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.


Thursday, July 3, 2014

Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Diabetes Part 3


Following last week’s post, this 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 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 another of these "top 12" abstracts (finishing up with the diabetes abstracts). Next week, we will turn to the top clinical abstracts dealing with the adrenal gland, and then finish with disorders of the thyroid over the next 2 weeks. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.


Bertalan AV, Drobatz KJ. Hess RS. NPH and Lispro Insulin for Treatment of Dogs with Diabetes Mellitus. J Vet Intern Med 2014;28:1026.

Some dogs, treated with twice-daily NPH insulin and Hill's W/D diet, have postprandial hyperglycemia despite having clinically well-regulated diabetes mellitus (DM). The goal of this study was to determine whether postprandial hyperglycemia and fructosamine concentration can be decreased by adding lispro insulin to the treatment protocol.
      Six dogs were enrolled into this ongoing prospective study. Dogs were enrolled if they had clinically well-regulated DM while treated with NPH insulin and W/D q12 hours and if they had postprandial hyperglycemia defined as an increase in blood glucose concentration (BG) within two hours of NPH insulin administration and feeding. Fructosamine was quantified and BG was measured just before feeding and NPH insulin administration (T0), every 30 minutes for the first 2
hours (T30, T60, T90, T120), and every two hours thereafter for eight additional hours. Dogs were then treated at home with the same NPH insulin dose and W/D, but a separate lispro insulin injection of 0.1 Unit/kg SC was added to the NPH insulin and W/D protocol. Serial BG and fructosamine were measured two weeks later and compared to the original values using the Wilcoxon Signed Rank Test. Median [range] fructosamine (400 μmol/L [289–624 μmol/L]), and BG at T60 (313 mg/dl [187–376 mg/dl]) and T90 (239 mg/dl [166–332 mg/dl]) were significantly higher before lispro insulin was introduced compared to two weeks later (390 μmol/L [253–486 μmol/L]), p = 0.046, 117 mg/dl [42–307 mg/dl]), p = 0.028, and 94 mg/dl [48–197 mg/dl]), p = 0.028, respectively). 
      It is concluded that addition of lispro insulin to an NPH and W/D treatment protocol may significantly decrease fructosamine and postprandial hyperglycemia.

Comments— In this study, addition of a rapid-acting insulin analog (insulin lispro; Humalog, Lilly) to a standard twice-daily NPH insulin regimen appeared to improve glycemic control in dogs with clinically controlled diabetes. This finding is not unexpected, since it is well known that the administration of a short-acting insulin at time of meals will help lessen post-prandial hyperglycemia and lead to improved overall glycemic control in diabetic patients (1-4).

Rapid-acting insulin analogs— Although human recombinant regular insulin is still used as a short-acting insulin by most veterinarians, this insulin has been replaced for the most part with one of the more rapid-acting insulin analogs in human medicine (5-7). One of these newer rapid-acting insulin analogs is insulin lispro, which was the first commercially available insulin analog produced (6,7). Compared with regular human insulin, this insulin analog offers the advantages of faster subcutaneous absorption, an earlier and greater insulin peak, and a shorter duration of action. Although not used frequently in dogs, insulin lispro has been reported by this same group of investigators to be as effective as regular insulin in the treatment of ketoacidosis (8).

Long-acting insulin analogs and analog mixtures—Like human regular insulin, use of human NPH insulin is gradually being phased out and replaced with a mixture of rapid- and long-acting insulin analogs (5-7, 9-11). For example, newly diagnosed insulin-dependent human patients may be treated with a combination of once to twice daily injections of glargine (Lantus) or detemir (Levemir), together with a rapid-acting analog (e.g., insulin lispro or aspart) given at time of meals (11-14). Pre-mixed combinations of a short-acting synthetic insulin analog (i.e., lispro or aspart insulin) with a longer-acting insulin analog (i.e., lispro or aspart protamine insulin) are also commercially available as Humalog Mix 75/25 (Eli Lilly) or NovoLog Mix 70/30 (Novo Nordisk) (5,10). Both of these insulin analog mixtures are given twice daily with meals.

Time interval between insulin injection and meal intake— When a short-acting insulin (either human recombinant regular insulin or lispro) is added to the overall insulin regimen, it is standard protocol that the rapid-acting insulin be given shortly prior to ingestion of the meal (2-4,15,16). This allows enough time for the injected insulin to be absorbed into the circulation and blunt the post-prandial rise in blood glucose concentration. If the insulin injection is delayed until after the meal, severe post-prandial hyperglycemia may develop, which can lead to a clinical state resembling insulin resistance in some patients.

Most veterinarians fail to consider the importance of the time interval between insulin injection and meal intake when evaluating glycemic control in their diabetic dogs on standard insulin protocols. Whenever possible, I like to have my owners inject insulin (NPH, Vetsulin, or NPH/regular combinations) about 20-30 minutes before the dog eats, which allows enough time for insulin to to be partially absorbed and prevent severe post-prandial hyperglycemia (17).  With a more rapidly absorbed insulin, such as lispro, the timing between insulin injection and feeding can likely be shortened to less than 20 minutes. Of course, administering insulin injections prior to feeding is not always possible or even advisable, especially if the dog's appetite is poor or variable.

It is unclear what the time interval was between insulin injection and meal intake in this study by Bertalan et al., since it was not stated. If not given prior to feeding, however, the results might have been improved by using such a protocol.

The Bottom Line— In dogs with problem diabetes, addition of a short-acting insulin to the overall insulin regime may be helpful, especially in those dogs that experience severe post-prandial hyperglycemia.  The interval between insulin injection and meal intake must be taken into consideration when employing this protocol, and the addition of a short-acting insulin would likely be less effective when injected after eating. In any case, further research needs to be done on the effect on the timing of insulin injections and meals in dogs with diabetes mellitus.

Although insulin lispro works well in dogs, a major disadvantage of using any insulin analog, including lispro, is the high cost. All of the insulin analogs are approximately 3 to 5 times more costly than conventional human recombinant NPH, regular, or mixtures of NPH 70/30 insulins.

On a practical basis, there is little reason to use insulin lispro over human regular insulin in dogs, especially when you consider the great difference in cost. Premixed NPH/regular insulin is commercially available as Humulin 70/30 (Eli Lilly) or Novolin 70/30. Both of these commercial preparations contain a 100 U/ml pre-mixed combination of 30% short-acting (regular insulin) and 70% intermediate-acting insulin (NPH). In the USA, the cheapest place to purchase human regular, NPH, and 70/30 combinations is at Walmart, which sells these insulins as the ReliOn Novolin brand for around $25 per vial (19).

Another option, of course, is porcine lente insulin (Caninsulin or Vetsulin), which is actually a mixture of rapid-acting and long-acting insulins (Semi-lente and Ultralente, respectively) (20,21). Although more expensive than the ReliOn Novolin 70/30 insulin, Vetsulin is certainly much more cost effective than any of the insulin analogues. With either insulin preparation, I like to give the injection about 20-30 minutes prior to feeding to ensure that adequate insulin concentrations will be present in the circulation when the meal is absorbed to blunt the rise in blood glucose concentration and help better control the diabetic state (17).

References:
  1. Brownlee M. Insulin treatment of diabetes. Hosp Pract 1979;14:85-94. 
  2. Phillips M, Simpson RW, Holman RR, et al. A simple and rational twice daily insulin regime. Distinction between basal and meal insulin requirements. Q J Med 1979;48:493-506. 
  3. Holman RR, Turner RC. A practical guide to basal and prandial insulin therapy. Diabet Med 1985;2:45-53. 
  4. Zinman B. Insulin regimens and strategies for IDDMDiabetes Care 1993;16 Suppl 3:24-28. 
  5. Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-183. 
  6. Campbell RK, Campbell LK, White JR. Insulin lispro: its role in the treatment of diabetes mellitus. Ann Pharmacother 1996;30:1263-1271. 
  7. Noble SL, Johnston E, Walton B. Insulin lispro: a fast-acting insulin analog. Am Fam Physician 1998;57:279-286, 289-292. 
  8. Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care (San Antonio) 2012; 22:211-218.
  9. Kalra S. Newer basal insulin analogues: degludec, detemir, glargine. J Pak Med Assoc 2013;63:1442-1444. 
  10. Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs 2006;66:31-49. 
  11. Hermansen K, Fontaine P, Kukolja KK, et al. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia 2004;47:622-629. 
  12. Ashwell SG, Gebbie J, Home PD. Optimal timing of injection of once-daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal-times. Diabet Med 2006;23:46-52. 
  13. Ashwell SG, Amiel SA, Bilous RW, et al. Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes. Diabet Med 2006;23:285-292. 
  14. Lucchesi MB, Komatsu WR, Gabbay MA, et al. A 12-wk follow-up study to evaluate the effects of mixing insulin lispro and insulin glargine in young individuals with type 1 diabetes. Pediatr Diabetes 2012;13:519-524. 
  15. MacGillivray MH, Mills BJ, Voorhess ML. Meal intolerance in type 1 diabetes mellitus: influence of time interval between insulin therapy and meal intake. J Med 1984;15:417-435. 
  16. Cobry E, McFann K, Messer L, et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010;12:173-177. 
  17. Peterson ME. New development in the use of insulin mixtures and analogs for the problem diabetic. Proceedings of the 2013 American College of Veterinary Internal Medicine (ACVIM) Forum 2013;534-537.
  18. ReliOn Insulins. http://relion.com/diabetes/insulin
  19. Horn B, Mitten RW. Evaluation of an insulin zinc suspension for control of naturally occurring diabetes mellitus in dogs. Aust Vet J 2000;78:831-834. 
  20. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682.

Thursday, June 26, 2014

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



Following last week’s post, this 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 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 2 more of these "top 12" abstracts (both dealing with issues in diabetes), followed by the remaining 6 abstracts in the next 3 weeks' posts. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.


Claus P, Gimenes, AM, Castro, JR, Schwartz DS. Fructosamine Levels Do Not Agree with Clinical Classification Regarding Diabetic Compensation in Diabetic Dogs Under Treatment. J Vet Intern Med 2014;28:1034-1035.

Fructosamine levels are measured for diabetes management in veterinary medicine, but are rarely used in human clinical practice. A prospective, cross-sectional study was conducted between January 2010 and August 2012 to assess serum fructosamine levels of diabetic dogs under treatment in order to determine glycemic control compared to clinical classification of "compensated" versus "non-compensated," based on clinical signs and owner evaluation of the animal clinical status.
     The study population included 86 dogs: 25 were healthy, non-diabetic dogs (controls), 14 were diabetic dogs at diagnosis, 24 were diabetic under treatment (at least 30 days), and 23 had diabetic ketoacidosis (DKA).
     Compared to controls, serum fructosamine levels were significantly higher for all the diabetic groups, which were similar between each other. Considering all dogs, 8.3% were within the lower level (300–350 mg/dL), 11.9% had excellent glycemic control (350–400 mg/dL), 14.3% had good glycemic control (400–450 mg/dL), 14.3% had regular glycemic control (450–500 mg/dL) and 51.2% had poor control (> 500 mg/dL). Considering dogs under treatment, 95.8% were classified as having poor glycemic control and only 4.2% had a good control. Although 17/24 (70.8%) were clinically classified as "compensated," they all had fructosamine levels > 500 μmol/L; therefore, a poor glycemic control. Only one dog in this group had fructosamine levels indicating good glycemic control, but in this case, the owner had reported polyuria, polydipsia, polyphagia, and therefore, had been classified as non-compensated. Further studies must assess if insulin therapy adjustment based on fructosamine levels, and not only on clinical status, would lead to hypoglycemia episodes.

Study overview— Plasma fructosamine measurements are widely used as an indicator of glycemic control in diabetic dogs and cats (1-6). Because fructosamine is the product of an irreversible reaction between glucose and the amino groups of plasma proteins, it is assumed that its concentration reflects the mean blood glucose concentration of the preceding 1 to 2 weeks. Circulating fructosamine concentrations increase when glycemic control worsens and decrease when glycemic control improves.

In this abstract, the investigators determined that the vast majority (95.8%) of the 24 treated diabetic dogs would have been classified as having poor control, based on their high fructosamine levels (> 500 µmol/L). However, 17 of these 24 poorly-controlled dogs (based on the fructosamine level) were classified as well controlled or "compensated” diabetics based upon the history (i.e., no polyuria, polydipsia, or polyphagia). In contrast, 1 of the treated diabetic dogs was classified as having good control based on the fructosamine concentration, yet was classified clinically as an “uncompensated diabetic” because of owner complaints of continued polyuria, polydipsia and polyphagia. This discordancy between the clinical signs of diabetes and plasma fructosamine levels raised the question whether insulin dose adjustments could be based on fructosamine concentrations alone.

Comments—The discordancy between the clinical status of a treated diabetic patient (compensated versus uncompensated diabetes) and fructosamine levels that indicated poor control was somewhat surprising compared to the results of other published studies (1-4). However, there are several explanations that may account for these findings. These include the following:
  1. The fructosamine reference interval “cut-off values” are too low.
  2. Plasma Fructosamine is a “rear-view mirror” assessment of glycemic control.
  3. Circulating fructosamine concentrations can be quite variable.
Reference interval cut-offs: Reference ranges for plasma fructosamine concentrations differ slightly between laboratories (5). This difference is often due to the commercially-available fructosamine test kit, and the reagents used by each laboratory. Claus et al. adopted a fructosamine reference range where the cut-off for poor regulation is > 500 µmol/L, while others have adopted a wider reference range where the cut-off for poor regulation is defined as a fructosamine > 600 µmol/L (5,6). If the reference range cut-off in this study was raised, many of the dogs categorized as having poor regulation would likely be reclassified as having moderate control.

Rear-view mirror assessment: Many dogs require at least 8 weeks or more to establish adequate glycemic control (6). Fructosamine determinations at 30-60 days may be too early to accurately assess the status of diabetic regulation. In other words, the finding of high plasma fructosamine concentrations, when sampled at 30-60 days after the start on insulin therapy, may be misleading, since fructosamine concentrations reflect the mean blood glucose levels over the preceding 1 to 2 weeks.

Variability: The range of plasma fructosamine concentrations associated with a given blood glucose concentration can be quite wide, even after the fructosamine concentration has plateaued (4). For example in one study, fructosamine concentrations ranged from 400 to 633 µmol/L, with a blood glucose concentration of 523 mg/d (4). Given the large range of plasma fructosamine concentrations for a given glucose concentration, the range of fructosamine concentrations from well controlled and poorly-controlled diabetics will likely overlap.

The Bottom Line—Fructosamine is far from a perfect test, but despite its shortcomings, it remains a valuable adjunct parameter to monitor glycemic control. However, it should always be interpreted in conjunction with the history, physical exam findings and body weight and never used alone to adjust an insulin dose (1,5-7).

References:
  1. Reusch CE, Liehs MR, Hoyer M, et al. Fructosamine. A new parameter for diagnosis and metabolic control in diabetic dogs and cats. J Vet Intern Med 1993;7:177-182.
  2. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996:37;64-68.
  3. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med1996:10:360-364.
  4. Link KR, Rand JS. Changes in blood glucose concentration are associated with relatively rapid changes in circulating fructosamine concentrations in cats. J Fel Med Surg 2008;10;583-592
  5. Reusch CE. Diabetic monitoring. In: Kirk’s Current Veterinary Therapy XV. Elsevier, St Louis, 2014; 193-199.
  6. Feldman EC, Nelson RW. Canine diabetes mellitus. In: Canine and Feline Endocrinology and Reproduction. 3rd ed, Elsevier, St Louis, 2004; 510.
  7. Briggs CE, Nelson RW, Feldman EC, et al. Reliability of history and physical examination findings for assessing control of glycemia in dogs with diabetes mellitus: 53 cases (1995-1998). J Am Vet Med Assoc 2000;217; 48-53.

Gostelow R, Scudder C, Keyte S, Forcada Y, Fowkes RC; Schmid HA, Church DB, Niessen SJM. Pasireotide (SOM230) Long-Acting Release Treatment for Feline Hypersomatotropism: A Proof of Concept Trial.  J Vet Intern Med 2014;28:1030.

Hypersomatotropism (HS) is a relatively common cause of feline diabetes mellitus. Attempts at its long-term medical management with somatostatin (sst) analogues have previously proven unrewarding. However, pasireotide (SOM230, Novartis, Basel, Switzerland), a novel sst analogue with binding affinity for sst receptor subtypes 1, 2, 3 and 5, was recently shown capable of decreasing serum insulin-like growth factor 1 (IGF-1) and improving insulin sensitivity in cats with HS when administered for 3 days as a short-acting, BID subcutaneous (SC) preparation. A long-acting release formulation (LAR) has been developed to allow convenient, once-monthly dosing and has led to successful biochemical control of human HS. The current study aimed to assess the potential of once-monthly pasireotide LAR as a treatment for feline HS.
      Feline HS was diagnosed in 12 diabetic cats based on increased serum IGF-1 (> 1000 ng/ml) and pituitary enlargement on computed tomography. Cats received 8 mg/kg SC pasireotide LAR once monthly for 6 months. Fructosamine concentration, IGF-1 concentration, and a 12-hour blood glucose curve (BGC) were performed at baseline and once monthly thereafter to monitor treatment response. A repeat CT-scan was performed at the end of the trial. A mixed-effects model was used to assess significance of changes in fructosamine, IGF-1 concentration, mean blood glucose (MBG) of BGCs, and insulin dose (U/kg).
       Seven of 12 cats completed the trial; 3 of 12 cats entered diabetic remission. Trial withdrawal occurred after a median of 2 months (range 1–4.5 months) due to persistence of uncontrolled diabetes mellitus (n = 1), diarrhoea (n = 2), a hypoglycemic event (n = 1), and an episode of diabetic ketoacidosis (n = 1). A significant decrease in IGF-1 (p < 0.001), insulin dose (p < 0.001), fructosamine (p = 0.04), though not MBG (p = 0.71) was documented. Adverse events included soft stools (9/12), worsening polyphagia (3/12), hypoglycaemia (4/12), and delayed hair regrowth (1/12). Maximum pituitary mass height had increased in 2/7, decreased in 4/7 and remained the same in 1/7 cats.
      In summary, pasireotide LAR is the first drug that shows potential to cause long-term biochemical and clinical improvement in cats with HS. In a proportion of cases, diabetic remission can even be achieved. Further work should focus on dose optimisation to enable higher success and lower withdrawal rates, specifically by trying to reduce adverse gastrointestinal events. The observed decrease in pituitary tumor size in some cats further establishes this as a useful primary, long-term treatment modality, although its preoperative use, enabling glycemic stabilization and tumor shrinkage before hypophysectomy, may also be of benefit.

Comments— Pasireotide (SOM230, trade name Signifor, Novartis) is an orphan drug approved for the treatment of Cushing’s disease in adult human patients when surgery has failed or is not an option (1). The drug is a somatostatin analog that targets multiple somatostatin receptors with high affinity. The result is apoptosis of those cells that produce ACTH, with significant lowering of plasma ACTH levels (2,3).

In addition, pasireotide has been shown to suppress GH and IGF -1 in rodents, as well as in human patients with acromegaly (4). Moreover, recent results of a phase III study of human patients treated with a long-acting release (LAR) form of pasireotide (Pasireotide LAR) showed that this novel form of therapy is significantly more effective than the current standard therapy with octreotide LAR or landreotide autogel (ATG) (5,6).

This study by Niessen's group showed that a once monthly injection of Pasireotide LAR to cats with acromegaly has the potential to cause a significant decrease in IGF-1 and GH levels, shrinkage of the GH-secreting pituitary tumor, and diabetic remission in cats with acromegaly.

The Bottom Line— To date, the only effectve treatment options for cats with acromegaly are transsphenoidal surgery or radiation therapy. Both of these treatments are quite costly and not widely available; in addition, they are associated with modest risk for patient morbidity and mortality and can have variable efficacy (7,8).

The idea that medical therapy for acromegaly is now a viable option is great news, but any new treatment that may change the therapeutic landscape for any disorder should be met with cautious optimism. In other words, it is important to remember that cats with acromegaly, just like in people with the same disorder, may have a variable response to medical therapy (9-12). For example, 5 of 12 cats in the current clinical trial had to be withdrawn from the study; 3 because of issues related to poor diabetes management and 2 because of diarrhea, which is a common adverse effect associated with somatostatin analogs. In addition, pituitary tumor shrinkage, which is a function of tumor size, tumor type (well differentiated versus poorly differentiated tumor cells), and the density and expression of specific somatostatin receptors, should not be expected to occur in all cases (9-12). Moreover, even if circulating GH values fall, diabetic remission or improved glycemic control may not occur for multiple reasons; for example, hyperglycemia is seen in a significant proportion of human patients treated with pasireotide, presumably because the drug inhibits insulin release (2-6).

And lastly, especially for cats, another drawback to use of pasireotide LAR is its high cost, which is estimated at $2000 per cat per year. However, it may be possible to use this agent at lower doses or at less frequent intervals, with obvious cost implications (13). Further research is obviously needed to determine these issues.

References:
  1. Signifor Official Site - Signifor (Pasireotide) Injection. Signifor. US. 
  2. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med 2012;366:914-924. 
  3. McKeage K. Pasireotide: a review of its use in Cushing's disease. Drugs 2013;73:563-574. http://www.ncbi.nlm.nih.gov/pubmed/23605695
  4. Petersenn S, Farrall AJ, Block C, et al. Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study. 2014;17:132-140. 
  5. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab 2014;99:791-799. 
  6. Gadalha M, Bronstein M, Brue T, et al. Pasireotide LAR demonstrates superior efficacy versus Octreotide LAR and landreotide ATG in patients with inadequately controlled acromegaly: Results from a Phase III, multicenter, randomized study. 16th European Congress of Endocrinology. 2014; 35: P907. 
  7. Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 2009;94:1509-1517. 
  8. Gittoes NJ, Sheppard MC, Johnson AP, et al. Outcome of surgery for acromegaly--the experience of a dedicated pituitary surgeon. QJM 1999;92:741-745. 
  9. Casarini AP, Jallad RS, Pinto EM, et al. Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 2009;12:297-303. 
  10. Casarini AP, Pinto EM, Jallad RS, et al. Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3. J Endocrinol Invest 2006;29:826-830. 
  11. Ezzat S, Kontogeorgos G, Redelmeier DA, et al. In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide. Eur J Endocrinol 1995;133:686-690. 
  12. Bhayana S, Booth GL, Asa SL, et al. The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab 2005;90:6290-6295. 
  13. Turner HE, Thornton-Jones VA, Wass JA. Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly. Clin Endocrinol (Oxf) 2004;61:224-231.