Saturday, November 15, 2014

Managing Diabetic Dogs with Exocrine Pancreatic Insufficiency

My problem patient is a 9-year old, female spayed Yorkie with concurrent exocrine pancreatic insufficiency (EPI) and diabetes mellitus. The stools, which had been very large and odoriferous, are smaller and not as smelly now that we have started the pancreatic enzyme replacement therapy.  However, the stools are still not completely normal. The dog remains very thin, but she has gained a pound over the past month.

The diabetic control has been more problematic. Six weeks ago, the dog was on 3 units of Novolin N every 12 hours and had serial blood glucose values running in the range of 400-600 mg/dl throughout the day.  After starting on the enzyme powder, the insulin dosage has fallen to only 0.5 unit twice daily. The current glucose curves start with a morning reading of 400 mg/dl, but the blood glucose then drops down during the day to values in the 100's or, at times, to as low as 45 mg/dl. The owner is trying to be as consistent as possible in feeding (the dog has a very good appetite) and giving the insulin. The dog has shown signs of clinical hypoglycemia, despite the low blood glucose values.  

What do you suggest? Is there a better insulin for this dog?  Would a special diet help?

My Response:

The vast majority of dogs with EPI have a concurrent B12 (cobalamin) deficiency; therefore, cobalamin should be part of this dog's treatment regimen (1). If this Yorkie weighs less than 7 kg, I would suggest administering 250 µg SC every 7 days for 8 weeks, then 250 µg every 14 days for 2 months, then 250 µg once monthly for a couple more months. The treatment may need to be repeated based on serum cobalamin levels.

In addition, some dogs with EPI have dysbiosis (the new term for bacterial overgrowth/gut microbial imbalance), so metronidazole or tylosin power given for a couple weeks plus a probiotic may be helpful. Lastly, if the stools don't get better with the above treatments then the dog may have inflammatory bowl disease (IBD) in addition to the EPI (2). This breed appears predisposed to developing IBD or lymphangietasia (2). As far as what to feed this dog, I'd recommend a diet low in fat because of the concurrent diabetes and GI issues (1).

As far as the insulin type, it looks like the duration of NPH activity is too short for this dog. Use of an insulin with a longer duration of action, such as Vetsulin or glargine, may be a better choice for this case. Based on the fact that the insulin dose is so small and the dog is so very sensitive to the insulin, I'd go with glargine, starting with 1 U,  twice daily. This insulin is much less potent than either NPH or Vetsulin in dogs, making hypoglycemia less unlikely (3).

References:
  1. Wieberg, M. Exocrine pancreatic insufficiency in dogs. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013;558-560.
  2. Simmerson SM, Armstrong PJ, Wünschmann A, J., et al. Clinical features, intestinal histopathology, and outcome in protein-losing enteropathy in Yorkshire Terrier dogs. J Vet Intern Med. 2014;28:331-7. 
  3. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. doi: 10.1136/vr.100070.

Sunday, November 2, 2014

Hyperthyroidism in Guinea Pigs: An Emerging Disease


PAPER REVIEW

Hyperthyroidism in Four Guinea Pigs: Clinical Manifestations, Diagnosis, and Treatment
by F. Künzel, B. Hierlmeier, M. Christian, and M. Reifinger

Background

Only limited information regarding hyperthyroidism in guinea pigs has been reported, much of which has been published as a general review article (1-3). Therefore, veterinarians may not be aware of this disease, resulting in under-diagnosis of this condition.

The purpose of this case series by Künzel et al. (4) is to describe the results of diagnosis, treatment, and outcome of guinea pigs with hyperthyroidism. The goal was to provide additional information about this disease to help clinicians dealing with guinea pigs that may be suspected of having this disease.

Case Series of 4 Guinea Pigs Suffering from Hyperthyroidism

Signalment: Hyperthyroidism was diagnosed in four guinea pigs (3 females and 1 male), ranging in age from 3 to 6 years. These 4 cases represented 1.3% of guinea pigs examined at the University clinic during the same 2.5-year period.

Clinical features: Clinical signs reported in all guinea pigs included weight loss despite the maintenance of a normal appetite.   Polyuria was noted in 2 of the 4 cases.

Physical examination findings: Physical examination revealed evidence for weight loss and a palpable mass in the ventral cervical region in all guinea pigs. Additional findings in individual guinea pigs included unkempt hair coat, tachycardia and tachypnea.

Serum chemistry results and thyroid hormone determinations: All 4 of the guinea pigs showed elevated serum alanine aminotransferase (ALT) activity. The diagnosis of hyperthyroidism was confirmed by demonstration of increased serum total thyroxine (T4) concentrations in all guinea pigs, as measured by chemiluminescent technique (5).

Treatment: Surgical thyroidectomy was attempted in 1 case but the guinea pig died during anesthetic induction. Histopathology confirmed thyroid adenoma.

The other 3 guinea pigs were treated with methimazole, using starting doses of 1-1.4 mg/kg/day. Based on clinical signs and results of follow-up serum T4 values, the final methimazole doses ranged from 2-3 mg/kg every 24 hours in 2 cases and 2.5 mg/kg every 8 hours in the third guinea pig. In this latter case, radioactive iodine treatment was eventually performed.

Response to treatment: All 3 of the treated guinea pigs showed progressive weight gain as serum T4 concentrations fell to within the reference interval. However, all died of unknown causes 18-28 months following initial treatment.

My Bottom Line:

Hyperthyroidism in guinea pigs represents a relatively new addition to the list of differential diagnoses for weight loss in guinea pigs (2-4). In many ways, the description and management of hyperthyroidism in these 4 guinea pigs mimics the situation we had with feline hyperthyroidism in the early 1980’s, as we were just starting to routinely recognize this common disease in cats (6,7).

The signalment (middle-aged to senior), clinical signs (weight loss despite a good appetite) and physical exam findings (palpable thyroid nodule) displayed by these guinea pigs are all remarkably similar to those of the typical hyperthyroid cat. The finding of a high total T4 concentration was diagnostic in all of these 4 guinea pigs, as it is in over 90% of hyperthyroid cats.

Treatment with methimazole was successful in management of 3 of the 4 guinea pigs. However, on a body weight basis, much higher daily doses were needed for the guinea pigs, at least compared to the typical hyperthyroid cat.  Use of radioiodine therapy also appears to be a safe and promising treatment for guinea pigs suffering from hyperthyroidism (2,5). However, more work needs to be done before this becomes an accepted therapeutic approach for hyperthyroidism in the guinea pig.

References:
  1. Mayer J, Hunt K, Eshar D, et al. Thyroid scintigraphy in a guinea pig with suspected hyperthyroidism. Exotic DVM 2009;11:25-29.
  2. Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in Guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509-523. 
  3. Brandao J, Vergneau-Grosset C, Mayer J. Hyperthyroidism and hyperparathyroidism in guinea pigs (Cavia porcellus). Vet Clin North Am Exot Anim Pract 2013;16:407-420. 
  4. Kunzel F, Hierlmeier B, Christian M, et al. Hyperthyroidism in four guinea pigs: clinical manifestations, diagnosis, and treatment. J Small Anim Pract 2013; 54:667-671
  5. Muller K, Muller E, Klein R, et al. Serum thyroxine concentrations in clinically healthy pet guinea pigs (Cavia porcellus). Vet Clin Pathol 2009;38:507-510. 
  6. Peterson ME, Johnson JG, Andrews LK. Spontaneous hyperthyroidism in the cat. Spontaneous hyperthyroidism in the cat. Proceedings of the American College of Veterinary Internal Medicine 1979: 108.
  7. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. J Am Vet Med Assoc 1983;183:103-110. 

Saturday, October 11, 2014

Unmasking Kidney Disease In Hyperthyroid Cats after Treatment


I have two hyperthyroid cats that both had "completely normal" kidney function until we started treating with methimazole. On treatment, the serum T4 concentrations in both cats have come down nicely to 1.2 and 2.0 µg/dl, respectively (reference interval, 1.0-4.0 µg/dl), so these values are within the low-normal range, which is what I aim for after treatment.

In the first cat, the serum creatinine has increased from 1.2 mg/dl up to 2.0 mg/dl, whereas the serum creatinine value in the second cat rose from 1.5 mg/dl up to 2.5 mg/dl. Based on the IRIS staging system, both cats could be classified as having stage 2 chronic kidney disease (CKD).

How do I manage such hyperthyroid cats that develop "new" CKD after treatment? Should I lower the methimazole or stop it all together in order to help improve the kidney function?

My Response:

Hyperthyroidism and CKD are both very common problems of the older cat and may occur concurrently in the same patient (1,2). Because hyperthyroidism increases the glomerular filtration rate (GFR) and renal blood flow (RBF), the kidney disease may be masked and only revealed once the cat is rendered euthyroid (3-5). As you know, that's what happened in these two feline patients.

However, it is very important to understand that treatment of hyperthyroidism doesn't cause new kidney problems; the CKD was already present in your cats before the methimazole treatment, but the serum creatinine values were normal, in part due to the high GFR associated with hyperthyroidism. Now that you have the hyperthyroidism under control, the lowering of circulating thyroid hormone concentrations has also resulted in a drop in GFR, unmasking the underlying CKD that was already there.

Management of hyperthyroid cats that develop kidney disease after treatment
So what do we do with hyperthyroid cats like your two patients here— cats that develop mild CKD after treatment of hyperthyroidism with methimazole?

It was once thought that if azotemia developed following medical treatment, then it would be best to stop the methimazole and leave the hyperthyroidism untreated (or at least under-treat it) to maximize renal function. This recommendation has now been widely abandoned, with the realization that hyperthyroidism could actually be causing renal injury in these cats through the process of glomerular hyperfiltration (1,2,6). This increase in glomerular pressure has been associated with proteinuria and evidence of tubular damage, which could result in progressive renal injury. In other words, hyperthyroidism has the potential to exacerbate these processes and worsen, rather than help, renal function.

On the other hand, it's also important not to over control hyperthyroidism. In other words, we don't want the post-treatment T4 concentrations to go too low because iatrogenic hypothyroidism will make the azotemia worse (7). Even mild degrees of hypothyroidism can worsen the azotemia in susceptible cats. This means that the serum T4 value does not have to be below reference range — even a serum T4 in the lower third of the reference range may be too low, especially if the serum TSH is high, diagnostic for mild hypothyroidism (8).

Because of this association between development of iatrogenic hypothyroidism and worsening of azotemia, my "goal" in treating cats with hyperthyroidism is to reduce the total T4 concentration into the middle of the reference range (e.g., 2.0-3.0 µg/dl with your lab). So in your first cat, you may want to lower the methimazole dose and allow the serum T4 to come up into the mid-normal range. This may help increase GFR and improve kidney function in that cat. One recent study found that restoration of euthyroidism in cats with iatrogenic hypothyroidism resulted in a significant reduction in serum creatinine concentration, with azotemia resolving in half of the cats (9).

Finally, if you unmask kidney disease after treatment of a hyperthyroid cat, this also means that you should take steps to attempt to slow the progression of CKD, just as you would in a geriatric cat with CKD alone. These steps may include one or more of the following, depending on secondary factors and stage of the CKD (10,11):
  • Antibiotics, if urinary tract infection
  • Antihypertensives, if hypertensive
  • Low-phosphate diet
  • Phosphorus binders
  • Calcitriol or ACE-inhibitors, if necessary
  • Subcutaneous fluids
Survival times of hyperthyroid cats that develop mild CKD after treatment
In most cats that develop newly-diagnosed azotemia after treatment for hyperthyroidism, the CKD is mild (usually IRIS stage 2) and associated with few clinical signs other than mild polyuria and polydipsia. Owners of cats that have developed azotemia still report that treatment of the hyperthyroidism has improved the clinical condition of their cat, as shown by weight gain and resolution of other clinical signs of hyperthyroidism.

The survival time of cats that develop azotemia following treatment of hyperthyroidism does not differ from those that do not develop any azotemia (7). This fact may be surprising to many practicing veterinarians who naturally assume that the development of CKD is associated with a worse prognosis. However, CKD progresses relatively slowly in cats, and only about half of all cats diagnosed with mild CKD will ultimately succumb to the disease (12). Many CKD cats die because of unrelated causes.

Survival times of hyperthyroid cats that are azotemic prior to treatment
The situation is completely different in cats that are already clearly azotemic (serum creatinine >2 mg/dl), even before any treatment for hyperthyroidism has been given. In general the survival of this group of cats with azotemic CKD prior to treatment is poor. In one study, the median survival time for azotemic cats was only 178 days; however, survival times in that study was very variable,  ranged from 0 days up to 1,505 days (4.1 years) (13).

Bottom Line:

Hyperthyroid cats that develop "new" CKD after treatment are common, but the azotemia is generally mild and we should not withhold methimazole treatment in those cats. However, we don't want to induce iatrogenic hypothyroidism, and steps should be taken to address the underlying CKD. Unless prior azotemia was present, the prognosis of most treated cats with mild CKD is good to excellent.

References:
  1. Langston CE, Reine NJ. Hyperthyroidism and the kidney. Clin Tech Small Anim Pract 2006;21:17-21.  
  2. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743.  
  3. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Res 1994;55:1745-1749.  
  4. Boag AK, Neiger R, Slater L, et al. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Vet Rec 2007;161:711-715.  
  5. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domest Anim Endocrinol 2009;36:45-56.  
  6. Syme H. Are methimazole trials really necessary? In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
  7. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092.  
  8. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compendium 2013;35:E4. 
  9. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255. 
  10. Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 2012;42:669-692.
  11. Polzin DJ. Chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract 2011;41:15-30. 
  12. Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 2000;41:235-242.
  13. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869. 

Monday, September 29, 2014

Top Endocrine Publications of 2013: The Feline Thyroid Gland


In my eighth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline thyroid gland.

Listed below are 26 papers published in 2013 that deal with a variety of thyroid gland topics of issues of clinical importance in cats.

These range from from studies of the duration of serum T4 suppression in cats treated with methimazole (1) to the results of a long-term follow-up study of cats treated with transdermal methimazole (2); and from case reports of methimazole or carbimazole-induced toxicity in cats (3,6,19) to the results of an online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications (5).

Other studies report the variability in iodine concentrations found in commercial cats foods in the USA (7) to investigation of the radioactivity in the excreta of hyperthyroid cats treated with radioiodine (8); from a comparison of computed tomography and scintigraphy for thyroid imaging in hyperthyroid cats (9) to a review of the clinical usefulness of an assay for measurement of circulating B-type natriuretic peptide (BNP) concentration in hyperthyroid cats (11); and from an overview of the diagnostic tests useful for confirming feline hyperthyroidism (4,12,13,15,17) and hypothyroidism (14) to a study of the effects of an iodine-restricted diet for management of cats with hyperthyroidism (22); from investigations of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats (24) to studies of the renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without hypertension (25).

References:
  1. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Duration of T4 suppression in hyperthyroid cats treated once and twice daily with transdermal methimazole. J Vet Intern Med 2013;27:377-381. 
  2. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Transdermal application of methimazole in hyperthyroid cats: a long-term follow-up study. J Feline Med Surg 2013;16:453-459. 
  3. Bowlt K, Cattin I, Stewart J. Carbimazole-associated hypersensitivity vasculitis in a cat. J Small Anim Pract 2013; doi: 10.1111/jsap.12154. 
  4. Bruyette D. Feline hyperthyroidism: Diagnosis and therapeutic modalities. Today's Veterinary Practice 2013;3:25-30.
  5. Caney SM. An online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications. J Feline Med Surg 2013;15:494-502. 
  6. Castro Lopez J, Lloret A, Ravera I, et al. Pyogranulomatous mural folliculitis in a cat treated with methimazole. J Feline Med Surg 2013;16:527-531. 
  7. Edinboro CH, Pearce EN, Pino S, et al. Iodine concentration in commercial cat foods from three regions of the USA, 2008-2009. J Feline Med Surg 2013;15:717-724. 
  8. Lamb V, Gray J, Parkin T, et al. Measurement of the radioactivity in the excreta of cats treated with iodine-131 for hyperthyroidism. Vet Rec 2013;172:45. 
  9. Lautenschlaeger IE, Hartmann A, Sicken J, et al. Comparison between computed tomography and Tc-Pertechnetate scintigraphy characteristics of the thyroid gland in cats with hyperthyroidism. Vet Radiol Ultrasound 2013;54:666-673. 
  10. North DL. Uptake of 131-I in households of thyroid cancer patients. Health Phys 2013;104:434-436. 
  11. Oyama MA, Boswood A, Connolly DJ, et al. Clinical usefulness of an assay for measurement of circulating N-terminal pro-B-type natriuretic peptide concentration in dogs and cats with heart disease. J Am Vet Med Assoc 2013;243:71-82. 
  12. Paepe D, Verjans G, Duchateau L, et al. Routine health screening: findings in apparently healthy middle-aged and old cats. J Feline Med Surg 2013;15:8-19. 
  13. Peterson ME. More than just T4: Diagnostic testing for hyperthyroidism in cats. J Feline Med Surg 2013;15:765-777. 
  14. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4. 
  15. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet 2013;35:E3. 
  16. Ramoo S, Bradbury L, Anderson G, et al. Sedation of hyperthyroid cats with subcutaneous administration of a combination of alfaxalone and butorphanol. Aust Vet J 2013;91:131-136. 
  17. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats (Letter). Vet Clin Pathol 2014;43:1-3. 
  18. Sabatino BR, Rohrbach BW, Armstrong PJ, et al. Amino acid, iodine, selenium, and coat color status among hyperthyroid, Siamese, and age-matched control cats. J Vet Intern Med 2013;27:1049-1055. 
  19. Snead E, Kerr M, Macdonald V. Cutaneous lymphoid hyperplasia mimicking cutaneous lymphoma in a hyperthyroid cat. Can Vet J 2013;54:974-978. 
  20. Sparkes A. Health screening of cats: some timely justification. J Feline Med Surg 2013;15:5. 
  21. Taylor BE, Leibman NF, Luong R, et al. Detection of carcinoma micrometastases in bone marrow of dogs and cats using conventional and cell block cytology. Vet Clin Pathol 2013;42:85-91.
  22. van der Kooij M, Becvarova I, Meyer HP, et al. Effects of an iodine-restricted food on client-owned cats with hyperthyroidism. J Feline Med Surg 2013;14:491-498. 
  23. Whitehouse-Tedd KM, Cave NJ, Ugarte CE, et al. Isoflavone metabolism in domestic cats (Felis catus): Comparison of plasma metabolites detected after ingestion of two different dietary forms of genistein and daidzein. J Anim Sci 2013;91:1295-1306. 
  24. 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. 
  25. Williams TL, Elliott J, Syme HM. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J Vet Intern Med 2013;27:522-529. 
  26. Wongbandue G, Jewgenow K, Chatdarong K. Effects of thyroxin (T4) and activin A on in vitro growth of preantral follicles in domestic cats. Theriogenology 2013;79:824-832. 

Wednesday, September 17, 2014

Confirming the Diagnosis of Addison's Disease in Dogs on Corticosteroids


Is it possible to confirm diagnosis of Addison's disease with an ACTH stimulation test after treatment has been initiated? My patient is a 6-year-old, male West Highland White Terrier seen on an emergency basis for severe lethargy, vomiting, diarrhea, and anorexia that all began shortly after he was at the groomers. There was no history of dietary indiscretion in this dog.

A serum chemistry profile revealed hypoglycemia (glucose, 61 mg/dl), hyperphosphatemia (phosphorus, 9.1 mg/dl), hyponatremia (130 mEq/L), and hyperkalemia (6.1 mg/dl). The dog was also moderately azotemic, with a serum urea nitrogen of 52 mg/dl and serum creatinine of 2.2 mg/dl.

The dog was treated at the emergency clinic overnight with IV dexamethasone and IV fluids (normal saline). The following morning, he was given an injection of IM Percorten-V (25 mg) and started on oral prednisone (2.5 mg once daily).

He has now been home a week and has shown a marked response to replacement therapy. The dog is scheduled to recheck with me in a few days to recheck his serum chemistry panel and electrolytes. Although this case certainly seems to fit a diagnosis of primary hypoadrenocorticism (Addison's disease), I'd be happier if we could confirm the diagnosis with an ACTH stimulation test.

Is that possible, now that the dog has been treated with dexamethasone, prednisone, and Percorten-V?

My Response:

Yes, you certainly can (and should) do an ACTH stimulation test to confirm the preliminary diagnosis of Addison's disease, even after treatment has been instituted.

Confirming the diagnosis by documenting low serum cortisol secretion before and after ACTH stimulation is always a very good idea, since many other diseases can mimic the clinical features seen with this disease. In addition, even having the classical electrolyte changes associated with Addison's disease (hyponatremia, hypocholemia, and hyperkalemia) are not totally diagnostic, inasmuch as other diseases (e.g., whipworms, renal failure, pancreatitis) can also produce the same electrolyte abnormalities in some dogs.

Diagnostic workup for dogs with suspected Addison's disease on treatment with glucocorticoids and mineralocorticoids
On your recheck in a week, this is what I'd recommend. First of all, if the dog is doing well, have the owners stop the prednisone for at least 24 hours before the recheck exam and ACTH stimulation test is scheduled (48 hours is even better). The Percorten-V has minimal to no glucocorticoid activity so that drug isn't going to interfere with the results of the ACTH stimulation test.

If the dog is normal or is suffering from nonadrenal illness (but does not have Addison's disease), the glucocorticoid treatment (both the IV dexamethasone and oral prednisone) might result in adrenocortical suppression, but not nearly to the degree that we see in dogs with Addison's disease.
  • Dogs with primary Addison's disease generally have very low basal and post-ACTH cortisol concentrations (both cortisol values less than 1.0 μg/dl in almost all dogs and always less than 2.0 μg/dl). 
  • In dogs treated with glucocorticoids that develop suppression of the hypothalamic-pituitary-adrenal axis, the basal cortisol value may be low and the cortisol response to ACTH stimulation may be abnormal and "blunted."
  • However, the serum cortisol values in dogs that do not have Addison's disease will rise to above 2-3 μg/dl after ACTH stimulation in these dogs, and many dogs will show a completely normal cortisol response. In these dogs, a search for other causes of hyperkalemia should be undertaken.
References:
  1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
  2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
  3. Kintzer PP, Peterson ME. Canine hypoadrenocorticism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014; pp 233-237.
  4. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Can Vet J 2010;51:179-184.

Saturday, August 9, 2014

Top Endocrine Publications of 2013: The Feline Adrenal Gland

In my next compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline adrenal gland.

Listed below are 12 research papers written in 2013 that deal with a variety of adrenal gland topics of issues of clinical importance in cats.

These range from a study of body condition on the bioavailability of prednisone and prednisolone in cats (1) to investigation of adrenal gland ultrasonography in normal and sick cats (2); from a study that designed an oral fludrocortisone suppression test for diagnosis of hyperaldosteronism (Conn's syndrome) in cats (3) to another that designed a corticotropin-releasing hormone (CRH) protocol for evaluation of the hypothalamic-pituitary-adrenal axis (4); and from a study which measured cortisol levels in cats' hair (5) to a case report of ACTH-secreting pituitary carcinoma causing Cushing's disease in a cat (6).

Other studies included a retrospective study of trilostane treatment of cats with Cushing's disease (7) to a review of hyperadrenocorticism and diabetes mellitus in cats (8); from studies of the effects of stress on glucocorticoid metabolites (9) to a case report of a cat with double GH- and ACTH-secreting pituitary adenomas (10); and finally, from a case report of a cat that presented in Addisonian crisis (11) to an investigation of the renin-angiotensin-aldosterone system in hyperthyroid cats with and without hypertension (12).

References:
  1. Center SA, Randolph JF, Warner KL, et al. Influence of body condition on plasma prednisolone and prednisone concentrations in clinically healthy cats after single oral dose administration. Res Vet Sci 2013;95:225-230. 
  2. Combes A, Pey P, Paepe D, et al. Ultrasonographic appearance of adrenal glands in healthy and sick cats. J Feline Med Surg 2013;15:445-457. 
  3. Djajadiningrat-Laanen SC, Galac S, Boeve SAEB, et al. Evaluation of the oral fludrocortisone suppression test for diagnosing primary hyperaldosteronism in cats. J Vet Intern Med 2013;27:1493-1499. 
  4. 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. 
  5. Galuppi R, Leveque JF, Beghelli V, et al. Cortisol levels in cats' hair in presence or absence of Microsporum canis infection. Res Vet Sci 2013;95:1076-1080. 
  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. Mellett Keith AM, Bruyette D, Stanley S. Trilostane therapy for treatment of spontaneous hyperadrenocorticism in cats: 15 cases (2004-2012). J Vet Intern Med 2013;27:1471-1477. 
  8. 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. 
  9. Ramos D, Reche-Junior A, Fragoso PL, et al. Are cats (Felis catus) from multi-cat households more stressed? Evidence from assessment of fecal glucocorticoid metabolite analysis. Physiol Behav 2013;122:72-75. 
  10. Sharman M, FitzGerald L, Kiupel M. Concurrent somatotroph and plurihormonal pituitary adenomas in a cat. J Feline Med Surg 2013;15:945-952. 
  11. 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. 
  12. Williams TL, Elliott J, Syme HM. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J Vet Intern Med 2013;27:522-529. 

Monday, August 4, 2014

Top Endocrine Publications of 2013: The Canine Adrenal Gland

I've decide to take a break from my review of the endocrine abstracts presented at the 2014 ACVIM forum and turn back to my review of the canine and feline endocrine publications of 2012. So in the next 2 posts, I'll cover the disorders of the canine and feline adrenal gland.

Listed below are 55 research papers written in 2013 that deal with a variety of adrenal gland issues of clinical importance in dogs.

These range from the investigations of trilostane protocols used in the treatment of dogs with Cushing's disease (1,7,12,23) to the pathogenesis, clinical features, or outcome of dogs with adrenal tumors (2,4,31-34); from adrenal imaging in normal dogs and dogs with Cushing's syndrome (3,16,24,46) to investigations involving diagnosis or treatment of hypoadrenocorticism (5,18,36,37,50); and from studies dealing with diagnostic testing for hyperadrenocorticism (6,8-11,14,42) to research studies investigating the effect of "stress" on adrenal function in dogs (15,45,49,51).

Other research studies involved diagnostic testing for pheochromocytoma in dogs (21,22) to reports of extra-adrenal paraganglioma or chemodectomas in dogs (25,27); and from studies of the renin-angiotensin-aldosterone (38,39) to studies of the complications of Cushing's syndrome, including hypercoagulability (43,44,47,48) and sudden acquired retinal degeneration syndrome (52).

As you can see from all of these many publications, it was a good year to study the canine adrenal gland!

References:
  1. Arenas C, Melian C, Perez-Alenza MD. Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism: twice daily versus once daily. J Vet Intern Med 2013;27:1478-1485. 
  2. Arenas C, Perez-Alenza D, Melian C. Clinical features, outcome and prognostic factors in dogs diagnosed with non-cortisol-secreting adrenal tumours without adrenalectomy: 20 cases (1994-2009). Vet Rec 2013;173:501. 
  3. Bargellini P, Orlandi R, Paloni C, et al. Contrast-enhanced ultrasonographic characteristics of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism. Vet Radiol Ultrasound 2013;54:283-292. 
  4. Barrera JS, Bernard F, Ehrhart EJ, et al. Evaluation of risk factors for outcome associated with adrenal gland tumors with or without invasion of the caudal vena cava and treated via adrenalectomy in dogs: 86 cases (1993-2009). J Am Vet Med Assoc 2013;242:1715-1721. 
  5. Bates JA, Shott S, Schall WD. Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism. Aust Vet J 2013;91:77-82.
  6. Behrend EN, Kooistra HS, Nelson R, et al. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med 2013;27:1292-1304. 
  7. Braun C, Boretti FS, Reusch CE, et al. Comparison of two treatment regimens with trilostane in dogs with pituitary-dependent hyperadrenocorticism. Schweiz Arch Tierheilkd 2013;155:551-558. 
  8. Bromel C, Nelson RW, Feldman EC, et al. Serum inhibin concentration in dogs with adrenal gland disease and in healthy dogs. J Vet Intern Med 2013;27:76-82. 
  9. Bryan HM, Adams AG, Invik RM, et al. Hair as a meaningful measure of baseline cortisol levels over time in dogs. J Am Assoc Lab Anim Sci 2013;52:189-196. 
  10. Bugbee AC, Smith JR, Ward CR. Effect of dexamethasone or synthetic ACTH administration on endogenous ACTH concentrations in healthy dogs. Am J Vet Res 2013;74:1415-1420. 
  11. Burkhardt WA, Boretti FS, Reusch CE, et al. Evaluation of baseline cortisol, endogenous ACTH, and cortisol/ACTH ratio to monitor trilostane treatment in dogs with pituitary-dependent hypercortisolism. J Vet Intern Med 2013;27:919-923. 
  12. Cho KD, Kang JH, Chang D, et al. Efficacy of low- and high-dose trilostane treatment in dogs (< 5 kg) with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2013;27:91-98. 
  13. Claude AK, Miller WW, Beyer AM, et al. Quantification and comparison of baseline cortisol levels between aqueous and plasma from healthy anesthetized hound dogs utilizing mass spectrometry. Vet Ophthalmol 2014;17:57-62. 
  14. Corradini S, Accorsi PA, Boari A, et al. Evaluation of hair cortisol in the diagnosis of hypercortisolism in dogs. J Vet Intern Med 2013;27:1268-1272. 
  15. Dalla Villa P, Barnard S, Di Fede E, et al. Behavioural and physiological responses of shelter dogs to long-term confinement. Vet Ital 2013;49:231-241. 
  16. de Chalus T, Combes A, Bedu AS, et al. Ultrasonographic adrenal gland measurements in healthy Yorkshire Terriers and Labrador Retrievers. Anat Histol Embryol 2013;42:57-64. 
  17. De Vries F, Leuschner J, Jilma B, et al. Establishment of a low dose canine endotoxemia model to test anti-inflammatory drugs: effects of prednisolone. Int J Immunopathol Pharmacol 2013;26:861-869. 
  18. Floettmann JE, Buckett LK, Turnbull AV, et al. ACAT-selective and nonselective DGAT1 inhibition: adrenocortical effects--a cross-species comparison. Toxicol Pathol 2013;41:941-950. 3
  19. Frank CB, Valentin SY, Scott-Moncrieff JC, et al. Correlation of inflammation with adrenocortical atrophy in canine adrenalitis. J Comp Pathol 2013;149:268-279. 
  20. Frank LA, Watson JB. Treatment of alopecia X with medroxyprogesterone acetate. Veterinary Dermatology 2013;24:624-e154. 
  21. Gostelow R, Bridger N, Syme HM. Plasma-free metanephrine and free normetanephrine measurement for the diagnosis of pheochromocytoma in dogs. J Vet Intern Med 2013;27:83-90. 
  22. Green BA, Frank EL. Comparison of plasma free metanephrines between healthy dogs and 3 dogs with pheochromocytoma. Vet Clin Pathol 2013;42:499-503. 
  23. Griffies JD. Old or new? A comparison of mitotane and trilostane for the management of hyperadrenocorticism. Compend Contin Educ Vet 2013;35:E3. 
  24. Haers H, Daminet S, Smets PM, et al. Use of quantitative contrast-enhanced ultrasonography to detect diffuse renal changes in Beagles with iatrogenic hypercortisolism. Am J Vet Res 2013;74:70-77. 
  25. Hardcastle MR, Meyer J, McSporran KD. Pathology in practice. Carotid and aortic body carcinomas (chemodectomas) in a dog. J Am Vet Med Assoc 2013;242:175-177. 
  26. Huang HP, Lien YH. Treatment of canine generalized demodicosis associated with hyperadrenocorticism with spot-on moxidectin and imidacloprid. Acta Vet Scand 2013;55:40. 
  27. Ilha MR, Styer EL. Extra-adrenal retroperitoneal paraganglioma in a dog. J Vet Diagn Invest 2013;25:803-806. 
  28. Ishibashi M, Akiyoshi H, Iseri T, et al. Skin conductance reflects drug-induced changes in blood levels of cortisol, adrenaline and noradrenaline in dogs. J Vet Med Sci 2013;75:809-813. 
  29. Kemppainen RJ. Inoculation of dogs with a recombinant ACTH vaccine. Am J Vet Res 2013;74:1499-1505. 
  30. Kol A, Nelson RW, Gosselin RC, et al. Characterization of thrombelastography over time in dogs with hyperadrenocorticism. Vet J 2013;197:675-681. 
  31. Kool MM, Galac S, Kooistra HS, et al. Expression of angiogenesis-related genes in canine cortisol-secreting adrenocortical tumors. Domest Anim Endocrinol 2013. 
  32. Kool MM, Galac S, Spandauw CG, et al. Activating mutations of GNAS in canine cortisol-secreting adrenocortical tumors. J Vet Intern Med 2013;27:1486-1492. 
  33. Larson RN, Schmiedt CW, Wang A, et al. Adrenal gland function in a dog following unilateral complete adrenalectomy and contralateral partial adrenalectomy. J Am Vet Med Assoc 2013;242:1398-1404. 
  34. Lee HC, Jung DI, Moon JH, et al. Clinical characteristics and outcomes of primary adrenal hemangioma in a dog. Res Vet Sci 2013;95:572-575. 
  35. Mak G, Allen J. Simultaneous pheochromocytoma and third-degree atrioventricular block in 2 dogs. J Vet Emerg Crit Care (San Antonio) 2013;23:610-614. 
  36. Massey J, Boag A, Short AD, et al. MHC class II association study in eight breeds of dog with hypoadrenocorticism. Immunogenetics 2013;65:291-297. 
  37. McGonigle KM, Randolph JF, Center SA, et al. Mineralocorticoid before glucocorticoid deficiency in a dog with primary hypoadrenocorticism and hypothyroidism. J Am Anim Hosp Assoc 2013;49:54-57. 
  38. Mochel JP, Fink M, Peyrou M, et al. Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology. Chronobiol Int 2013;30:1144-1159. 
  39. Mochel JP, Peyrou M, Fink M, et al. Capturing the dynamics of systemic renin-angiotensin-aldosterone system (RAAS) peptides heightens the understanding of the effect of benazepril in dogs. J Vet Pharmacol Ther 2013;36:174-180. 
  40. Mongillo P, Prana E, Gabai G, et al. Effect of age and sex on plasma cortisol and dehydroepiandrosterone concentrations in the dog (Canis familiaris). Res Vet Sci 2014;96:33-38.
  41. Naan EC, Kirpensteijn J, Dupre GP, et al. Innovative approach to laparoscopic adrenalectomy for treatment of unilateral adrenal gland tumors in dogs. Veterinary Surgery 2013;42:710-715. 
  42. Ouschan C, Kuchar A, Mostl E. Measurement of cortisol in dog hair: a noninvasive tool for the diagnosis of hypercortisolism. Vet Derm 2013;24:428-431, e493-424. 
  43. Pace SL, Creevy KE, Krimer PM, et al. Assessment of coagulation and potential biochemical markers for hypercoagulability in canine hyperadrenocorticism. J Vet Intern Med 2013;27:1113-1120. 
  44. Park FM, Blois SL, Abrams-Ogg AC, et al. Hypercoagulability and ACTH-dependent hyperadrenocorticism in dogs. J Vet Intern Med 2013;27:1136-1142. 
  45. Perego R, Proverbio D, Spada E. Increases in heart rate and serum cortisol concentrations in healthy dogs are positively correlated with an indoor waiting-room environment. Vet Clin Pathol 2014;43:67-71. 
  46. Pey P, Daminet S, Smets PM, et al. Contrast-enhanced ultrasonographic evaluation of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 2013;74:417-425. 
  47. Romao FG, Campos EF, Mattoso CR, et al. Hemostatic profile and thromboembolic risk in healthy dogs treated with prednisone: a randomized controlled trial. BMC Vet Res 2013;9:268. 
  48. Rose L, Dunn ME, Bedard C. Effect of canine hyperadrenocorticism on coagulation parameters. J Vet Intern Med 2013;27:207-211. 
  49. Shiverdecker MD, Schiml PA, Hennessy MB. Human interaction moderates plasma cortisol and behavioral responses of dogs to shelter housing. Physiol Behav 2013;109:75-79. 
  50. Short AD, Boag A, Catchpole B, et al. A candidate gene analysis of canine hypoadrenocorticism in 3 dog breeds. J Hered 2013;104:807-820. 
  51. Siniscalchi M, McFarlane JR, Kauter KG, et al. Cortisol levels in hair reflect behavioural reactivity of dogs to acoustic stimuli. Res Vet Sci 2013;94:49-54. 
  52. Stuckey JA, Pearce JW, Giuliano EA, et al. Long-term outcome of sudden acquired retinal degeneration syndrome in dogs. J Am Vet Med Assoc 2013;243:1425-1431. 
  53. Winnick JJ, Ramnanan CJ, Saraswathi V, et al. Effects of 11-beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis. Am J Physiol Endocrinol Metab 2013;304:E747-756. 
  54. Yu J, Fu X, Chang M, et al. The effects of intra-abdominal hypertension on the secretory function of canine adrenal glands. PLoS One 2013;8:e81795. 
  55. Zeugswetter FK, Neffe F, Schwendenwein I, et al. Configuration of antibodies for assay of urinary cortisol in dogs influences analytic specificity. Domest Anim Endocrinol 2013;45:98-104.

Wednesday, July 30, 2014

Top 10 Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Adrenal 3


Below is the next installment of our review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum. As with all of these ACVIM research abstract reviews, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine.

In this post, we will review another of these "top 12" abstracts in our adrenal gland selections.


Midence JN, Drobatz KJ, Hess RS. Low Cortisol Concentrations in Well-Regulated Trilostane-Treated Dogs with Hyperadrenocorticism. J Vet Intern Med 2014;28:1032-1033.

     Currently there are no clear treatment guidelines for dogs with clinically well-regulated hyperadrenocorticism in which cortisol concentration before and after ACTH stimulation test performed 3–6 hours after trilostane (Vetoryl) administration is < 2.0 μg/dL. The goal of this study was to determine if an ACTH stimulation test performed 9–12 hours after trilostane administration may clarify treatment guidelines. 
     Ten client-owned dogs were enrolled into this ongoing prospective study if they had clinically well-regulated hyperadrenocorticism and had serum cortisol concentrations < 2.0 μg/dL before (Pre1) and after (Post1) ACTH stimulation performed 3–6 hours following trilostane administration. Dogs then had a second ACTH stimulation test (Pre2 and Post2) performed 9–12 hours after trilostane administration, on the same day they had the first ACTH stimulation test. 
     Mean (± standard deviation) pre- and post-ACTH stimulation cortisol concentrations were compared using a paired t-test. Mean Pre1 and mean Post1 cortisol concentrations (1.23 ± 0.35 μg/dL and 1.35 ± 0.27 μg/dL, respectively) were significantly lower than mean Pre2 cortisol concentration (2.74 ± 1.18 μg/dL, p = 0.002 each). Mean Post1 cortisol concentration was also significantly lower than mean Post2 cortisol concentration (4.62 ± 2.07 μg/dL, p = 0.006). 
     These results suggest that in dogs with clinically well-regulated, trilostane treated, hyperadrenocorticism, in which Pre1 and Post1 cortisol concentrations are < 2 μg/dL, a second ACTH stimulation test performed 9–12 hours after treatment may result in significantly higher cortisol concentrations that could support continued trilostane treatment.

Comments— First of all, we were somewhat surprised by the first sentence (introduction) of this abstract stating that there are no clear treatment guidelines for dogs with clinically well-regulated hyperadrenocorticism, in which serum cortisol concentrations before and after ACTH stimulation test performed 3–6 hours after trilostane administration are < 2.0 μg/dL. We thought that that the current recommendations about what action steps to take in such a scenario were already fairly clear (1-5).

For example, in a 2010 chapter on hyperadrenocorticism in dogs published in Ettinger and Feldman's Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (2), this issue is addressed rather specifically:
If a dog on SID or BID trilostane is doing clinically well but the serum cortisol values are low (post-ACTH cortisol less than 2 µg/dL), we recommend that one stop the trilostane for 5-7 days and restart treatment at a 25-50% lower dose. Then one should retest after 2 weeks of treatment with the lower dose. If the serum cortisol values remain subnormal on the reduced dosage, the trilostane should be discontinued indefinitely, with repeat ACTH stimulation testing scheduled for 1 month and every 3-6 months thereafter. The trilostane should only be restarted in these dogs if clinical signs of hyperadrenocorticism return and the post-ACTH cortisol becomes high once again.
Even in the Vetoryl product drug insert (1), in which the desired cortisol ranges are wider than what we recommend, it states the following:
If the ACTH stimulation test is < 1.45 µg/dL (< 40 nmol/L) and/or if electrolyte imbalances characteristic of hypoadrenocorticism (hyperkalemia and hyponatremia) are found, Vetoryl capsules should be temporarily discontinued until recurrence of clinical signs consistent with hyperadrenocorticism and test results return to normal (1.45-9.1 µg/dL or 40-250 nmol/L). Vetoryl capsules may then be re-introduced at a lower dose.
So, at least in our opinion, we have pretty clear monitoring guidelines for what to do when post-ACTH cortisol concentrations are low— we should temporary stop the trilostane completely for 5-7 days, then restart treatment at a 25-50% lower dose (if doing well), and finally, repeat the ACTH stimulation test in 2 weeks. Or we can be more cautious and completely stop and withhold the drug until we prove that cortisol concentrations recover (1-5).

The fact that the low serum cortisol values in the dogs of this study were higher when tested later in the day is not surprising, and indeed is exactly what you might expect in a dog with no clinical signs of hypoadrenocorticism. In healthy dogs, trilostane reaches peak concentrations at 1.5-2 hours and concentrations return to baseline levels after 10-18 hours (1-4). The duration of cortisol suppression appears to vary substantially between dogs with hyperadrenocorticism; however, cortisol concentrations generally remain suppressed for less than 13 hours, which explains the higher cortisol values when tested later in the day.

Yes, we all know that some dogs do very well with low cortisol concentrations at peak trilostane action, but I believe that this could be dangerous. Once a dog is on trilostane, we should worry about safety first and efficacy second. We know that the lower serum cortisol values in these dogs, the greater the chance of hypoadrenocorticism and possibly the greater risk for adrenal necrosis (2-4). If a dog is doing well and basal and post-ACTH cortisol values are < 2 µg/dL, this is too close for comfort, at least if one of our safety goals is to prevent the development of iatrogenic hypoadrenocorticism.  In addition, we also know that many dogs treated with trlostane will have a slow decrease in adrenal reserve over time, necessitating a gradual reduction in the daily trilostane dose over time. 

Bottom Line— In dogs that develop low cortisol levels on trilostane, the safest action to take is to lower the daily dose, or, if on once daily treatment (as the dogs of this study), divide the total daily dose into BID administration. We do not know what doses were used in the dogs of this study by Midence et al, but we do know that using lower dosages of trilostane and maintaining cortisol values within a more normal range will help prevent hypocortisolism and hopefully will greatly reduce the change of acute adrenal necrosis (8).  

References:
  1. Dechra website. Veteryl product insert.
  2. 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 Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
  3. Ramsey IK. Trilostane in dogs. Vet Clin North Am Small Anim Pract 2010;40:269-283.
  4. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:167-189.
  5. Griffies JD. Old or new? A comparison of mitotane and trilostane for the management of hyperadrenocorticism. Compend Contin Educ Vet 2013;35:E3.
  6. Feldman EC. Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2011;238:1441-1451.
  7. Arenas C, Melian C, Perez-Alenza MD. Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism: twice daily versus once daily. J Vet Intern Med 2013;27:1478-1485.
  8. Reusch CE, Sieber-Ruckstuhl N, Wenger M, et al. Histological evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane. Vet Rec 2007;160:219-224.


Saturday, July 26, 2014

Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Adrenal Part 2



Below is the next installment of my review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum. As with all of these ACVIM research abstract reviews, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine.

In this post, we will review another of these "top 12" abstracts in our adrenal gland selections.


Aldridge C, Behrend E, Kemppainen R, Lee-Fowler T, L. Martin L, Ward C. Comparison of Two Doses for ACTH Stimulation Testing in Dogs Suspected of or Treated for Hyperadrenocorticism. J Vet Intern Med 2014;28:1025.

     The ACTH stimulation test, using cosyntropin at 5 mcg/kg IV, is the preferred method for monitoring medical management of hyperadrenocorticism (HAC) and is a screening test for diagnosing HAC. Previous studies have shown maximal stimulation of the adrenal glands using 1 mcg/kg cosyntropin in normal dogs. No studies have evaluated the efficacy of the lower dose in dogs suspected of or being treated for HAC. Our objective was to compare 1 mcg/kg to 5 mcg/kg cosyntropin IV to determine if both doses result in a similar adrenocortical response. 
     Testing was prospectively performed in dogs suspected of and being treated for pituitary- dependent HAC (PDH) with mitotane or trilostane. Dogs suspected of having HAC or being treated with mitotane received 1 mcg/kg cosyntropin IV followed four hours later by 5 mcg/kg cosyntropin IV. Blood samples were obtained pre- and one hour post-ACTH for each dose (4 measurements total). Preliminary studies were conducted to confirm the validity of performing two ACTH stimulation tests using this timing on the same day. Dogs receiving trilostane therapy were tested on consecutive days at the same time post-pill (4–6 hours post). Cortisol was measured using a previously validated radioimmunoassay. To detect differences in cortisol concentration between cosyntropin doses (1 and 5 mcg/kg) and between time points (baseline and 60-min), data were analyzed using a repeated-measures ANOVA by a commercial statistical computer program. Data for each group of dogs (suspect HAC, mitotane-treated and trilostane-treated) were evaluated separately. Significance was set at the p ≤ 0.05 level. 
     Overall, 46 dogs were included, with 26 suspected of HAC, 12 being treated for PDH with mitotane and 8 being treated for PDH with trilostane. No significant difference was detected between the post-ACTH cortisol concentrations within each group, comparing responses to both doses. For the suspect dogs and dogs treated with mitotane, the pre- and post-ACTH cortisol concentrations were significantly different with both doses (p < 0.001 and p = 0.001 respectively). For dogs treated with trilostane, no difference was detected between pre-ACTH and post-ACTH cortisol concentrations for either dose. 
    Therefore, the 1 mcg/kg IV dose of cosyntropin causes maximal adrenal response as does the standard 5 mcg/kg IV dose. The lower dose is sufficient for ACTH stimulation testing in those patients suspected of HAC or diagnosed with PDH and being treated with mitotane or trilostane. A lower dose of Cortrosyn may be used to help lower cost of diagnosing and monitoring this disease.

Comments—In the past, one of the most commonly used ACTH preparations for adrenal function testing was ACTH gel, in which ACTH is extracted from bovine and porcine pituitary glands. In the USA, the only FDA-approved, brand-name ACTH gel preparation is H.P. Acthar gel Repository Injection (80 U/ml; Questor Pharmaceuticals) (1). This ACTH preparation was widely used in veterinary medicine until 2007, when Questor Pharmaceuticals announced a new "pricing mode" for the H.P. Acthar gel (2), effectively raising the price of a vial almost 100-fold!

Due to the high cost of this brand-name gel ACTH, compounding pharmacies responded by offering compounded forms of ACTH gel. However, studies have shown that such preparations have variable potency and may be unreliable (3). Therefore, cosyntropin (e.g., Cortrosyn), a pure synthetic form of ACTH, has become the recommended product to use when performing an ACTH stimulation test (3-5). Cosyntropin has many advantages over ACTH gel preparations, including the following:
  1. Cosyntropin can be administered intravenously (important in the dehydrated dog with suspected Addison's disease), as well as intramuscularly. All forms of ACTH gel must be given by the IM route.
  2. Cosyntropin requires less time for the completion of the test than does ACTH gel (1 hour versus 2 hours), which makes monitoring more convenient.
  3. The serum cortisol response to cosyntropin administration is more consistent than ACTH gel.
  4. Finally, variations in potency is not an issue with cosyntropin, since it is a pure synthetic product, not extracted from pituitary glands like ACTH gel.
The use of synthetic ACTH in dogs was first reported in the 1970’s using a total dose of 250 µg per dog (4,5); this dose was equivalent to that recommended for testing in humans (6). Interestingly, no justification was given for the choice of 250 µg in people other than the notation that it was clearly "more than enough" required to produce a maximal adrenal response (6).

The practice of using 250 µg (the entire vial of cosyntropin) for the ACTH stimulation test in dogs persisted until the late 1990’s, when it was determined that a dose of 5 µg/kg of cosyntropin (i.e., Cortrosyn) resulted in maximal stimulation of the adrenal cortex in clinically normal dogs and dogs with hyperadrenocorticism (7,8). This new,” low-dose” ACTH response test using the 5 µg/kg dose of cosyntropin was quickly and widely adopted as the ACTH-testing protocol of choice, primarily because of cost-saving considerations (9).

It's important to note that accurate administration of such low doses of cosyntropin required dilution of the product with saline, and stability studies have only been reported for brand-name Cortrosyn, made by Amphastar Phamaceuticals (10) and generally available only in the USA. The effects of dilution or storage of other commercially available cosyntropin products have not been reported; this includes both the generic cosyntropin preparation made by Sandoz (11) in the USA or the brand-name product tetacosactide or Synacthen Ampoules (12) available in most countries outside of the USA.

The Bottom Line— In this abstract, the “mini-dose” of 1 µg/kg of cosyntropin could be a welcome alternative to the low-dose (5 µg/kg) and high-dose (250 µg/dog) ACTH stimulation test protocols for several reasons. There is valid concern that the escalating cost of cosyntropin may deter some practicing veterinarians from using the ACTH stimulation test to screen animals with suspected adrenocortical disease (i.e., hyper- and hypoadrenocorticism). Even more importantly, the high cost may prevent or alter the frequency of monitoring dogs treated with trilostane or mitotane. Other veterinarians continue to use the lower-cost compounded ACTH gels, despite their variable potency and known unreliability (3). In other words, if higher costs associated with performing the ACTH response test present a financial obstacle to the veterinarian or the pet owner, the ramifications of under-diagnosis and case mismanagement could be serious for dogs afflicted with these potentially fatal adrenocortical disorders.

Obviously, use of the 1 µg/kg mini-dose protocol allows for the testing of many more dogs compared to the 5 µg/kg protocol and especially the 250 µg/dog protocol. This would result in substantial savings for veterinary practices that adopt this mini-dose protocol. However, there are certain guidelines that should be followed when using the mini-dose cosyntropin protocol to ensure accurate results.
  1. First, the 1 µg/kg dose should only be administered IV, as done in this abstract, since the cosyntropin may not be completely absorbed into the circulation when given by the intramuscular route. For the larger doses, such incomplete absorption is not a problem but IM administration of these mini-doses might not result in high enough circulating ACTH concentrations to maximally stimulate the adrenal cortex.
  2. Secondly, the post-ACTH blood sample for cortisol determination should be obtained as close to 1 hour as possible after administration of cosyntropin. A delay in serum sample collection could miss the peak of maximum cortisol stimulation and result in lower-than-maximum peak concentrations (7). Again, this is less of a problem when higher doses of cosyntropin are given, since the higher doses results in a more prolonged adrenocortical stimulation,
  3. Thirdly, but not least, we must store the reconstituted cosyntropin for periods of weeks to months to allow for its use at a later date when needed.  Once reconstituted with saline, the synthetic ACTH is stable in plastic syringes or vial for up to 4 months at 4 C (13), or it can be stored in frozen syringes at -20 C (or colder) for up to 6 months with no loss of bioactivity (7-9,13). Being able to store unused cosyntropin for extended periods is another way veterinarians can use the entire contents of each vial without waste.  
  4. When aliquoting and freezing diluted cosyntropin, however, it is imperative for the ACTH be stored properly; if this "mini-dose" degrades even a bit, that might lead to an inadequate cortisol response. Use of a regular "household" frostless freezer should never be used to freeze these ACTH aliquoted vials or syringes.  These frostless freezers undergo periodic thawing and refreezing, which leads to degradation of the ACTH molecule. A dedicated freezer that does not undergo such thaw freeze cycles must be used if we decide to store the diluted cosyntropin in this way.
In the end, however, we must ask one simple question: Will the average veterinary practice perform enough ACTH stimulation tests to make a difference if the 1 µg/kg mini-dose protocol is chosen over the now standard 5 µg/kg protocol? If not, then why use the lower dose, given the potential disadvantages? With the higher 5 µg/kg protocol, we have a bit more leeway with sampling times and can get by with some loss of potency of the cosyntropin.

Because of these issues, most veterinarians will likely still be better off using the "old" 5 µg/kg rather than this "new" 1 µg/kg protocol. As we know, sometimes being "new" does not necessarily make it better!

References:
  1. H.P. Acthar Gel, Repository Corticotropin Injection, package insert. Questcor, Union City, CA. Available at: http://www.acthar.com/Pdf/Acthar_PI_pdf
  2. Questcor Board approves new strategy and business model for H.P. Acthar Gel. Union City, CA: Questcor; August 2007. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=89528&p=irol-newsArticle&ID=1044912&highlight
  3. Kemppainen RJ, Behrend EN, Busch, KA. Use of compounded ACTH for adrenofunction testing in dogs. J Am Anim Hosp Assoc 2005;41:368-372. http://www.jaaha.org/content/41/6/368.abstract
  4. Campbell JR, Watts C. Assessment of adrenal function in dogs. Br Vet J 1973;129:134-145. 
  5. Feldman EC, Tyrrell JB., Bohannon NV. The synthetic ACTH stimulation test and measurement of endogenous plasma ACTH levels: useful diagnostic indicators for adrenal disease in dogs. J Am Anim Hosp Assoc 1978;14:524-531
  6. Wood JB, Frankland AW, James VH, et al. A rapid test of adrenocortical function. Lancet 1965: 30;243-245. 
  7. Kerl ME, Peterson ME, Wallace MS, et al. Evaluation of a low-dose ACTH stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism. J Am Vet Med Assoc 1999;214:1497-1501. 
  8. Frank LA, Oliver JW. Comparison of serum cortisol concentrations in clinically normal dogs after administration of freshly reconstituted versus reconstituted and stored frozen cosyntropin. J Vet Med Assoc 1998;212:1569-1571. 
  9. Peterson ME: Containing the cost of the ACTH-stimulation test. J Am Vet Med Assoc 2004;224:198-199.
  10. Cortrosyn package insert. Amphastar Phamaceuticals Inc, Rancho Cucamonga, CA. Available at: http://www.pharmacistconnection.com/images/ch/cortrosyn_111909/printable.pdf
  11. Cosyntropin Injection (Generic) package insert. Sandoz, Princeton, NJ. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022028lbl.pdf
  12. Synacthen Ampoules, Produce information. Available at : https://www.medicines.org.uk/emc/medicine/7621
  13. Dickstein G, Shechner C, Nicholson WE, et al.Adrenocorticotropin stimulation test: Effect of basal cortisol level, time of day, and suggest new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773-778.  

Friday, July 18, 2014

Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Adrenal Part 1


Below is the next installment of my review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum.

As with all of these ACVIM research abstract reviews, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.

In this post, we will review another of these "top 12" abstracts (starting with the adrenal gland abstracts). Next week, we will finish up the top clinical abstracts dealing with the adrenal gland, and then go on to disorders of the thyroid over the next 2 weeks.


Schrage A, Appleman E, Langston C. Iatrogenic Hypoadrenocorticism Following Trilostane Therapy for Pituitary-Dependent Hyperadrenocorticism in Dogs. J Vet Intern Med 2014;28:1035.

     This retrospective case series identified 13 dogs that developed iatrogenic hypoadrenocorticism (iHAC) following administration of trilostane for treatment of pituitary-dependent hyperadrenocorticism (PDH). Inclusion criteria required a previous diagnosis of PDH, monotherapy with trilostane (i.e., no other medications used for treatment of PDH), and a post- ACTH stimulated cortisol concentration of < 1 μg/dL while receiving trilostane. 
     Clinical signs of PDH resolved in 92% (12/13) of dogs prior to development of iHAC. At the time of diagnosis, 7/13 (53%) dogs had clinical signs consistent with iHAC. Lethargy and inappetence were the most common signs. Median age of dogs was 12 years with a median weight of 10 kilograms. No single breed was overrepresented. Dogs were treated with trilostane for a median of 8.5 months at a median dosage of 4.75 mg/kg/day prior to development of iHAC. Mineralocorticoid deficiency (hyperkalemia ± hyponatremia) was identified in 3/13 (23%) dogs. Trilostane was discontinued in all 7 dogs displaying clinical signs and later restarted at a lower dose in 2 dogs. Permanent hypoadrenocorticism developed in 4 dogs. No dog died or was euthanized as a result of iHAC. 
     This report illustrates that, while trilostane is an effective treatment for PDH, transient or permanent iatrogenic hypoadrenocorticism may occur. Development of mineralocorticoid deficiency is less common in comparison to glucocorticoid deficiency. These dogs were being closely evaluated and had received manufacturer-recommended doses of trilostane prior to development of iHAC. Close monitoring of dogs on trilostane therapy is warranted, with special emphasis on clinical signs, electrolyte levels, and cortisol concentrations.

Comments— This report emphasizes that trilostane (Vetoryl) is not a benign drug. Although safer to use than mitotane, trilostane can certainly result in hypoadrenocorticism (cortisol deficiency) and even complete hypoadrenocorticism (cortisol and mineralocorticoid deficiency; Addison's disease) (1-8). Therefore, it is imperative to use the lowest daily dose possible and to monitor the dog very closely while on treatment with this drug.

The median dose used in the dogs of this retrospective study (4.75 mg/kg/day) was indeed within the dosage recommended on the Vetoryl package insert (2.2-6.7 mg/kg/ day) (9). However, that dose is much higher than the starting dose we normally recommend (≈2 mg/kg/day) (10). The higher doses given to the dogs of this report was the likely reason for the very high rate of hypocortisolism (53% of dogs), as well as the high rate of concurrent mineralocorticoid deficiency seen in these dogs (23% of dogs). Over the years, we have learned that lower starting doses are generally much safer and result in fewer severe side effects (11-15), and we have not personally had a dog develop complete hypoadrenocorticism for the last decade. Such high rates of hypoadrenocorticism generally indicate drug overdosage and are not acceptable, at least in our opinion.

We do not know from this abstract what initial dose was given, when the dogs were rechecked, or exactly how the investigators decided that a dosage increase was indicated. We recommend that dogs on trilostane treatment should be evaluated at 14 days, 1 month, 3 months, and every 3 months thereafter (10). At each recheck, we collect a complete history, do a complete examination, and perform a serum biochemical panel with electrolytes. In addition, we do an ACTH stimulation test at each visit by collecting the basal cortisol sample and administering cosyntropin (Cortrosyn) ≈3-4 hours after the morning trilostane dose to evaluate the peak effect on lowering cortisol levels.

We base dose adjustments on the dog's clinical response, routine blood tests, and cortisol testing. The ideal post-ACTH cortisol range that we recommend is 2.0-7.5 µg/dl (50-200 nmol/L). If`a dog continues to show clinical signs of hyperadrenocorticism and post-ACTH cortisol is above 7.5 µg/dl, we then increase the trilostane dose. If the signs of hyperadrenocorticism have resolved but the post-ACTH cortisol is above 7.5 µg/dl, we generally do not raise the daily dose but we would closely monitor for signs consistent with relapse.

If a Cushing's dog on trilostane is doing clinically well, but the serum cortisol values are low (post-ACTH cortisol less than 2 µg/dl [50 nmol/L]), we recommend that one stop the trilostane for 5-7 days and restart treatment at a 25-50% lower dose. Then, one should retest after 2 weeks of treatment on the new, lower dose. If the serum cortisol values remain subnormal on the reduced dosage, the trilostane should be discontinued indefinitely, with repeat ACTH stimulation testing scheduled for 1 month and every 3-6 months thereafter. The trilostane should only be restarted in these dogs if clinical signs of hyperadrenocorticism return and the post-ACTH cortisol concentrations once again become high. If Addison’s disease is confirmed (i.e., low cortisol concentrations with hyperkalemia, hyponatremia, or both), one should discontinue trilostane and treat the dog with glucocorticoids and mineralocorticoids, as needed.

Bottom line— The introduction of trilostane in many countries around the world has increased the options for the management of canine Cushing's disease. For most veterinarians, this drug has replaced the use of mitotane due to its greater safety. It is nearly as effective as mitotane and has a lower frequency of serious adverse reactions (15,16).

That all said, the drug can certainly lead to adverse side effects, including hypoadrenocorticism and adrenal necrosis (1-10). All of the side effects appear to be at least partially related to the dose given, so we recommend lower initial doses, close and frequent monitoring, and gradual increases in the daily dose as needed for control of clinical and biochemical signs of hyperadrenocorticism.

References:
  1. Neiger R, Ramsey I, O'Connor J, et al. Trilostane treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. Vet Rec 2002;150:799-804. 
  2. Braddock JA, Church DB, Robertson ID, et al. Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism. Aust Vet J 2003;81:600-607.
  3. Wenger M, Sieber-Ruckstuhl NS, Muller C, et al. Effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 2004;65:1245-1250. h
  4. Chapman PS, Kelly DF, Archer J, et al. Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism. J Small Anim Pract 2004;45:307-310. 
  5. Reusch CE, Sieber-Ruckstuhl N, Wenger M, et al. Histological evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane. Vet Rec 2007;160:219-224.
  6. Ramsey IK, Richardson J, Lenard Z, et al. Persistent isolated hypocortisolism following brief treatment with trilostane. Aust Vet J 2008;86:491-495. 
  7. Richartz J, Neiger R. Hypoadrenocorticism without classic electrolyte abnormalities in seven dogs. Tierarztliche Praxis Ausgabe K, Kleintiere/Heimtiere 2011;39:163-169. 
  8. Griebsch C, Lehnert C, Williams GJ, et al. Effect of trilostane on hormone and serum electrolyte concentrations in dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2014;28:160-165. 
  9. Dechra Animal Heath website. Veteryl Product Insert
  10. 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 Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
  11. Vaughan MA, Feldman EC, Hoar BR, et al. Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2008;232:1321-1328. 
  12. Arenas C, Melian C, Perez-Alenza MD. Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism: twice daily versus once daily. J Vet Intern Med 2013;27:1478-1485. 
  13. Braun C, Boretti FS, Reusch CE, et al. Comparison of two treatment regimens with trilostane in dogs with pituitary-dependent hyperadrenocorticism. Schweiz Arch Tierheilkd 2013;155:551-558. 
  14. Feldman EC. Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2011;238:1441-1451. 
  15. Clemente M1, De Andrés PJ, Arenas C, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Vet Rec 2007;15;161:805-809.
  16. Griffies JD. Old or new? A comparison of mitotane and trilostane for the management of hyperadrenocorticism. Compend Contin Educ Vet 2013;35:E3. 


Kool MMJ, Galac S, van der Helm N, Corradini S, Kooistram HS, Mol JA. Targeting Phosphatidylinositol-3-Kinase Signaling in Canine Cortisol-Secreting Adrenocortical Tumors - Novel Therapeutic Prospects? J Vet Intern Med 2014;28:1030.

     Hypercortisolism is one of the most common endocrinopathies in dogs, and is caused by cortisol- secreting adrenocortical adenomas or carcinomas in 15% of cases. The aim of this study was to investigate involvement of the insulin-like growth factor (IGF)-phosphatidylinositol-3-kinase (PI3K) signaling pathway in the pathogenesis of adrenocortical tumors (ATs), in order to identify components of this pathway that may hold promise as future therapeutic targets, prognostic and/or diagnostic markers.
     The tumor group consisted of histologically confirmed cortisol-secreting adenomas (n = 14) and carcinomas (n = 30). Whole tissue explants of normal adrenal glands (n = 10) were used as controls. Quantitative RT-PCR was used to assess the relative mRNA expression levels of IGF1 and 2, IGF- and EGF-receptors, IGF-binding proteins, PI3K inhibitor PTEN and downstream target genes of the PI3K signaling pathway. Localization of PTEN was immunohistochemically evaluated. Additionally, mutation analysis was performed on the full coding region of PTEN and the PI3K catalytic subunit, on mRNA level.
     When compared to normal adrenals, in carcinomas the differential expression of PI3K target genes indicated activation of the pathway. Also, carcinomas showed a decreased expression of PI3K inhibitor PTEN and an increased expression of the EGF receptor ErbB2. Gene expression levels in adenomas were mostly unchanged. Immunohistochemical staining of PTEN was predominantly negative in both ATs and normal adrenals. No missense mutations of PTEN and the PI3K catalytic subunit were detected.
     Based on gene function and reports in human ATs, the low expression of PTEN in carcinomas is of particular interest with regard to tumor pathogenesis. Target gene expression suggests PI3K activation in carcinomas, possibly due to decreased PTEN and/or increased ErbB2 expression. Based on these results, targeting of ErbB2, PI3K or its downstream effectors may have potential as a therapeutic option in canine cortisol-secreting adrenocortical carcinomas.

Comments—To adequately understand the importance of this investigational study the molecular biology of PI3Ks, PTEN, IGF-1 and IGF-2, IGF- and EGF- receptors and IGF- binding proteins and their link to adrenocortical tumors is briefly reviewed.

Phosphoinositide 3-kinases (also called PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, and survival (1). More specifically, PI3Ks phosphorylate cell membrane lipids to modulate the activity of intracellular protein effectors that regulate many aspects of cell function. For example, it is estimated that every cell has 50-100 “downstream” effectors of PI3Ks. In essence, the PI3K pathway is an intracellular signaling pathway important in apoptosis and hence cancer and longevity. In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. Consequently, many experimental cancer drugs are designed to inhibit the signaling sequence at some point using PI3K inhibitors. Impact point: Expression of target genes suggests activation of the PI3K pathway in adrenocortical tumors.

Phosphatase and tensin homolog (PTEN) is a protein that, in humans, is encoded by the PTEN gene (2). PTEN acts as a tumor suppressor gene but is mutated in a large number of cancers with high frequency (3). When the PTEN protein is functioning properly, it acts as part of a chemical pathway that signals cells to stop dividing and can cause cells to undergo apoptosis when necessary. These functions prevent uncontrolled cell growth that can lead to the formation of tumors. Impact point: The low expression of PTEN and negative immunohistochemical staining with adrenocortical tumors suggests that lack of this PI3K inhibitor may play a role in tumor pathogenesis.

Epidermal growth factor or EGF is a growth factor that stimulates cell growth, proliferation, and differentiation by binding to its receptor EGFR (4). The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases (ErbB1-4); receptor tyrosine kinases are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones (5). Increased activity of the receptor for EGF has been observed in certain types of cancer, often correlated with mutations in the receptor and abnormal function (8). Impact point: Adrenocortical tumors showed an increased expression of the ECG receptor ErbB-2.

Insulin-like growth factors (IGFs) are proteins with an amino acid sequence similar to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF "axis") consists of two cell-surface receptors (IGF1R and IGF2R), two ligands - insulin-like growth factor 1 (IGF-I) and insulin-like growth factor 2 (IGF-2), and a family of six high-affinity IGF-binding proteins which modulate IGF action in many ways (6). The IGF axis has been shown to play a key role in cancer cell proliferation, differentiation, and the inhibition of programmed cell death (apoptosis) using intracellular signaling through the PI3K pathway (see below). Impact point: Unlike in humans and for reasons that are unclear (see Bottom Line summary), the IGFs and IGF receptors apparently do not play a role in the pathogenesis of adrenocortical tumors in the dog.

The Bottom Line— To date, the most common treatment approach in dogs with an cortisol-secreting adrenal tumor is surgery and/or medical therapy with mitotane or trilostane (7-12). In human medicine, several novel approaches are under study for treatment of advanced adrenal carcinoma, many of which represent molecularly targeted therapies. For example, the finding that over 80% of adrenal tumors express the epidermal growth factor receptor (EGFR) (13, 14) provides a rationale for the study of agents that target the EGFR. In addition, approximately 80% of adrenocortical tumors also over express insulin-like growth factor type 2 (IGF-2), which is known to signal predominantly through the IGF-1 receptor (IGFR1).

Preclinical studies targeting the IGF-1 receptor (15) and two phase I trials have shown promising results (16, 17), and ongoing phase II and III trials are close to completion. The recent work by Kool et al in dogs, would suggest that targeting a specific EGFR (i.e., ErbB2) or PK3K or its downstream effectors may have potential as a therapeutic option in canine cortisol-secreting adrenal tumors. Clearly more investigational studies are needed to determine the efficacy, adverse effects, and cost of molecular targeting therapy before it becomes an accepted form of treatment for adrenocortical tumors in the dog.

References:
  1. Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signaling: the path to discovery and understanding. Nat Rev Mol Cell Biol 2012;13:195-203.
  2. Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate for a tumor suppressor gene that is mutated in multiple advanced cancers. Nat Genet 1997;15: 356–62.
  3. Chu EC, Tarnawski AS. PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit 2004; 10:235–41.
  4. Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 2004;59 (2 Suppl): 21–26.
  5. Zhang H, Berezov A, Wang Q, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest 2007;117:2051–2058.
  6. Le Roith D. Insulin-like growth factors. N Engl J Med 1997; 336; 633-640.
  7. van Sluijs FJ1, Sjollema BE, Voorhout G, et al. Results of adrenalectomy in 36 dogs with hyperadrenocorticism caused by adrenocortical tumor. Vet Q 1995;17:113-116.
  8. Anderson CR, Birchard SJ, Powers BE, et al. Surgical treatment of adrenocortical tumors: 21 cases (1990-1996). J Am Anim Hosp Assoc 2001;37:93-97.
  9. Scavelli TD, Peterson ME, Matthiesen DT. Results of surgical treatment for hyperadrenocorticism caused by adrenocortical neoplasia in the dog: 25 cases (1980-1984). J Am Vet Med Assoc 1986;189:1360-1364.
  10. Kintzer PP, Peterson ME. Mitotane treatment of 32 dogs with cortisol-secreting adrenocortical neoplasms. J Am Vet Med Assoc 1994;205;54-60.
  11. Feldman EC, Nelson RW, Feldman MS, et al. Comparison of mitotane treatment for adrenal tumor versus pituitary-dependent hyperadrenocorticism in dogs. J Am Vet Med Assoc 1992;200:1642-1647
  12. Helm JR, McLauchlan G, Boden LA, et al. Comparison of factors that influence survival in dogs treated with mitotane and trilostane with adrenal-dependent hyperadrenocorticism. J Vet Intern Med 2011;25:251-260.
  13. Edgren M, Eriksson B, Wilander E, et al. Biological characteristics of adrenocortical carcinoma: a study of p53, IGF, EGF-r, Ki-67 and PCNA in 17 adrenocortical carcinomas. Anticancer Res 1997;17:1303-1309.
  14. Kamio T, Shigematsu K, Sou H, et al. Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma. Hum Pathol 1990; 21:277-282.
  15. Barlaskar FM, Spalding AC, Heaton JH, et al. Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J Clin Endocrinol Metab 2009;94:204-212.
  16. Haluska P, Worden F, Olmos D, et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 2010;65:765–773.
  17. Carden CP, Frentzas S, Langham M, et al. Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors. J Clin Oncol 2009; 27:1344.