Showing posts with label Hypoadrenocorticism (Addison's disease). Show all posts
Showing posts with label Hypoadrenocorticism (Addison's disease). Show all posts

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, November 20, 2013

Trilostane, Prednisone, and ACTH Stimulation Testing in Dogs with Cushing's Disease



My problem patient is Buddy, an 8-year old, male neutered Labrador Retriever weighing 42 kg. Buddy first developed diabetes, which was difficult to control because of insulin resistance. He was later found to have concurrent pituitary-dependent Cushing's disease, confirmed by both ACTH simulation and low-dose dexamethasone suppression testing).

Buddy has been doing well on insulin and trilostane (Vetoryl) for the past 5 months. We started him on a Vetoryl dose of 60 mg, given twice daily with food (2.9 mg/kg/day). When we repeated the ACTH stimulation test after a month, we had a low-normal serum cortisol value (1.4 µg/dl) with absolutely no increase in the post-ACTH cortisol value. This blunted response worried us, so we reduced his Vetoryl dose to 30 mg once a day in the morning (1.4 mg/kg/day).

Recently, Buddy's appetite began to wane, so we added 5-mg of prednisone to his treatment regime. Almost immediately after adding the glucocorticoid treatment, his appetite perked up. 

Buddy has just started showing signs of polyuria and polydipsia, so we repeated his ACTH stimulation test once again. Results of this testing showed a basal serum cortisol value of 2.3 µg/dL, but the post-ACTH cortisol value was only 2.0 µg/dL. 

My question is this: Could the low-dose prednisone treatment that we are administering be suppressing this dog's adrenal response to the ACTH injection and providing us with inaccurate information? With the polyuria and polydipsia, I would have expected high cortisol levels, not low cortisol values.

My Response:

Effects of prednisone supplementation on ACTH stimulation test results
In a dog with pituitary-dependent Cushing's disease, we generally are dealing with an ACTH–secreting pituitary adenoma, which is resistant to negative-feedback suppression with glucocorticoids. This is the basis for using the low- and high-dose dexamethasone suppression tests, which we use to diagnose and differentiate the causes of Cushing's syndrome in these dogs (1).

Therefore, adding 5-mg of prednisone (0.12 mg/kg/day) to this large breed dog's treatment regime would not suppress pituitary ACTH secretion or change your ACTH stimulation test results. If the dog was normal, that small dose of glucocorticoid could possibly be enough to suppress or blunt pituitary ACTH secretion, but it is much too small of a dose to change ACTH secretion in dogs with Cushing's syndrome.

It is possible, however, that you are measuring some of the prednisone in the assay for cortisol, especially if you are giving the prednisone within 24 hours of the ACTH stimulation test. Prednisone and prednisolone will both cross-react in the cortisol assay to falsely increase the measured serum cortisol values. If this is true, basal and post-ACTH stimulated cortisol values in this dog could be very low, and the dose of the trilostane may need to be decreased even further or possibly discontinued.

Adjusting the trilostane dose when ACTH-stimulated cortisol values fall too low
Even even if the prednisone isn't having any effect on cortisol measurements, a post-ACTH stimulated cortisol value of 2.0 µg/dL is too low for me (1,2). I'd recommend that you decrease the trilostane (Vetoryl) dose down to 30 mg once a day, and repeat the ACTH stimulation test again in 2-4 weeks. If the post-ACTH serum cortisol value remains less than 2-2.5 µg/dl on the lowered Vetoryl dosage, I'd even stop the drug completely for 2 weeks to see if the cortisol concentrations will go back up (generally to above 10 µg/dL), as an untreated dog with Cushing's disease should do within a few hours to days.

In many dogs that I treat with Vetoryl, the dose can be decreased over time. In some of these dogs, the dose can even be permanently stopped, and their cortisol secretion remains "normal" and never goes up high enough again to cause signs of Cushing's disease (3,4). The aldosterone secretion is not affected in these dogs, and they never develop any serum electrolyte changes associated with hypoadrenocorticism. This "cure" presumably is the result of mild adrenal necrosis, but we don't know for certain. In any case, when it does happen it certainly is not a bad thing, and the owners are generally thrilled!

Permanent adrenal necrosis, however, can result in life-threatening adrenal crisis (undetectably cortisol values with hyperkalemia and hyponatremia) if the dog is not properly monitored and the dose of the drug lowered or stopped as needed.

What is the cause of dog's polyuria and polydipsia?
Obviously, based on the information we have, it's impossible for me to determine the cause of this dog's polyuria and polydispsia. However, the list of possible differentials in this dog is quite long and includes poor diabetic control or urinary tract infection. A serum chemistry panel and a glucose curve is certainly recommended.

In addition, since both diabetic and Cushingoid dogs are predisposed to having urinary tract infections, a complete urinalysis with culture must be done (6,7). Even without clinical signs of an urinary tract infection, I'd recommend performing a urine culture twice a year since these infections are commonly subclinical and these urinary tract infections are so common in these dogs.

Bottom Line

Again, permanent adrenal necrosis can result in a life-threatening adrenal crisis in dogs treated with trilostane if not properly monitored. For this reason, we never want to "cover up" trilostane-induced lowering of the circulating cortisol values by adding in a glucocorticoid supplement, as you did in this dog. We want to lower the dose of the trilostane instead.

References:
  1. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
  2. Ramsey IK. Trilostane in dogs. Vet Clin North Am Small Anim Pract 2010;40:269-283. 
  3. 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. 
  4. Ramsey IK, Richardson J, Lenard Z, et al. Persistent isolated hypocortisolism following brief treatment with trilostane. Aust Vet J 2008;86:491-495. 
  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. Nichols R. Complications and concurrent disease associated with canine hyperadrenocorticism. Vet Clin North Am Small Anim Pract 1997;27:309-320.  
  7. Forrester SD, Troy GC, Dalton MN, et al. Retrospective evaluation of urinary tract infection in 42 dogs with hyperadrenocorticism or diabetes mellitus or both. J Vet Intern Med 1999;13:557-560.  

Wednesday, October 2, 2013

Top Endocrine Publications of 2012: The Feline Adrenal Gland


In my eighth compilation of the canine and feline endocrine publications of 2012, I’m moving on to disorders of the feline adrenal gland.

Listed below are 11 research papers written in 2012 that deal with adrenal gland issues of clinical importance in cats.

These range from an investigation of the plasma ACTH and ACTH precursors in diagnosis of cats with pituitary-dependent Cushing's disease (1) to a report of severe hypertension associated with Cushing's disease in a cat (2); and from studies of the effects of hyperthyroidism on adrenal size and adrenal function (3,9) to a case report of a cat with severe insulin resistance associated with a pituitary tumor secreting ACTH, MSH, and growth hormone (4).

Other studies ranged from a report of severe hypoglycemia associated with Addison's disease in a cat (6), to a cat with congenital adrenal hyperplasia (8); and finally, from the use of laparoscopic adrenalectomy for adrenal tumor in cats (10), to a review of primary hyperaldosteronism (Conn's syndrome) in 7 cats (11).

References:
  1. Benchekroun G, de Fornel-Thibaud P, Dubord M, et al. Plasma ACTH precursors in cats with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2012;26:575-581. 
  2. Brown AL, Beatty JA, Lindsay SA, et al. Severe systemic hypertension in a cat with pituitary-dependent hyperadrenocorticism. J Small Anim Pract 2012;53:132-135. 
  3. Combes A, Vandermeulen E, Duchateau L, et al. Ultrasonographic measurements of adrenal glands in cats with hyperthyroidism. Vet Radiol Ultrasound 2012;53:210-216. 
  4. Cross E, Moreland R, Wallack S. Feline pituitary-dependent hyperadrenocorticism and insulin resistance due to a plurihormonal adenoma. Top Companion Anim Med 2012;27:8-20. 
  5. Fanson KV, Wielebnowski NC, Shenk TM, et al. Comparative patterns of adrenal activity in captive and wild Canada lynx (Lynx canadensis). J Comp Physiol B 2012;182:157-165. 
  6. Kasabalis D, Bodina E, Saridomichelakis MN. Severe hypoglycemia in a cat with primary hypoadrenocorticism. J Feline Med Surg 2012;14:755-758. 
  7. O'Neill D, Hendricks A, Summers J, et al. Primary care veterinary usage of systemic glucocorticoids in cats and dogs in three UK practices. J Small Anim Pract 2012;53:217-222. 
  8. Owens SL, Downey ME, Pressler BM, et al. Congenital adrenal hyperplasia associated with mutation in an 11beta-hydroxylase-like gene in a cat. J Vet Intern Med 2012;26:1221-1226. 
  9. Ramspott S, Hartmann K, Sauter-Louis C, et al. Adrenal function in cats with hyperthyroidism. J Feline Med Surg 2012;14:262-266. 
  10. Smith RR, Mayhew PD, Berent AC. Laparoscopic adrenalectomy for management of a functional adrenal tumor in a cat. J Am Vet Med Assoc 2012;241:368-372. 
  11. Willi B, Kook PH, Quante S, et al. Primary hyperaldosteronism in cats. Schweizer Archiv fur Tierheilkunde 2012;154:529-537. 

Tuesday, September 24, 2013

Performing an ACTH Stimulation Test in Dogs Treated with Fludrocortisone (Florinef)

Fludrocortisone acetate (Florinef), a drug used as mineralocorticoid replacement in dogs with primary hypoadrenocorticism (Addison's disease) 

Thanks for your last post on "Confirming the Diagnosis of Addison's Disease after Treatment of an Adrenal Crisis." I found it to very helpful in managing these dogs in my practice. However, after reading it, I have 2 questions:
  1. Are you at all concerned about the glucorticoid effect of fludrocortisone (Florinef) and its effect on the hypothalamic-pituitary-adrenal (HPA) axis?
  2. Will fludrocortisone cross-react in the cortisol assay to falsely elevate the measured cortisol result? I've read that the cross reaction is limited to 6% or less — is that correct?
  3. How long would I have to stop this drug before I do an ACTH stimulation test in a dog suspected of having Addison's disease?
My Response:

All of your questions are good ones. When we consider mineralocorticoid replacement for dogs with Addison's disease, we have two choices — fludrocortisone acetate (Florinef), administered orally on a daily basis, or desoxycorticosterone pivalate (Percorten-V) generally administered by injection every 3-5 weeks (1-3).

Fludrocortisone acetate is a synthetic adrenocortical steroid that has potent mineralocorticoid and glucocorticoid activities. Compared to cortisol, this drug has 125-times the mineralocorticoid activity and has 10-times the glucocorticoid activity. In this regard, fludrocortisone is very different than desoxycorticosterone pivalate, which is a pure mineralocorticoid agent and possesses no glucocorticoid activity.

The potent glucocorticoid activity of fludrocortisone explains why some dogs will develop polyuria and other signs of iatrogenic Cushing's syndrome, especially when on high daily doses of the drug. It also is the reason why many dogs treated with fludrocortisone do not require additional daily prednisone or prednisolone supplementation.

Because of its glucocorticoid activity, fludrocortisone will indeed cross-react in the cortisol assay to a some extent, as you noted. But even more importantly, it can suppress the HPA axis, especially when given in large doses (4,5), and may lead to a lowering of the basal cortisol concentration and blunting of the cortisol response to ACTH stimulation.

Ideally, we would do the ACTH stimulation test early in the course of the disease, before the dog has been treated for more than a few days with fludrocortisone but especially before the drug dosage has been increased to high daily levels. In these dogs, I simply withhold the drug for 24 hours prior to doing the ACTH stimulation test. That time interval will allow most of the drug to be eliminated so we don't have to worry about measuring the fludrocortisone in the cortisol assay.

If a dog has been on long-term and high-dose fludrocortisone therapy, it is always a good idea to switch to Percorten-V therapy for their mineralocorticoid supplementation for a month or two prior to ACTH stimulation testing. Because Percorten doesn't have any glucocorticoid activity, this might allow the HPA to recover if it has been chronically suppressed by the high-dose fludrocortisone therapy.

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, 2013;in press.
  4. Otte C, Jahn H, Yassouridis A, et al. The mineralocorticoid receptor agonist, fludrocortisone, inhibits pituitary-adrenal activity in humans after pre-treatment with metyrapone. Life sciences 2003;73:1835-1845. 
  5. Karamouzis I, Berardelli R, Marinazzo E, et al. The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic-pituitary-adrenal (HPA) axis in humans. Pituitary 2013;16:378-385. 

Wednesday, September 18, 2013

Confirming the Diagnosis of Addison's Disease after Treatment of an Adrenal Crisis

I have a question about using ACTH stimulation testing to confirm primary hypoadrenocorticism (Addison's disease) in dogs. My patient is a 9-year old female spayed Standard Poodle (weighing 25 kg) that was diagnosed with an acute Addisonian crisis at an emergency hospital. At the time of clinical presentation, she was very weak and had collapsed, and had been anorexic for 2 days; physical exam revealed severe dehydration with a normal heart rate (100 bpm).

Routine laboratory workup showed hypoglycemia (glucose, 46 mg/dl), mild azotemia (serum creatinine 1.8 mg/dl), and moderate to severe hyperkalemia (potassium, 7.5 mEq/L) with a normal sodium level (142.4 mg/dl).

At presentation, the owner declined an ACTH stimulation test due to the expense, so the emergency clinic only did a baseline cortisol, which was low at < 0.8 µg/dl. The dog was treated with IV fluids and a shock dose of dexamethasone. She had a good clinical response was discharged after 2 days. On the day of release, she was treated with Percorten-V (50 mg, IM) and started on oral prednisone (2.5 mg BID for 3 days, then 2.5 mg SID).

Today, the owner called me and asked me about doing an ACTH stimulation test to make sure we have the right diagnosis.

My many questions are listed below:
  1. Is it always better to do the ACTH stimulation test prior to any glucocorticoid treatment? 
  2. Can we do an ACTH stimulation test during the initial adrenal crisis? 
  3. If I stop the prednisone and do an ACTH stimulation test now, will I be able to interpret the results?
  4. How long does she need to be off of the prednisone before doing the ACTH stimulation test?
  5. The owners are concerned that the dog could develop another adrenal crisis if she doesn't get the prednisone every day. How concerned do we have to be worried about that issue?
My Response:

To make a definitive diagnosis of hypoadrenocorticism (Addison's disease), we need to prove that the dog has inadequate adrenal reserve. As you know, this is done by performing an ACTH stimulation test, which is considered to be the gold standard diagnostic test for hypoadrenocorticism in both man and dogs (1-3).

Ideally, the ACTH stimulation test would be done prior to administration of any glucocorticoid agent. The reason for this is two-fold.

Reason 1— Many glucocorticoids (e.g., cortisone, hydrocortisone, prednisolone and prednisone) will cross­-react in the cortisol assay to falsely elevate the measured cortisol value. Therefore, to accurately measure a dog's circulating cortisol concentrations, the ACTH response test should either be performed before these glucocorticoids are administered or after stopping them for at least 24 hours to allow their elimination from the circulation (2,3). The only glucocorticoid that does not cross-react in most cortisol assays is dexamethasone (see below).

Reason 2— Secondly, if high doses of any glucocorticoid preparation are administered, the circulating glucocorticoid will feedback to the hypothalamus and pituitary gland to shut off the secretion of corticotropin-releasing hormone and ACTH, respectively (see Figure 1). This is certainly true for dexamethasone as well, since it is a very potent glucocorticoid.

In the normal dog, this will lead to an acute decrease in circulating ACTH concentrations, and within a few hours to days, lead to mild atrophy of the adrenal cortex. Remember that without circulating ACTH, the basal cortisol value will fall and the response to ACTH stimulation will also become "blunted," even if that dog is not suffering from Addison's disease (2-4).

Figure 1
ACTH stimulation testing during initial treatment of adrenal crisis with dexamethasone
The ACTH stimulation test can be performed at time of initial glucocorticoid treatment for acute adrenal crisis, but only if dexamethasone is used for glucocorticoid replacement. Again, since dexamethasone does not interfere with the cortisol assay, it will not lead to falsely high measured cortisol values.

As noted above (under Reason 2), however, dexamethasone is a very potent glucocorticoid and will act via negative feedback on the HPA axis to inhibit endogenous cortisol production. However, this effect usually takes at least 4–6 hours to be expressed. Consequently, any artifactual lowering of post­-ACTH cortisol concentrations can be avoided by ensuring that the ACTH response test is completed within 2–3 hours of dexamethasone administration (3).

Overall, it is always best to delay glucocorticoid therapy until the ACTH response test is completed. This is rarely problematic, provided that concurrent intravenous fluid therapy is instituted.

Protocol for ACTH stimulation testing in suspect Addison's dogs that have been treated with oral prednisone or another glucocorticoid 
Once a day or more has passed and the dog has received large doses of IV and/or oral glucocorticoids, interpretation of ACTH stimulation test results becomes more problematic. Remember that administration of even moderate doses of a glucocorticoid can result in suppression of the HPA axis and lead to mild to moderate atrophy of the adrenal cortex. Even in a dog without Addison's disease, this can result in a low basal cortisol level with a "blunted" or suppressed response to ACTH stimulation.

If large doses of potent IV glucocorticoids, such as dexamethasone, have been administered for adrenal crisis, it may be best to postpone testing for a week or more to allow the HPA axis to partially recover. If oral prednisone or prednisolone is being administered, the dosage should be tapered down to the low maintenance range (0.1 mg/kg/day) for a few days. The prednisone or prednisolone should then be withheld for at least 24 hours before ACTH stimulation testing to ensure that the glucocorticoid is not detected in the cortisol assay.

As long as the dog has received mineralocorticoid treatment and has normal serum electrolytes, withholding all glucocorticoids for 1 day will not result in adrenal crisis.

Interpreting the results of ACTH stimulation testing in dogs treated with oral prednisone or another glucocorticoid 
In normal dogs administration of a supraphysiologic dose of ACTH produces a rise in serum cortisol to values usually above 10 µg/dl (275 nmol/L). In contrast, dogs with hypoadrenocorticism have an absent or blunted response to ACTH administration. Basal and post-ACTH serum cortisol concentrations are less than 1 µg/dl (27 nmol/L) in over 75% of dogs and less than 2 µg/dl (55 nmol/L) in virtually all dogs with primary hypoadrenocorticism (1-3). Similarly, the great majority of dogs with secondary hypoadrenocorticism also have ACTH-stimulated cortisol concentrations of less than 2 µg/dl.

So what kind of ACTH stimulation response can we expect to find in a dog without Addison's disease that is being treated with chronic glucocorticoids supplementation?  If we are lucky, the dog may show a completely normal cortisol response, thereby making it clear that Addison's disease is ruled out.

However, many of these dogs will show low basal cortisol concentrations or have a slightly blunted response to ACTH stimulation. Even in the these dogs, however, their post-ACTH stimulated cortisol values tend to be higher than 3-4 µg/dl (>80-110 nmol/L). Because we know that dogs with naturally-occurring hypoadrenocorticism will have a much lower adrenocortical reserve than this, and we also know that exogenous glucocorticoids can suppress the HPA axis to inhibit endogenous cortisol production, this type of cortisol response also helps exclude Addison's disease.

References:
  1. Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc 1996;208:85-91. 
  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, 2013;in press.
  4. Kemppainen RJ, Sartin JL, Peterson ME. Effects of single intravenously administered doses of dexamethasone on response to the adrenocorticotropic hormone stimulation test in dogs. Am J Vet Res 1989;50:1914-1917. 

Wednesday, September 4, 2013

Top Endocrine Publications of 2012: The Canine Adrenal Gland


In my seventh compilation of the canine and feline endocrine publications of 2012, I’m moving on to disorders of the canine adrenal gland.

Listed below are 40 research papers written in 2012 that deal with a variety of adrenal gland issues of clinical importance in dogs. I've already reviewed 4 of these papers; to read my reviews, see the links at the bottom of the reference list.

These range from the investigations of trilostane and dosing (1,11,35) or its effect on steroid hormone metabolism in adrenal glands and corpora lutea (32) to a study of an evaluation of compounded trilostane (6); from investigations of the sudden acute blindness that can develop in dogs with pituitary-dependent hyperadrenocorticism (PDH) (3,4) to the vitamin-D status in dogs with PDH (7); and from studies of the effect of cortisol excess (Cushing's syndrome) on renal function (37-39) to the use of low-dose insulin administration to prevent the onset on overt diabetes in dogs with PDH (27).

Other research studies included a review of the animal models of adrenocortical tumorigenesis (2) to a review of diagnostic tests for Cushing's syndrome (21); from studies to compare IV and IM formulations of ACTH in dogs (5) to ultrasound studies of the adrenal gland in normal dogs, dogs treated with steroids, or dogs with adrenal tumor (8,9,33); from reports of adrenalectomy for treatment of dogs with adrenal tumor causing  hyperaldosteronism (12,15), or pheochromocytoma (17); and finally, from studies of the relationship between gallbladder mucoceles and glucocorticoid excess (22) to a number of studies of the effects of exogenous glucocorticoids and iatrogenic Cushing's syndrome in dogs (18,20,22-24,26,31,33,40)

References:
  1. Augusto M, Burden A, Neiger R, et al. A comparison of once and twice daily administration of trilostane to dogs with hyperadrenocorticism. Tierarztl Prax Ausg K Kleintiere Heimtiere 2012;40:415-424. 
  2. Beuschlein F, Galac S, Wilson DB. Animal models of adrenocortical tumorigenesis. Mol Cell Endocrinol 2012;351:78-86. 
  3. Cabrera Blatter MF, del Prado A, Gallelli MF, et al. Blindness in dogs with pituitary dependent hyperadrenocorticism: relationship with glucose, cortisol and triglyceride concentration and with ophthalmic blood flow. Res Vet Sci 2012;92:387-392. 
  4. Cabrera Blatter MF, Del Prado B, Miceli DD, et al. Interleukin-6 and insulin increase and nitric oxide and adiponectin decrease in blind dogs with pituitary-dependent hyperadrenocorticism. Res Vet Sci 2012. 
  5. Cohen TA, Feldman EC. Comparison of IV and IM formulations of synthetic ACTH for ACTH stimulation tests in healthy dogs. J Vet Intern Med 2012;26:412-414. 
  6. Cook AK, Nieuwoudt CD, Longhofer SL. Pharmaceutical evaluation of compounded trilostane products. J Am Anim Hosp Assoc 2012;48:228-233. 
  7. Corbee RJ, Tryfonidou MA, Meij BP, et al. Vitamin D status before and after hypophysectomy in dogs with pituitary-dependent hypercortisolism. Domest Anim Endocrinol 2012;42:43-49. 
  8. Davis MK, Schochet RA, Wrigley R. Ultrasonographic identification of vascular invasion by adrenal tumors in dogs. Vet Radiol Ultrasound 2012;53:442-445. 
  9. de Chalus T, Combes A, Bedu AS, et al. Ultrasonographic adrenal gland measurements in healthy Yorkshire Terriers and Labrador Retrievers. Anat Histol Embryol 2012. 
  10. Donnelly K, DeClue AE, Sharp CR. What is your diagnosis? 12-year-old spayed female Labrador Retriever with a history of polyuria and polydipsia. J Am Vet Med Assoc 2012;240:1283-1285. 
  11. Feldman EC, Kass PH. Trilostane dose versus body weight in the treatment of naturally occurring pituitary-dependent hyperadrenocorticism in dogs. J Vet Intern Med 2012;26:1078-1080. 
  12. Frankot JL, Behrend EN, Sebestyen P, et al. Adrenocortical carcinoma in a dog with incomplete excision managed long-term with metastasectomy alone. J Am Anim Hosp Assoc 2012;48:417-423. 
  13. Fukuta H, Mori A, Urumuhan N, et al. Characterization and comparison of insulin resistance induced by Cushing Syndrome or diestrus against healthy control dogs as determined by euglycemic-hyperinsulinemic glucose clamp profile glucose infusion rate using an artificial pancreas apparatus. J Vet Med Sci 2012;74:1527-1530. 
  14. Ginel PJ, Sileo MT, Blanco B, et al. Evaluation of serum concentrations of cortisol and sex hormones of adrenal gland origin after stimulation with two synthetic ACTH preparations in clinically normal dogs. Am J Vet Res 2012;73:237-241. 
  15. Gojska-Zygner O, Lechowski R, Zygner W. Functioning unilateral adrenocortical carcinoma in a dog.  Can Vet J 2012;53:623-625. 
  16. Gow AG, Gow DJ, Bell R, et al. Insulin concentrations in dogs with hypoadrenocorticism. Res Vet Sci 2012;93:97-99. 
  17. Guillaumot PJ, Heripret D, Bouvy BM, et al. 49-month survival following caval venectomy without nephrectomy in a dog with a pheochromocytoma. J Am Anim Hosp Assoc 2012;48:352-358. 
  18. Hicks CW, Sweeney DA, Danner RL, et al. Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock. Crit Care Med 2012;40:199-207. 
  19. Hoglund K, Hanas S, Carnabuci C, et al. Blood pressure, heart rate, and urinary catecholamines in healthy dogs subjected to different clinical settings. J Vet Intern Med 2012;26:1300-1308. 
  20. Hsu K, Snead E, Davies J, et al. Iatrogenic hyperadrenocorticism, calcinosis cutis, and myocardial infarction in a dog treated for IMT. J Am Anim Hosp Assoc 2012;48:209-215. 
  21. Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing's syndrome in dogs. Top Companion Anim Med 2012;27:21-24. 
  22. Kook PH, Schellenberg S, Rentsch KM, et al. Effects of iatrogenic hypercortisolism on gallbladder sludge formation and biochemical bile constituents in dogs. Vet J 2012;191:225-230. 
  23. Kovalik M, Thoday KL, Berry J, et al. Prednisolone therapy for atopic dermatitis is less effective in dogs with lower pretreatment serum 25-hydroxyvitamin D concentrations. Vet Dermatol 2012;23:125-130, e127-128. 
  24. Kovalik M, Thoday KL, Evans H, et al. Short-term prednisolone therapy has minimal impact on calcium metabolism in dogs with atopic dermatitis. Vet J 2012;193:439-442. 
  25. Lowrie M, De Risio L, Dennis R, et al. Concurrent medical conditions and long-term outcome in dogs with nontraumatic intracranial hemorrhage. Vet Radiol Ultrasound 2012;53:381-388. 
  26. Melamies M, Vainio O, Spillmann T, et al. Endocrine effects of inhaled budesonide compared with inhaled fluticasone propionate and oral prednisolone in healthy Beagle dogs. Vet J 2012;194:349-353. 
  27. Miceli DD, Gallelli MF, Cabrera Blatter MF, et al. Low dose of insulin detemir controls glycaemia, insulinemia and prevents diabetes mellitus progression in the dog with pituitary-dependent hyperadrenocorticism. Res Vet Sci 2012;93:114-120. 
  28. Miller AG, Dow S, Long L, et al. Antiphospholipid antibodies in dogs with immune mediated hemolytic anemia, spontaneous thrombosis, and hyperadrenocorticism. J Vet Intern Med 2012;26:614-623. 
  29. Monroe WE, Panciera DL, Zimmerman KL. Concentrations of noncortisol adrenal steroids in response to ACTH in dogs with adrenal-dependent hyperadrenocorticism, pituitary-dependent hyperadrenocorticism, and nonadrenal illness. J Vet Intern Med 2012;26:945-952. 
  30. Muntener T, Schuepbach-Regula G, Frank L, et al. Canine noninflammatory alopecia: a comprehensive evaluation of common and distinguishing histological characteristics. Vet Dermatol 2012;23:206-e244. 
  31. O'Neill D, Hendricks A, Summers J, et al. Primary care veterinary usage of systemic glucocorticoids in cats and dogs in three UK practices. J Small Anim Pract 2012;53:217-222. 
  32. Ouschan C, Lepschy M, Zeugswetter F, et al. The influence of trilostane on steroid hormone metabolism in canine adrenal glands and corpora lutea-an in vitro study. Vet Res Commun 2012;36:35-40. 
  33. Pey P, Daminet S, Smets PM, et al. Effect of glucocorticoid administration on adrenal gland size and sonographic appearance in beagle dogs. Vet Radiol Ultrasound 2012;53:204-209. 
  34. Proverbio D, Spada E, Perego R, et al. Potential variant of multiple endocrine neoplasia in a dog. J Am Anim Hosp Assoc 2012;48:132-138. 
  35. Reine NJ. Medical management of pituitary-dependent hyperadrenocorticism: mitotane versus trilostane. Top Companion Anim Med 2012;27:25-30. 
  36. Schteingart DE, Sinsheimer JE, Benitez RS, et al. Structural requirements for mitotane activity: development of analogs for treatment of adrenal cancer. Anticancer Res 2012;32:2711-2720. 
  37. Smets PM, Lefebvre HP, Aresu L, et al. Renal function and morphology in aged Beagle dogs before and after hydrocortisone administration. PLoS One 2012;7:e31702. 
  38. Smets PM, Lefebvre HP, Kooistra HS, et al. Hypercortisolism affects glomerular and tubular function in dogs. Vet J 2012;192:532-534. 
  39. Smets PM, Lefebvre HP, Meij BP, et al. Long-term follow-up of renal function in dogs after treatment for ACTH-dependent hyperadrenocorticism. J Vet Intern Med 2012;26:565-574. 
  40. Van der Heyden S, Croubels S, Gadeyne C, et al. Influence of P-glycoprotein modulation on plasma concentrations and pharmacokinetics of orally administered prednisolone in dogs. Am J Vet Res 2012;73:900-907. 

Tuesday, July 9, 2013

Top 10 Clinical Endocrinology Research Abstracts, Part 2

Following last week’s post, this is the next installment of my review of the "top 10 list" clinical endocrinology research abstracts presented at last month's American College of Veterinary Internal Medicine Forum.

As with last week's post, 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.  Rhett also serves as a consultant for the Animal Endocrine Clinic, so I talk to him almost every day about the more difficult cases I see in my practice.

In this post, we will review 3 more of these "top 10" abstracts, followed by the remaining 4 abstracts in next week's post. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.


Lobetti R, Lindquist E, Frank J, et al. Adrenal gland ultrasonography in dogs with hypoadrenocorticism. J Vet Intern Med 2013:691. 

Hypoadrenocorticism can be a life-threatening disease if not treated immediately. Although a tentative diagnosis can be made on clinical signs and laboratory findings, a definitive diagnosis can only be made on an ACTH stimulation test. Unfortunately, typical clinical signs and laboratory findings are not evident in all cases and ACTH stimulation test results are usually not immediately available. As abdominal ultrasonography is widely used, it would be ideal as a diagnostic aid for hypoadrenocorticism. To date, there are only 2 studies that have shown small adrenal glands in dogs with hypoadrenocorticism on ultrasound. The purpose of this study was to identify a reliable set of adrenal ultrasonography parameters that could be used to identify dogs with hypoadrenocorticism. The records of 81 privately owned dogs that had abdominal ultrasonography done as well as an ACTH stimulation test were retrospectively evaluated. The dogs were divided into three groups: Group 1 consisted of 37 dogs with clinical signs and/or a sonogram appearance of their adrenal glands suspicious of hypoadrenocorticism and confirmed on an ACTH stimulation test. Group 2 consisted of 19 dogs with clinical signs and/or a sonogram appearance of their adrenal glands suspicious of hypoadrenocorticism but ruled out by a normal ACTH stimulation test. Group 3 consisted of 25 dogs that had no clinical signs or biochemical evidence of hypoadrenocorticism, normal sonogram appearance of their adrenal glands, and a normal ACTH stimulation test. Descriptive statistics were used to describe the data and one-way analysis of variance with Bonferroni and Tukey-Kramer comparisons used to test for statistical differences between the groups. The level of significance was set at p < 0.05. Results showed that the median right adrenal length in Group 1-3 was 1.75 cm, 1.8 cm, and 2.03 cm, respectively. Median left adrenal length in Group 1-3 was 1.77 cm, 2.08 cm, and 2.1 cm, respectively. There was no statistical difference between the right and left adrenal gland and within groups. Median right adrenal thickness in Group 1-3 was 0.34 cm, 0.37 cm, and 0.6 cm, respectively. Median left adrenal thickness in Group 1-3 was 0.31 cm, 0.4 cm, and 0.6 cm, respectively. In both right and left measurements, groups 1 and 2 were statistically different from group 3 but there was no statistical difference between groups 1 and 2. The study concluded that the ultrasound finding of small, flattened, isoechoic adrenal glands should be an alert for possible hypoadrenocorticism, prompting additional confirmatory function testing and/or therapeutic intervention.
  
 Comments—An abdominal ultrasound is often included as part of a diagnostic work-up for various disorders and clinical complaints. The ultrasound finding of bilaterally small adrenal glands, even if unexpected, should send an alert signal regarding the possibility of underlying adrenal insufficiency (1-3).

In general, dogs with hypoadrenocorticism have thinner adrenals than dogs with diseases that mimic the disorder or healthy dogs (2). Often, the left adrenal gland is easier to find than the right adrenal gland, and the left adrenal is less than 3.2 mm in diameter in dogs with confirmed hypoadrenocorticism (2). In this study, however, there was no statistical difference between the length or thickness of the either adrenal gland between the dogs with confirmed Addison's disease and sick dogs proven not to have hypoadrenocorticism.

The Bottom Line— Sonographic evidence of bilaterally small adrenal glands is a sensitive —but not specific —marker for hypoadrenocorticsm. Such findings should be followed-up with an ACTH response test, which remains the gold standard for the definitive diagnosis of hypoadrenocorticism.

References:
  1. Hoerauf A, Reusch C. Ultrasonographic evaluation of the adrenal glands in six dogs with hypoadrenocorticism. J Am Anim Hosp Assoc 1999;35:214-218. 
  2. Codreanu M, Şerdean C, Fernoagă C, et al. Study concerning the importance of ultrasound examination in adrenal glands diseases in dog. Lucrari Stiintifice 2009;52:483-486. 
  3. Wenger M, Mueller C, Kook PH, et al. Ultrasonographic evaluation of adrenal glands in dogs with primary hypoadrenocorticism or mimicking diseases. Vet Rec 2010;167:207-210. 

Lourenco BN, Lunn KF. Abdominal ultrasound findings acromegalic cats. J Vet Intern Med 2013:689.

Acromegaly is increasingly recognized as a cause of insulin-resistance in diabetic feline patients. This study was designed to describe the sonographic changes in the abdominal organs of acromegalic cats. Cats were included if they presented to North Carolina State University or Colorado State University from January 2002 to October 2012 with poorly controlled diabetes mellitus, IGF-1 concentrations >100 nmol/L and had an abdominal ultrasound examination (AUS) performed with report available. A control group included age-matched cats that had an AUS performed for investigation of disease unlikely to affect liver, kidneys, pancreas or adrenal glands (e.g. lower urinary tract disease). Twenty five cats were included in each group. IGF-1 concentrations in the acromegaly group ranged from >148 to 638 mmol/l. Median left and right kidney length were significantly greater in the acromegaly group compared to controls (acromegaly—left: 47.0 mm; control-left: 38.1 mm; p < 0.0001; acromegaly—right: 47.0 mm; control-right: 42.2 mm; p = 0.0003). Hepatomegaly and bilateral adrenomegaly were reported in 63% and 53% of acromegalic cats respectively, and in none of the controls. Median left and right adrenal width were significantly greater in the acromegaly group compared to controls (acromegaly—left: 5.4 mm; control-left: 3.5 mm; p < 0.0001; acromegaly—right: 5.4 mm; control-right: 3.6 mm; p < 0.0001). Median pancreatic thickness was significantly greater in acromegalic patients compared to controls (13.5 mm vs. 6.1 mm; p = 0.0003). Pancreatic changes were described in 79% of the acromegalic cats and 9% of the controls. These findings indicate that compared to non-acromegalic cats, acromegalic patients have larger kidneys, liver, adrenals and pancreas.

Comments— It is well-known that growth hormone (GH) excess in the adult animal causes soft tissue (including the viscera) to grow.  Therefore, it is not unexpected that the sonographic appearance of the kidneys, liver, pancreas, and adrenal glands are enlarged in cats with acromegaly (1-6).

The Bottom Line— Acromegaly and hyperadrenocorticism are always on the rule-out list for any diabetic cat with insulin-resistance (2,5,6). In addition, both of these disorders share sonographic similarities such as liver and adrenal gland enlargement, which sometimes creates diagnostic confusion. However, it is important to keep in mind that sonographic evidence of bilateral adrenal enlargement is a sensitive, but not specific, marker for hyperadrenocorticism.

Clues that would point toward a diagnosis of hyperadrenocorticism instead of acromegaly in cats include weight loss, lack of or only mild-to-moderate insulin-resistance, muscle wasting, dermatologic signs, a generalized poor body condition, and a normal serum IGF-1 level (6). In contrast, cats with acromegaly frequently show weight gain, severe insulin-resistance, lack of muscle wasting or dermatologic signs, a good body condition, and an elevated IGF-1 level (1-6).

References:
  1. Peterson ME, Taylor RS, Greco DS, et al. Acromegaly in 14 cats. J Vet Intern Med 1990;4:192-201. 
  2. Berg RI, Nelson RW, Feldman EC, et al. Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly. J Vet Intern Med 2007;21:892-898. 
  3. Niessen SJ, Petrie G, Gaudiano F, et al. Feline acromegaly: an underdiagnosed endocrinopathy? J Vet Intern Med 2007;21:899-905. 
  4. Peterson ME. Acromegaly in cats: are we only diagnosing the tip of the iceberg? J Vet Intern Med 2007;21:889-891. 
  5. Niessen SJ. Feline acromegaly: an essential differential diagnosis for the difficult diabetic. J Feline Med Surg 2010;12:15-23. 
  6. 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. 

Reeve-Johnson MK, Rand JS, Vankan D, et al. Diagnosis of prediabetes in cats: cutpoints for impaired fasting glucose and impaired glucose tolerance in cats 8 years and older using ear or paw samples and a portable glucose meter calibrated for cats. J Vet Intern Med 2013:693.

Humans with fasting glucose above normal, but below diabetic, are classed as having impaired fasting glucose. Impaired glucose tolerance is diagnosed based on increased glucose concentration at 2 h after oral or iv glucose administration in a standardized test. Humans with impaired fasting glucose or impaired glucose tolerance below levels considered diabetic, are classed as prediabetic, and at high risk of developing type 2 diabetes. Human prediabetics outnumber diabetics 3-4:1. We have previously reported the upper cutpoint for casual blood glucose in cats, but tests for pre-diabetes and subclinical diabetes in cats are not well characterized, and therefore, cats are not typically diagnosed until clinical diabetes is evident. The aims were to establish cutpoints for healthy neutered cats > 8 years of age for fasting and 2 h glucose using a standardized test protocol with paw or ear samples and a portable glucose meter calibrated for feline blood. All cats were client-owned and healthy on the basis of client history, physical examination and a routine blood profile. Of the 82 cats tested (aged 8-18 years), 21 were Burmese and 61 non-Burmese (22 lean-BCS 3-5/9), 20 overweight-BCS 6-7/9; and 19 obese-BCS 8-9/9). Following >18 h fast, a catheter was inserted into the cephalic vein. After 3 h, fasting glucose was measured from the ear or paw using the Abbott AlphaTRAK. Glucose (0.5 g/kg bwt) was administered i.v. over 30s and glucose measured at 2 min and 2 h. Reference intervals were determined after Box-Cox transformation and exclusion of outliers. The cutpoints were defined as the upper limits of the 95% reference intervals. Based on a priori knowledge that overweight and obese cats have abnormal glucose tolerance, cats of BCS 7-9/9 were excluded from the fasting and 2 h reference interval calculations. Reference intervals for Burmese were pooled with non-Burmese because the percentage differences of the medians and interquartile ranges for the sub-groups were 50% and 100%, respectively. Based on the 95% reference interval, the fasting glucose cut-point for cats with BCS 6/9 (n = 44) was 6.3 mmol/L (113 mg/ dL); the associated 90% confidence interval was 6.1-6.5 mmol/L (110-117 mg/dL). 2/82 cats were classed as having impaired fasting glucose (BCS 5 and 7/9). The cutpoint for 2 h glucose established using cats with BCS 6/9 was 10.0 mmol/L (180 mg/dL) (90% confidence interval 9.1-10.8 mmol/L (164-194 mg/dL). Six of 82 cats were classed as having impaired glucose tolerance (4 with BCS 8 or 9/9 including 1 Burmese, 2 with BCS 7/9). We recommend that 6.3 mmol/l (113 mg/dL) be used as the cutpoint between normal and impaired fasting glucose, and that 10.0 mmol/L (180 mg/dL) be used as the 2-h glucose cutpoint between normal and impaired glucose tolerance in a simplified intravenous glucose tolerance test using a glucose dose of 0.5 g/kg with blood glucose measured from ear or pad samples using a portable glucose meter calibrated for feline blood. 

Comments—Humans with mild fasting hyperglycemia and/or slightly impaired glucose tolerance are classified as prediabetic and are at higher risk for type 2 diabetes mellitus (1). Interestingly, approximately 50% of human patients with diabetes go undiagnosed, and it is estimated that prediabetes is 4 times more common than is overt diabetes (1).

Until recently, little attention has been paid to the definition of prediabetes in cats, especially as it relates to blood glucose concentrations. In clinical practice, cats are not typically diagnosed until overt clinical diabetes (often severe and advanced) is evident. However, because most cats suffering from diabetes have a form similar to type 2 diabetes in people, it is likely that most cats will also go through a subclinical or prediabetic phase that goes undiagnosed (2). Obviously, better guidelines for early diagnosis of this common feline disorder is needed.

This group of investigators, lead by Jacquie Rand, have previously reported an upper cutoff value (174 mg/dl) for random blood glucose sampling that helps define the onset of pre-diabetes in cats (3). A random or casual blood glucose refers to measuring blood glucose whenever the cat arrives for an examination, so this may or may not be a fasted sample.

In this abstract, these investigators report that determination of a blood glucose concentration, measured after a prolonged fast, followed by glucose tolerance testing can act as more specific diagnostic tests for prediabetes and subclinical diabetes in cats.

The Bottom Line— Although measuring a fasted blood glucose value, followed by an IV glucose tolerance test, appear to be the best diagnostic tests for prediabetes,  performing these tests are not simple, and they are not going to be very useful in a busy clinical practice. The proper implementation of these tests involves prolonged fasting, hospitalization for several hours, intravenous catheter placement, and IV administration of 50% glucose (4).

In most clinical situations, a random blood glucose remains most practical test we have for diagnosing  early diabetes or prediabetes in cats. The finding of a random blood glucose concentration >180 mg/dl should never be ignored, even if the cat is showing no overt clinical signs.

In people, the treatment of prediabetes involves intensive lifestyle management such as weight loss or weight control, exercise, special diets, management of hypertension and dyslipidemias, and the occasional use of glucose-lowering agents such as metformin and acarbose (5,6). In the cat with suspected prediabetes, the most sensible and useful strategy to combat the risk of overt diabetes is to initiate a low-carbohydrate diet (7); if overweight or obese, this should be combined with a weight loss program.

However, in the future, if specific drugs designated for the treatment of prediabetes are developed and become available for use in cats, the rules regulating the use of these drugs may be based on strict guidelines for diagnosing prediabetes (i.e., fasting blood glucose and glucose tolerance testing).

References:
  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012;35 (Supp 1): S64-71.
  2. Rand JS, Fleeman LM, Farrow HA, et al. Canine and feline diabetes mellitus: nature or nurture? J Nutr 2004:134 (Supp 8):2072S-80S
  3. Reeves-Johnson M, Rand J, Anderson S, et al. Determination of reference values for blood glucose concentration in clinically-healthy, aged cats measured with a portable glucose meter from an ear or paw sample. J Vet Intern Med 2012;36:755
  4. Appleton DJ, Rand JS, Priest J, et al. Determination of reference values for glucose tolerance, insulin tolerance, and insulin sensitivity tests in clinically normal cats. Am J Vet Res 2001;62:630-636. 
  5. Bloomgarden ZT. Approaches to treatment of pre-diabetes and obesity and promising new approaches to type 2 diabetes. Diabetes Care 2008;31:1461-1466.
  6.  Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011;17 Suppl 2:1-53. 
    1. Zoran DL, Rand JS. The role of diet in the prevention and management of feline diabetes. Vet Clin North America Small Animal Practice 2013:43:233-243.

    Wednesday, December 19, 2012

    Low-Dose ACTH Stimulation Testing in Cats


    Cortisol and Aldosterone Response to Various Doses of Cosyntropin in Healthy Cats

    Amy E. DeClue, Linda G. Martin, Ellen N. Behrend, Leah A. Cohn, David I. Dismukes, and Hollie P. Lee

    Adrenocorticotropic hormone (ACTH) stimulation testing is commonly used to evaluate adrenocortical function in both dogs and cats (1-3). In cats, ACTH stimulation testing has been used primarily to test adrenocortical production of cortisol (4-6), but has also been used to evaluate the adrenal sex steroid (progestins and androgens) response (7-10).

    Although the primary regulators of aldosterone secretion are the renin-angiotensin system and extracellular potassium concentration (11,12), ACTH acts as an additional stimulant (13). In accord with that fact, administration of exogenous ACTH to cats has been reported to cause a reliable increase in aldosterone secretion. Therefore, ACTH stimulation testing can also be used for evaluation of adrenal mineralocorticoid function (14).

    Traditionally, a standard dose of cosyntropin (125 μg/cat, IV) has been recommended for ACTH stimulation testing (5). A previous study (15) documented that lower doses of cosyntropin will stimulate maximal cortisol secretion in cats. However, that study used per-cat dosing as opposed to per-body-weight dosing and did not evaluate the serum aldosterone response to ACTH stimulation.

    The purpose of the study reported here by DeClue et al (16) were to determine the lowest dose of cosyntropin (Cortrosyn) on a per-body-weight basis that would produce maximal cortisol and aldosterone secretion in cats.  A secondary purpose was to determine the ideal timing of blood sample collection for cortisol and aldosterone concentrations after ACTH injection in these healthy cats.

    Objective—To determine the lowest dose of cosyntropin on a per body weight basis that would produce maximal cortisol and aldosterone secretion and the ideal timing of blood sample collection after ACTH stimulation in healthy cats.

    Design—Randomized crossover trial.

    Animals—7 adult sexually intact male purpose-bred cats.

    Procedures—Each cat received saline (0.9% NaCl) solution (control) and 5 doses (125 μg/cat and 10, 5, 2.5, and 1 μg/kg) of cosyntropin IV with a 2-week washout period between treatments. Blood samples were obtained before (baseline) and at 15, 30, 45, 60, 75, and 90 minutes after administration of saline solution or cosyntropin.

    Results—Serum cortisol and aldosterone concentration increased significantly, compared with baseline values, after administration of all cosyntropin doses. Lower doses of cosyntropin resulted in an adrenocortical response equivalent to the traditional dose of 125 μg/ cat.

    The lowest doses of cosyntropin that stimulated a maximal cortisol and aldosterone response were 5 and 2.5 μg/kg, respectively. Lower doses of cosyntropin resulted in a shorter interval between IV administration of cosyntropin and peak serum cortisol and aldosterone concentrations.

    Conclusions and Clinical Relevance—Low-dose ACTH stimulation testing with IV administration of cosyntropin at 5 μg/kg followed by blood sample collection at 60 to 75 minutes resulted in concurrent peak serum cortisol and aldosterone concentrations that were equivalent to those achieved following administration of cosyntropin at 125 μg/cat, the standard dose currently used.

    My Bottom Line:

    This study confirms our earlier work that low doses of ACTH (e.g., 5 μg/kg body weight of cosyntropin) will maximally stimulate cortisol secretion in cats (15). In the cats of this study, as in our previous study, lower doses of cosyntropin resulted in an adrenocortical response that was equivalent to the traditional dose of 125 μg/cat (15, 16). The efficacy of of this low-dose ACTH stimulation testing protocol is also well documented in dogs (17-19), and has become a widely used testing dosage in clinical practice for evaluation of both hyper- and hypoadrenocorticism.

    Based on the results of these cat studies, the following test protocol can be recommended:
    1. Collect blood sample for basal cortisol (± aldosterone or sex steroids).
    2. Calculate the cosyntropin (Cortrosyn) dosage (5 μg/kg of cat's body weight). To draw up this amount, it's best to reconstitute and dilute the Cortrosyn powder and store the remaining ACTH product (20).
    3. Administer the cosyntropin dose to the cat by the IV route.
    4. Collect a post-ACTH blood sample at 60-75 minutes after cosyntropin injection.
    It is extremely important to point out that cosyntropin must be administered by the IV route in cats, especially when this low-dose protocol is used for ACTH stimulation testing. When given intramuscularly (IM) to cats, cosyntropin is not well absorbed and will not produce a maximal adrenocortical response (21). In cats, ACTH given by the IV route induces a greater and more prolonged adrenocortical stimu­lation than intramuscular administration.

    This difference in the cortisol response between IV and IM administration is in contrast to the situation in dogs, in which IV or IM low-dose ACTH stimulation protocols produce similar adrenocortical responses (22). This difference between cats and dogs should not surprise us— we all know that cats are not just small dogs, especially when it comes down to endocrinology!

    References:
    1. Behrend EN, Kemppainen RJ. Diagnosis of canine hyperadrenocorticism. Vet Clin North Am Small Anim Pract 2001;31:985-1003.
    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. 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.
    4. Peterson ME, Greco DS, Orth DN. Primary hypoadrenocorticism in ten cats. J Vet Intern Med 1989;3:55-58. 
    5. Duesberg C, Peterson ME. Adrenal disorders in cats. Vet Clin North Am Small Anim Pract 1997;27:321-347. 
    6. Peterson ME. Feline hyperadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;199-203.
    7. DeClue AE, Breshears LA, Pardo ID, et al. Hyperaldosteronism and hyperprogesteronism in a cat with an adrenal cortical carcinoma. J Vet Intern Med 2005;19:355-358. 
    8. Briscoe K, Barrs VR, Foster DF, et al. Hyperaldosteronism and hyperprogesteronism in a cat. J Feline Med Surg 2009;11:758-762. 
    9. Quante S, Sieber-Ruckstuhl N, Wilhelm S, et al. Hyperprogesteronism due to bilateral adrenal carcinomas in a cat with diabetes mellitus. Schweiz Arch Tierheilkd 2009;151:437-442. 
    10. Meler EN, Scott-Moncrieff JC, Peter AT, et al. Cyclic estrous-like behavior in a spayed cat associated with excessive sex-hormone production by an adrenocortical carcinoma. J Feline Med Surg 2011;13:473-478. 
    11. Gogerly RL, Coghlan JP, Morgenroth P, et al. A compartmental model of acute stimulation of aldosterone secretion in vivo by potassium and ANG II. Am J Physiol 1993;265:E190-196. 
    12. Pratt JH. Role of angiotensin II in potassium-mediated stimulation of aldosterone secretion in the dog. J Clin Invest 1982;70:667-672. 
    13. Crabbe J, Reddy WJ, Ross EJ, et al. The stimulation of aldosterone secretion by adrenocorticotropic hormone (ACTH). J Clin Endocrinol Metab 1959;19:1185-1191. 
    14. Zimmer C, Horauf A, Reusch C. Ultrasonographic examination of the adrenal gland and evaluation of the hypophyseal-adrenal axis in 20 cats. J Small Anim Pract 2000;41:156-160. 
    15. Peterson ME, Kemppainen RJ. Dose-response relation between plasma concentrations of corticotropin and cortisol after administration of incremental doses of cosyntropin for corticotropin stimulation testing in cats. Am J Vet Res 1993;54:300-304. 
    16. DeClue AE, Martin LG, Behrend EN, et al. Cortisol and aldosterone response to various doses of cosyntropin in healthy cats. J Am Vet Med Assoc 2011;238:176-182. 
    17. 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 Am Vet Med Assoc 1998;212:1569-1571. 
    18. Kerl ME, Peterson ME, Wallace MS, et al. Evaluation of a low-dose synthetic adrenocorticotropic hormone stimulation test in clinically normal dogs and dogs with naturally developing hyperadrenocorticism. J Am Vet Med Assoc 1999;214:1497-1501. 
    19. Lathan P, Moore GE, Zambon S, et al. Use of a low-dose ACTH stimulation test for diagnosis of hypoadrenocorticism in dogs. J Vet Intern Med 2008;22:1070-1073. 
    20. Peterson ME. How to extend your supply of cortrosyn and lower the cost of ACTH stimulation testing. Insights into Veterinary Endocrinology, Blog post, March 22, 2011.
    21. Peterson ME, Kemppainen RJ. Comparison of intravenous and intramuscular routes of administering cosyntropin for corticotropin stimulation testing in cats. Am J Vet Res 1992;53:1392-1395. 
    22. Behrend EN, Kemppainen RJ, Bruyette DS, et al. Intramuscular administration of a low dose of ACTH for ACTH stimulation testing in dogs. J Am Vet Med Assoc 2006;229:528-530.