Feline Adrenal Disease
David Bruyette United States
Hyperadrenocorticism develops most commonly in middle-aged to older cats (mean age = 10.4 years; range 6–15 years). Of the 26 reported cases of feline Cushing's syndrome and one previously unreported case, 21 (78%) have been females. This female sex predilection resembles the human syndrome and contrasts with canine hyperadrenocorticism, where no sex predilection occurs. The most common historical and clinical signs associated with feline hyperadrenocorticism are polyuria, polydipsia, and polyphagia. These signs likely correspond to the high incidence of concurrent diabetes mellitus (76%) found in cats with hyperadrenocorticism, and are consistent with the lack of overt signs preceding marked glucose intolerance observed in experimentally-induced disease.
The typical “Cushingoid” pot-bellied appearance with hepatomegaly, weight gain, and generalized muscle wasting is common in cats as in dogs. Dermatologic abnormalities frequently recognized include an unkempt haircoat with patchy alopecia, and very thin skin prone to traumatically induced tears and secondary infections. Hyperglycemia is the most common laboratory abnormality found on serum biochemistries. Cats appear more sensitive to the diabetogenic effects of glucocorticoid excess than dogs. Cats with concurrent diabetes mellitus often exhibit cortisol-induced insulin resistance, requiring high daily doses of insulin to control their hyperglycemia and glucosuria. Hypercholesterolemia is also common, and may relate to insulin resistance and increased lipolysis. Increases in SAP and the hepatocellular enzyme ALT appear to correspond with the regulation of the diabetic state, rather than representing direct indicators of glucocorticoid excess. These enzymes frequently normalize with adequate regulation of diabetes, even without therapy directed towards the hyperadrenocorticism.
Hematologic findings associated with hypercortisolemia (lymphopenia, eosinopenia, and neutrophilic leukocytosis) occur inconsistently in feline hyperadrenocorticism. Despite clinical polyuria and polydipsia, cats appear to maintain urine specific gravities of greater than 1.020 more frequently than dogs; they only occasionally exhibit the dilute urine and decreased blood urea nitrogen concentrations commonly seen in dogs with hyper-adrenocorticism.
Endocrinologic evaluation of cats suspected of hyperadrenocorticism involves screening tests to confirm the diagnosis, and differentiating tests to distinguish pituitary-dependent disease (PDH) from adrenal tumors (AT). Adrenocorticotropin (ACTH) stimulation testing in adrenocortical hyperfunction is not as definitive as for hypoadrenocorticism. Fifteen to 30% of cats with confirmed hyperadrenocorticism have had normal cortisol response to ACTH administration (false negatives). In addition, stressed cats and those with non-adrenal illnesses may show an exaggerated response to ACTH in the absence of hyperadrenocorticism (false positives). A normal urine cortisol-to-creatinine ratio (UCCR) can be used to exclude the diagnosis of hyperadrenocorticism in cats as described in dogs. The UCCR is attractive due to the ease of sampling compared to other endocrine function tests, but is non-specific and will be elevated in a variety on non-adrenal illnesses. An exaggerated ACTH stimulation test or an elevated UCCR should be pursued with suppression testing prior to initiating any therapy.
Normal cats are more variable than dogs with respect to the degree and duration of adrenocortical suppression following dexamethasone administration. Intravenous doses of dexamethasone that have been evaluated in the cat range from 0.005 to 1.0 milligrams per kilogram. A dosage of 0.01 mg/kg of dexamethasone, commonly used in low-dose dexamethasone suppression testing in dogs, led to a significant drop in serum cortisol levels in ten normal cats, but two of the cats showed a slight escape from suppression by eight hours after injection. Intravenous dexamethasone sodium phosphate (DSP), 0.01 and 0.1 mg/kg, produced equivalent reductions of plasma cortisol levels, but suppression was sustained below baseline longer with the higher dosage.
Cats with various non-adrenal illnesses have also shown inadequate cortisol suppression after a low-dose (0.01 mg/kg) of DSP. The 0.1 mg/kg dosage of dexamethasone seems to more reliably suppress cortisol levels in normal cats and cats with non-adrenal illnesses. Elevated cortisol levels eight hours post-dexamethasone injection, using the 0.1 mg/kg dosage, appears to be as sensitive a diagnostic test for feline hyperadrenocorticism (8/9; 89%) as the low-dose (0.01 mg/kg) screening test in the dog.
The combined dexamethasone suppression/ACTH stimulation test has been used successfully to diagnose hyperadrenocorticism in the cat. Hyperadrenocorticoid cats displayed inadequate suppression of cortisol two to four hours after an injection of 0.1 mg/kg of dexamethasone, and an exaggerated response one to two hours after ACTH stimulation. The ability of the combined test to discriminate PDH from AT is unclear. Several cats with confirmed pituitary disease failed to suppress 2-4 hours after dexamethasone. Extending the duration of post-dexamethasone monitoring, or using higher doses of DSP may improve the ability of the combined test to distinguish PDH from AT. Currently, the combined test does not appear to offer more clinical utility than either the ACTH stimulation or dexamethasone suppression test evaluated separately. An ultra-high dose, 1.0 mg/kg, dexamethasone suppression test has been used to distinguish PDH from AT in the cat. Two cats with hyperadrenocorticism diagnosed by the combined high dose dexamethasone suppression/ ACTH stimulation test had exaggerated responses to ACTH with no cortisol suppression two to four hours after 0.1 mg/kg DSP. These cats did suppress following the ultra-high dose of dexamethasone and were later confirmed to have PDH.
Cortisol levels should be monitored at several time points following dexamethasone administration to determine if any suppression (a 50% or greater reduction in pre-test values) is occurring. Cats with PDH may show suppression 2, 4, or 6 hours into the test only to escape from the suppressive effects of dexamethasone by eight hours. One cat with an adrenal adenoma failed to suppress following dexamethasone doses ranging from 0.1 to 1.0 mg/kg. As is the case in dogs, suppression following high doses of dexamethasone is diagnostic for PDH, but failure to suppress requires further testing to distinguish pituitary from adrenal disease.
Determination of plasma ACTH concentrations was performed in 10 cats. All nine cats with PDH exhibited elevations of plasma ACTH. The normal range of plasma ACTH is lower in cats than in dogs, and many normal cats may have concentrations of ACTH below the lower limits of the sensitivity of the assay. One cat with an adrenocortical adenoma had undetectable plasma ACTH levels.
Plasma ACTH samples need to be collected and handled carefully. Veterinarians should consult their diagnostic laboratory for specific instructions prior to performing the test. Incorrect sample handling can falsely lower measured values. Normal to elevated plasma ACTH levels support a diagnosis of PDH, whereas low concentrations may require additional diagnostic testing. As in the differentiation of canine hyperadrenocorticism, ACTH levels should only be used to distinguish PDH from AT after hyperadrenocorticism has been confirmed by other screening diagnostics. Pituitary-adrenal function tests need to be interpreted in conjunction with historical, clinical, and clinicopathologic findings before any conclusions can be drawn.
No single diagnostic test is infallible. Equivocal results or discordant findings should be reevaluated. Hyperadrenocorticism is an uncommon disorder in cats. Consequently, false positive test results should be anticipated. Interpretation of endocrinologic testing should incorporate all available information before any therapeutic intervention is attempted. Diagnostic imaging can facilitate differentiation of PDH from AT when screening tests and clinical findings suggest hyperadrenocorticism.
Approximately half of canine adrenal tumors are mineralized and can be recognized radiographically. The frequency of mineralization in feline adrenocortical tumors is unknown, but up to 30% of normal cats may have calcification of their adrenal glands. Abdominal radiographic findings in cats with hyperadrenocorticism included hepatomegaly (69%; 11/16) and obesity. None of the cats had evidence of adrenal calcification.
Ultrasonographic evaluation of adrenal size and morphology has been described for dogs and cats.(39) Nonfunctional adrenal tumors can be incidental findings in humans undergoing abdominal imaging. The incidence of “silent” adrenal masses in the cat is unknown. The presence of unilateral adrenomegaly or distortion of adrenal architecture in a cat suspected of hyperadrenocorticism is strong evidence of AT.
Abdominal computerized tomography (CT) and magnetic resonance imaging (MRI) are available at several veterinary institutions, and may offer improved resolution for the detection of adrenal tumors or hyperplasia. CT and MRI detection of pituitary masses is also now feasible for small animal patients. Adrenal tumors accounted for 22% (6/27) of the reported cases of feline hyperadrenocorticism. Half of the adrenocortical tumors were found histologically to be adenomas and half carcinomas. The treatment of choice for adrenal tumors is surgical adrenalectomy. Two cats with adrenocortical adenomas responded well to unilateral adrenalectomy, with clinical signs resolving over four to eight weeks. One cat with an adrenal adenoma removed surgically developed a recurrence of signs 12 months postoperatively. An adenoma of the contralateral adrenal gland was diagnosed. The cat survived a second adrenalectomy and was disease-free for over two years following the second procedure.
Surgical therapy and long-term follow-up for adrenocortical carcinomas in cats has not been reported. Treatment options for pituitary dependent hyperadrenocorticism in the cat include both surgical and medical alternatives. Bilateral adrenalectomy followed by mineralocorticoid and glucocorticoid replacement therapy was performed in 11 cats. Nine cats responded well to surgery with cessation of polyuria and polydipsia, regrowth of haircoat, and marked improvement (4) or resolution (5) of diabetes mellitus. One cat developed acute signs of circling, wandering aimlessly, and apparent blindness two months post-operatively. An expanding pituitary tumor was suspected, but no necropsy was performed. Two cats died within one week of surgery from sepsis. Survival times for six cats with adequate follow-up after bilateral adrenalectomy for PDH ranged from one to 12+ months (median five months). Two cats are still alive, one year post-operatively. These results suggest that surgical complications of bilateral adrenalectomy may be less frequent in cats than in dogs.
Mitotane, o,p'-DDD, is an adrenal cytotoxic agent and has been used successfully to treat dogs with pituitary dependent hyperadrenocorticism and with adrenal tumors. Use of mitotane in cats has been discouraged due to the feline sensitivity to chlorinated hydrocarbons. Three of four normal cats treated with o,p'-DDD at dosages ranging from 25–50 mg/kg, divided twice a day, tolerated the drug well, and remained clinically normal throughout treatment with mitotane. Only two of the four cats showed a decreased responsiveness to ACTH with mitotane. The cat with the largest reduction in post-ACTH cortisol levels developed vomiting, diarrhea, and partial anorexia lasting two weeks after a 50-mg/kg dosage of mitotane.
Two cats with PDH treated with o,p'-DDD (25 mg/kg/day x 25 days, and 25–50 mg/kg/day x 59 days) tolerated the drug without apparent toxicity, but therapy was ineffective in controlling clinical signs in either cat. A cat with PDH treated with mitotane (50 mg/kg/day x one week, then 50 mg/kg/week) developed signs compatible with iatrogenic hypoadrenocorticism after 40 weeks of therapy with o,p'-DDD. At that time, the cat was anorectic, lethargic, and exhibiting neurologic signs, including mydriasis, pacing, and head pressing. Computerized tomography revealed a large pituitary mass extending above the sella turcica. Mitotane was discontinued, and the cat was treated with 60Co teletherapy. Subsequent CT examinations revealed shrinkage and then disappearance of the mass 10 months post-irradiation. The cat was euphemized for continued diabetes mellitus and post-irradiation cataracts two years after the initial diagnosis of hyperadrenocorticism. We have had three other cases where a positive response to mitotane was observed clinically.
Metyrapone, an inhibitor of the 11-b-hydroxylase enzyme that converts 11-deoxycortisol to cortisol, has been used effectively in man to reduce the clinical signs of hypercortisolemia. A reciprocal rise in plasma ACTH levels occurs with falling cortisol concentrations and can eventually override the enzymatic block, allowing a return of clinical signs. In humans, metyrapone is utilized as an adjunctive therapy with pituitary irradiation or surgery. Dosages ranging from 195–250 mg/day have been used in cats with hyperadrenocorticism without observed toxicity. Two of three other cats reported in the literature also showed clinical improvement with metyrapone therapy, but follow-up periods were short (less than six months). Whether long-term therapy with metyrapone can control hypercortisolemia in cats, or whether rising ACTH levels eventually overwhelm enzymatic blockade has not been determined. Metyrapone appears to permit rapid correction of hyperadrenocorticism in some cats, and may be useful for pre-surgical stabilization prior to adrenalectomy.
Primary hypoadrenocorticism has been described in ten cats. Addisonian cats were middle-aged, with a median age of four years (mean 5.8 +/- 3.7 years). Cats ranged in age from 1.5 to 14 years. No sex predilection was seen (five males, five females), and all ten cats were of mixed breeding. The most common historical problems included lethargy (10/10), anorexia (10/10), and weight loss (9/10). Unlike dogs with adrenal insufficiency, diarrhea was not noted in Addisonian cats. Four cats had histories of episodic vomiting. Similar to hypoadrenocorticism in the canine, several cats had a waxing and waning clinical course (4/10), including temporary “remissions” associated with parenteral fluid and/or corticosteroid administration.
The most common findings on physical examination included depression (10/10), weakness (9/10), and mild to severe dehydration (9/10). Eight cats were hypothermic and five were in severe shock with weak pulses, slow capillary refill times, and extreme weakness or collapse. The duration of clinical signs preceding the diagnosis of hypoadrenocorticism ranged from five to 100 days, with a median of 14 days.
Clinicopathologic findings in cats with primary hypoadrenocorticism parallel the patterns seen in the dog. Serum electrolyte changes characteristic of mineralocorticoid deficiency were seen in all 10 cats. Serum sodium:potassium ratios were less than 24 in all cats (range 17.9–23.7). Ten cats were hyponatremic, nine hypochloremic, and nine hyperkalemic. All cats had mild to severe azotemia (blood urea nitrogen 31–80 mg/dl, normal range 5-30 mg/dl; creatinine 1.6–6.0 mg/dl, normal range 0.5–1.5 mg/dl), and hyperphosphatemia (inorganic phosphorus 6.1-9.1 mg/dl; normal range 3.0–6.0 mg/dl). Hypercalcemia was noted in one cat. Despite signs of dehydration and prerenal azotemia, urine specific gravity was greater than 1.030 in only four cats. The loss of renal medullary solutes, particularly sodium, is believed to result in impaired renal concentrating ability.
Distinguishing hypoadrenocorticism from acute or chronic renal failure is critical to establishing an appropriate prognosis for clients. Long-term management of cats with primary hypoadrenocorticism requires lifetime mineralocorticoid and glucocorticoid supplementation. Oral fludrocortisone acetate (0.1 mg/day) or intramuscular injections of repositol desoxycorticosterone pivalate (DOCP; 10–12.5 mg/month) have been successful in maintaining Addisonian cats. The dose of mineralocorticoid is adjusted as needed based on follow-up serum electrolyte concentrations monitored every one to two weeks during the initial maintenance period. Normal electrolyte parameters two weeks following DOCP suggests adequate dosing, but does not provide information concerning the duration of action of each injection. Eighty percent of dogs require DOCP more frequently than every 30 days (5% need to receive DOCP every three weeks), so frequent sampling during the early management period is recommended. Prednisone, 1.25 mg orally once per day, or intramuscular methylprednisolone acetate, 10 mg once a month, can be used to provide adequate long-term glucocorticoid supplementation. Cats surviving the initial adrenal crisis can be managed successfully for many years. Six of the 10 cats diagnosed with primary hypoadrenocorticism were alive a median of 2¾ years after diagnosis. With appropriate glucocorticoid and mineralocorticoid supplementation, cats with adrenocortical insufficiency should have a normal life expectancy.
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