Top Endocrine Publications of 2012: The Canine Thyroid Gland

In my fifth compilation of the canine and feline endocrine publications of 2012, I’m moving on to disorders of the canine thyroid gland. Listed below are 26 research papers written in 2012 that deal with a variety of thyroid gland topics and issues of clinical importance.

These range from use of recombinant human thyrotropin for diagnosis and an an aid to treatment in dogs with hypothyroidism and thyroid tumors (1,2) to case reports of congenital hypothyroidism in dogs (3,5,9); from studies of the effects of hypothyroidism on glucose metabolism (6) or aggression (20) to studies of thyroid carcinoma (7,11,17,19,25,26).

Other studies included dietary hyperthyroidism in a dog (8) to the reproductive effects of hypothyroidism in dogs (16); and finally, from ectopic thyroid tissue (7,22) to an evaluation of quantitative thyroid scintigraphy as a diagnostic test for dogs (24).

References:

1. Campos M, Peremans K, Vandermeulen E, et al. Effect of recombinant human thyrotropin on the uptake of radioactive iodine (123-I) in dogs with thyroid tumors. PLoS One 2012;7:e50344. 
2. Campos M, van Hoek I, Peremans K, et al. Recombinant human thyrotropin in veterinary medicine: current use and future perspectives. J Vet Intern Med 2012;26:853-862. 
3. Dodgson SE, Day R, Fyfe JC. Congenital hypothyroidism with goiter in Tenterfield terriers. J Vet Intern Med 2012;26:1350-1357. 
4. Fyfe JC, Lynch M, Olsen J, et al. A thyroid peroxidase (TPO) mutation in dogs reveals a canid-specific gene structure. Mamm Genome 2012. 
5. Gal A, Raetzman LT, Singh K. Congenital adenohypophyseal hypoplasia associated with secondary hypothyroidism in a 2-week-old Portuguese water dog. Can Vet J 2012;53:659-664. 
6. Hofer-Inteeworn N, Panciera DL, Monroe WE, et al. Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs. Am J Vet Res 2012;73:529-538. 
7. Kang MH, Kim DY, Park HM. Ectopic thyroid carcinoma infiltrating the right atrium of the heart in a dog. Can Vet J 2012;53:177-181. 
8. Köhler B, Stengel D, Neiger R. Dietary hyperthyroidism in dogs. J Small Anim Pract 2012;53:182-184.
9. Kuczynski LA, Schwartz P, Peddle G, et al. Goiter with vascular anomalies in a litter of Polish Lowland sheepdogs. J Am Anim Hosp Assoc 2012;48:278-283. 
10. Lowrie M, De Risio L, Dennis R, et al. Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage. Vet Radiol Ultrasound 2012;53:381-388. 
11. Metivier KS, Deitz K, Xu WW, et al. Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs. Vet Comp Oncol 2012;doi: 10.1111/j.1476-5829.2012.00348:1-17. 
12. Muntener T, Schuepbach-Regula G, Frank L, et al. Canine noninflammatory alopecia: a comprehensive evaluation of common and distinguishing histological characteristics. Vet Dermatol 2012;23:206-e244. 
13. Nakamura RK, Russell NJ, Shelton GD. Adult-onset nemaline myopathy in a dog presenting with persistent atrial standstill and primary hypothyroidism. J Small Anim Pract 2012;53:357-360. 
14. Narula HS. Accidental thyrotoxicosis caused by inadvertent ingestion of levothyroxine "dog-tabs" by a veterinarian with hypothyroidism. Am J Med 2012;125:e3. 
15. Nelson LL, Coelho JC, Mietelka K, et al. Pharyngeal pouch and cleft remnants in the dog and cat: a case series and review. J Am Anim Hosp Assoc 2012;48:105-112. 
16. Panciera DL, Purswell BJ, Kolster KA, et al. Reproductive effects of prolonged experimentally induced hypothyroidism in bitches. J Vet Intern Med 2012;26:326-333. 
17. Pessina P, Castillo V, Araujo M, et al. Expression of thyroid-specific transcription factors in thyroid carcinoma, contralateral thyroid lobe and healthy thyroid gland in dogs. Res Vet Sci 2012;93:108-113. 
18. Piechotta M, Jens R, Rick M, et al. Serum transthyretin concentration is decreased in dogs with nonthyroidal illness. Vet Clin Pathol 2012;41:110-113. 
19. Proverbio D, Spada E, Perego R, et al. Potential variant of multiple endocrine neoplasia in a dog. J Am Anim Hosp Assoc 2012;48:132-138. 
20. Radosta LA, Shofer FS, Reisner IR. Comparison of thyroid analytes in dogs aggressive to familiar people and in non-aggressive dogs. Vet J 2012;192:472-475. 
21. Ricci R, Bevilacqua F. The potential role of leptin and adiponectin in obesity: a comparative review. Vet J 2012;191:292-298. 
22. Roth DR, Perentes E. Ectopic thyroid tissue in the periaortic area, cardiac cavity and aortic valve in a Beagle dog - a case report. Exp Toxicol Pathol 2012;64:243-245. 
23. Scott-Moncrieff JC. Thyroid disorders in the geriatric veterinary patient. Vet Clin North Am Small Anim Pract 2012;42:707-725.
24. Shiel RE, Pinilla M, McAllister H, et al. Assessment of the value of quantitative thyroid scintigraphy for determination of thyroid function in dogs. J Small Anim Pract 2012;53:278-285. 
25. 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.
26. Urie BK, Russell DS, Kisseberth WC, et al. Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelet derived growth factor receptors-alpha and -beta, KIT, and RET in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma. BMC Vet Res 2012;8:67. 

Medical Treatment of Insulinomas

Dietary or medical management of insulinoma is recommended for animals that are showing signs of hypoglycemia and have previously undergone surgery and in those whose owners have declined surgery (1-6).

Specific chemotherapy can also be considered in animals in which all of the tumor cannot be resected and in those that have undergone previous surgery and again are showing signs of hypoglycemia. Just over half of dogs with insulinoma have metastases at the time of diagnosis (1-4), so it is reasonable to discuss the possibility of follow-up chemotherapy after surgery. Chemotherapy should be given only to patients with a confirmed histologic diagnosis of insulinoma.

Dietary management of hypoglycemia
Animals with insulinoma should be fed a diet that is high in protein, fat, and complex carbohydrates. Simple sugars, often contained in semimoist pet foods, should be avoided. Dogs should be fed small meals three to four times daily. Cats and ferrets may be fed free choice if they do not become obese. Exercise should be controlled and owners should attempt to limit excitement in these pets.

Glucocorticoids
Glucocorticoids are recommended when frequent feedings are no longer successful in controlling clinical signs of hypoglycemia. These drugs raise blood glucose by inhibiting glucose uptake in the peripheral tissues (creating insulin resistance) and stimulating hepatic glucose production (7-9).

Oral prednisone (or prednisolone) is started at the dosage of 0.25 mg/kg, twice daily (1-6). This dosage may be increased gradually as needed to control clinical signs or may be decreased if the disease is well controlled at the initial dosage. We should remember, however, that dosages of 1.1 mg/kg or higher given twice daily are considered immunosuppressive.

Diazoxide
Diazoxide (Proglycem, Teva Pharmaceuticals) is a nondiuretic benzothiadiazide that decreases insulin secretion, promotes gluconeogenesis and glycogenolysis, and inhibits the cellular uptake of glucose (10-12). Diazoxide can be difficult to obtain in the United States; however, reputable compounding pharmacies can often supply this drug.

The recommended starting dosage of diazoxide is 5 mg/kg, given orally twice daily (1-6,13). As with prednisone, the dosage may be increased as needed to control clinical signs. The maximal recommended dosage is 30 mg/kg twice daily.

The most common side effects of diazoxide are anorexia, vomiting, and diarrhea (1-6,13). These signs may be avoided or lessened by giving the medication with food. Ferrets find the diazoxide suspension distasteful, but because only small volumes are required, owners usually are able to administer it. Other potential side effects of diazoxide are hyperglycemia, bone marrow suppression, and sodium retention.

Octreotide acetate
Somatostatin is a polypeptide hormone that inhibits the secretion of insulin, glucagon, gastrin, secretin, and motilin. Octreotide acetate (Sandostatin, Novartis) is a long-acting somatostatin analogue that can be used in the management of patients with insulinoma (14).

Reports on the use of octreotide acetate in veterinary patients are limited and the response is mixed (4,12,15). About half of dogs with refractory hypoglycemia will show a response to octreotide acetate.  Ferrets refractory to other forms of treatment may show improvement in clinical signs in some, but certainly not all, cases.

The recommended dosage is 1 to 2 μg/kg given subcutaneously two to three times daily. This drug is relatively expensive, but may be practical for use in small dogs, cats, or ferrets due to their small size.

Currently, there is no way of predicting which patients will respond to octreotide acetate. Metastatic lesions may express fewer somatostatin receptors than the primary mass, so octreotide may be less effective in patients with advanced disease. This agent does appear to be safe and can be administered by owners at home. Thus, it should be considered for the treatment of animals with insulinoma that are refractory to or unable to tolerate traditional medical or surgical therapy (4,12).

Streptozotocin
Streptozotocin (Zanosar, Teva Pharmaceuticals) is a chemotherapeutic drug that selectively destroys pancreatic beta cells (16-19). When given alone, this drug may cause severe, acute renal failure in dogs. However, the drug can be administered safely if given with aggressive saline diuresis (17-19). Treatment is discontinued if there is clear tumor progression, resistant or recurrent hypoglycemia, or drug toxicity.

Streptozotocin may induce diabetes in some dogs, but the chemotherapy drug may be given along with appropriate insulin therapy if gross disease is still present.  No reports have described the use of streptozotocin in cats or ferrets with insulinoma. Further study of this agent is needed in all species.

Prognosis

The short-term prognosis for dogs with insulinoma is good, although most will eventually die of this disease. While survival time depends on the stage of the disease and the success of surgery, it also depends on the owners’ willingness to treat aggressively and follow up with symptomatic therapy once signs of hypoglycemia return.

Approximately two-thirds to three-quarters of dogs survive 6 months or longer after surgery (often over a year) before intractable hypoglycemia recurs. Reported median survival time is much longer in dogs initially treated with surgery than in those treated with medical management alone (1-5,20,21). Individualizing therapy with the use of combinations of medical and surgical therapy based on the stage and extent of disease may improve prognosis and survival time in any given patient.  

References:

1. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
2. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
4. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
5. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
6. Nelson RW, Foodman MS. Medical management of canine hyperinsulinism. J Am Vet Med Assoc 1985;187:78-82. 
7. Olefsky JM, Kimmerling G. Effects of glucocorticoids oncarbohydrate metabolism. Am J Med Sci 1976;271:202-210. 
8. Chap Z, Jones RH, Chou J, et al. Effect of dexamethasone onhepatic glucose and insulin metabolism after oral glucose in conscious dogs. J Clin Invest 1986;78:1355-1361. 
9. Moore GE, Hoenig M. Effects of orally administeredprednisone on glucose tolerance and insulin secretion in clinically normal dogs. Am J Vet Res 1993;54:126-129.
10. Tabachnick, II, Gulbenkian A. Mechanism of diazoxide hyperglycemia in animals. Ann N Y Acad Sci 1968;150:204-218. Koch-Weser J. Diazoxide. N Engl J Med 1976;294:1271-1273. 
11. Paulissian R. Diazoxide. Int Anesthesiol Clin 1978;16:201-237. 
12. Meleo K. Management of insulinoma patients with refractory hypoglycemia. Prob Vet Med 1990;2:602-609. 
13. Parker AJ, Musselman EM, O'Brien D. Diazoxide treatment of canine insulinoma. Vet Rec 1981;109:178-179. 
14. Maton PN. The use of the long-acting somatostatin analogue,octreotide acetate, in patients with islet cell tumors. Gastroenterol Clin North Am 1989;18:897-922. 
15. Simpson KW, Stepien RL, Elwood CM, et al. Evaluation of the long-acting somatostatin analogue octreotide in the management of insulinoma in three dogs. J Small Anim Pract 1995;36:161-165. 
16. Meyer DJ. Temporary remission of hypoglycemia in a dog with an insulinoma after treatment with streptozotocin. Am J Vet Res 1977;38:1201-1204. 
17. Moore AS, Nelson RW, Henry CJ, et al. Streptozocin for treatment of pancreatic islet cell tumors in dogs: 17 cases (1989-1999). J Am Vet Med Assoc 2002;221:811-818. 
18. Bell R, Mooney CT, Mansfield CS, et al. Treatment of insulinoma in a springer spaniel with streptozotocin. J Small Anim Pract 2005;46:247-250. 
19. Northrup NC, Rassnick KM, Gieger TL, et al. Prospective evaluation of biweekly streptozotocin in 19 dogs with insulinoma. J Vet Intern Med 2013;27:483-490. 
20. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999;215:226-230. 
21. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156. 

Surgical Treatment of Insulinomas

Surgery is the initial treatment of choice for the long-term management of animals with insulinoma. Exploratory celiotomy is useful in confirming the diagnosis, staging the patient, and removing all identifiable pancreatic nodules (1-4). When possible, these pancreatic masses should be removed by partial pancreatectomy to ensure a more complete resection.

Preoperative Management
The serum glucose concentration should be stabilized before induction of anesthesia and surgery. While it is not necessary for the serum glucose to be in the normal range, the measured levels should be stable and the patient should be seizure-free for a few days prior to surgery.

Frequent feedings, continuous intravenous infusion of dextrose solution (5% dextrose or higher), or both, are the best ways to control symptomatic hypoglycemia (1-4). In some cases, use of prednisone or prednisolone may be helpful to help increase the low blood glucose concentrations. If these methods are unsuccessful, more aggressive medical management should be considered. In dogs, a constant rate infusion of glucagon can be considered to stabilize refractory patients (5). For more information, see my last post on Emergency management of hypoglycemia.

Identifying the Pancreatic Nodule(s)
Careful palpation of the entire pancreas and visualization of the liver and mesenteric lymph nodes is critical (4,6). Insulinomas are typically firmer than the normal parenchyma and may be small and obscured by the normal pancreatic tissue. Therefore, it can be difficult to localize a pancreatic nodule at time of surgery, especially in dogs (4,6-9).

When a nodule cannot be identified intraoperatively, biopsy specimens should be taken from the pancreas, liver, and mesenteric lymph nodes. In dogs, insulinoma develops within the right and left pancreatic lobes with equal frequency, and occult nodules are most common in the body of the pancreas. In addition, multiple nodules are seen in approximately 15% of dogs.  Thus, random removal of an entire pancreatic lobe offers no advantage and is not recommended (1-4,6).

In contrast to dogs, occult insulinoma appears to be rare in the ferret, making the pancreatic nodules less challenging to find. However, as compared to dogs and cats, multiple pancreatic nodules are more common than solitary nodules in ferrets. Full abdominal exploratory celiotomy is strongly recommended in ferrets, since concurrent nonpancreatic neoplasia (e.g., adrenal tumors) are not uncommon in this species (3,10,11).

Surgical Techniques for Partial Pancreatectomy
Surgical technique is similar in both the dog and cat (4,6,9). During surgery, the pancreas should be handled gently, and the surgeon should pay special attention to preserving the blood supply to the pancreas when performing a partial pancreatectomy. Any identifiable pancreatic nodules should be removed by partial pancreatectomy if possible, as this has been reported to result in longer survival times than simple excision of the tumor (12).

Partial pancreatectomy can be performed by the suture-fracture technique, the dissection-ligation technique, or through the use of an electrothermal bipolar vessel-sealing device (4,6,9,13). The bipolar vessel-sealing device (BVSD) denatures collagen and elastin within vessel walls and thus safely seals tissue and vessels while causing less tissue damage than is seen with the higher temperatures used in traditional cautery (13).

Using the BVSD to perform partial pancreatectomy in dogs decreases the incidence of post-operative pancreatitis when compared to dogs undergoing the suture fractionation technique. The BVSD is likely more effective in sealing pancreatic ducts during partial pancreatectomy and minimizes the leakage of pancreatic juices in to the remaining tissue that could cause local or generalized pancreatitis (13).

Whether or not metastatic lesions are visible, biopsy of the liver and mesenteric lymph nodes is recommended for staging (1-4).

Glucose Monitoring During and After Surgery
It is important to monitor the serum glucose concentration throughout and after surgery. Surgical manipulation of insulinoma can enhance the release of insulin from the tumor(s). Anesthesia will mask the signs of neuroglycopenia; thus, the only way of preventing serious hypoglycemia is to monitor the patient carefully and administer dextrose as needed.

While the surgeon is manipulating the pancreas and any metastatic lesions, the serum glucose concentration should be evaluated every 10-20 minutes. After surgery, the glucose concentration should be monitored every 30-60 minutes for the first 4-6 hours, and then every 2-4 hours until the glucose concentration has stabilized and the appropriate concentration of dextrose solution has been selected (1-4). The patient may have hyperglycemia after surgery, and intravenous fluids without dextrose may be appropriate.

Complications of Pancreatectomy
Potential complications include hyperglycemia, persistent hypoglycemia and pancreatitis (1-4,6,9).

• Hyperglycemia and diabetes mellitus— In some animals, the high concentration of circulating insulin secreted by the tumor suppresses the function of normal beta cells, leading to hyperglycemia once the insulin producing tumor is removed. As function of the beta cells returns, postsurgical hyperglycemia is resolved. If treatment with insulin is required after resection of an insulinoma, the clinician and the owner should be aware that endogenous insulin eventually may be produced either by the normal beta cells or by recurrent tumor cells. The owner should monitor glucose in the urine several times per week, and serum glucose should be checked at least monthly to avoid an iatrogenic hypoglycemic crisis.
• Persistent hypoglycemia—Persistent or recurrent hypoglycemia detected any time postoperatively should prompt consideration of symptomatic medical management or the use of chemotherapy. In patients who have had a significant hypoglycemia-free period after surgery, a second operation may result in several months of normoglycemia unless gross metastatic disease is present. In these cases medical management is indicated. This will be discussed in my next post.
• Pancreatitis— In dogs, the most common postoperative complication is pancreatitis. Documented or suspected pancreatitis has been reported in cats and ferrets as well postoperatively.

Relapse of Insulinoma
Although surgery is the most successful treatment we have for controlling hypoglycemia and prolonging survival, surgery will not be able to cure most animals with insulinoma. Almost all will show relapse of hypoglylcemia as the remaining tumor tissue grows and secretes high levels of insulin (1-4).

When a patient that has previously undergone surgery for insulinoma begins to show signs of hypoglycemia, a second surgery may be attempted or medical management instituted (see last post). If all visible tumor can be resected again, animals may remain symptom free for a number of additional months. Alternatively, many of these animals showing relapse can be controlled medically; I'll be discussing long-term medical management in my next post.

References:

1. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
4. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
5. Fischer JR, Smith SA, Harkin KR. Glucagon constant-rate infusion: A novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. J Am Anim Hosp Assoc 2000;36:27-32. 
6. Birchard SJ. The pancreas In: Williams M, Niles JD, eds. BSAVA Manual of Canine and Feline Abdominal Surgery. Gloucester: BSAVA Publications, 2005;210–219.
7. Mehlhaff CJ, Peterson ME, Patnaik AK, et al. Insulin producing islet cell neoplasms: Surgical considerations and general management in 35 dogs. J Am Anim Hosp Assoc 1985;21:607-612.
8. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
9. Matthiesen DT, Mullen HS. Problems and complications associated with endocrine surgery in the dog and cat. Prob Vet Med 1990;2:627-667.
10. Caplan ER, Peterson ME, Mullen HS, et al. Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994). J Am Vet Med Assoc 1996;209:1741-1745. 
11. Chen S. Pancreatic endocrinopathies in ferrets. Vet Clin North Am Exot Anim Pract 2008;11:107-123.
12. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999;215:226-230. 
13. Wouters EG, Buishand FO, Kik M, et al. Use of a bipolar vessel-sealing device in resection of canine insulinoma. J Small Anim Pract 2011;52:139-145. 

Emergency Management of Insulinoma and Other Causes of Hypoglycemia

Karo syrup can be used by owners at home to help control hypoglycemia.
Figure from www.gotoaid.com.

Hypoglycemia is a medical emergency that may result in seizures and permanent brain damage (1-5). Mild cases of hypoglycemia can quickly become serious and life threatening if the low blood glucose concentration continues to fall.

Untreated, severe, prolonged hypoglycemia can lead to stupor, coma, and even death in some animals.

Emergency Management of Hypoglycemia

Oral glucose administration
Owners who witness a hypoglycemic seizure can be instructed to rub a sugar solution (e.g., Karo syrup or honey) on their pet’s gums. Most animals will respond rapidly. However, owners should be warned not to place their hands directly into the mouth of an animal that is having a seizure and not to pour a sugar solution into the mouth of an unconscious pet (2,3,6).

If the animal responds to intravenous or oral glucose administration, it then should be fed a small, high-protein meal and kept as quiet as possible. Owners who notice a pet is becoming weak may prevent a hypoglycemic seizure by feeding.

Intravenous glucose administration
All patients with serious neurologic signs referable to hypoglycemia should be treated immediately by intravenous administration of a 50% dextrose solution (1-5 ml is given slowly over 10 minutes).  If the animal responds clinically, continuous intravenous administration of fluids with a 5% dextrose solution should be considered  (2,3,6). Some clinicians prefer to dilute the initial dose in 5% dextrose or sterile water to create a 20-25% solution prior to injection and thereby reduce the osmolality of the infused solution.

Regardless of the glucose concentration chosen to be administered in an emergency, it is important to keep in mind that it is not necessary to completely normalize the serum glucose concentration, but rather, to eliminate the clinical signs related to hypoglycemia.

Intravenous glucagon infusion
When glucose is administered intravenously to a patient with insulinoma, the tumor may be stimulated to release massive amounts of insulin, leading to severe hypoglycemia. This may result in a viscous cycle of the patient receiving larger volumes and more frequent dosing of intravenous dextrose even as clinical signs become more severe (2,3,6,7).

In dogs with insulinoma, intravenous glucagon should be considered if hypoglycemia and associated clinical signs cannot be not stabilized with infusions of dextrose alone. Glucagon stimulates hepatic gluconeogensis and glycogenolysis, thereby raising the circulating glucose concentrations.

One milligram of lyophilized glucagon USP should be reconstituted according to package directions and mixed with 1 liter of 0.9% saline solution. This resulting 1.0 µg/ml solution is given at 5-10 ng/kg/minute (2,6,7). The rate of infusion is adjusted, as needed, to maintain the serum glucose at a concentration of 50-100 mg/dl.

When the dog is able to eat and maintain its own blood sugar, and/or other surgical or medical therapy is used to treat the insulinoma, the glucagon infusion may be slowly tapered over 1-2 days as the serum glucose and clinical signs are monitored (6,7).

Complications of Prolonged Hypoglycemia and Its Treatment

Acquired seizure disorder
Prolonged hypoglycemia can cause focal laminar and pseudolaminar necrosis of the cerebral cortex, which can result in an acquired seizure disorder (2-6). Anticonvulsants may be required long-term for some animals recovering from hypoglycemic seizures.

If seizures persist despite the correction of hypoglycemia, cerebral hypoxia and edema may be responsible. Glucocorticoids, mannitol, or both, should be administered to help treat cerebral edema. Diazepam and phenobarbital may be required to control the seizures. However, we should also consider the possibility that a condition other than hypoglycemia may be the cause of the seizures.

Secondary hypokalemia
Uptake of glucose by cells is accompanied by the transport of potassium from the circulation to the intracellular space. This can result in severe hypokalemia in some cases (2,6). Therefore, the serum potassium concentration should be monitored in patients receiving dextrose infusions and animals supplemented with potassium in most cases (e.g., 16 mEq KCl per liter of intravenous fluids). This is particularly important for animals that are unable or refuse to eat.

References:

1. Elie MS, Zerbe CA. Insulinoma in dogs, cats, and ferrets. Compend Contin Educ Vet 1995;17:51-59.
2. Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. 3rd ed. St Louis: Elsevier Saunders; 2004;616–644.
3. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
4. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc  2012;48:151-163. 
5. Kraje AC. Hypoglycemia and irreversible neurologic complications in a cat with insulinoma. J Am Vet Med Assoc 2003;223:812-814.
6. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD,Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013 (in press)
7. Fischer JR, Smith SA, Harkin KR. Glucagon constant-rate infusion: a novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. J Am Anim Hosp Assoc 2000;36:27-32.

Insulinoma in Dogs, Cat, and Ferrets: Confirming the Diagnosis

Insulinoma, or functional beta-cell tumor, originates from the islet cells of the endocrine portion of the pancreas (1,2). Insulinoma has been described most commonly in dogs and ferrets, and less commonly in cats. Although insulinoma cells produce a variety of polypeptides, most animals with insulinoma are examined because of clinical signs related to hyperinsulinism and resultant hypoglycemia.

Signalment
Insulinoma has been reported in dogs ranging from 3-15 years old but is most common in dogs older than 8 years old (3-8). Insulinoma is very common in domestic ferrets, with an age range from 2-7 years (9-11). No sex predilection has been reported in dogs, but male ferrets seem to be affected more commonly than females. Insulinoma appears to be a rare condition in cats, with only five cats having been reported; these cats ranged in age from 12-17 years (12-15).

Clinical Signs
Clinical signs in animals with insulinoma are caused by hyperinsulinism, which leads to hypoglycemia. In response to a low blood glucose concentration, catecholamines, glucagon, cortisol, ACTH, and growth hormone are released.

When there is a drop in blood glucose in clinically normal animals, these hormones (i.e., catecholamines, glucagon, cortisol, and growth hormone), in conjunction with a decrease in circulating insulin, help prevent progressive and potentially dangerously low blood glucose concentration. In animals with insulinoma, insulin is secreted even in the face of hypoglycemia and the increase in the counterregulatory hormones listed above. In these patients, the blood glucose is not stabilized, but continues to fall.

Dogs with insulinoma may be examined because of clinical signs related to neuroglycopenic symptoms produced by glucose deprivation of the central nervous system (e.g., hypoglycemia). Less commonly, some animals show adrenergic symptoms caused by catecholamines such as epinephrine (e.g., nervousness, tachycardia) (1,2,16).

The most common complaint for dogs with insulinoma is seizures (1-8). Other signs include collapse, lethargy, weakness, ataxia, mental dullness, muscle fasciculation, trembling, and nervousness (Table 1). Similar signs have been reported in cats with insulinoma (1,12-15). Peripheral neuropathy in association with insulinoma and hypoglycemia has been rarely reported in dogs with insulinoma (17,18).

Table 1: Clinical signs associated with insulinoma in dogs, cats, or ferrets (from reference 2).

Ferrets with insulinoma also commonly show signs of weakness and lethargy (9-11). As in dogs, these symptoms may be episodic. However, seizures are relatively uncommon in this species. Ptyalism is a clinical sign associated with insulinoma in ferrets that has not been described in dogs. The cause of this sign is not known, but ptyalism in ferrets may indicate nausea.

Confirming the Diagnosis— Fulfilling Whipple's Triad
A complete history may lead the clinician to suspect that a patient’s presenting clinical signs are related to hypoglycemia, and thus consider insulinoma as a differential diagnosis. A plasma glucose concentration of 40 mg/dl (2 mmol/L) or less supports the conclusion that the signs are caused by hypoglycemia (16).

If administration of glucose relieves the clinical signs of weakness, disorientation, seizures or trembling, we can conclude that these symptoms are caused by hypoglycemia. This full fills Whipple's triad (i.e, signs of hypoglycemia, biochemical confirmation of low blood glucose at time of clinical signs, and relief of clinical signs after glucose administration) (19,20). This positive response may be seen in animals with hypoglycemia for any reason, however, and is not diagnostic of insulinoma.

Other Causes of Hypoglycemia
In addition to insulinoma, there are many other possible causes of hypoglycemia in animals (1,2,16,21) (Table 2).

Table 2: Causes of hypoglycemia in the mature animal

Many of these differential diagnoses can be ruled out quickly during the initial history and physical examination. After consideration of these diseases is eliminated, insulinoma should be seriously considered in a mature patient with clinical signs of hypoglycemia.

Confirming the Diagnosis—Documenting Hyperinsulinemia
Hyperinsulinism is best diagnosed by the interpretation of serum insulin and glucose concentrations obtained from the patient at the same time. If the clinician suspects hyperinsulinism at the time of initial examination of an animal showing signs of hypoglycemia, serum samples for glucose and insulin measurements are best obtained at that time.

If attempts are made to document hyperinsulinism at a later date, blood samples should be obtained after fasting when the glucose is less than 50 mg/dl (<3.0 mmol/L). It is essential that patients suspected of having hyperinsulinism fast under supervision to allow intervention should signs of hypoglycemia occur.

A high insulin concentration in any animal with concurrent hypoglycemia is consistent with hyperinsulinism (1,2,16,22). If a hypoglycemic patient has an insulin concentration that is within the reference range, the animal again should fast, and the test should be repeated when two consecutive serum glucose readings of 50 mg/dl or less are obtained. If the patient is consistently hypoglycemic, an insulin level within the normal range is considered inappropriate and the patient likely has hyperinsulinism.

Identifying the Pancreatic Nodule
Whenever possible, abdominal ultrasound should be performed in dogs and cats with suspected insulinoma. It can be difficult to detect small pancreatic nodules via ultrasound, but it may be helpful in identifying abdominal metastases (2,22,23). In all species, abdominal ultrasonography may help rule out other neoplasms as a cause of hypoglycemia.

Computed tomography (CT) can also be used to accurately identify pancreatic nodules, and this procedure may be helpful in surgical planning (23).

Bottom Line

Although an accurate diagnosis of insulinoma can generally be made by clinical pathologic testing, histologic examination is required for a definitive diagnosis. Exploratory celiotomy is recommended in all patients with insulinoma if the owner wishes to pursue treatment, but long-term medical management can be helpful in many of these animals.

In my next post, I'll be discussing emergency management of hypoglycemia associated with insulinoma.  This is a critical issue—  if we can't control the immediate clinical signs of hypoglycemia, we will never be able to proceed to definitive or long-term treatment of this serious disorder.

References:

1. Elie MS, Zerbe CA. Insulinoma in dogs, cats, and ferrets. Compend Contin Educ Vet 1995;17:51-59.
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Kruth SA, Feldman EC, Kennedy PC. Insulin-secreting islet cell tumors: establishing a diagnosis and the clinical course for 25 dogs. J Am Vet Med Assoc 1982;181:54-58. 
4. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
5. Schrauwen E. Clinical peripheral polyneuropathy associated with canine insulinoma. Vet Rec 1991;128:211-212.
6. Trifonidou MA, Kirpensteijn J, Robben JH. A retrospective evaluation of 51 dogs with insulinoma. Vet Q 1998;20 Suppl 1:S114-115. 
7. Madarame H, Kayanuma H, Shida T, et al. Retrospective study of canine insulinomas: eight cases (2005-2008). J Vet Med Sci 2009;71:905-911. 
8. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc  2012;48:151-163. 
9. Caplan ER, Peterson ME, Mullen HS, et al. Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994). J Am Vet Med Assoc 1996;209:1741-1745.
10. Ehrhart N, Withrow SJ, Ehrhart EJ, et al. Pancreatic beta cell tumor in ferrets: 20 cases (1986-1994). J Am Vet Med Assoc 1996;209:1737-1740.
11. Weiss CA, Williams BH, Scott MV. Insulinoma in the ferret: clinical findings and treatment comparison of 66 cases.  J Am Anim Hosp Assoc 1998;34:471-475.
12. McMillan FD, Feldman EC. Functional pancreatic islet cell tumor in a cat. J Am Anim Hosp Assoc 1985;21:741-746.
13. Hawks D, Peterson ME, Hawkins KL, et al. Insulin-secreting pancreatic (islet cell) carcinoma in a cat. J Vet Intern Med 1992;6:193-196.
14. Kraje AC. Hypoglycemia and irreversible neurologic complications in a cat with insulinoma. J Am Vet Med Assoc 2003;223:812-814.
15. Greene SN, Bright RM. Insulinoma in a cat. J Small Anim Pract 2008;49:38-40. 
16. Schoeman JP. Investigation of hypoglycaemia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;259-264.
17. Schrauwen E, Van Ham L, Desmidt M, et al. Peripheral polyneuropathy associated with insulinoma in the dog: Clinical, pathological, and electrodiagnostic features. Prog Vet Neurol 1996;7:16-19.
18. Braund KG, Steiss JE, Amling KA, et al. Insulinoma and subclinical peripheral neuropathy in two dogs. J Vet Intern Med 1987;1:86-90. 
19. Ariamkina OL, Doroshenko GM, Petrenko LV. On diagnostic value of Whipple's triad: a case of insulinoma diagnosis. Klin Med (Mosk) 1997;75:61-63. 
20. Hirshberg B, Livi A, Bartlett DL, et al. Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endo Metab 2000;85:3222-3226. 
21. Murphy LA, Coleman AE. Xylitol toxicosis in dogs. Vet Clin North Am Small Anim Pract 2012;42:307-312. 
22. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
23. Robben JH, Pollak YW, Kirpensteijn J, et al. Comparison of ultrasonography, computed tomography, and single-photon emission computed tomography for the detection and localization of canine insulinoma. J Vet Intern Med 2005;19:15-22. 

Top Endocrine Publications of 2012: Insulinoma and Other Causes of Hypoglycemia

Insulinoma in a dog, showing up a solidary pancreatic nodule

In my fourth compilation of the canine and feline endocrine publications of 2012, I’m going back to disorders of the pancreas. But now let’s move on to islet cell tumors (e.g., insulinoma) and other causes of hypoglycemia.

Listed below are 13 research papers written in 2012 that review endocrine hypoglycemia in dogs and cats. These include new aspects in pathogenesis of hypoglycemia associated with insulin-secreting tumors of the pancreas (1,3,5), portosystemic shunts (2), or hypoadrenocorticism (4,8).

Other papers review the hypoglycemia and liver toxicosis associated with xylitol toxicosis in dogs (7,10), as well as the hypoglycemia associated with insulin treatment of diabetes mellitus (6,11-13).

2012 Papers on Canine and Feline Islet Cell Tumors of the Pancreas and Other Causes for Hypoglycemia:

1. Buishand FO, van Erp MG, Groenveld HA, et al. Expression of insulin-like growth factor-1 by canine insulinomas and their metastases. Vet J 2012;191:334-340. 
2. Collings AJ, Gow AG, Marques A, et al. A prospective study of basal insulin concentrations in dogs with congenital portosystemic shunts. J Small Anim Pract 2012;53:228-233. 
3. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
4. Gow AG, Gow DJ, Bell R, et al. Insulin concentrations in dogs with hypoadrenocorticism. Res Vet Sci 2012;93:97-99. 
5. Hambrook LE, Kudnig ST. Tumor thrombus formation in two dogs with insulinomas. J Am Vet Med Assoc 2012;241:1065-1069. 
6. Hugler S. Diabetic alert dogs: A good nose for hypoglycemia. Dtsch Med Wochenschr 2012;137:p25. 
7. Imai A, Nishita T, Ichihara N, et al. Binding affinity of anti-xylitol antibodies to canine hepatic vessels. Vet Immunol Immunopathol 2012;149:108-111. 
8. Kasabalis D, Bodina E, Saridomichelakis MN. Severe hypoglycemia in a cat with primary hypoadrenocorticism. J Feline Med Surg 2012;14:755-758. 
9. Mazaki-Tovi M, Segev G, Yas-Natan E, et al. Serum gastrin concentrations in dogs with liver disorders. Vet Rec 2012;171:19. 
10. Murphy LA, Coleman AE. Xylitol toxicosis in dogs. Vet Clin North Am Small Anim Pract 2012;42:307-312. 
11. Niessen SJ. Glucagon: are we missing a (life-saving) trick? J Vet Emerg Crit Care (San Antonio) 2012;22:523-525. 
12. Niessen SJ, Powney S, Guitian J, et al. Evaluation of a quality-of-life tool for dogs with diabetes mellitus. J Vet Intern Med 2012;26:953-961. 
13. Zeugswetter FK, Schornsteiner E, Haimel G, et al. Metabolic and hormonal responses to subcutaneous glucagon in healthy beagles. J Vet Emerg Crit Care (San Antonio) 2012;22:558-563. (See my blog post entitled "Use of a Glucagon Emergency Kit for Insulin-Induced Hypoglycemia" to see my review of this paper.)

What's the Best Insulin for Diabetic Cats and Dogs?

With the reintroduction of Vetsulin (porcine insulin zinc suspension) to the U.S. market (1-3), I've received a number of questions concerning the use of this insulin in dogs and cats. Here are the major questions I've received:

• Is this the initial insulin of choice for dogs? 
• How about for cats? Should this be an insulin that we turn to for our newly diagnosed feline diabetics?  
• If we have a dog or cat that isn't responding well to the current insulin, should they be switched to Vetsulin?
• How will this insulin compare to NPH, glargine (Lantus), detemir (Levemir), or PZI (ProZinc) in cats or dogs?  How does the cost compare to these other insulin preparations?

Is this the initial insulin of choice for dogs?
In my opinion, the answer to that is yes, this is the initial insulin of choice for most dogs. Because it's composed of both short and long-acting insulin components, Vetsulin helps control postprandial hyperglycemia and has a longer duration of action than NPH in most dogs (4-7). The cost is approximately the same as NPH, but less than the insulin analogues (e.g., detemir and glargine). See more below, where I do my cost-comparisons for the various insulin preparations.

Is this the initial insulin of choice for cats?
A number of studies have proven that Vetsulin will certainly control hyperglycemia in cats, especially if combined with a low carbohydrate diet (<10% of calories) (8-11). However, the duration of action may be too short in some diabetic cats, and most feel that the longer acting insulin preparations (glargine, detemir or ProZinc) work better to maintain better control of hyperglycemia in cats (11-13).

Of course, maintaining glycemic control throughout the day is more important if diabetic remission is the goal (13,15,16)— if not, Vetsulin might be less expensive and certainly would be more than adequate in most cats (8-10).

If we have a dog or cat that isn't responding well to the current insulin, should they be switched to Vetsulin?
For diabetic dogs not regulated on NPH, the answer is a definite "yes." For cats that are on NPH, Vetsulin would certainly be a better choice, but switching to one of the  longer-acting insulin preparations (insulin glargine, detemir, or PZI) would be a better choice.

How will this insulin compare to NPH, detemir, glargine, or PZI in cats or dogs?  
In dogs, I generally use 3 insulin preparations: Vetsulin, NPH, and insulin detemir. Again, the main problem with NPH insulin in dogs is that the duration of action is too short, and many of these dogs will respond better to Vetsulin. Insulin detemir is the most potent insulin we have for use in dogs, with a longer duration of action (14), but it's much more expensive than either NPH or Vetsulin.

In cats, I never use NPH because of it's short duration, but I will sometimes use Vetsulin as an intermediate-acting insulin.  Most authorities would rank insulin glargine as the first choice of insulin in cats, then insulin detemir or PZI (not the compounded product (17), but FDA-approved ProZinc), then Vetsulin, then finally NPH as a very last choice.

How does the cost of Vetsulin compare to these other insulin preparations?
NPH insulin, insulin glargine, and insulin detemir are all available as 10-mL vials at a U-100 insulin concentration. The retail prices of an individual vial of NPH insulin, insulin glargine, and insulin detemir vary, depending on the pharmacy and its location. I checked out the prices today at my local Walmart, CVS, and Rite Aid pharmacies, and here are the range of prices I was quoted:

• NPH —$24.88 (Walmart's ReliOn brand) to $100.39 (CVS) and $107.99 (Rite Aid)!
• Glargine — $152.84 (Walmart) to $169.99 (CVS) and $188.99 (Rite Aid)
• Detemir — $160.32 (Walmart) to $190.99 (CVS)

Vetsulin (porcine insulin zinc suspension) is available as a 10-mL vial of insulin in a U-40 insulin concentration. The wholesale cost of the updated Vetsulin product is inexpensive ($23.97 per vial), similar to the original product. In most veterinary practices, the retail price of a vial of Vetsulin will be approximately $50.

Therefore, the cost of a bottle of Vetsulin is similar or even less than the price of NPH insulin and costs much less (about 25-30%) than that of insulin glargine or detemir.  But remember, the total amount of insulin in a vial of NPH, glargine, and detemir (all U-100 insulins) is 1000 units, where a vial of Vetsulin (a U-40 insulin) contains 400 units, only 40% as much. So in the end, the cost per unit of most of these insulins preparations woud generally turn out to be similar.

Therefore, the cost of all of these insulin preparations would be similar in most diabetic cats and smaller dogs receiving a typical daily dose of insulin (0.5-0.7 U/kg). Because the concentration of Vetsulin is 40 U/mL, owners of larger diabetic dogs, owner will often go through a bottle within a few days. In these dogs, if insulin resistance is present, it's sometimes cheaper to use a U-100 insulin, such as detemir.

However, the bottom line is clear: it doesn't matter how much money we are saving if the insulin isn't working. Instead, for most pet owners, it's more important use an insulin preparation that best controls the diabetic state. And for most diabetic dogs, that insulin would be Vetsulin, followed by insulin detemir.

References:

1. Peterson ME. Vetsulin Insulin Updated and Approved for Release in USA. Insights into Veterinary Endocrinology. April 17, 2013.
2. Vetsulin website. www.vetsulin.com
3. Vetsulin website: Veterinary Product Updates. www.vetsulin.com/vet/Product_Update.aspx
4. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682. 
5. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237. 
6. Nelson RW. Canine diabetes mellitus In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition ed. St. Louis: Saunders Elsevier, 2010;1449-1474.
7. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
8. Martin GJ, Rand JS. Pharmacology of a 40 IU/ml porcine lente insulin preparation in diabetic cats: findings during the first week and after 5 or 9 weeks of therapy. J Feline Med Surg 2001;3:23-30. 
9. Martin GJ, Rand JS. Control of diabetes mellitus in cats with porcine insulin zinc suspension. Vet Rec 2007;161:88-94. 
10. Michiels L, Reusch CE, Boari A, et al. Treatment of 46 cats with porcine lente insulin—a prospective, multicentre study. J Feline Med Surg 2008;10:439-451. 
11. Rand JS. Feline diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;133-147.
12. Marshall RD, Rand JS, Morton JM. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. J Vet Pharmacol Ther 2008;31:205-212.
13. Marshall RD, Rand JS, Morton JM. Treatment of newly diagnosed diabetic cats with glargine insulin improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. J Feline Med Surg 2009;11:683-691. 
14. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci 2011;90:396-403.
15. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009;11:668-682.
16. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
17. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605. 
18. Drugstore.com. www.drugstore.com. (accessed 2006 Oct 3).
19. http://www.relion.com/diabetes/insulin

Predicting Which Dogs will Develop Hypocalcemia after Parathyroidectomy for Primary Hyperparathyroidism

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)

Melissa Arbaugh, Daniel Smeak, and Eric Monnet

Journal of the American Veterinary Medical Association  2012;24:233-236

In dogs, primary hyperparathyroidism causes hypercalemia through the excessive secretion of parathyroid hormone (PTH), usually by an adenoma affecting one of the parathyroid glands (1-6). Such autonomous hypersecretion of PTH by the parathyroid tumor may lead to disuse atrophy of the remaining parathyroid glands (7).

Removal or ablation of the affected parathyroid tumor(s) is the treatment of choice for dogs with primary hyperparathyroid (1-6,8). Following surgery, these dogs may develop transient hypocalcemia while the suppressed parathyroid glands regain appropriate function. If hypocalcemia occurs, it generally does so within the first 7 days following surgery, and affected dogs often require extensive hospitalization and monitoring of serum ionized calcium concentrations (1-6,8).

It has been suggested that hyperparathyroid dogs with more severe hypercalcemia (total serum calcium concentrations > 14 mg/dL) should be started on supplementation with oral calcium and vitamin D prior to surgery (4,5). These dogs with more severe hypercalcemia may be at a greater risk for developing iatrogenic hypocalcemia after parathyroidectomy, since it is likely that their severe hypercalcemia would result in atrophy of the remaining parathyroid glands. These recommendations, however, are not based on clinical studies. If it turns out that theses dog did not actually require the calcium and vitamin D supplementation to prevent clinical hypocalcemia, then these supplements become unnecessary treatments that may delay recovery of the suppressed parathyroid glands to normal function.

Currently, there are no published predictors to indicate which hyperparathyroid dogs will become hypocalcemic and require calcium supplementation following parathyroidectomy. The purpose of the study reported by Arbaugh, et al (9) was to evaluate predictors of postoperative hypocalcemia in dogs following parathyroidectomy. They hypothesized that both the absolute preoperative calcium concentrations and its rate of decrease would aid in predicting clinical hypocalcemia.

Objective—To determine whether preoperative serum ionized calcium (iCa) or parathyroid hormone (PTH) concentrations help predict postoperative hypocalcemia following parathyroidectomy in dogs with primary hyperparathyroidism.

Design—Retrospective case series.

Animals— 17 dogs with primary hyperparathyroidism treated with parathyroidectomy.

Procedures—Medical records were evaluated from years 2001 to 2009. Data evaluated included age, breed, sex, clinical signs, diagnostic tests performed, preoperative and postoperative iCa concentrations, preoperative PTH concentrations, and whether calcium supplementation was provided following surgery. Two groups were identified on the basis of whether dogs became hypocalcemic (iCa < 1.2 mmol/L) following parathyroidectomy.

Results—12 dogs developed hypocalcemia after surgery. Preoperative (within 24 hours before surgery) iCa concentrations for the hypocalcemic group (mean ± SD, 1.82 ± 0.22 mmol/L) and the nonhypocalcemic group (1.83 ± 0.29 mmol/L) were not significantly different.

Calcium concentrations decreased in a linear fashion during the 24 hours following parathyroidectomy, and the slopes of the decrease over that time were not significantly different between the 2 groups of dogs. Preoperative PTH concentrations were not significantly different between the hypocalcemic and nonhypocalcemic groups.

Conclusions and Clinical Relevance —Preoperative iCa and PTH concentrations were not predictive of postoperative hypocalcemia in dogs undergoing parathyroidectomy for primary hyperparathyroidism. Future studies to evaluate whether calcium supplementation should be provided on an individual basis with perhaps more emphasis on clinical signs than iCa concentrations after surgery may be warranted.

My Bottom Line

Can preoperative calcium or PTH predict postoperative hypocalcemia?
The results of the this study by Arbaugh (9) indicate that preoperative serum concentrations of iCa or PTH concentrations are not reliable predictors of postoperative hypocalcemia in dogs undergoing parathyroidectomy for primary hyperparathyroidism.

These results agree with studies reported in human patients with  primary hyperparathyroidism, in which no difference could be detected in the preoperative serum values for calcium or PTH and the development of postoperative hypocalcemia (10). In addition, in a recent study by Milovancev and Schmiedt (11) of 62 dogs that had parathyroidectomy for primary hyperparathyroidism, these investigators arrived at the same conclusion. No correlation existed between preoperative serum total and ionized calcium concentrations and the development of postoperative hypocalcemia in these 62 dogs (11).

The hypothesis that dogs with higher preoperative serum concentrations of calcium would have more severe postoperative hypocalcemia versus dogs with lower preoperative serum concentrations of calcium would appear on the surface to be a logical one.  However, since this hypothesis is not supported by any these research studies (9-11), it must, therefore, be seriously questioned.

How often does postoperative hypocalcemia develop?
In the present study by Arbaugh (9), only 4 (24%) of the 17 dogs developed postoperative hypocalcemia, but none of the dogs developed clinical signs of hypocalcemia, even those with low iCa concentrations. Similarly, in the recent study reported by Milovancev and Schmiedt (11), approximately one-third of their 62 dogs became hypocalcemic following parathyroidectomy, but only a quarter of those dogs developed associated clinical signs. Of all 62 dogs in that study, less than 10% developed clinical hypocalcemia and required treatment with calcium and vitamin D (11).

When does postoperative hypocalcemia require treatment?
Overall, these two studies indicate an important fact about the need for treatment— that is, although postoperative hypocalcemia is a common complication in dogs after surgical parathyroidectomy, associated life-threatening clinical signs (e.g., tetany, seizures) are very uncommon (9,11).

These findings suggest that dogs treated with parathyroidectomy should be supplemented with calcium and vitamin D only when they have clinical signs of hypocalcemia, rather than started on these medications prophylactically or based solely on the postoperative iCa concentration.

References:

1. Berger B, Feldman EC. Primary hyperparathyroidism in dogs: 21 cases (1976-1986). J Am Vet Med Assoc 1987;191:350-356. 
2. Bonczynski J. Primary hyperparathyroidism in dogs and cats. Clin Tech Small Anim Pract 2007;22:70-74. 
3. 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.  
4. 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. 
5. Feldman EC, Nelson RW. Hypercalcemia and primary hyperparathyroidism. Canine and Feline Endocrinology and Reproduction. 3rd ed. St. Louis: Saunders Elsevier, 2004;660–715.
6. 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.
7. Thiele J, Kärner J, Fischer R. Ultrastructural morphometry on human parathyroid tissue. Morphological and functional implications. J Submicrosc Cytol Pathol. 1988;20:491-500. 
8. Rasor L, Pollard R, Feldman EC. Retrospective evaluation of three treatment methods for primary hyperparathyroidism in dogs. J Am Anim Hosp Assoc 2007;43:70-77. 
9. 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. 
10. Strickland PL, Recabaren J. Are preoperative serum calcium, parathyroid hormone, and adenoma weight predictive of postoperative hypocalcemia? Am Surg 2002;68:1080-1082. 
11. 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. 

Vetsulin Insulin Updated and Approved For Release in USA

Merck Animal Health just announced that Vetsulin (porcine insulin zinc suspension) will again be available for distribution in the USA this week (1). This is welcome news, especially for dogs with diabetes mellitus that are not well regulated with other available insulin preparations, such as human recombinant NPH. Most authorities consider Vetsulin, known as Caninsulin outside the USA (2), to be the initial insulin of choice for treatment of dogs with diabetes mellitus (3-6). It can also be used to successfully manage cats with diabetes (7,8), but we have many other good options for treatment of feline diabetes.

As you may know, Vetsulin has had its share of problems in the last few years, which lead to the FDA having it withdrawn from the US market. All of these manufacturing issues have been resolved, and the FDA has re-approved the drug for release.

How is the "new" Vetsulin different than the original insulin product?

According to the company, the updated Vetsulin product has the same characteristics as the original insulin preparation, and the action in diabetic patients is expected to be the same as before. There have been no changes in the safety profile of Vetsulin for use in either dogs or cats.

The only difference in the Vetsulin itself is a slight change in the listed proportion of the short-acting amorphous fraction and long-acting crystalline fraction. The short-acting amorphous fraction is now listed as 35% (it was 30%), whereas the long-acting crystalline fraction is now reported as 65% (it was 70%).

Vetsulin will now be available only in 10-ml vials. The 2-5 ml vial formulation of Vetsulin has been discontinued.

Two important differences in the updated Vetsulin Package Insert: (9)

1. Prior to use, vials of Vetsulin should be shaken thoroughly (manually) until a homogeneous, uniformly, milky suspension is obtained. Foam on the surface of the suspension formed during shaking should be allowed to disperse before the product is used.
2. Vetsulin contents should be used within 42 days after the vial is first punctured.  

For the first new vials of Vetsulin that are released, the initial product dating will be only 12 months from the manufactured date. The company expects that Vetsulin will eventually have a 24-month shelf-life.

Additional information can be found on the Veterinary Home Page under the Product Update section (10). Also, see the package insert for full information regarding contraindications, warnings, and precautions (9).

Bottom line:

It's great to have Vetsulin, an FDA-approved insulin for use in both dogs and cats, back on the market. The company has done a great deal of work showing that Vetsulin is stable and effective, and they have made a few minor but good improvements in this insulin preparation.

Vigorous manual shaking of the Vetsulin? How will that impact accurate dosing?
We have all been taught that vigorous shaking will interfere with accurate dosing because of air bubbles that form when the insulin bottle is shaken (5,11). When the dose is drawn up, the insulin suspension may come out into the syringe together with lots of air bubbles.  In addition, we tend to worry that too vigorous shaking may damage the insulin protein structure itself. For these reasons, we generally instruct owners to gently roll the insulin vial than to vigorously shake it!

According to the company, the instructions are now to give the Vetsulin bottle a vigorous shake on initial use; then let it settle for a few minutes to let the bubbles rise before drawing up the dose. Upon subsequent insulin dosing, the bottle should only need a quick shake (less vigorous) to resuspend the insulin prior to drawing up the insulin dose.

Why this difference in vigorous shaking vs. rolling? I don't know, but I suspect it has something to do with the way the study was designed and input from the FDA. In any case, Merck Animal Health actually has done the studies to prove that this vigorous manual shaking does not interfere with the measured insulin concentration in the product (10).

Why was the proportion in the short-and long-acting insulin fractions changed? 
According to the company, the proportions of the short-acting amorphous fraction and long-acting crystalline fraction have not actually changed, as compared to the original Vetsulin product. Instead, the new stated ratio (65% long-acting and 35% short-acting insulin) represents a more accurate reflection of the actual composition of both the original and updated Vetsulin product (10).

Nevertheless, on a clinical basis, such a small change in the short- vs. the long-acting insulin fractions would not be expected to make any difference in the animal's glycemic control, even if the composition of the product did change slightly.

Vetsulin (porcine insulin zinc suspension), with it's 2 peaks of insulin activity

Must Vetsulin really be discarded after only 42 days? 
The Vetsulin product insert (9) clearly states that the product should be used within "42 days of first vial puncture."

Has the efficacy really been determined to decrease after 42 days?  The answer to that is no — it's almost certain that the potency of this preparation will extend many days (or even weeks) longer than this 42 days.  However, because Merck Animal Health only did the FDA studies for a period of 42 days, that's what they have been required to put on the package insert. But remember, in addition to efficacy, we must also worry about bacterial contamination secondary to repeated puncture of the insulin vial (11).

Why such a short expiration date? 
Again, for the first new vials of Vetsulin that are released, the initial product dating will be only 12 months from the manufactured date. This is not because the updated Vetsulin is unstable, but the FDA requires ongoing studies of the insulin's duration. The company expects that Vetsulin will eventually have a 24-month shelf-life (10).

Since we do not have to worry about Vetsulin disappearing again, at least anytime soon, I wouldn't recommend purchasing too many insulin vials now, since the initial "expiration" date will be only a few months.

References:

1. Vetsulin website. www.vetsulin.com
2. Caninsulin website. www.caninsulin.com
3. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682. 
4. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237. 
5. Nelson RW. Canine diabetes mellitus In: Ettinger SJ,Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition ed. St. Louis: Saunders Elsevier, 2010;1449-1474.
6. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
7. Michiels L, Reusch CE, Boari A, et al. Treatment of 46 cats with porcine lente insulin—a prospective, multicentre study. J Feline Med Surg 2008;10:439-451. 
8. Martin GJ, Rand JS. Control of diabetes mellitus in cats with porcine insulin zinc suspension. Vet Rec 2007;161:88-94. 
9. Vetsulin Package Insert. www.vetsulin.com/PDF/Vetsulin-Package-Insert.pdf
10. Vetsulin website: Veterinary Product Updates. www.vetsulin.com/vet/Product_Update.aspx
11. American Diabetes Association. Insulin administration. Diabetes Care 2001;24:1984-1987. 

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.