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. 

Top Endocrine Publications of 2011: Canine & Feline Parathyroid & Calcium Disorders

In my fourth compilation of the canine and feline endocrine publications of 2011, I’m moving on to disorders of the parathyroid gland, including the clinical problems of hypercalcemia and hypocalcemia.

Listed below are 20 research papers written in 2011 that deal with a variety of topics and issues related to calcium, parathyroid or vitamin D metabolism.

These range from the hypercalcemia of malignancy (4,14,17,18) to metabolic causes of seizures (1); from calcium oxalate stones (2,6,15) to idiopathic hypercalcemia in cats (10); from hypercalcemia and soft tissue mineralization associated with Heterobilharzia americana infection, the causative agent of canine schistosomiasis (3,10) to
hypercalcemia causes by blastomycosis in a cat (19); and from surgical hypoparathyroidism (5) to ionized hypocalcemia in dogs following trauma (11).

Other papers discuss clinical issue ranging from hypercalcemia associated with canine hypothyroidism (12) to treatment of rickets in a cat (13); from a study of hypovitaminosis D in dogs with inflammatory bowel disease (8) to a review of osteocalcin, a hormone secreted by osteoblasts that may play an important role in energy metabolism (7).

References:

1. Brauer C, Jambroszyk M, Tipold A. Metabolic and toxic causes of canine seizure disorders: A retrospective study of 96 cases. Vet J 2011;187:272-275. 
2. 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. Br J Nutr 2011;106 Suppl 1:S128-130.
3. Corapi WV, Ajithdoss DK, Snowden KF, et al. Multi-organ involvement of Heterobilharzia americana infection in a dog presented for systemic mineralization. J Vet Diagn Invest 2011;23:826-831. 
4. Dank G, Rassnick KM, Kristal O, et al. Clinical characteristics, treatment, and outcome of dogs with presumed primary hepatic lymphoma: 18 cases (1992-2008). J Am Vet Med Assoc 2011;239:966-971. 
5. de Brito Galvao JF, Chew DJ. Metabolic complications of endocrine surgery in companion animals. Vet Clin North Am Small Anim Pract 2011;41:847-868. 
6. Dijcker JC, Plantinga EA, van Baal J, et al. Influence of nutrition on feline calcium oxalate urolithiasis with emphasis on endogenous oxalate synthesis. Nutr Res Rev 2011:1-15. 
7. Fernandez-Real JM, Ricart W. Osteocalcin: a new link between bone and energy metabolism. Some evolutionary clues. Curr Opin Clin Nutr Metab Care 2011;14:360-366. 
8. Gow AG, Else R, Evans H, et al. Hypovitaminosis D in dogs with inflammatory bowel disease and hypoalbuminaemia. J Small Anim Pract 2011;52:411-418. 
9. Graves TK. When normal is abnormal: keys to laboratory diagnosis of hidden endocrine disease. Top Companion Anim Med 2011;26:45-51. 
10. Hanzlicek AS, Harkin KR, Dryden MW, et al. Canine schistosomiasis in Kansas: five cases (2000-2009). J Am Anim Hosp Assoc 2011;47:e95-e102. 
11. Holowaychuk MK, Monteith G. Ionized hypocalcemia as a prognostic indicator in dogs following trauma. J Vet Emerg Crit Care (San Antonio) 2011;21:521-530. 
12. Lobetti RG. Hypercalcaemia in a dog with primary hypothyroidism. J S Afr Vet Assoc 2011;82:242-243. 
13. MacKenzie JM, Crawford J, Ghantous S. Successful therapy of vitamin D-dependant rickets in a kitten. J Am Anim Hosp Assoc 2011;47:290-293. 
14. Marconato L, Stefanello D, Valenti P, et al. Predictors of long-term survival in dogs with high-grade multicentric lymphoma. J Am Vet Med Assoc 2011;238:480-485. 
15. Palm C, Westropp J. Cats and calcium oxalate: strategies for managing lower and upper tract stone disease. J Feline Med Surg 2011;13:651-660. 
16. Phillips AM, Fawcett AC, Allan GS, et al. Vitamin D-dependent non-type 1, non-type 2 rickets in a 3-month-old Cornish Rex kitten. J Feline Med Surg 2011;13:526-531. 
17. Rebhun RB, Kent MS, Borrofka SA, et al. CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma. Vet Comp Oncol 2011;9:38-44. 
18. Saba C, Ellis A, Cornell K. Hypocalcemia following surgical treatment of metastatic anal sac adenocarcinoma in a dog. J Am Anim Hosp Assoc 2011;47:e173-177. 
19. Stern JA, Chew DJ, Schissler JR, et al. Cutaneous and systemic blastomycosis, hypercalcemia, and excess synthesis of calcitriol in a domestic shorthair cat. J Am Anim Hosp Assoc 2011;47:e116-120. 
20. 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.

A 5-Tiered Approach for Medical Treatment of Hypercalcemia in Dogs

The definitive treatment of hypercalcemia involves treating or removing the underlying cause (see my post on the Top 10 Differentials for Hypercalcemia. Unfortunately, the etiology may not be readily apparent, and if the hypercalcemia is severe, it may be life-threatening. In those dogs, supportive medical measures should be used to help decrease the serum calcium concentration (1-3).

A mild degree of hypercalcemia may not be immediately dangerous and provides time to establish a definitive diagnosis before starting any treatment. However, in dogs with severe hypercalcemia, diagnostic and therapeutic efforts may need to proceed concurrently. Most dogs with a total calcium concentration >15.0 mg/dl will show systemic signs, and those with a calcium concentrations >18.0 mg/dl are critically ill.

Fluid Therapy and Diuresis: The First Tier of Medical Treatment
Fluid therapy with sodium chloride (saline) infusion is the first step in treating moderate to severe hypercalcemia. Sodium and calcium share the same renal reabsorptive system, so providing additional sodium to renal tubules will diminish calcium reabsorption, and increase calciuresis (1-4).

Diuretics can be administered following rehydration and fluid volume expansion for treatment of persistent and severe hypercalcemia that is not associated with renal failure. Loop diuretics such as furosemide (2-4 mg/kg, IV or SQ, every 8-12 hours) will increase calcium excretion by the kidneys.

In contrast to the loop diuretics, thiazide diuretics are contraindicated in hypercalcemia because these agents will decrease calcium excretion by the kidneys and therefore cause worsening of the hypercalcemia.

Gluococorticoids: The Second Tier of Medical Treatment
Glucocorticosteroids provide a second tier of treatment for hypercalcemic cases that do not respond adequately to IV fluids and furosemide. Glucocorticoids, such as prednisone (1-2 mg/kg, IM, every 12 hours) or dexamethasone (0.1-0.2 mg, IV or IM, every 12 hours), reduce bone resorption of calcium, reduce intestinal calcium absorption, and increase renal calcium excretion (1-3).

In addition, glucocorticoids are cytotoxic to malignant lymphocytes, leading to substantial reduction in serum calcium concentration in dogs with hypercalcemia secondary to lymphoma or myeloma, hypervitaminosis D, granulomatous disease, and hypoadrenocorticism. However, use of glucocorticoids may make definitive diagnosis of the underlying cause of the hypercalcemia difficult. This is especially true with lymphosarcoma because steroids are lymphocytolytic and may alter lymph node architecture and patterns of lymphocyte infiltration in bone marrow.

Calcitonin: The Third Tier of Medical Treatment
If hypercalcemia is severe, use of calcitonin as a third tier of treatment may be a valuable adjunctive therapy when fluid deficit replacement, saline diuresis, furosemide, and prednisone have failed to lower the serum calcium concentration (3,4). This drug has a rapid calcium-lowering effect, evident within 2 hours of administration, due to inhibitory effects on osteoclastic activity and renal tubular reabsorption of calcium.

The response to calcitonin, while rapid in onset, is usually short lived. Therefore, the drug (calcitonin-salmon for injection; 200 IU/ml; Miacalcin, Novartis) is generally administered at the dosage of 4 IU/kg IV, followed by 4–8 IU/kg, SC, every 12-24 hours as needed to control hypercalcemia.

Bisphosphonates: The Fourth Tier of Medical Treatment
The fourth tier of treatment is to add a bisphosphonate for the more prolonged control of hypercalcemia (2,5,6). Bisphosphonates act to lower serum calcium by reducing the number and action of osteoclasts. However, because these drugs do not act to rapidly lower the serum calcium, they are not as helpful in the acute management of life-threatening hypercalcemia. That said, because parenteral bisphosphonates are so effective in controlling hypercalcemia, many internists would use these agents even before salmon calcitonin is administered.

Pamidronate is the most commonly used parenteral bisphosphonate in dogs; the recommended dosage is 1.0-2.0 mg/kg administered in 0.9% saline as an slow infusion given over 4 hours (5,6). Adequate hydration is essential when treating with bisphosphonates since these drugs may cause nephrotoxicity, especially at higher doses. Pamidronate is now available as a generic preparation (e.g., from Florida Infusion), making it very cost effective.  The pamidronate insfusion can be repeated at 3-4 week intervals as needed to maintain normocalcemia.

Oral bisphosphonates, such as alendronate (Fosamax, Merck), are more convenient to use and can be administered once weekly at the dose of 2-4 mg/kg, PO (2). However, oral alendronate does not work as well to lower the serum calcium concentration as IV pamidronate. In addition, alendronate is more expensive and can cause esophagitits.

Calcimimetics: The Fifth Tier of Medical Treatment
Calcimimetics are the newest class of drugs, which act to mimics the action of calcium on tissues (i.e, they are calcium-sensing receptor agonists). The mostly commonly used drug of this class is cinacalcet (Sensipar; Amgen), available as 30 mg tablets.

These drugs, by interacting with the calcium-sensing receptors in the parathyroid glands to reduce the secretion of PTH, can effectively suppress circulating PTH in all forms of hyperparathyroidism (7). They have become a major therapy for secondary hyperparathyroidism associated with renal failure (7) as well as for treatment of certain patients with primary hyperparathyroidism (8,9). These drugs would be of no benefit for dogs with hypercalcemia of malignancy or vitamin D toxicosis.

Administration of cinacalcet will not cure hyperparathyroidism. It can only decrease parathyroid hormone secretion to a certain extent. In human patients with primary hyperparathyroidism, the drug  decreases mean serum calcium concentrations only by about 1 mg/dl.

In dogs, the dose is empirical, with a recommended starting dose being 7.5 to 3 0 mg per dog once daily. Cinacalcet is very expensive, with the cost of each 30-mg tablet of being over $10! Becasue of it's limited effectiveness and expense, cinacalcet is generally used as the "last resort" for medical treatment.

References:

1. Schenck PA, Chew DJ, Nagode LA, et al. Disorders of calcium: hypercalcemia and hypocalcemia. In: Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, ed. DiBartola SP, 3rd ed., pp. 122–194. Saunders Elsevier, St. Louis, MO, 2006. 
2. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 4th ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233. 
3. Nelson RW, Delany SJ. Elliott DE. Metabolic and electrolyte disorders. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine, 4th Ed. St. Louis, Mosby: 2008. 
4. Ralson SH. Medical management of hypercalcemia. British Journal of Clinical Pharacology 1992; 34:11-20. 
5. Fan TM. The role of bisphosphonates in the management of patients that have cancer. Veterinary Clinics of North America Small Animal Practice 2007;37:1091-110. 
6. Hostutler RA, Chew DJ, Jaeger JQ, et al. Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia. Journal of Veterinary Internal Medicine 2005;19:29-33.
7. Wuthrich RP, Martin D, Bilezikian JP. The role of calcimimetics in the treatment of hyperparathyroidism. European Journal of Clinical Investigation 2007; 37:915-922. 
8. Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism 2005; 90:135-141. 
9. Rothe HM, Liangos O, Biggar P, et al. Cinacalcet treatment of primary hyperparathyroidism. International Journal of Endocrinology 2011;2011:415719. Epub 2011 Mar 6.

5 Steps in the Workup of Dogs with Hypercalcemia

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

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

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

Important Initial Steps in Workup of All Hypercalemic Dogs

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

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

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

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

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

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

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

Bottom Line

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

References:

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

Top 10 Differentials for Hypercalcemia in the Dog

Hypercalcemia in the dog can have many etiologies, including malignancy (e.g., humoral hypercalcemia of malignancy, primary hyperparathyroidism, multiple myeloma, and neoplasia in bone), increased vitamin D activity (e.g., rodenticides containing cholecalciferol, anti-psoriasis creams containing calcipotriene or calcipotriol, plants containing calcitriol glycosides, excess dietary supplementation), granulomatous inflammation, adrenal insufficiency, or renal disease (1-10).

Two Helpful Mnemonics to Remember the Differential Diagnosis of Hypercalcemia

HARD IONS

• H—Hyperparathyroidism, Humoral hypercalcemia of malignancy, Houseplants
• A—Addison’s disease; Aluminum or vitamin A toxicity
• R—Renal disease, Raisins (Grapes)
• D—Vitamin D toxicosis
• I—Idiopathic (particularly in cats; very rare in dogs)
• O—Osteolytic
• N—Neoplasia (humoral hypercalcemia of malignancy)
• S—Spurious

GOSH DARN IT

• G—Granulomatous disease, Grapes
• O—Osteolytic
• S—Spurious
• H—Hyperparathyroidism, Humoral hypercalcemia of malignancy, House plants
• D—Vitamin D toxicity, Dehydration
• A—Addison’s, Vitamin A, or Aluminum toxicity
• R—Renal disease
• N—Neoplasia (humoral hypercalcemia of malignancy)
• I—Idiopathic
• T—Temperature (hypothermia)

My Top 10 Differential List for Canine Hypercalcemia

Even though these mnemonics can be helpful in recalling all of the various causes of hypercalcemia, I find my list below to be more helpful.

This is my top-10 list for potential rule outs for hypercalcemia in dogs, in an approximate incidence order as seen in practice, starting with the most common to least common problem:

1. Spurious (lab error, lipemic sample causing false elevation of calcium)
2. Lymphosarcoma  
3. Hypoadrenocorticism (Addison's disease)
4. Primary hyperparathyroidism (parathyroid tumor)
5. Renal failure
6. Vitamin D toxicosis
7. Apocrine gland carcinoma of the anal sac  
8. Multiple myeloma of bone (10-15% of cases have high calcium)
9. Other carcinomas (e.g., lung, mammary, nasal, pancreatic, thymic, thyroid, testicular)
10. Granulomatous diseases (e.g., blastomycosis, histoplasmosis, schistosomiasis)

Steps in Workup for the Dog with Hypercalemia

In some dogs with hypercalcemia, the primary diagnosis becomes obvious after analysis of history and findings from physical examination. In most dogs, however, the underlying cause for the hypercalcemia is not all that clear and further testing must be done.

In these dogs, a stepwise approach to diagnosis of the underlying cause of the hypercalcemia is recommended. I'll discuss my approach to diagnosis of these difficult cases in my next post.

References:

1. Schenck PA, Chew DJ, Nagode LA, et al.  Disorders of calcium: hypercalcemia and hypocalcemia. In: Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, ed. DiBartola SP, 3rd ed., pp. 122–194. Saunders Elsevier, St. Louis, MO, 2006.
2. Schenck PA, Chew DJ. Hypercalcemia: a quick reference. Veterinary Clinics of North America Small Animal Practice 2008;38:449–453.
3. Schenck PA, Chew DJ. Investigation of hypercalcaemia and hypocalcaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;221-233.
4. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration in dogs. American Journal of Veterinary Research 2005; 66:1330–1336.
5. Peterson ME, Fineman JM. Hypercalcemia associated with hypoadrenocorticism in sixteen dogs. Journal of the American Veterinary Medical Association 1982; 181:802-804.
6. Hare WR, Dobbs CE, Slayman KA, et al. Calcipotriene poisoning in dogs. Veterinary Medicine 2000; 95:770–778.
7. Gwaltney-Brant S, Holding JK, Donaldson CW, et al. Renal failure associated with ingestion of grapes or raisins in dogs. Journal of the American Veterinary Medical Association 2001; 218:1555–1556.
8. Feldman EC, Hoar B, Pollard R, et al. Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). Journal of the American Veterinary Medical Association  2005;227:756.
9. Gear RN, Neiger R, Skelly BJ, et al. Primary hyperparathyroidism in 29 dogs: diagnosis, treatment, outcome and associated renal failure. Journal of Small Animal Practice 2005;46:10-16.
10. 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.
    

Top Endocrine Publications of 2010: Canine and Feline Parathyroid and Calcium Disorders

In my third compilation of the canine and feline endocrine publications of 2010, I’m moving on to disorders of the parathyroid gland, including the clinical problems of hypercalcemia and hypocalcemia.

Listed below are 18 research papers written in 2010 that deal with a variety of topics and issues related to calcium, parathyroid or vitamin D metabolism.

These range from the nutritional secondary hyperparathyroidism (2, 10) to calcium and phosphorus homeostasis in chronic kidney disease (1, 13) and in the whelping bitch (9); from studies of the feline calcium-sensing receptor (6) to investigations of feline tooth resorptive lesions and vitamin D3 status (7); and from studies of ionized calcium assays (15) to rapid parathyroid hormone assays (8).

Other papers discuss clinical issue ranging from primary hyperparathyroidism (14) to hypercalcemia of malignancy (5, 12, 16, 17); and from the hypercalcemia associated with Heterobilharzia and Leishmaniasis infections (3,4) to treatment of idiopathic hypercalcemia in cats with oral alendronate (18).

References:

1. Cortadellas O, Fernandez del Palacio MJ, Talavera J, et al. Calcium and phosphorus homeostasis in dogs with spontaneous chronic kidney disease at different stages of severity. Journal of Veterinary Internal Medicine 2010;24:73-79.
2. Dimopoulou M, Kirpensteijn J, Nielsen DH, et al. Nutritional secondary hyperparathyroidism in two cats: evaluation of bone mineral density with dual-energy X-ray absorptiometry and computed tomography. Veterinary and Comparative Orthopaedics and Traumatology 2010;23:56-61.
3. Fabrick C, Bugbee A, Fosgate G. Clinical features and outcome of Heterobilharzia americana infection in dogs. Journal of Veterinary Internal Medicine 2010;24:140-144.
4. Freeman KS, Miller MD, Breitschwerdt EB, et al. Leishmaniasis in a dog native to Colorado. Journal of the American Veterinary Medical Association 2010;237:1288-1291.
5. Gajanayake I, Priestnall SL, Benigni L, et al. Paraneoplastic hypercalcemia in a dog with benign renal angiomyxoma. Journal of Veterinary Diagnostic Investigation 2010;22:775-780.
6. Gal A, Ridge TK, Graves TK. Cloning and sequencing of the calcium-sensing receptor from the feline parathyroid gland. Domestic Animal Endocrinology 2010;38:57-61.
7. Girard N, Servet E, Hennet P, et al. Tooth resorption and vitamin D3 status in cats fed premium dry diets. Journal of Veterinary Dentistry 2010;27:142-147.
8. 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. Veterinary Surgery 2009;38:122-132.
9. Hollinshead FK, Hanlon DW, Gilbert RO, et al. Calcium, parathyroid hormone, oxytocin and pH profiles in the whelping bitch. Theriogenology 2010;73:1276-1283.
10. Krook L, Whalen JP. Nutritional secondary hyperparathyroidism in the animal kingdom: report of two cases. Clinical Imaging 2010;34:458-461.
11. Liles SR, Linder KE, Cain B, et al. Ultrasonography of histologically normal parathyroid glands and thyroid lobules in normocalcemic dogs. Veterinary Radiology & Ultrasound 2010;51:447-452.
12. Neihaus SA, Winter JE, Goring RL, et al. Primary clitoral adenocarcinoma with secondary hypercalcemia of malignancy in a dog. Journal of the American Animal Hospital Association 2010;46:193-196.
13. Pusoonthornthum R, Pusoonthornthum P, Krishnamra N. Calcium-phosphorus homeostasis and changes in parathyroid hormone secretion in cats with various stages of spontaneous chronic renal failure. Comparative Clinical Pathology 2010;19:287-293.
14. Sakals SA, Gillick MS, Kerr ME, et al. Diagnosing the etiology of hypercalcemia in a dog: a case of primary hyperparathyroidism. Veterinary Pathology 2010;47:579-581.
15. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by serum total calcium measurement in cats. Canadian Journal of Veterinary Research 2010;74:209-213.
16. Schoen K, Block G, Newell SM, et al. Hypercalcemia of malignancy in a cat with bronchogenic adenocarcinoma. Journal of the American Animal Hospital Association 2010;46:265-267.
17. Seelig DM, Perry JA, Avery AC, et al. Monoclonal gammopathy without hyperglobulinemia in 2 dogs with IgA secretory neoplasms. Veterinary Clinical Pathology 2010;39:447-453.
18. Whitney JL, Barrs VR, Wilkinson MR, et al. Use of bisphosphonates to treat severe idiopathic hypercalcaemia in a young Ragdoll cat. Journal of Feline Medicine and Surgery 2011;13:129-134.

Assay for Parathyroid Hormone Related Protein (PTHrp) Is Back

About a month ago, I posted that the Diagnostic Center for Population and Animal Health (DCPAH) at Michigan State University had announced that the reagents for their parathyroid hormone related protein assay (PTHrP) were not longer available.

This week Michigan State University's DCPAH announced that they are back in business and can again run serum samples for both parathyroid hormone (PTH) as well as PTHrp.

This is the only laboratory that offers the PTHrp test used in the workup for dogs and cats with hypercalcemia. So this is great news that this important assay is up and running again soon.

See the Announcement page on the DCPAH website for more information.

Q & A: Hypercalcemia in an Older Lab - Is This Primary Hyperparathyroidism?

My patient is an 11-year-old spayed female Lab who has polyuria, polydipsia, and weight loss but is otherwise normal. Diagnostic testing has been relatively normal except that she has isosthenuria, hypercalcemia, and hypophosphatemia. These abnormalities are repeatable. 

Her serum parathyroid hormone (PTH) concentration is high (32.3, normal 3.0-17.0), ionized calcium is high (1.92, normal 1.25-1.45), and the parathyroid hormone-related polypeptide (PTHrp) is negative (0.0, normal 0.0-1.0). No gross evidence of perianal masses are seen including on rectal exam, and no lymph node enlargement can be palpated.

Will this be enough evidence to say that this dog definitely has primary hyperparathyroidism? Or should we do more to rule out other malignancy as the cause of hypercalcemia in this dog?

My Response:

Yes, it certainly does appear that your dog has primary hyperparathyroidism. I'd recommend chest radiographs and abdominal ultrasound to complete the workup, but they will likely be normal.

If you can do a parathyroid ultrasound, that would be recommended especially if surgical parathyroidectomy is planned.

Next Question:

Sorry to be a bother, but no chance that this dog couldn't have hypercalcemia of malignancy?

How about renal renal secondary hyperparathyroidism or nutritional secondary hyperparathyroidism?

My Response:

Hypercalcemia of malignancy is possible but extremely unlikely in this dog. While hypercalcemia of malignancy does not always produce high levels of PTH-rp, the PTH concentration should be low in that situation, not high as is the case in your dog.

Unless the dog is eating some bizarre diet, we can rule out nutritional disease in a dog of this age, and I assume the dog is not in renal failure at this time, which largely eliminates that consideration. So primary hyperparathyroid disease remains the most likely by far.

Follow-up and Final Diagnosis:

A single, parathyroid mass was identified and removed at time of exploratory surgery. Results of histopathology confirmed parathyroid adenoma.

The dog developed iatrogenic hypoparathyroidism and hypocalcemia during the immediate post-operative period. But now, 2 months after surgery, the serum calcium concentration is normal without any calcium or vitamin D supplementation.

Test for Parathyroid Hormone Related Protein (PTHrP) No Longer Available

The Diagnostic Center for Population and Animal Health (DCPAH) at Michigan State University recently announced that the reagent for their parathyroid hormone related protein assay (PTHrP) is no longer available.

Currently, Michigan State University's DCPAH is the only laboratory that offers this particular test used in the workup for dogs and cats with hypercalcemia. They are looking in other assay reagents and will hopefully will be have this important assay up and running again soon.

See the DCPAH website at www.animalhealth.msu.edu for more information.

Q & A: PTH Assay Not Currently Available: Alternatives for Workup of Hypercalcemia?

I have a 12 year, F/S, Shih Tzu with hypercalcemia. A tumor search (lymph node aspirates, rectal exam, chest and abdominal radiographs) have revealed nothing so far. I sent a PTH, iCa, to the Michigan State Endocrine Laboratory (part of the Diagnostic Center for Population and Animal Health). After two weeks of waiting, I just received notification that the lab can't run the PTH due to unavailability of the reagents and may not be able to run the test for several weeks.

Are there any alternatives to confirming the diagnosis of primary hyperparathyroidism? Are there other veterinary laboratories that run PTH?

My Response:

The only other thing to consider diagnostically while waiting for the PTH result would be cervical ultrasound by an experienced sonographer armed with the proper transducer. If a large parathyroid mass mass is identified, that would be pretty decent presumptive evidence of primary hyperparathyroidism

If you haven't already done so, I'd repeat the total calcium and confirm the hypercalcemia by also measuring an ionized calcium. It is possible to have a high total calcium with a normal ionized calcium value. If that's the case, it's probably nothing to worry about. If the dog ill or showing any renal compromise? If the dog is stable, I'd just be patient. There's usually no need to rush to treatment if the underlying cause of the hypercalcemia is a parathyroid tumor.

Update: 
We just got notification from the Michigan State Endocrine Laboratory that they received the PTH reagents and that all back ordered test results would be available soon. So the good news is the the PTH assay is back up and running. See the link below for more information.
www.animalhealth.msu.edu/News/Announcements.php#85

It turns out that all of the commercial laboratories (Antech and Idexx), as well as most (if not all of the veterinary labs (e.g., Cornell, CSU, UC-Davis, Minnesota, Auburn, and Tennessee) all send their PTH samples to the Michigan State Endocrine Laboratory.