Cushing syndrome is any disorder characterized by elevated cortisol concentrations. The main types are pituitary-dependent hyperadrenocorticism (Cushing disease) and adrenal-dependent hyperadrenocorticism, in which a unilateral or bilateral adrenal tumor secretes cortisol. Clinical signs include polyuria/polydipsia, polyphagia, a pendulous abdomen, panting, muscle wasting, and dermatological changes. History, physical examination, clinicopathological testing, endocrine testing, and diagnostic imaging are all part of diagnosis. Surgery and adrenocortical suppressants are used for treatment.
The term "Cushing syndrome" refers to a collection of disorders characterized by elevated concentrations of cortisol.
Pituitary-dependent hyperadrenocorticism (PDH), or Cushing disease, is due to an ACTH-secreting tumor of the pituitary gland. It is the most common form of hyperadrenocorticism, accounting for 80%–85% of reported cases.
Adrenal-dependent hyperadrenocorticism (ADH) results from the autonomous secretion of glucocorticoids from an adrenal cortical tumor. It accounts for 10%–15% of cases.
Less common causes of hyperadrenocorticism include ectopic secretion of ACTH, episodic Cushing disease, meal-induced hypercortisolemia, and occult (or atypical) hyperadrenocorticism.
Cushing syndrome results from prolonged exposure to excessive quantities of glucocorticoids. Dogs appear to be more susceptible than cats to the effects of glucocorticoids, and Cushing syndrome is most common in dogs; however, cats can also be affected.
Most cases of canine and feline Cushing syndrome are the PDH form discussed in Cushing Disease (Hyperadrenocorticism). The ADH form can be benign or malignant.
Cushing syndrome occurs in middle-aged to older animals and can affect any breed or size of dog; however, ADH tends to occur more commonly in larger dogs, and most cases of PDH are reported in small dog breeds.
Clinical Findings of Cushing Syndrome in Animals
Clinical signs of Cushing syndrome reflect the myriad effects of cortisol on the body and vary from case to case.
In dogs, the most common clinical signs include polyuria/polydipsia, polyphagia, a pendulous abdomen, panting, muscle wasting, and dermatological changes, including alopecia, pyoderma, and thin skin (see alopecia image). Many dogs with Cushing syndrome have systemic hypertension.
Courtesy of Dr. Stephen White.
Most cats with Cushing syndrome have concurrent diabetes mellitus, which is often poorly regulated. A unique feature of feline Cushing syndrome is severe thinning of the skin, which is susceptible to tearing (referred to as feline fragile skin syndrome).
Diagnosis of Cushing Syndrome in Animals
History and clinical signs
Clinicopathological findings
Endocrine testing
Cushing syndrome is much more commonly diagnosed in dogs than in cats.
Routine laboratory evaluation in cases of Cushing syndrome typically reveals multiple abnormalities resulting from the effects of excessive glucocorticoid secretion.
Increased alkaline phosphatase (ALP) activity is the most common laboratory abnormality in dogs because of the corticosteroid-induced form of this enzyme.
Mild increases in alanine aminotransferase (ALT) activity can also occur. The magnitude of increase in ALT activity is usually less than that of ALP activity.
Hyperlipidemia, mild hyperglycemia, stress leukogram, thrombocytosis, low urine specific gravity, and mild to moderate proteinuria are also common.
In cats, there are no consistent clinicopathological abnormalities on routine laboratory testing for Cushing syndrome, other than hyperglycemia in cats with concurrent diabetes mellitus. In addition, other laboratory abnormalities often reflect comorbid conditions rather than the effects of hyperadrenocorticism itself.
For patients whose history, physical examination findings, and routine laboratory findings suggest Cushing syndrome, specific endocrine testing should be pursued.
Canine Adrenal and Pituitary Function Tests
The low-dose dexamethasone suppression test (LDDST) is the screening test of choice for Cushing syndrome because of its high sensitivity and its ability not only to confirm the presence of hyperadrenocorticism but also to differentiate between PDH and ADH in many cases.
The LDDST consists of evaluation of baseline blood cortisol concentration, followed by the administration of dexamethasone (for dogs: 0.01 mg/kg, IV, once; for cats: 0.1 mg/kg, IV, once). The blood cortisol concentration is measured again 4 and 8 hours after dexamethasone is administered.
Patients with Cushing syndrome show a decreased responsiveness to negative feedback inhibition by exogenous glucocorticoids on the hypothalamic-pituitary-adrenal (HPA) axis, and an 8-hour cortisol concentration above the laboratory reference interval is consistent with a diagnosis of Cushing syndrome.
In some cases the LDDST can be used as both a screening test for hyperadrenocorticism and a test to differentiate between PDH or ADH.
Results of the LDDST should be interpreted as follows:
An 8-hour cortisol concentration greater than the reference interval (supporting the diagnosis of Cushing syndrome), combined with one or more of the following criteria, is consistent with PDH:
The 4-hour cortisol concentration is < 50% of the baseline concentration.
The 4-hour cortisol concentration is less than the reference interval.
The 8-hour cortisol is < 50% of the baseline concentration.
If none of these three criteria are met, the LDDST does not differentiate between PDH or ADH, and further testing is needed.
The ACTH stimulation test is another screening test for hyperadrenocorticism. This test is not recommended as a first-line diagnostic test, because it is less sensitive than the LDDST and cannot be used to differentiate between PDH and ADH. The ACTH stimulation test is particularly insensitive with adrenal tumors, and nearly 50% of dogs with ADH are likely to have a normal result. The test consists of measuring a baseline blood cortisol concentration, administering a synthetic form of ACTH (eg, cosyntropin), and measuring a blood cortisol concentration again 1 hour after ACTH administration. A high postadministration cortisol concentration indicates an exaggerated response to ACTH stimulation of the adrenal glands and is consistent with hyperadrenocorticism.
If the screening test used to confirm Cushing syndrome does not differentiate between PDH and ADH, further diagnostic evaluation is indicated.
A high-dose dexamethasone test (HDDST), a differentiating test performed after the diagnosis of Cushing syndrome is confirmed, is conducted in the same way as the LDDST but with a 10-fold higher dose of dexamethasone (for dogs: 0.1 mg/kg, IV; for cats: 1 mg/kg, IV). The HDDST supports a diagnosis of PDH if either the 4- or the 8-hour cortisol concentration is below the reference interval or less than 50% of the baseline concentration.
Detection of a high blood concentration of endogenous ACTH in a dog with Cushing syndrome suggests PDH; a low endogenous ACTH concentration suggests ADH.
Abdominal imaging (ultrasonography or CT) is an important part of the diagnostic workup in cases of confirmed Cushing syndrome because it can help differentiate between PDH and ADH by identifying bilateral symmetrical adrenal glands or a unilateral adrenal tumor, respectively. Additional specific tests of adrenal function (LDDST, HDDST, ACTH stimulation test) can still be indicated in imaging cases that are not straightforward, such as those with bilateral tumors. Abdominal imaging is also important for surgical planning.
Differentiating test options for cats are similar to those available in dogs. Because Cushing syndrome is an uncommon diagnosis in cats and they are often affected by one or more comorbid conditions, a combination of abdominal imaging and tests of endocrine function is often needed to make a definitive diagnosis.
Treatment of Cushing Syndrome in Animals
Surgery
Adrenocortical suppressants
Treatment for PDH is described under Cushing Disease in the pituitary gland chapter.
The treatment of choice for ADH is adrenalectomy. Patient selection should be made carefully because this surgical approach is associated with high perioperative rates of morbidity and mortality. Smaller tumors are more likely to be benign, and removal can be curative.
Dogs with functional adrenocortical tumors that cannot be surgically removed respond well to medical management; however, some evidence suggests that dogs with ADH do not respond as well to medical management as do dogs with PDH.
Trilostane and mitotane have both been successful in managing ADH in dogs. The use of these drugs is described in Cushing Disease.
Key Points
Hyperadrenocorticism, or Cushing syndrome, is due to excessive glucocorticoid secretion.
Cushing syndrome is most often caused by an ACTH-secreting pituitary tumor. It can also result from a cortisol-secreting tumor of the adrenal cortex.
Cushing syndrome is common in dogs but can also occur in cats.
Diagnosis of Cushing syndrome requires clinical suspicion, confirmation via supportive screening tests such as the LDDST, and usually one or more additional tests to determine the cause and guide treatment.
Surgical removal of the adrenal gland is the treatment of choice for ADH; medical management can also be effective.
For More Information
Bugbee A, Rucinsky R, Cazabon S, et al. 2023 AAHA selected endocrinopathies of dogs and cats guidelines. J Am Anim Hosp Assoc. 2023;59(3):113-135. doi:10.5326/JAAHA-MS-7368
Behrend EN, Kooistra HS, Nelson R, Reusch CE, Scott-Moncrieff JC. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med. 2013;27(6):1292-1304. doi:10.1111/jvim.12192
Behrend, EN. Canine hyperadrenocorticism. In Feldman EC, Nelson RW, Reusch C, Scott-Moncrieff, JCR. Canine & Feline Endocrinology. 4th ed. Elsevier Saunders; 2015:377-451.
Also see pet health content regarding Cushing syndrome in dogs and cats.
