Feline Adrenal Disorders

Feline Adrenal Disorders Deirdre Chiaramonte, DVM, DACVIM,* and Deborah S. Greco, DVM, PhD, DACVIM† Although only recently discovered, feline adrenal disorders are becoming increasingly more recognized. Feline adrenal disorders include diseases such as hyperadrenocorticism (Cushing’s syndrome) and hyperaldosteronism (Conn’s syndrome). The clinical signs of feline hyperadrenocorticism, which include unregulated diabetes mellitus and severe skin atrophy, are unique to the cat. Other signs of feline hyperadrenocorticism, such as potbellied appearance, polydipsia, polyuria, and susceptibility to infections are also seen in dogs with hyperadrenocorticism. Conn’s syndrome has only recently been described in the cat and is in fact more common in cats than in dogs. Characterized by severe hypokalemia, hypertension, and muscle weakness, Conn’s syndrome may be misdiagnosed as renal failure. The clinician should become familiar with the clinical signs of adrenal disorders in cats and the common diagnostic tests used to diagnose these syndromes in cats as they differ from those in the dog. Treatment of feline adrenal disorders may be challenging; the clinician should become familiar with common drugs used to treat adrenal disorders in cats. Clin Tech Small Anim Pract 22:26-31 © 2007 Elsevier Inc. All rights reserved. KEYWORDS adrenal disorder, Cushing’s syndrome, hyperadrenocorticism, Conn’s syndrome

F

eline Cushing’s syndrome (FCS) is a disorder of excessive cortisol secretion by the adrenal glands. FCS is most often caused by a pituitary adenoma with subsequent corticotrophic hyperplasia and excess adrenocortical cortisol secretion.1-7 Also found in cats with FCS are autonomously functioning benign adenomas (50%) or malignant adrenal carcinomas (50%).4,6 Iatrogenic FCS due to glucocorticoid administration is rare in cats.8,9 Differential diagnoses include diabetes mellitus, insulin resistance, acromegaly, hepatopathy, renal disease, sex hormone-secreting adrenal tumors, and hyperthyroidism.10

in cats are insulin-resistant DM, cutaneous atrophy, polydipsia, polyuria, polyphagia, lethargy, abdominal enlargement or potbelly, panting, obesity, muscle weakness, and recurrent upper respiratory and urinary tract infections.1-8 On physical examination, the most commonly noted abnormalities include abdominal enlargement, hepatomegaly, bilaterally symmetric alopecia, cutaneous atrophy with open sores, and seborrhea (Figs. 1-3). Lethargy (dullness) has been reported due to muscle weakness or the effects of a pituitary mass. Excess sex hormones, such progesterone, have also been identified in cats with FCS.6,7

Age, Breed, and Sex

Routine Laboratory Findings

Pituitary-dependent hyperadrenocorticism (HAC) is usually a disease of the middle-aged to older cat in the range of 5 to 16 years and a median age of 10 years.1-7 There is a slight difference in sex distribution in feline HAC; female cats are slightly more (60%) likely to develop the disease than males.3-5 No breed predilection has been found.

In the dog, the most common serum chemistry abnormality observed in association with HAC is an increased serum alkaline phosphatase activity (ALP), which is high in 85 to 90% of dogs.1-6 However, in the cat serum ALP is not elevated because of hypercortisolemia but rather is a result of poorly regulated concomitant DM. This occurs because cats lack the glucocorticoid-induced isoenzyme for ALP. High serum alanine transferase activity (ALT), hypercholesterolemia, hyperglycemia, and low blood urea nitrogen (BUN) are also common findings. The hemogram may reveal a mild erythrocytosis as well as a classic “stress leukogram” (ie, eosinopenia, lymphopenia, and mature leukocytosis). Although in dogs with HAC, the urine specific gravity is usually less than 1.015, cats often show concentrated urine specific gravity (⬎1030) despite profound polydipsia and polyuria resulting from the concurrent DM.11 Finally, many cats with HAC have evidence of urinary tract infection without pyuria (positive culture), bacteriuria, and proteinuria resulting from glomerulosclerosis.1-7

History, Clinical Signs, and Physical Examination Feline HAC is usually (80%) accompanied by diabetes mellitus (DM).10 The most common clinical signs associated with HAC

*The Animal Medical Center, New York, New York. †Nestle Purina Petcare, St. Louis, Missouri. Address reprint requests to Deirdre Chiaramonte, DVM, DACVIM, The Animal Medical Center, 510 East 62nd Street, New York, NY 10021. E-mail: [email protected]

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1096-2867/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.ctsap.2007.02.004

Feline adrenal disorders

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Figure 1 Cat with pituitary-dependent hyperadrenocorticism showing potbellied appearance. (Color version of figure is available online.)

Screening Tests Urinary Cortisol: Creatinine Ratio The urine cortisol:creatinine ratio (UCCR) is a simple and valuable screening test for HAC in cats.11 To perform this test, the owner is instructed to collect morning urine samples from an empty litter box at the same time of day on two to

three consecutive days. Special precautions are needed for the urine collection itself (no contamination with litter) and the urine samples should be kept refrigerated. This home-collection protocol avoids the “stress” of a visit to the veterinary clinic. After submission of the cat’s morning urine samples to the laboratory for determination of cortisol and creatinine con-

Figure 2 Skin lesions in a cat with hyperadrenocorticism. (Color version of figure is available online.)

D. Chiaramonte and D.S. Greco

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Figure 3 Alopecia, rat tail, and pendulous abdomen in a cat suffering from hyperadrenocorticism. (Color version of figure is available online.)

centrations, the veterinarian should average the results of the two to three UCCR. The mean urine UCCR differentiates between clinically normal cats and cats with HAC. A high mean cortisol:creatinine ratio will be found in most cats with hyperadrenocorticism; however, the cortisol:creatinine ratio is also high (false-positive) in many cats with nonadrenal illness.11,12 A high cortisol:creatinine ratio in a cat with concurrent disease should be confirmed with a low-dose dexamethasone suppression test. Although the low-dose dexamethasone suppression test is typically performed by measuring serum or plasma cortisol concentrations before and after dexamethasone injection, measurement of UCCR in samples collected before and after administration of a low dose of oral dexamethasone has also been described. This protocol is described in the article on diagnosis of Cushing’s syndrome in dogs by Peterson in this issue. Low-Dose Dexamethasone Suppression Test The low-dose dexamethasone suppression test is considered by many to be the test of choice for the diagnosis of HAC in cats.3,4 It requires 10 times the dose used in dogs or 0.1 mg/kg IV. Plasma is obtained for cortisol concentrations before, 4 hours after, and 8 hours after dexamethasone administration. If the low dose of dexamethasone (0.1 mg/kg) fails to adequately suppress circulating cortisol concentrations in a cat with compatible clinical signs, this is consistent with a diagnosis of HAC. Normal cats and cats with nonadrenal illness will show adequate suppression of serum or plasma cortisol (ie, ⬍1 \’6 dg/dL or ⬍30 nmol/L) at 4 and 8 hours post dexamethasone administration. However, in contrast to dogs with pituitary dependent hyperadrenocorticism (PDH), many cats with PDH will not suppress at 4 hours and a few cats will suppress at 8 hours after dexamethasone administration. Corticotropin (ACTH) Stimulation Test The ACTH stimulation test, mainly a test of adrenal reserve, requires little time, is easy to interpret, and can be used to

document iatrogenic HAC.6,13 Only 50 to 60% of cats with HAC have an exaggerated response to ACTH administration, with post-ACTH serum cortisol concentrations rising to greater than 16 \’6 dg/dL (⬎400 nmol/L). The preferred method for ACTH stimulation testing in cats is to determine serum cortisol concentrations 30 minutes before and 1 hour after the intravenous or intramuscular injection of cosyntropin (Cortrosyn, Amphastar Pharmaceuticals, Rancho Cucamonga, CA), administered at a dosage of at least 5 \’6 dg/kg.3,4,19,20

Differentiation Tests High-Dose Dexamethasone Suppression Test The high-dose dexamethasone suppression test (HDDST) is performed by administering a high dose of dexamethasone (1 mg/kg IV) in a protocol identical to the low-dose dexamethasone suppression test (LDDST). An at-home version using multiple UCCRs and oral dexamethasone is easier to perform and interpret than the in-hospital protocol. Plasma Endogenous ACTH Concentration Endogenous ACTH concentrations are normal to high in cats with pituitary-dependent HAC (eg, ⬎80 pg/mL or ⬎18 pmol/L), whereas ACTH concentrations are usually low or undetectable (eg, ⬍20 pg/mL or ⬍4.4 pmol/L) in cats with adrenal tumors or with iatrogenic HAC. Samples for accurate endogenous ACTH concentration determination must be collected in EDTA tubes and centrifuged immediately; the plasma is then placed into plastic or polypropylene tubes (ACTH will stick to glass) and immediately frozen until the assay is performed. Abdominal Ultrasonography As with the dog, ultrasonography can be used to differentiate between PDH from adrenal tumors in the cat.14 Symmetric adrenal glands of normal or enlarged size are suggestive of PDH, whereas unilateral enlargement supports ATH. With

Feline adrenal disorders abdominal ultrasonography, small or noncalcified unilateral adrenal tumors can generally be readily detected, and bilateral adrenal enlargement can be visualized in cats with pituitary-dependent HAC.14 Ultrasonography may, in addition, detect the presence of liver metastasis or invasion of the vena cava from an adrenal carcinoma. The contralateral adrenal gland would be expected to be small in cats with unilateral cortisol-secreting tumor due to the fact that pituitary ACTH secretion has been chronically suppressed. Computed Tomography and Magnetic Resonance Imaging Computed tomography (CT) and magnetic resonance imaging (MRI) are reliable methods to image either the adrenals or the pituitary glands.15 As with dogs, bilateral adrenal enlargement can be readily differentiated from a unilateral adrenal tumor in most cats. CT or MRI is most helpful in diagnosis of pituitary tumors; however, MRI provides superior soft-tissue contrast as compared with CT and also is more accurate for visualization of smaller pituitary tumors.

Treatment Medical therapy has been successful in some cats with HAC; however, the majority of cats do not respond to mitotane (Lysodren (o=p=-DDD)–Bristol-Myers Squibb).16 Trilostane is an orally administered competitive inhibitor of 3-betahydroxysteroid dehydrogenase, the enzyme that mediates the conversion of pregnenolone to progesterone and, hence, its end-products (cortisol, aldosterone, and androstenedione) in the adrenals. Studies in cats with HAC have shown that trilostane is an effective steroid inhibitor that is associated with minimal side effects.17-19 Trilostane is administered at a dosage of 30 to 60 mg per cat per day. Trilostane therapy is monitored with weekly ACTH stimulation tests to obtain cortisol concentrations of ⬍5 ␮g/dL on the pre- and postACTH samples. Although currently unavailable in the United States, trilostane may prove to be a reasonable alternative to mitotane therapy for HAC in cats. Surgical Therapy Surgical treatment of feline HAC consists of unilateral or, more commonly, bilateral adrenalectomy.20-22 The reader is referred to surgical texts for an explanation of the surgical procedure; however, medical management of the cat during the operative and postoperative period is essential for a good outcome. Before adrenalectomy, the cat should be regulated on trilostane until the skin lesions of HAC have resolved and DN, if present, is reasonably well controlled (no ketones). With bilateral adrenalectomy, glucocorticoid (10-20 mg methylprednisolone acetate, DepoMedrol IM) and mineralocorticoid (deoxycorticosterone acetate, 12.5 mg IM) supplementation should be initiated immediately before adrenalectomy and monthly thereafter for the rest of the cat’s life. Complications following adrenalectomy include dehiscence, poor wound healing, Addisonian crises, and enlargement of the pituitary tumor, which may result in blindness or seizures (Nelson’s syndrome). Response to bilateral adrenalectomy is usually good, with most cats having a resolution of clinical signs in 2 to 4 months. In approximately 50% of cases, DM resolves completely and in the other 50% insulin requirements are decreased dramatically. Transsphenoidal hypoph-

29 ysectomy for the treatment of feline PDH is a viable alternative to adrenalectomy; however, this procedure is not performed in the United States.23 Radiation Therapy Because approximately 85% of cats with HAC have PDH, radiation therapy is another treatment option for many patients; however, radiation therapy is expensive ($1500 to $2000) and time-consuming (3 weeks’ duration). Radiation therapy is an effective method of treatment in cats associated with low morbidity, but signs of PDH may take several months to subside in treated animals.24 The major advantage of pituitary irradiation is that the primary disorder, a pituitary tumor, has been addressed. Cats with FCS that undergo bilateral adrenalectomy followed by pituitary irradiation have the best prognosis and many will live a normal life (with resolution of the DM) following these procedures.24

Feline Hyperaldosteronism Feline hyperaldosteronism may be caused by a unilateral aldosterone-secreting adrenal tumor or bilateral adrenal hyperplasia.25-30 Tumors of the adrenal are usually benign; however, reports of an adrenocortical carcinoma secreting aldosterone have been described.28 Oversecretion of aldosterone results in the classic electrolyte changes of hypokalemia, hypernatremia, and metabolic alkalosis (opposite of Addison’s disease). However, primary hyperaldosteronism and secondary hyperaldosteronism caused by renal disease may be difficult to differentiate (Fig. 4). Hyperaldosteronism is associated with clinical signs resulting from systemic hypertension caused by expansion of blood volume or by polymyopathy resulting from hypokalemia. There is no breed predilection; however, reported cases tend to occur in older cats with a mean age of about 10 years and a range of 6 to 13 years. In a report of 13 cases of primary hyperaldosteronism in cats, the most common clinical sign was hypokalemic polymyopathy (n ⫽ 13), presenting as ventroflexion of the neck (Fig. 5), in 11 cats, paresis in 3 cats, and hindlimb weakness in 3 cats.26 Less commonly, hypertension (n ⫽ 11), fundic changes (n ⫽ 5; Fig. 6), blindness (n ⫽ 2 cats), polydipsia and polyuria (n ⫽ 3), and polyphagia (n ⫽ 2) were observed.26

Figure 4 Classification of primary versus secondary hyperaldosteronism.

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D. Chiaramonte and D.S. Greco

Figure 5 Cat with severe cervical ventroflexion from hypokalemia secondary to hyperaldosteronism. (Color version of figure is available online.)

The most common laboratory findings were moderate to severe hypokalemia (mean, 2.5 mmol/L; range, 1.9-3.2) in all 13 cats; elevations in serum creatine kinase was observed in 10 cats. Only one cat exhibited hypernatremia and no cats showed metabolic alkalosis (a characteristic of hyperaldosteronism in human beings).26 Also surprising was the low in-

cidence of azotemia in these cats with only two cases showing elevations of both serum creatinine and BUN. Urine-specific gravity was normal in most of the cats; however, two cats did show isosthenuria. Elevated plasma aldosterone concentrations were measured in all 13 cases; the values ranged from 877 to 14,653 pmol/L with a mean value of 5820 pmol/L.

Figure 6 Retinal hemorrhage in a cat with bilateral adrenal hyperplasia, high blood pressure (⬎200 mm Hg), and evidence of primary hyperaldosteronism. (Color version of figure is available online.)

Feline adrenal disorders Plasma renin activity (PRA) was not measured in any of the cases. Abdominal ultrasonography revealed unilateral adrenal enlargement (1-3.5 cm) with an adrenal mass in 11/13 cases, all of which were biopsied and diagnosed as adrenal adenomas (seven cats) or carcinomas (six cats); two cats had bilateral adrenal enlargement with adenomas on postmortem examination.26 Treatment of cats with primary hyperaldosteronism resulting from a unilateral adrenal tumor consists of potassium supplementation (Tumil K, 2-6 mmol PO), an aldosterone blocker such as spironlolactone (2.5 mg q 12 h PO), and amlodipine (0.125 mg q 24 h PO). None of the reported cases showed a normalization of serum potassium with supplementation; however, all cats showed resolution of the clinical signs of hypokalemia.26 All but 2 of the 11 hypertensive cats became normotensive on calcium channel therapy. Three cats were treated medically and eventually euthanatized due to chronic progressive renal failure. Surgical removal of the adrenal mass has been considered the treatment of choice in most cases.25,26,29 Eight cats were taken to surgery and five survived for 240 to 1803 days at the time of the article was written.26 In cats with primary hyperaldosteronism caused by benign bilateral adrenal hyperplasia, hypertension, blindness, and renal failure are more common than signs of hypokalemia (ie, muscle weakness, cervical ventroflexion, paresis).26,30 In a study of 11 cats with primary hyperaldosteronism, the cats were more likely to be older (range, 11-18 years) and have higher systolic blood pressure (185-270 mm Hg) than the cats with adrenal tumors.30 Many of the affected cats exhibited ocular signs of hypertension such as retinal hemorrhage, hyphema, retinal detachments, and blindness (Fig. 6); in contrast, only two cats with adrenal tumors exhibited blindness as a clinical sign. Classic laboratory abnormalities observed in primary aldosteronism such as hypokalemia (6/11), elevated CK, and metabolic alkalosis are less commonly observed in cats with bilateral adrenal hyperplasia.30 Hypernatremia was not observed in cats with bilateral adrenal hyperplasia. Azotemia was observed in 8 of the 11 cats.30 In the case of bilateral adrenal hyperplasia, diagnosis was achieved by documentation of increased plasma aldosterone (N ⫽ 150-430 pmol/L), low to undetectable PRA, and/or increased plasma aldosterone concentration (PAC) to PRA ratios (PAC:PRA, normal ⫽ 0.3-3.8). In contrast to the previous study of adrenal tumors producing aldosterone, only four cats with bilateral adrenal hyperplasia had elevated PAC.30 PRA was measured in all 11 cats in this study and was found to be abnormally low in 7 of the 11 cats.30 However, all 11 cats showed a high PAC:PRA ratio (range, 4.0 to ⬎41). Because idiopathic adrenal hyperplasia resulting in hyperaldosteronism is a bilateral disease, medical treatment is the only option available. Treatment of cats with primary hyperaldosteronism resulting from a bilateral adrenal hyperplasia consists of potassium supplementation (Tumil K, 2-6 mmol 2 PO), an aldosterone blocker such as spironlolactone(6.25 mg q 12 h PO), and antihypertensive therapy such as amlodipine (0.125 mg q 24 h PO) or beta-blockers (atenelol). Most of the cats with bilateral adrenal hyperplasia eventually succumb to progressive renal insufficiency.30

References 1. Peterson ME, Steele P: Pituitary-dependent hyperadrenocorticism in a cat. J Am Vet Med Assoc 189(6):680-683, 1986

31 2. Zerbe CA, Nachreiner RF, Dunstan RW, et al: Hyperadrenocorticism in a cat. J Am Vet Med Assoc 190(5):559-563, 1987 3. Nelson RW, Feldman EC, Smith MC: Hyperadrenocorticism in cats: seven cases (1978-1987). J Am Vet Med Assoc 193(2):245-250, 1988 4. Immink WF: Four cats with Cushing’s syndrome. Tijdschr Diergeneeskd 116:87S-88S, 1991 (suppl 1) 5. Rossmeisl JH Jr, Scott-Moncrieff JC, Siems J, et al: Hyperadrenocorticism and hyperprogesteronemia in a cat with an adrenocortical adenocarcinoma. J Am Anim Hosp Assoc 36(6):512-517, 2000 6. Watson PJ, Herrtage ME: Hyperadrenocorticism in six cats. J Small Anim Pract 39(4):175-184, 1998 7. Boord M, Griffin C: Progesterone secreting adrenal mass in a cat with clinical signs of hyperadrenocorticism. J Am Vet Med Assoc 214(5): 666-669, 1999 8. Schaer M, Ginn PE: Iatrogenic Cushing’s syndrome and steroid hepatopathy in a cat. J Am Anim Hosp Assoc 35(1):48-51, 1999 9. Ferasin L: Iatrogenic hyperadrenocorticism in a cat following a short therapeutic course of methylprednisolone acetate. J Feline Med Surg 3(2):87-93, 2001 10. Nichols R: Complications and concurrent disease associated with diabetes mellitus. Semin Vet Med Surg (Small Anim) 12(4):263-7, 1997 11. Goossens MM, Meyer HP, Voorhout G, et al: Urinary excretion of glucocorticoids in the diagnosis of hyperadrenocorticism in cats. Domest Anim Endocrinol 12(4):355-362, 1995 12. de Lange MS, Galac S, Trip MR, et al: High urinary corticoid/creatinine ratios in cats with hyperthyroidism. J Vet Intern Med 18(2):152-155, 2004 13. Schoeman JP, Evans HJ, Childs D, et al: Cortisol response to two different doses of intravenous synthetic ACTH (tetracosactrin) in overweight cats. J Small Anim Pract 41(12):552-557, 2000 14. Widmer WR, Guptill L: Imaging techniques for facilitating diagnosis of hyperadrenocorticism in dogs and cats. J Am Vet Med Assoc 206(12): 1857-1864, 1995 15. Mauldin GN, Burk RL: The use of diagnostic computerized tomography and radiation therapy in canine and feline hyperadrenocorticism. Probl Vet Med 2(4):557-564, 1990 16. Moore LE, Biller DS, Olsen DE: Hyperadrenocorticism treated with metyrapone followed by bilateral adrenalectomy in a cat. J Am Vet Med Assoc 217(5):691-694, 673, 2000 17. Skelly BJ, Petrus D, Nicholls PK: Use of trilostane for the treatment of pituitary-dependent hyperadrenocorticism in a cat. J Small Anim Pract 44(6):269-272, 2003 18. Boag AK, Neiger R, Church DB: Trilostane treatment of bilateral adrenal enlargement and excessive sex steroid hormone production in a cat. J Small Anim Pract 45(5):263-266, 2004 19. Neiger R, Witt AL, Noble A, et al: Trilostane therapy for treatment of pituitary-dependent hyperadrenocorticism in 5 cats. J Vet Intern Med 18(2):160-164, 2004 20. Schwedes CS: Mitotane (o,p=-DDD) treatment in a cat with hyperadrenocorticism. J Small Anim Pract 38(11):520-524, 1997 21. Duesberg CA, Nelson RW, Feldman EC, et al: Adrenalectomy for treatment of hyperadrenocorticism in cats: 10 cases (1988-1992). J Am Vet Med Assoc 207(8):1066-1070, 1995 22. Ivan Sluijs FJ, Sjollema BE: Adrenalectomy in 36 dogs and 2 cats with hyperadrenocorticism. Tijdschr Diergeneeskd 117:29S, 1992 (suppl 1) 23. Meij BP, Voorhout G, Van Den Ingh TS, et al: Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats. Vet Surg 30(1):72-86, 2001 24. Mayer MN, Greco DS, LaRue SM: Outcomes of pituitary tumor irradiation in cats. J Vet Intern Med 20(5):1151-1154, 2006 25. Flood SM, Randolph JF, Gelzer AR, et al: Primary hyperaldosteronism in two cats. J Am Anim Hosp Assoc 35(5):411-416, 1999 26. Ahn A: Hyperaldosteronism in cats. Semin Vet Med Surg (Small Anim) 9(3):153-157, 1994 27. DeClue AE, Breshears LA, Pardo ID, et al: Hyperaldosteronism and hyperprogesteronism in a cat with an adrenal cortical carcinoma. J Vet Intern Med 19(3):355-358, 2005 28. Rijnberk A, Voorhout G, Kooistra HS, et al: Hyperaldosteronism in a cat with metastasised adrenocortical tumour. Vet Q 23(1):38-43, 2001 29. MacKay AD, Holt PE, Sparkes AH: Successful surgical treatment of a cat with primary aldosteronism. J Feline Med Surg 1(2):117-122, 1999 30. Javadi S, Djajadiningrat-Laanen SC, Kooistra HS, et al: Primary hyperaldosteronism, a mediator of progressive renal disease in cats. Dom Anim Endocrinol 28:85-104, 2005