations of calcium (2.93 mmol/L [11.7 mg/dl]), T4 (32 nmol/L), TSH (0.11 ng/ml), and PTH (20 pg/ml) were all within the respective reference ranges.

Bottom Line
Little is known about the effects of hypothyroidism on calcium metabolism in adult dogs (1-3), but the effects appear to be mild and clinically insignificant. In agreement with that, humans with adult-onset hypothyroidism serum concentrations of calcium and phosphorus are typically within normal limits (7-9). However, up to 25% of children with congenital hypothyroidism can exhibit mild degrees of hypercalcemia (10), and mild hypercalcemia has been reported in puppies with congenital hypothyroidism (4,5). The proposed mechanism for the hypercalcemia in hypothyroidism is decreased renal clearance and/or increased gastrointestinal absorption of calcium (11).

In the closing paragraph of this paper, Dr. Lobettia concludes that “the only logical explanation for the cause of the hypercalcemia in this dog would be hypothyroidism, as no other etiology was discovered, the hypercalcemia resolved with thyroxine therapy, and the PTH normalized.”

Unfortunately, another cause for this dog’s hypercalcemia must be considered — spurious total hypercalcemia, rather than true ionized hypercalcemia (12-14). In this dog, only the total calcium concentrations were measured, despite the well-documented fact that it is the ionized calcium fraction that has biologic activity.

Why ionized calcium was never measured in this dog is unclear, but it is possible that the serum ionized calcium value would have been normal, and the dog’s signs of polyuria may not have been caused by hypercalcemia after all.

In one study, it was documented that measuring total calcium concentrations tended to overestimate the perceived calcium value in dogs that were truly normocalcemic based on ionized calcium measurements. (13)  Use of total calcium or adjusted total calcium concentrations to predict the ionized calcium status in dogs could cause serious mistakes in diagnosis and case management, and that may have been the situation in the dog of this case report.

So before we add another differential to the differential list for hypercalcemia in dogs, just remember — always measure an ionized calcium to confirm true hypercalcemia (12-14)!

References:

1. Messinger JS, Windham WR, Ward CR. Ionized hypercalcemia in dogs: a retrospective study of 109 cases (1998-2003). Journal of Veterinary Internal Medicine 2009;23:514-519.
2. Feldman EC. Disorders of the parathyroid glands. In Ettinger S J, Feldman E C (eds), Textbook of Veterinary Internal Medicine (7th ed). Saunders Elsevier, St Louis. 2010;1722–1750.
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. Greco D S, Peterson M E, Cho D Y, et al. Juvenile-onset hypothyroidism in a dog. Journal of the American Medical Veterinary Association 1985;187: 948–950. 
5. Greco D S, Feldman E C, Peterson M E, et al. Congenital hypothyroid dwarfism in a family of giant schnauzers. Journal of Veterinary Internal Medicine 1991;5: 57–65.
6. Lobetti RG. Hypercalcaemia in a dog with primary hypothyroidism. Journal of the South African Veterinary Association 2011;82:242-243. 
7. Auwerx J, Bouillon R. Mineral and bone metabolism in thyroid disease: a review. Quarterly Journal of Medicine 1986;60: 737–752. 
8. Begic-Karup S, Wagner B, Raber W, et al. Serum calcium in thyroid disease. Wiener Klinische Wochenschrift 2001; 113: 65–68. 
9. Shivaleela MB, Poornima RT, Jayaprakash Murthy DS. Serum calcium and phosphorous levels in thyroid dysfunction. Indian Journal of Fundamental and Applied Life Sciences 2012;2:179 -183.
10. Verrotti A, Greco R, Altobelli E, et al. Bone metabolism in children with congenital hypothyroidism – a longitudinal study. Journal of Pediatric Endocrinology and Metabolism 1998;11: 699–705. 
11. Pérez A V, Picotto G, Carpentieri A R et al. Mini-review on regulation of intestinal calcium absorption. Emphasis on molecular mechanisms of transcellular pathway. Digestion 2008;77: 22–34. 
12. Schenck PA. Calcium homeostasis in thyroid disease in dogs and cats. Veterinary Clinics of North America: Small Animal Practice 2007;37:693–708. 
13. 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.
14. Schenck PA, Chew DJ. Calcium: total or ionized? Veterinary Clinics of North America: Small Animal Practice 2008;38:497-502.