Wednesday, April 16, 2014

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



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

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

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

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

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

Thursday, April 10, 2014

Escalating Costs of Insulin Glargine (Lantus): Can We Switch to Another Insulin?


My patient is a 14-year-old male Toy Poodle (weighing only 5 kg) that has been maintained on insulin glargine (Lantus; Sanofi-Aventis) for several years. Currently, the dog is receiving an insulin dose of 6 units twice daily and is doing well (i.e., no obvious polyuria, normal appetite with stable body weight). However, over the last few months, the price of Lantus has skyrocketed to over $250 for a 10-ml vial. The owner would like to switch to a more affordable insulin, if possible. At 12 units a day, she is going through a 10-ml vial of Lantus every 2.5 months or so.

My question is this: would another long-acting insulin —such as detemir (Levemir) or PZI (ProZinc)— be more cost-effective in this dog? Or would you suggest that I start over with an intermediate-acting insulin, such as NPH (Humulin N or Novolin N) or Vetsulin?

I did not start this dog on Lantus, but the owner claims that they had great difficulty in regulating him after his initial diagnosis. Therefore, I'm a bit hesitant to "rock the boat" when the Lantus seems to be doing the job. Do you have any ideas why the price has gone up so much over the last year or so?

My Response:

Long-acting insulins, such as glargine, are not commonly used in dogs with diabetes, although they can work fine to control clinical signs in some dogs (1-3). However, because these insulins have a less potent glucose-lowering effect than do more commonly used intermediate-acting insulins (NPH, Vetsulin), larger doses of the long-acting insulin preparation are often needed (1,2). Therefore, use of glargine or PZI (ProZinc) are generally cost-effective only in smaller dogs.

For example, notice that the daily glargine dose in this Toy Poodle is over 1 U/kg twice a day, which is in the expected dose range for a long-acting insulin in dogs (1-3). If this dog weighed 50 kg rather than only 5 kg, this would equate to a dose of 60 U twice a day, which means that we would go through a 10-ml vial of Lantus every two weeks or so! In contrast, most diabetic dogs on an intermediate-acting insulin can be well-regulated using doses of 0.5-0.7 U/kg per injection (4,5).

What's leading to the steady increase in the price for insulin glargine(Lantus)?
The drug maker Sanofi-Aventis has steadily raised its price of Lantus (insulin glargine) during the past 12 months, prompting angst among many pet owners and veterinarians alike. These concerns, of course, are inconsequential to Sanofi, since Lantus is FDA-approved for human diabetic patients (a huge market), and the insulin is not marketed for use in either dogs or cats.

Since I don't work for Sanofi-Aventis, I do not know what’s driving the escalating price increases that we have seen over the past few months. However, we do know that Sanofi's patent for Lantus expires in 2015, opening the market to competitors who can then release generic glargine insulins. Therefore, it is likely that Sanofi is trying to generate as much income as the company can from this branded insulin preparation before the patent expires and generic glargine preparations hit the market.

In support of that, it's known that Eli Lilly also has a generic equivalent in the works (6). Sanofi recently responded by suing Eli Lilly for alleged patent infringement (7). The lawsuit triggered a stay of approval by the FDA, delaying the release of Eli Lilly’s generic to mid-­2016.

However, Merck & Co. also recently announced that it's version of generic glargine is in the late stages of clinical trials (8). It's likely that Sanofi will also sue Merck in order to delay their release of a generic product too, but again, I don't know.

Do you understand why I sometimes hate using these human insulin analogs? We, as veterinarians, have absolutely no say or control in anything that is going to happen to price or availability, and it's certainly no use to complain. These companies don't market their products to us and really do not even want to know we use them in our patients.

Are other long-acting insulins less expensive than Lantus?
Unfortunately, when we look at the cost of other long-acting insulin preparations, the cost is not much cheaper than the current cost of Lantus, at least when we look at the cost per unit of insulin. The dose of ProZinc would likely be approximately the same as the glargine in this dog— at about $100 per 10-ml vial, the cost of ProZinc seems significantly less, at least at first glance. However, we must remember that each vial of ProZinc (a U-40 insulin) contains only 400 units of insulin, so this dog (on 6 units, twice a day) would need about one new vial per month. Since each 10-vial of Lantus contains 1,000 units, the cost per unit of insulin is about the same when these two insulin preparations are compared.

Insulin detemir (Levemir, Novo Nordisk) is another story. Although the cost of this U-100 insulin is equivalent to Lantus (about $250 per vial), this insulin is a very potent insulin when used in dogs (this is not true in cats). The average determir dose that most diabetic dogs require ranges from only 0.1-0.2 U/kg per injection — 5 to 10 times less that the average glargine dose needed for diabetic dogs (9,10).

That all said, I would hesitate to use detemir in this toy breed dog because of it's high potency. The calculated starting dose for a 5 kg dog would only be 0.5 U, and it's unlikely that more than 1 U per injection would ever be needed. As we all know, it's very difficult to measure 0.5 units of insulin accurately and overdosage might be expected. Because of its potent glucose-lowering effects, hypoglycemia is more common with detemir than the other longer-acting insulins.

Should a switch to an intermediate-acting insulin be considered?
Most diabetic dogs that we treat are not started on a long-acting insulin. In fact, use of an intermediate acting insulin, such as NPH or Vetsulin, are generally considered to be the insulins of choice when starting treatment for dogs with diabetes mellitus (4,5).

NPH is a much less expensive human U-100 insulin that is available at Walmart as their ReliOn brand of Novolin-N for only about $25 (11). Personally, I find that Vetsulin (Merke Animal Health) is a better choice than NPH in most dogs since it's a bit longer acting, and this insulin is also made by a veterinary company (Merck Animal Health) and licensed for use in dogs. As you know, the veterinarian cost for Vetsulin is around $30 per 10-vial, but, again, each insulin vial contains only 400 units rather than the 1000 units in each vial of NPH. Therefore, the cost is indeed a bit more for Vetsulin than NPH, at least when we look at the price of the Walmart ReliOn brand.

No matter what insulin we change to (ProZinc, Levemir, NPH, or Vetsulin), the dog will have to again be regulated. This may go very smoothly—but then again, this is a diabetic, it's always difficult to predict what is going to happen with certainty. I'd give the owner the pro's and con's of continuing the Lantus vs switching, but in the long-run, it may be best to stick with the Lantus and hope that the generic versions hit the market sooner than Sanofi would like!

References:
  1. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. 
  2. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med 2012;26:109-115. 
  3. Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc 2013;243:1154-1161. 
  4. Palm CA, Boston RC, Refsal KR, et al. An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. J Vet Intern Med 2009;23:50-55. 
  5. 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. 
  6. Eli Lilly Press Release, Dec. 20, 2013. Eli Lilly and Company and Boehringer Ingelheim announce new drug application filing in the U.S. for new insulin glargine product
  7. Reuters,  Jan 30, 2014. Sanofi sues Eli Lilly over patents for top-selling insulin drug.
  8. Merck Newsroom.com, February 10, 2014. Merck and Samsung Bioepis Enter Collaboration Agreement to Develop and Commercialize Insulin Glargine Candidate for Diabetes.
  9. Mori A, Sako T, Lee P, et al. Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Vet Res Commun 2008;32:563-573. 
  10. 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. 
  11. ReliOn Insulins. http://relion.com/diabetes/insulin

Thursday, April 3, 2014

Humulin Versus Novolin NPH Insulin: Are They Bioequivalent?

Two available brands of NPH insulin, manufactured by Eli Lilly (Humulin N) and Novo Nordisk (Novolin N)

Recently, several of my diabetic dog owners have asked if they can switch their NPH brand to Walmart's Relion/Novolin insulin to replace the Humulin N insulin that they are now using. It turns out that the Walmart ReliOn brand of NPH is much cheaper (only $25 per vial).

Though the two insulins both seem to be NPH insulin, I have some concerns about this change. Any concerns with the ReliOn brand or in switching from Humulin N to Novolin N insulin?

My Response:

In theory, you'd think that Humulin N (Eli Lilly) and Novolin N (Novo Nordisk) would be bioequivalent (and therefore interchangeable), as they're just different brands of NPH insulin. However, that is not always the case.

Humulin N and Novolin N are made using different ingredients and manufacturing techniques, so they are not identical (1,2). Like you noted, Walmart sells NPH insulin as the Novolin/ReliOn brand for much less than most other pharmacies do, at only about $25 per vial (3).

A number of dogs have now been reported where they were stable and doing well on Humulin N. However, when switched to the same dose of Novolin N, their diabetic state was no longer regulated and the dogs developed signs of either hypo- or hyperglycemia, requiring significant dose adjustments (4).

Bottom Line:

Most dogs will respond well to the Novolin/ReliOn brand of insulin, which is indeed much less expensive than most other brands of NPH insulin. However, we cannot just assume that the two insulin preparations would be equivalent. I would not recommend switching from one insulin to the other without close monitoring (including blood glucose curves) so that the dose can be adjusted as needed.

References:
  1. Humulin.com website
  2. Humulin N Prescribing Information
  3. Novolin N Prescribing Information.  
  4. ReliOn Insulins. http://relion.com/diabetes/insulin
  5. VIN News Service. Changing insulin brands may disrupt diabetics. February 5, 2013. 

Tuesday, March 25, 2014

Can Twice-Daily Insulin Be Injected at Any Time of the Day?

I have questions regarding treatment of a 8-year old, male labrador retriever with poorly-regulated diabetes. He has been treated with once daily insulin (Vetsulin), administered once a day in the morning at 11 pm for the last 3 months. Despite insulin treatment, the dog remains hyperglycemic and glycosuric and if very thin.

The owner has a very odd work schedule, and he is not generally home in the early morning when the AM dose of insulin is generally given, so that's why the insulin shot is given in the late morning. I would like to put him on twice daily insulin; however, I was hesitant because the dog would have to get the two doses of insulin at 11 am and 11 pm if we are going to give the insulin at 12-hour intervals.

I have always assumed there was some sort of diurnal influence on blood glucose concentrations that mandated that we give the insulin first thing in the morning (6-8 am at time of breakfast) and then again in the early evening at dinner time. But when I actually dug out my physiology textbook and did not some on-line research, I didn't find any mention of this.

So my questions— is there any reason to not give him insulin injections at different times during the day? Why do we routinely start injections in the earlier morning— is just because that's when animals (and people) typically get fed?

My Response:

The problem of nocturnal hypoglycemia in human diabetics
In human patients treated with insulin (type 1 diabetes), nocturnal hypoglycemia is a well-recognized complication that can lead to major problems in regulation (1-7). Almost half of all episodes of severe hypoglycemia that develops in human patients occur at night during sleep. Such episodes of nocturnal hypoglycemia can be prolonged and can lead to seizures or coma in rare cases (7). In addition, this nocturnal hypoglycemia can lead to rebound hyperglycemia (Somogyi phenomenon) (1,8).

The problems of overnight hypoglycemia in human type I diabetes are further complicated by the dawn phenomenon (1,9,10). The dawn phenomenon is the combination of an initial decrease in insulin requirements between ~2400 and ~0300, followed by an increase in the insulin needs (and therefore, a tendency to develop hyperglycemia) between ~0500 and ~0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients (1,9,10).

Overall, this brings up the questions: does nocturnal hypoglycemia or the dawn phenomenon occur in dogs with diabetes?

Studies of canine diabetics
In a recent study, Mori and colleagues (11) monitored 5 diabetic dogs (treated with either NPH or insulin detemir) with a continuous glucose monitoring system (CGMS) over a 2-week period. They evaluated the daily glycemic profiles obtained with CGMS and compared glucose fluctuations between day- and night-time in these diabetic dogs. For data analyses, day-time was defined as 9:00 am-9:00 pm and night-time as 9:00 pm-9:00 am.

Using these glucose profiles, the investigators evaluated the following parameters: 1) the mean blood glucose concentrations (1- and 12-hr intervals); 2) the time spent in the hyperglycemic range (greater than 200 mg/dl); and 3) the time spent in the hypoglycemic range (less than 60 mg/dl)None of these parameters differed significantly between day-time and night-time in these insulin-treated dogs. 

Overall, this study confirmed that there are no differences in glucose fluctuations between day- and night-time, in diabetic dogs on a similar feeding regimen and insulin administration when monitoring carefully using CGMS. These studies also indicate that diabetic dogs do not frequently develop nocturnal hypoglycemia, unlike the situation in human patients with diabetes. Finally, dogs do not appear to develop the dawn phenomenon, as manifested by a morning surge in hyperglycemia, which again occurs in nearly all human diabetic patients.

Bottom line:

Based on these studies, there does not appear to be any physiologic reason why we must administer insulin injections first thing in the morning (with breakfast) and then again later at dinnertime. The reason we tend to give in the morning and evening is that most folks go to work during the day, not at night.

It doesn't matter when we give the insulin injections, but dogs almost always need twice-daily insulin injections, so we would want to give the injections about 12 hours apart. In this dog, I see no reason not to give insulin injections at 11 am and 11 pm if that schedule works best for the owner.

References:
  1. Bolli GB, Perriello G, Fanelli CG, et al. Nocturnal blood glucose control in type I diabetes mellitus. Diabetes Care 1993;16 Suppl 3:71-89. 
  2. Matyka KA. Sweet dreams?--nocturnal hypoglycemia in children with type 1 diabetes. Pediatr Diabetes 2002;3:74-81.
  3. Yale JF. Nocturnal hypoglycemia in patients with insulin-treated diabetes. Diabetes Res Clin Pract 2004;65 Suppl 1:S41-46. 
  4. Raju B, Arbelaez AM, Breckenridge SM, et al. Nocturnal hypoglycemia in type 1 diabetes: an assessment of preventive bedtime treatments. J Clin Endocrinol Metab 2006;91:2087-2092. 
  5. Greenhill C. Diabetes: Nocturnal hypoglycemia is frequent in patients with type 1 diabetes mellitus. Nat Rev Endocrinol 2010;6:299. 
  6. Ahmet A, Dagenais S, Barrowman NJ, et al. Prevalence of nocturnal hypoglycemia in pediatric type 1 diabetes: a pilot study using continuous glucose monitoring. J Pediatr 2011;159:297-302. 
  7. Bay C, Kristensen PL, Pedersen-Bjergaard U, et al. Nocturnal continuous glucose monitoring: accuracy and reliability of hypoglycemia detection in patients with type 1 diabetes at high risk of severe hypoglycemia. Diabetes Technol Ther 2013;15:371 377. 
  8. Nocturnal hypoglycemia as a cause of fasting hyperglycemia (Somogyi phenomenon). N Engl J Med 1988;318:1537-1538.
  9. Campbell PJ, Bolli GB, Cryer PE, et al. Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. N Engl J Med 1985;312:1473-1479. 
  10. Carroll MF, Schade DS. The dawn phenomenon revisited: implications for diabetes therapy. Endocr Pract 2005;11:55-64. 
  11. Mori A, Kurishima M, Oda H, et al. Comparison of glucose fluctuations between day- and night-time measured using a continuous glucose monitoring system in diabetic dogs. J Vet Med Sci 2013;75:113-117. 

Tuesday, March 18, 2014

Top Endocrine Publications of 2013: Canine Diabetes Mellitus


In my second compilation of the canine and feline endocrine publications of 2013, I’m moving on to the theme of canine diabetes mellitus.

Listed below are 27 research papers written in 2013 that deal with a variety of topics and issues related primarily to the pathophysiology, diagnosis, monitoring, and treatment of diabetes mellitus in dogs.

These range from studies of the possible gene defects that may be involved in the pathogenesis of diabetes mellitus and obesity (1,5) to a review of diabetic nephropathy in animals (2); from a study of the impaired immune response of dogs with hyperglycemia (3) to a novel treatment of diabetic dogs with insulin and glucokinase gene therapy (4); from studies of the influence of diet on glucose metabolism in the dog (6,7,14,18) to investigations of glucagon-like peptide (GLP) receptor agonists and antagonists as antidiabetic agents (9,11,15,17); from studies of the use of insulin glargine (Lantus) in dogs with diabetes (12) to the effect of chronic diabetes on the loss of optic nerve axons and development of retinopathy in dogs (13).

Other studies included a review of the use continuous glucose monitoring systems in dogs (22) to the use of a continuous glucose monitoring system to investigate if nocturnal hypoglycemia occurs in diabetic dogs, as it does in man (16); from a study of diabetic remission in dogs after ovariohysterectomy and resolution of progesterone excess (19) to an investigation of the mechanism of insulin production in canine bone marrow-derived stem cells (23); and from a large study detailing the clinical features associated with the acquired proximal renal tubulopathy in dogs fed dried chicken treats (24) to the evaluation of a large series of dogs with the hyperosmolar hyperglycemia syndrome (25).

Finally, I've included 3 studies that involve human rather than canine diabetic patients, in which dogs are trained as "glycemia alert" animals to detect pending hypoglycemia in these human diabetic patients (8,10,21).

2013 Papers on Canine Diabetes Mellitus:
  1. Batchelor DJ, German AJ, Shirazi-Beechey SP. Relevance of sodium/glucose cotransporter-1 (SGLT1) to diabetes mellitus and obesity in dogs. Domest Anim Endocrinol 2013;44:139-144. 
  2. Bloom CA, Rand JS. Diabetes and the kidney in human and veterinary medicine. Vet Clin North Am Small Anim Pract 2013;43:351-365. 
  3. Bosco AM, de Almeida BF, Pereira PP, et al. High concentrations of glucose reduce the oxidative metabolism of dog neutrophils in vitro. BMC Vet Res 2013;9:24. 
  4. Callejas D, Mann CJ, Ayuso E, et al. Treatment of diabetes and long-term survival following insulin and glucokinase gene therapy. Diabetes 2013;62:1718-1729. 
  5. Catchpole B, Adams JP, Holder AL, et al. Genetics of canine diabetes mellitus: Are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs? Vet J 2013;195:139-147. 
  6. Coate KC, Kraft G, Irimia JM, et al. Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs. Diabetes 2013;62:392-400. 
  7. Coate KC, Smith MS, Shiota M, et al. Hepatic glucose metabolism in late pregnancy: normal versus high-fat and fructose diet. Diabetes 2013;62:753-761. 
  8. Dehlinger K, Tarnowski K, House JL, et al. Can trained dogs detect a hypoglycemic scent in patients with type 1 diabetes? Diabetes Care 2013;36:e98-99. 
  9. Edgerton DS, An Z, Johnson KM, et al. Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab 2013;305:E132-139. 
  10. Gonder-Frederick L, Rice P, Warren D, et al. Diabetic alert dogs: a preliminary survey of current users. Diabetes Care 2013;36:e47. 
  11. Guzman-Perez A, Pfefferkorn JA, Lee EC, et al. The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus. Bioorg Med Chem Lett 2013;23:3051-3058. 
  12. Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc 2013;243:1154-1161. 
  13. Howell SJ, Mekhail MN, Azem R, et al. Degeneration of retinal ganglion cells in diabetic dogs and mice: relationship to glycemic control and retinal capillary degeneration. Mol Vis 2013;19:1413-1421. 
  14. Kimura T. The regulatory effects of resistant starch on glycaemic response in obese dogs. Arch Anim Nutr 2013;67:503-509. 
  15. Moore MC, Werner U, Smith MS, et al. Effect of the glucagon-like peptide-1 receptor agonist lixisenatide on postprandial hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab 2013;305:E1473-1482. 
  16. Mori A, Kurishima M, Oda H, et al. Comparison of glucose fluctuations between day- and night-time measured using a continuous glucose monitoring system in diabetic dogs. J Vet Med Sci 2013;75:113-117. 
  17. Oda H, Mori A, Lee P, et al. Characterization of the use of liraglutide for glycemic control in healthy and Type 1 diabetes mellitus suffering dogs. Res Vet Sci 2013;95:381-388. 
  18. Ogbu SO, Agwu KK, Asuzu IU. Gongronema latifolium delays gastric emptying of semi-solid meals in diabetic dogs. Afr J Tradit Complement Altern Med 2013;10:325-331. 
  19. Poppl AG, Mottin TS, Gonzalez FH. Diabetes mellitus remission after resolution of inflammatory and progesterone-related conditions in bitches. Res Vet Sci 2013;94:471-473. 
  20. Ramnanan CJ, Kraft G, Smith MS, et al. Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog. Diabetes 2013;62:74-84. 
  21. Rooney NJ, Morant S, Guest C. Investigation into the value of trained glycaemia alert dogs to clients with type I diabetes. PLoS One 2013;8:e69921. 
  22. Surman S, Fleeman L. Continuous glucose monitoring in small animals. Vet Clin North Am Small Anim Pract 2013;43:381-406. 
  23. Takemitsu H, Zhao D, Ishikawa S, et al. Mechanism of insulin production in canine bone marrow derived mesenchymal stem cells. Gen Comp Endocrinol 2013;189:1-6. 
  24. Thompson MF, Fleeman LM, Kessell AE, et al. Acquired proximal renal tubulopathy in dogs exposed to a common dried chicken treat: retrospective study of 108 cases (2007-2009). Aust Vet J 2013;91:368-373. 
  25. Trotman TK, Drobatz KJ, Hess RS. Retrospective evaluation of hyperosmolar hyperglycemia in 66 dogs (1993-2008). J Vet Emerg Crit Care (San Antonio) 2013;23:557-564.  
  26. Winnick JJ, An Z, Kraft G, et al. Liver glycogen loading dampens glycogen synthesis seen in response to either hyperinsulinemia or intraportal glucose infusion. Diabetes 2013;62:96-101. 
  27. Winnick JJ, Ramnanan CJ, Saraswathi V, et al. Effects of 11beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis. Am J Physiol Endocrinol Metab 2013;304:E747-756. 

Tuesday, March 11, 2014

What's the Best Dosage of Desmopressin when Injected Subcutaneously?


In a recent blog, you mentioned using compounded desmopressin (0.01%) that could be injected subcutaneously (SC).  I have 3 questions about the use of this desmopressin preparation:
  1. What dose do you recommend for this formulation (per patient or per kg)? 
  2. I've read elsewhere that the dose should be 2 µg per patient, administered once or twice daily. Would you agree with this (i.e., dosing independent of the weight of the patient)? 
  3. I believe 0.01% is 100 µg/ml, correct?  If I use a U-100 insulin syringe, would this mean 2 units of the compounded formulation per dose? 
My Response:

Dose of desmopressin for SC injection
The empirical starting dose that I use for injectable desmopressin administered subcutaneously is 1–5 μg once or twice daily, depending on the size of the dog and response to therapy (1,2). As might be expected, larger-breed dogs tend to need more drug to control polyuria and polydipsia, and these bigger dogs will tolerate higher doses.

To make dosing easier, I usually have the owners draw up and administer the desmopressin with a U-100 low-dose insulin syringe. You are correct in that 0.01% is 100 µg/ml, so injecting 1-5 µg would be 1-5 units in this syringe.

Water intoxication is possible with use of this drug, so I do recommend monitoring of serum sodium concentrations, especially when high doses are given (1,3,4).

Formulations of desmopressin that can be injected
An injectable sterile solution of desmopressin acetate (4 µg/ml) marketed for intravenous use is available commercially and can be used in animals with diabetes insipidus (2). However, the cost of the injectable desmopressin is approximately 7 to 15 times higher per µg than the intranasal preparation, making this formulation cost-prohibitive for use in most dogs and cats.

The human nasal preparation of desmopressin can also be administered subcutaneously, but that preparation is not sterile and not authorized for this route (1,2).

Therefore, I generally use a compounded, veterinary, injectable formulation, which has already been sterilized by the compounding pharmacy and is safe to inject subcutaneously. This form is much cheaper than the injectable solution of desmopressin marketed for parenteral use in human patients.

References:
  1. Shiel RE. Disorders of vasopressin production. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology, Fourth ed. Gloucester: British Small Animal Veterinary Association; 2012:1-13. 
  2. Peterson ME. What Drugs Do We Use to Treat Diabetes Insipidus? Insights in to Veterinary Endocrinology blog post, January 13, 2011. 
  3. Robson WL. Water intoxication in patients treated with desmopressin. Pharmacotherapy 1996;16:969-970.
  4. Bernstein SA, Williford SL. Intranasal desmopressin-associated hyponatremia: a case report and literature review. J Fam Pract 1997;44:203-208.

Wednesday, March 5, 2014

Differentiating Diabetes Insipidus from Psychogenic Polydipsia in Dogs

My problem case is a  7-year old male-neutered Labrador retriever-mix that presented to me for moderate to severe polyuria and polydipsia (PU/PD).  While doing well at home, his owner did mention he also has had some recent weight gain (current weight is 29 kg). He has a history of arthritis, which the owner is treating with some type of holistic supplementation.

I did a CBC and complete biochemistry profile, with all values being within normal range. Results of complete thyroid panel (serum T4, T3, free T4, and TSH) also showed that all values were within the reference intervals.  

Urine was collected by cystocentesis for complete urinalysis and urine culture and susceptibility. The urinalysis showed a specific gravity of 1.010, with a normal sediment; the urine culture was negative. A urine cortisol:creatinine ratio was also normal.

We next performed serial measurements for urine specific gravity over a 24-hour period. The results are listed below:
  • 6:30 AM 1.028 
  • 3:15 PM 1.004
  • 6:15 PM 1.000
  • 8:10 PM 1.005
  • 6:30 AM 1.019
The water consumption measured over this 24-hour period was 96 ounces (2.9 liters), which appears to be in quite high for a dog of this weight.

On an abdominal ultrasound examination, the liver, adrenal glands, bladder, and kidneys were all found to be normal.  

At this time, I've excluded the common rule outs for PU/PD, including Cushing's disease, kidney disease, diabetes mellitus, hypercalcemia, liver disease, and hyperthyroidism. My two major rule outs are either psychogenic polydipsia or diabetes insipidus (DI).

My questions:
  1. Have we sufficiently ruled out diabetes insipidus based on the higher morning urine specific gravities?
  2. Could this dog still be suffering from psychogenic polydipsia?
  3. Any other possibilities or suggestions?
My Response:

Differential diagnoses for
polyuria & polydipsia in dogs
Your dog certainly doesn't have complete central or nephrogenic diabetes insipidus (DI). He could have partial DI, but from the history, psychogenic polydipsia (compulsive water drinking) is a major rule out (1-3).

Whenever we see such wide fluctuations in urine specific gravity measurement, we must move a behavioral problem to near the top of our differential list.

My biggest concern is that we don't want to miss a serious cause of PU/PD, such as occult pyelonephritis— remember that you have collected urine from the bladder for culture, so it's still possible that the dog has an infection in the kidneys that is difficult to detect.

There are a number of ways we could proceed at this point, but this step-wise approach is what I'd recommend.

Step 1 — Stop all supplements: First, I'd start by stopping the holistic supplements for a couple of weeks to see if that helps.  If they are giving the dog any other drugs or supplements, they should all be discontinued, at least temporarily. It is unlikely that these supplements are the problem, but we don't always know what compounds holistic or herbal supplements contain or what effects they will have on an individual dog.

Step 2—Rule out atypical leptospirosis: If no improvement is seen after discontinuing the holistic supplements, I'd next consider leptospirosis serology and urine PCR testing (4-6). Occasionally, we see an atypical form of leptospirosis in dogs that present with a relatively acute onset PU/PD, hyposthenuria or isosthenuria, but no other laboratory abnormalities (azotemia does not generally develop in these dogs). The urine concentration defect is thought to be an acquired form of nephrogenic DI (3).

In dogs not previously vaccinated for leptospirosis, Leptospira infection can be confirmed by positive leptospirosis serology or use of molecular detection of leptospiral DNA by PCR testing of urine samples. In dogs previously vaccinated for leptospirosis, a 4-fold rise in convalescent titers is often diagnostic of the atypical form of this disease.

Step 3— Rule out occult pyelonephritis: If testing for atypical leptospirosis is negative, then I'd next do an antibiotic trial for 2 weeks to rule out occult pyelonephritis (3).

The antibiotics that I would recommend for this trial are either enrofloxacin (Baytril) at the dosage of 10 mg/kg/day or amoxicillin/clavulanic acid (Clavamox) at the dosage of 12.5 mg/kg/day. Since this is a relatively large dog, generic ciprofloxacin would be a cheaper alternative than brand-name enrofloxacin. The dose of ciprofloxacin, however, is 1.5-2 times greater than Baytril because of poorer intestinal absorption of the drug (7).

If the dog's PU/PD markedly diminishes during the antibiotic trial period, then we can make a presumptive diagnosis of occult pyelonephritis.  In that case, the antibiotic treatment would be extended for a full 6-week period.

Step 4— Do water deprivation test: If we see no clinical response to the antibiotic treatment, then I'd go on and do a water deprivation test next. The water deprivation test is generally considered by most authorities to be the best diagnostic test for differentiating between central DI, nephrogenic DI, and psychogenic polydipsia. However, the classical water deprivation test is labor-intensive, difficult to perform correctly, unpleasant for the dog, relies heavily on repeated emptying of the bladder, and can lead to untoward complications and misdiagnosis in some animals (3).

What I'd recommend in this dog is to first do an abbreviated, overnight water deprivation test. With this method, the owner walks the dog late at night to empty the bladder, and the dog is then put in a room (or a cage) overnight without access to water. The first thing the next morning (before the dog is given any food or water), the owner again walks the dog and collects a urine sample.  The urine sample should then be dropped off at your office so you can measure the urine specific gravity after the overnight water deprivation. If the sample is concentrated (> 1.030-1.035), then we can rule out partial DI, leaving us with a diagnosis of psychogenic polydipsia (1-3).

Step 5— Evaluate the response to desmopressin:  If the dog fails to adequately concentrate after the overnight water deprivation test, you could do an official, in-hospital water deprivation test. However, I'd try a desmopressin trial to evaluate the response instead (3,8).

If the desmopressin does work to control the PU/PD and to raise the urine specific gravity, that is consistent with partial DI (either central or nephrogenic DI).  On the other hand, if desmopressin fails to have any effect on the water consumption or urination in this dog, that would be most consistent with psychogenic polydipsia (compulsive water drinking).

References:
  1. Dunn JK. The dog with polydipsia and polyuria In: Torrance AG, Mooney CT, eds. BSAVA Manual of Small Animal Endocrinology. 2nd ed. Shurdington, Cheltenham: British Small Animal Veterinary Association, 1998;3-9.
  2. Nichols R. Polyuria and polydipsia. Diagnostic approach and problems associated with patient evaluation. Vet Clin North Am Small Anim Pract 2001;31:833-844.
  3. Nichols, R., Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Gloucester: British Small Animal Veterinary Association, 2012;215-220.
  4. Harkin KR, Roshto YM, Sullivan JT. Clinical application of a polymerase chain reaction assay for diagnosis of leptospirosis in dogs. J Am Vet Med Assoc 2003;222:1224–1229
  5. Greene CE, Sykes JE, Brown CA et al. Leptospirosis. In: Infectious Diseases of the Dog and Cat, 3rd edn. 2006;402–417.  
  6. Van De Maele I, Claus A, Haesebrouck F, et al. Leptospirosis in dogs: a review with emphasis on clinical aspects. Vet Rec 2008;163:409–413.
  7. Papich MG. Ciprofloxacin pharmacokinetics and oral absorption of generic ciprofloxacin tablets in dogs. Am J Vet Res 2012;73:1085-1091.
  8. Nichols R, Hohenhaus AE. Use of the vasopressin analogue desmopressin for polyuria and bleeding disorders. J Am Vet Med Assoc 1994;205:168-173.

Wednesday, February 26, 2014

What's the Best Route of Administration for Desmopressin in Dogs with Diabetes Insipidus?


My patient is a 10-year old, female spayed Italian greyhound suffering from diabetes insipidus that I have been treating for several years with desmopressin, with a good overall response. I'm not certain how the diagnosis of diabetes insipidus (DI) was confirmed, however, since the dog was worked up and started on desmopressin by another veterinarian.

Initially, the dog was treated with twice daily administration of desmopressin drops (0.01%) by the intraocular route. In the past 2 years, she developed severe ocular problems (uncontrolled glaucoma) and had to have both eyes enuclueated a few months ago.

Because we could no longer use the intraocular route of administration, the owner has been giving her the desmopressin intranasally. This seemed to work initially, but now polyuria and polydipsia have returned, even with 3-times-a-day intranasal treatments. Her bloodwork remains fine, with no evidence of azotemia, hypercalcemia, or hyperglycemia. The dog is showing no clinical or laboratory signs of Cushing's syndrome, and a recent low-dose dexamethasone screening test was normal.

Is there a better way to dose the desmopressin in this case? Is there anything else I should look for or rule out in this dog other than DI?

My Response:

Well, this is a first for me. I've never had a dog that was being medicated with eye drops in which both eyes had to be removed. Wow —poor dog.

Best route of administration
I've never had a dog or cat in which intranasal administration of desmopressin was successful. Intranasal formulations of desmopressin have been available for over 40 years and remain a commonly used route of administration for human patients (1,2), but most dogs just do not tolerate it very well.  Dogs tend to sneeze out the desmopressin solution before it has a chance to be absorbed from the nasal mucosa.

I'd change to either the demopressin tablets or a compounded desmopressin injectable solution (2-4). The tablets are the most expensive option, but work well in many dogs. I find that subcutaneous admintration of the desmopressin is the most effect route of administration, which also tends to be less expensive since lower doses have to be given.

You can purchase a commercially available injectable desmopressin preparation, but it's quite expensive. I generally use a compounded desmopressin injectable (0.01%) preparation, which I purchase from Wedgewood Pharmarcy. For a 5-ml vial, my cost is about $50-60. This is the cheapest price that I can find, at least with a product that works. It's already been sterilized so you don't have to do anything but start injecting it.

Other differentials for undefined polyuria and polydipsia
There are many causes for polyuria and polydipsia in the dog, almost all of which are much more common than diabetes insipidus (DI), which is a rare disorder (Table 1). Therefore, we should always question the diagnosis of DI in the adult dog, especially if an underlying cause of the DI is not apparent (e.g.,  pituitary mass).

Differential rule outs for polyuria and polydipsia in dogs and cats,
listed from most to least common (3).
It's important to realize that many dogs with polyuria will respond, at least transiently, to desmopressin, so a positive response to the drug can never be considered 100% diagnostic for DI. For example, many dogs that I suspect having mild Cushing's disease will respond to desmopressin with a decrease in thirst and urination. I will use this treatment in some of these dogs, especially if I'm not totally convinced that the cause is really Cushing's disease, but the owners need me to do something to control the polyuria.

Continued monitoring of dogs with suspected DI is recommended
So with all dogs with suspected DI, it is always a good idea to continue to monitor them for development of another disorder which could be responsible for their polyuria and polydispia  (Table 1), even when these disorders were ruled out on initial examination.

To that end, I would recommend obtaining a complete history and physical examination every 6 to 12 months. At each of these visits, I also like to monitor a complete blood count, serum chemistry panel, and complete urinalysis with culture. In many dogs with early Cushing's disease or renal disease, the diagnosis may not be obvious when they initially present for polyuria, but with time, the primary cause will become apparent.

References:
  1. Richardson DW, Robinson AG. Desmopressin. Ann Intern Med 1985;103:228-239. 
  2. Vande Walle J, Stockner M, Raes A, et al. Desmopressin 30 years in clinical use: a safety review. Curr Drug Saf 2007;2:232-238. 
  3. Nichols, R., Peterson ME. Investigation of polyuria and polydipsia In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Gloucester: British Small Animal Veterinary Association, 2012;215-220.
  4. Peterson ME. What Drugs Do We Use to Treat Diabetes Insipidus? Insights in to Veterinary Endocrinology blog post, January 13, 2011. 

Wednesday, February 19, 2014

Top Endocrine Publications of 2013: The Canine and Feline Pituitary Gland


As I've done for the last four years, I’ve now finished compiling a fairly extensive list of references concerning canine and feline endocrinology that were written last year (in 2013). I’ll be sharing these with you over the next few weeks, as well as reviewing a few of the best papers from my lists of clinical endocrine publications.

In this post, I am going to start off with papers that deal with the theme of diagnosis and treatment of pituitary problems in dogs and cats.

Listed below are 13 clinical and research papers written in 2013 that deal with a variety of pituitary gland issues of clinical importance in dogs and cats.

These range from studies of the pathogenesis of acromegaly (and diabetes) in cats (2) to two excellent reviews of the clinical features, diagnosis, and treatment of feline acromegaly (8,9); from a case report of a cat with pituitary adenomas secreting both ACTH and GH (12) to another case report of a cat suffering from a pituitary carcinoma causing hyperadrenocorticism (6); and from a study of the accuracy of CT and MRI for contouring the feline apparatus for radiation therapy planning (for treatment of feline acromegaly) (10) to studies validating an assay for feline ACTH determination (3).

Other publications include a case report of two dogs that presented with severe polyuria and polydipsia due to thyroid carcinoma and hyperthyroidism (1) to diabetes insipidus (DI) in a cat secondary to head trauma (11); and a report on acute iatrogenic water intoxication in cats (7) to a study of the disturbances of water metabolism (normovolemic hypernatremia) secondary to pituitary gland/hypothalamic dysfunction (13).

References:
  1. Bosje T, den Hertog E, Dijksta M. Does the T4 measurement belong in the standard blood analysis in polyuria/polydipsia? Tijdschr Diergeneeskd 2013;138:230-231. 
  2. Dirtu AC, Niessen SJ, Jorens PG, et al. Organohalogenated contaminants in domestic cats' plasma in relation to spontaneous acromegaly and type 2 diabetes mellitus: A clue for endocrine disruption in humans? Environ Int 2013;57-58:60-67. 
  3. Eiler KC, Bruyette DS, Behrend EN, et al. Comparison of intravenous versus intramuscular administration of corticotropin-releasing hormone in healthy cats. J Vet Intern Med 2013;27: 516-521. 
  4. Frischknecht M, Niehof-Oellers H, Jagannathan V, et al. A COL11A2 mutation in Labrador retrievers with mild disproportionate dwarfism. PLoS One 2013;8:e60149. 
  5. Goericke-Pesch S, Georgiev P, Fasulkov I, et al. Basal testosterone concentrations after the application of a slow-release GnRH agonist implant are associated with a loss of response to buserelin, a short-term GnRH agonist, in the tom cat. Theriogenology 2013;80:65-69. 
  6. Kimitsuki K, Boonsriroj H, Kojima D, et al. A case report of feline pituitary carcinoma with hypercortisolism. J Vet Med Sci 2014;76:133-138. 
  7. Lee JY, Rozanski E, Anastasio M, et al. Iatrogenic water intoxication in two cats. J Vet Emerg Crit Care (San Antonio) 2013;23:53-57. 
  8. Niessen SJ. Update on feline acromegaly. In Practice 2013;35:2-6. 
  9. Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:319-350. 
  10. Nolan MW, Randall EK, LaRue SM, et al. Accuracy of CT and MRI for contouring the feline optic apparatus for radiation therapy planning. Vet Radiol Ultrasound 2013;54:560-566. 
  11. Oliveira KM, Fukushima FB, Oliveira CM, et al. Head trauma as a possible cause of central diabetes insipidus in a catJ Feline Med Surg 2013;15:155-159. 
  12. Sharman M, FitzGerald L, Kiupel M. Concurrent somatotroph and plurihormonal pituitary adenomas in a catJ Feline Med Surg 2013;15:945-952. 
  13. Weingart A, Gruber AD, Kershaw O, et al. Disturbances of water metabolism in two dogs and one cat with central nervous system disorders. Schweiz Arch Tierheilkd 2013;155:463-469. 

Wednesday, February 12, 2014

Alendronate Dosing Protocol for Cats with Idiopathic Hypercalcemia


I have a quick question for you about the use of alendronate for treatment of cats with idiopathic hypercalcemia. First of all, I wanted to find out if you recommend this treatment, and what your experience is with the drug.

The protocol that I've been using is to start with an oral dose of 10 mg once weekly, and then increase the dose to 20 mg once weekly if needed. In a few cats, I've had to go as high as 30 mg per week to lower the total and ionized calcium concentrations.

Have you ever done twice weekly dosing? I was recently referred a hypercalcemic cat whose dose was changed from 20 mg once a week to 10 mg twice a week by the veterinarian in the hopes that twice weekly dosing would be more effective. I know it theoretically can be given twice weekly, but was wondering if you've found that twice weekly dosing was more effective.

Thank you for your help.

My Response:

As you know, treatment for idiopathic hypercalcemia in cat is currently empiric, since the cause of the disorder remains unknown. I generally start with a change in diet as a first step in treatment (1), since normocalcemia is sometimes restored after a change to a different diet. However, even in cats that show an initial response to dietary intervention, the duration of normocalcemia may be short-lived and the hypercalcemia can relapse. In these cats, I then turn to medical therapy (i.e., glucocorticoids or bisphosphonates) to help control the hypercalcemia.

Even though not extensively reported, I consider bisphosphonate therapy with alendronate (i.e, Fosamax, Merck; generic formulations also available) to be a better alternative than prednisolone for most cats with idiopathic hypercalcemia that fail dietary intervention (2-4). The complications I commonly see with chronic high-dose glucocorticoid treatment include muscle wasting and iatrogenic diabetes. Remember that steroids are catabolic for muscle tissue (5,6) and will produce insulin-resistance that can lead to hyperglycemia and overt diabetes mellitus (7).

Alendronate dosing protocol
Most cats with idiopathic hypercalcemia will respond to oral alendronate, at a dose range of 10-40 mg once weekly. Like you, I start with an initial oral dose of 10 mg per week, and then gradually increase the dose based on ionized calcium concentrations monitored at 4-6 week intervals (4).

This treatment protocol will restore normocalcemia in over two-thirds of the hypercalcemic cats treated with an average weekly dose of 15 mg (4). As with dietary therapy, many will eventually show relapse and will require an increase in alendronate dosage or the addition of glucocorticoid therapy. In a few cats, the serum ionized calcium will drop too far, and the dose can be decreased to 5 mg per week or 10 mg given every other week (2,4).

Alendronate is poorly absorbed from the GI tract
The oral bioavailability of alendronate in cats is poor. In one study, the percentage of the drug that was actually absorbed when administered to cats was found be only 3% (8). This percentage fell about 10-fold when alendronate was formulated in tuna juice.

To maximize intestinal absorption of this drug, we recommend that the cats be fasted overnight (12-18 hour fast) prior to the administration of the alendronate. The medication should then be given with 6-ml of plain water (to ensure passage of the tablet into the stomach), and the fast continued for at least 2-4 additional hours (4).  We do not recommend any kind of alendronate that has been formulated by compounding pharmacies in flavored solution or suspension because that will likely lead to a marked decrease in the intestinal absorption.

Twice weekly dosing of alendronate?
I don't see any problem with twice-weekly dosing of the alendronate. However, based on the pharmacokinetics of the drug, it's unlikely to be any more effective than once-weekly dosing. In humans, the original treatment protocols recommended a dosage of 10 mg once a day, but this was subsequently changed to 70 mg per week based on pharmacokinetic studies (9).

Remember, however, that the biggest issue with the use of this drug in cats is the need for prolonged fasting in order to even achieve 3% absorption. If the owners are giving the drug with food, less than 0.5% of the drug will be absorbed, if it's going to be absorbed at all.

Because of the issues associated with the prolonged fasting, I would not recommend twice-weekly dosing in my feline patients. We know that once-weekly dosing works in most cats, and the "stress" associated with twice-weekly prolonged fasting (as well tablet administration followed by a 6-ml flush of water) is just too much for the cat or the owner.

References:
  1. Peterson ME. Nutritional management of endocrine disease in cats. Proceedings of the Royal Canin Feline Medicine Symposium 2013;23-28.
  2. Hostutler RA, Chew DJ, Jaeger JQ, et al. Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia. J Vet Intern Med. 2005;19:29-33.
  3. 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.
  4. de Brito Galvao JF, Chew DJ, Parker VJ. Management of idiopathic hypercalcemia. In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, in press.
  5. Horber FF, Scheidegger JR, Grunig BE, et al. Thigh muscle mass and function in patients treated with glucocorticoids. Eur J Clin Invest 1985;15:302-307. 
  6. Menconi M, Fareed M, O'Neal P, et al. Role of glucocorticoids in the molecular regulation of muscle wasting. Crit Care Med 2007;35:S602-608. 
  7. Lowe AD, Graves TK, Campbell KL, et al. A pilot study comparing the diabetogenic effects of dexamethasone and prednisolone in cats. J Am Anim Hosp Assoc 2009;45:215-224. 
  8. Mohn KL, Jacks TM, Schleim KD, et al. Alendronate binds to tooth root surfaces and inhibits progression of feline tooth resorption: a pilot proof-of-concept study. J Vet Dent. 2009;26:74-81.
  9. Fosamax (Alendronate sodium). Product insert. www.merck.com.

Wednesday, February 5, 2014

Diagnosing Subclinical Hyperthyroidism in Cats


I have a quick question about a "problem" case, a 9-year old M/C DSH. This cat has lost about 3 pounds over the last year, but weighed 22 pounds last year so the owner has been trying hard to get the cat to lose weight.

The cat came in for his recheck last week. His physical examination was normal and we ran a routine blood panel (CBC, serum chemistry panel, and total T4). His serum T4 was high-normal at 3.7 µg/dl (reference range, 0.8-4.0 µg/dl). I then added on a free T4 by dialysis, which came back as slightly high at 54 pmol/L (10-50 pmol/L). Looking back in his records, his free T4 concentrations were also slightly high when checked a year ago (58 pmol/L).

This cat is not clinical at all otherwise for hyperthyroidism. He has strange seizure-like episodes, about once every 3 months, but these have been happening since he was a young cat. There has been no change in these episodes.

My gut is telling me that because this cat is not clinical and his thyroid values have remained stable over the last year, we probably should not treat hyperthyroidism at this time. However, I wanted to get your opinion and see if you think that this cat is indeed hyperthyroid, and if so, if he may be a candidate for I-131 at this time.

My Response:

In our studies, we have found that up to 30% of cats that present like this (asymptomatic, high-normal T4, slightly high free T4 concentration) will be normal when evaluated by thyroid scintigraphy (1-3). So basically, this cat certainly could be in the preclincal stages of becoming hyperthyroid, but it's also very possible that the free T4 is falsely high and he is euthyroid.

Determination of free T4 is far from being a perfect test, and a diagnosis of hyperthyroidism should NEVER be based on the finding of a high free T4 alone (1,2,4). This is especially true in a cat like this one, that presents without a palpable thyroid nodule or clinical features of thyroid disease.

So you and the owners have 2 options at this time:
  1. Do a thyroid scan (scintigraphy) to better define the cat's thyroid function (1-3,5,6). If the thyroid lobes are of normal size and display normal thyroid uptake of the radionuclide, we can definitely rule out hyperthyroidism. If, on the other hand, a small hyperfunctional thyroid adenoma is found, then we know that the cat has early hyperthyroidism and could be treated.
  2. The second option is to continue to monitor the cat every 3-6 months (body weight, heart rate, neck palpation, and complete thyroid profile, including serum concentrations of total T4, free T4, and TSH). If hyperthyroid, the serum T4 and free T4 should continue to go higher, where as the TSH should be undetectable (1,2,7,8). If the serum TSH is found to be measurable, that goes against hyperthyroidism since even mild increases in circulating T4 and T3 should feedback to the pituitary to shut off TSH secretion.

Thyroid scintigraphy in a normal cat (on right) and cat with preclinical hyperthyroidism (on left).
Notice that the hyperthyroid cat has a small left thyroid adenoma with complete suppression of the right thyroid lobe. In cats with unilateral hyperthyroid disease, this lack of radionuclide uptake by the normal thyroid lobe is due to the fact that circulating TSH becomes suppressed in almost all hyperthyroid cats, even those with mild disease.

Either option is acceptable - just depends on what the owner wants to do. The cat is not going to be hurt by waiting, as long as he is closely monitored. At 9-years of age, he is still on the young side for being hyperthyroid, but about 5-10% of my cats are less than 10-years, so it's very possible that he is just preclinical at this time and will develop overt signs of hyperthyroidism within the next year.

References:
  1. Peterson ME. More than just T4: Diagnostic testing for hyperthyroidism in cats. J Fel Med Surg 2013;15:765-777. 
  2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet 2013;35:E3.
  3. Peterson ME, Broome MR. Radioiodine for feline hyperthyroidism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014.
  4. Peterson ME, Melian C, Nichols R. Measurement of serum concentrations of free thyroxine, total thyroxine, and total triiodothyronine in cats with hyperthyroidism and cats with nonthyroidal disease. J Am Vet Med Assoc 2001;218:529-536. 
  5. Broome MR. Thyroid scintigraphy in hyperthyroidism. Clin Tech Small Anim Pract 2006;21:10-16. 
  6. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. J Vet Intern Med 2012;26:754.
  7. Wakeling J, Elliott J, Syme H. Evaluation of predictors for the diagnosis of hyperthyroidism in cats. J Vet Intern Med 2011;25:1057-1065. 
  8. Wakeling J. Use of thyroid stimulating hormone (TSH) in cats. Can Vet J 2010;51:33-34. 

Wednesday, January 29, 2014

Seizures and Bilateral Adrenal Enlargement in an Older Boxer: Insulinoma, Cushing's Disease, or Something Else?


I'm looking for some advice for Alex, a 10-year old M/N Boxer who has been a long-term patient of mine. Alex's serious medical problems started a year ago, when he had his first seizure event. Blood work following this seizure was unremarkable aside from a mild elevation in the serum alkaline phosphate activity (219 IU/L; reference range, 5-131 IU/L). Alex's owner began keeping a seizure log, and Alex had further neurological issues until 7 months ago when he suffered another tonic-clonic seizure event, which lasted approximately 3 minutes.

Following this second seizure, Alex was examined by a neurologist, who found no abnormalities on his examination. Routine blood work again showed a mild elevation in the serum alkaline phosphate with all other serum chemistry values being normal. Due to Alex's age and breed, one obvious rule-out was a brain tumor or other intracranial disease, so an MRI was performed. Fortunately, the results of Alex's MRI was normal, with no brain or pituitary masses found.

Alex did well until about 4 months ago, when he had a severe seizure lasting about 5 minutes. A week later, Alex had multiple episodes of severe weakness and disorientation. His physical examination the following day was normal, but blood work revealed a further increase in the serum alkaline phosphate activity (382 IU/L), as well as a slightly low blood glucose concentration (58 mg/dl). Alex had not eaten since the night before, but in light of his clinical signs over the past few days, we sent out a serum insulin:glucose panel, which came back as follows:
  • Glucose: 61 mg/dl (reference range, 70-140 mg/dl)
  • Insulin: 32.2 µU/ml (reference range, 520 µU/ml)
In light of these findings, we referred Alex for an abdominal ultrasound looking for an insulinoma. No pancreatic nodules were seen. However, bilateral adrenal enlargement was noted, and the radiologist recommended a workup for Cushing's disease. Needless to say, Alex's owners were upset and frustrated with the results and recommendations, although they were told beforehand that there was a fair chance that an insulinoma would not be visible on an ultrasound examination (even if a pancreatic islet cell tumor was there).

Despite the lack of clinical signs consistent with Cushing's disease, we performed both an ACTH stimulation test as well as a low-dose dexamethasone suppression test, both of which came back completely normal. However, at the time of this same visit, Alex's blood glucose again read low (58 mg/dl) on our glucometer so we repeated a insulin:glucose panel. The serum results again came back in the borderline range for insulinoma:
  • Glucose: 64 mg/dl (reference range, 70-140 mg/dl)
  • Insulin: 29.2 µU/ml (reference range, 5-20 µU/ml)
By now, I'm sure that you're thanking every deity you've ever heard of that you have reached the bottom of this case history! My question is this—do we have enough evidence to make a diagnosis of insulinoma in this dog and initiate therapy? I know most specialists require a lower blood glucose (i.e., below 60 mg/dl) before they begin to interpret glucose:insulin ratios. However, in Alex, he has had a number of slightly low glucose values with slightly high insulin readings; in light of his clinical signs, insulinoma still remains my primary differential.

As I was writing this post, I just got a call from the owner — Alex had another episode of severe weakness this morning that seemed to respond to Karo syrup applied to his gums.  As you can see, we've been through the ringer with this dog and are just hoping to get the owners some answers at this point so they can sleep a little more soundly.

Thanks very much in advance for your help and very sorry for the length of this post!

My Response:

In the face of hypoglycemia, the serum insulin level should be low, so this dog's high-normal to slightly high insulin value is inappropriate given the low blood glucose values (1-4). Many dogs suffering from insulinoma can be difficult to diagnose, since many have borderline glucose and insulin values similar to what you are describing in this dog.

Could this dog have Cushing's disease?
Hyperadrenocorticism (Cushing's disease) is a clinical diagnosis and is based primarily on the finding of compatible signs (e.g., polydipsia, polyphagia hepatomegaly, hair loss, pot-belly). In a dog suspected of suffering from Cushing's syndrome, we confirm the diagnosis by using one or more of the adrenal function tests (e.g, ACTH stimulation or low-dose dexamethasone suppression tests) (5-7).

One should never make a diagnosis of hyperadrenocorticism based on the finding of large adrenal gland size alone. Remember that the stress of any nonadrenal illness commonly leads to an overactive hypothalmic-pituitary-adrenal axis. Therefore, any dog with chronic stress or illness can develop bilateral adrenocortical hyperplasia as a physiological response. I know that some radiologists like to diagnose Cushing's disease based on adrenal gland size, but this just cannot be done using this criteria alone (5,6). Dogs with Cushing's disease certainly tend to have larger adrenal glands, but large adrenal glands alone are not diagnostic for this disease.

The way I see it, it's highly unlikely that this dog has Cushing's disease. First of all, this dog doesn't have any of the classical signs associated with glucocorticoid excess (5-7). The slightly high serum alkaline phosphatase could be secondary to Cushing's disease, of course, but there is a long list of reasons what that enzyme could be high, including primary liver or bone disease, neoplasia, and other endocrine disease (8).  The history of seizures could go along with a macrotumor of the pituitary gland, but your MRI excluded a CNS or pituitary mass as the cause of the seizures. So the obvious question is this— if this dog has Cushing's disease, how do we explain the seizures and low blood glucose values, which have NOTHING to do with Cushing's syndrome! If anything, the glucocorticoid excess associated with Cushing's can lead to mild to moderate hyperglycemia, with overt diabetes developing in 5-10% of Cushing's dogs (5,6).

So let's not get sidetracked. Let's get back to why this dog has periodic weakness and seizures. Working up and treating Alex for Cushing's syndrome, even if he does have that disease, will not help the dog's main clinical problems.

Confirming or excluding insulinoma as the cause of hypoglycemia
Insulinoma is more likely in this dog, but your blood glucose values have not been very low and your insulin levels are just above reference range limits. It would be great to collect samples during a seizure episode but that's not always possible.

This is what I would recommend: I'd fast the dog overnight at home and have the owners drop the dog off at your clinic in the morning. Then collect samples for glucose and insulin every 1-2 hours throughout the day, stopping when the blood glucose falls to below 45 mg/dl, or when the dog has signs of hypoglycemia. Then submit the sample or samples that have a low glucose for insulin determination.

Ideally, we would see clinical signs of hypoglycemia, document significant hypoglycemia (less than 55
and the lower the better) together with significant hyperinsulinemia, and then give glucose (or feed) and see the signs resolve.

If you are monitoring him and you get a blood glucose of 55 mg/dl on your in-house machine, I'd go another hour (if not symptomatic) and get another sample. If that one isn't lower, I'd continue to sample through the day but monitor closely. You don't want to do this again if possible.

If the dog isn't becoming hypoglycemic by the middle of the day, it's sometimes helpful to take the dog for a brisk walk of 5 to 10 minutes and then check a blood glucose (and insulin) concentration. This exercise can help induce hypoglycemia and hyperinsulinemia in some dogs and therefore, increasing the diagnostic yield of this prolonged fast.

Follow-up Testing and Response to Treatment on Alex:

We performed fasted "glucose curve" in our hospital as you suggested. Alex's serum glucose concentration continued to decrease throughout the day, bottoming out at 42 mg/dl (glucometer reading) after a short afternoon walk. He had minimal clinical signs but did start hypersalivating, so we stopped the test at that point. We collected blood samples for serum insulin and glucose to send out to our lab, and fed the dog. Alex ate well and the hypersalivating resolved almost immediately thereafter.

The serum results came back as follows:
  • Glucose: 39 mg/dl (reference range, 70 - 140 mg/dl)
  • Insulin: 52 µU/ml (reference range, 5 - 20 µU/ml)
Based on these results — severe symptomatic hypoglycemia that responding to feeding together with overt hyperinsulinemia, we made a diagnosis of insulinoma.

I am happy to report that Alex has been doing well on treatment with prednisone and an adjusted feeding schedule (many smaller meals throughout the day). To this point our spot checks in the hospital have been very normal, and the seizure episodes have resolved.

We know that we are only controlling signs of hypoglycemia in this dog and growth and metastasis of Alex's insulinoma is likely within the next few months, Due to his age, the owners have declined exploratory surgery for now and just want to control the hypoglycemia medially at this time.  

References:
  1. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
  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. 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. 
  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. Peterson ME. Diagnosis of hyperadrenocorticism in dogs. Clin Tech Small Anim Pract 2007;22:2-11. 
  6. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
  7. Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing's syndrome in dogs. Vet Clin North Am Small Anim Pract 2010;40:259-267. 
  8. Fernandez NJ, Kidney BA. Alkaline phosphatase: beyond the liver. Vet Clin Pathol 2007;36:223-233. 
My Other Blog Posts that Discuss Insulinoma and Hypoglycemia:

Wednesday, January 22, 2014

How to Best Manage Non-functional Thyroid Tumors in Cats


I have a 3½ year old castrated male DLH that was found to have a 1-cm mass in the region of the left thyroid gland on a wellness exam 10 months ago. The owner declined cytology at that time, and on followup last week the mass has now grown to ~2-cm (22mm) in size. This is an incidental finding on physical exam, and the cat is maintaining his weight and otherwise seems normal at home. The body condition score, muscle condition score, and heart rate are all normal in this cat.

Routine lab work, including a CBC, serum chemistry profile, and urinalysis were all normal. Results of a serum concentrations of total T4 (2.5 µg/dl; normal, 0.8-4.0 µg/dl) and free T4 (26 pmol/L; normal, 10-50 pmol/L) were also well within reference range limits. The results of my aspiration cytology of the mass is as follows:
  • The slides are of moderate to high cellularity containing scattered clusters of epithelial cells in a background of peripheral blood and scattered bare round nuclei. The epithelial cells display round to oval nuclei with a moderate amount of encircling, indistinct, pale basophilic cytoplasm. These cells display mild anisocytosis and anisokaryosis. No infectious organisms are observed. 
  • This is an epithelial cell tumor and cytologically it appears to be benign. This is likely a thyroid gland tumor; if so, the majority of thyroid tumors in cats are benign adenomas. Rarely, thyroid carcinomas occur in cats and are very difficult to distinguish from adenomas cytologically. Histopathology is required to specifically identify the origin of these epithelial cells. It should be emphasized that other epithelial cell tumors other than thyroid tumors in this area have similar cytologic appearance.
I spoke with a consultant at the lab, who recommended just monitoring the mass rather than surgical removal, as it appears to be benign. The owner doesn't want surgery unless the mass is likely to cause the cat problems in the future. 

Is it reasonable to just monitor the cat rather than treat? I've heard about enormous thyroid masses that can become cystic and develop into thyroid carcinoma so I don't want that to happen. While we can certainly monitor for growth and deal with the mass if it gets larger, I'd like to remove it now if it's pretty much guaranteed to continue to grow and has potential to cause issues in the future.

Thanks for your advice!

My Response:

First of all, as the pathologist indicates, we can not make a definitive diagnosis of thyroid adenoma based on cytology alone. If this is thyroid adenoma, the tumor will likely continue to grow with time (1,2), as you have already seen in this case. It's also possible for an adenoma to become cystic (3), which can make treatment much more complicated.

Finally, in addition to tumor growth, it is also possible to see transformation from thyroid adenoma into carcinoma with time (2,4,5). Based on my studies, this would most likely occur in cats with long-standing hyperthyroidism treated with methimazole (longer than 3-4 years) (5). Since this cat is so young, he certainly has a long time to develop thyroid tumor growth and hyperthyroidism.

That all said, not all cats with a thyroid mass will become hyperthyroid (6-8), and not all of these thyroid tumors will continue to grow rapidly, become cystic, or transform into a malignancy. However, if this was my cat, I would certainly like to know if the mass is a thyroid adenoma or another type of tumor. In this cat, that should be the first step in managing this cat — we need to know what it is before we can recommend the "best" treatment.

Is the cervical mass of thyroid origin?
If the owner doesn't want to do surgery to remove the mass and submit the tissue for histopathology (the gold standard means of confirming the diagnosis), then the next best test to determine if the mass is of thyroid origin would be thyroid scintigraphy (9-11).

Figure 1: Thyroid scintigraphy in a normal cat
On a normal thyroid scan, only the 2 normal thyroid lobes, salivary glands, and stomach take up the injected radionuclide (see Figure 1). Therefore, if this is not a thyroid tumor (but another type of tumor), it will not be seen on the thyroid scan.

It is also possible that we could have a nonfunctional thyroid tumor that would fail to have any thyroid uptake, but these are very rare, especially in cats. If that were the case, we would only see a single thyroid lobe on the scan— not the 2 normal thyroid lobes, as shown in Figure 1.

Figure 2: Thyroid scintigraphy in a cat with a right thyroid adenoma. 
So the bottom line is this: if the mass takes up radionuclide on thyroid scan (Figure 2), then we know it's a thyroid tumor (most likely an adenoma). If we see two normal thyroid lobes and the mass doesn't take up any of the radionuclide (Figure 1), then the tumor is not of thyroid origin and must be surgically removed to get the answer.

Radioiodine treatment of non-function thyroid tumors
If the thyroid scan does confirm thyroid tumor, and it displays normal to enhanced radionuclide uptake (Figure 2), then the tumor could be treated with radioiodine, even if the cat was not hyperthyroid.

However, if the normal thyroid lobe also takes up some of the injected radionuclide, we may want to consider suppressing the normal thyroid lobe by giving exogenous L-thyroxine for a week or two to shut off pituitary TSH secretion (12). In these cats, I like to repeat the thyroid scan after administration of L-T4 to ensure that the normal lobe no longer takes up the radionuclide. If it does, that means that it will likely take up the administered I-131 and the cat will become hypothyroid.

No treatment with periodic monitoring
Now if the owner does not want to do a thyroid scan (or scintigraphy is not available in your area) and surgical removal is still out, then you have no other option other than to monitor thyroid hormone values and tumor size.

If the mass continues to grow, then surgical or radiation treatment should be strongly considered. If the cat develops hyperthyroidism at some time in the future, then medical treatment could also be considered. However, in such a young cat, I'd still recommend definitive treatment. Who would want to give methimazole to a young cat for up to 15 years or even longer, especially when we know that the thyroid tumor will continue to growth larger over time?

References:
  1. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
  2. Peterson M. Hyperthyroidism in cats: What's causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 2012;14:804-818. 
  3. Hofmeister E, Kippenes H, Mealey KL, et al. Functional cystic thyroid adenoma in a cat. J Am Vet Med Assoc 2001;219:190-193. 
  4. Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. J Feline Med Surg 2009;11:116-124. 
  5. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. J Vet Intern Med 2012;26:1523. 
  6. Norsworthy GD, Adams VJ, McElhaney MR, et al. Palpable thyroid and parathyroid nodules in asymptomatic cats. J Feline Med Surg 2002;4:145-151. 
  7. Ferguson D, Freeman R. Goiter in apparently euthyroid cats In: August JR, ed. Consultations in Feline Internal Medicine. St. Louis: Elsevier Saunders, 2006.
  8. Boretti FS, Sieber-Ruckstuhl NS, Gerber B, et al. Thyroid enlargement and its relationship to clinicopathological parameters and T4 status in suspected hyperthyroid cats. J Feline Med Surg 2009;11:286-292. 
  9. Daniel GB, Brawnier WR. Thyroid scintigraphy In: Daniel GB, Berry CR, eds. Textbook of Veterinary Nuclear Medicine. 2nd ed. Harrisburg, PA: American College of Veterinary Radiology, 2006;181-199.
  10. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. J Vet Intern Med 2012;26:754.
  11. Feeney DA, Anderson KL. Nuclear imaging and radiation therapy in canine and feline thyroid disease. Vet Clin North Am Small Anim Pract 2007;37:799-821, viii. 
  12. Szumowski P, Rogowski F, Abdelrazek S, et al. Iodine isotope 131-I therapy for toxic nodular goitre: treatment efficacy parameters. Nucl Med Rev Cent East Eur 2012;15:7-13.