Hyperadrenocorticism may be divided into 2 broad categories. One category, pituitary-dependent hyperadrenocorticism, arises from adenomatous enlargement of the pituitary gland resulting in excessive ACTH production. The other category, adrenal-dependent disease, is associated with functional adenomas or adenocarcinomas of the adrenal gland. Ectopic ACTH secretion has not been reported in dogs; however, in humans ectopic ACTH secretion is associated with certain lung tumors. Iatrogenic hyperadrenocorticism results from chronic excessive exogenous steroid administration.
Hyperadrenocorticism is found in middle-aged to older dogs (7–12 yr of age); ~85% have pituitary-dependent hyperadrenocorticism (PDH), and ~15% have adrenal tumors. Breeds in which PDH is commonly seen include Miniature Poodles, Dachshunds, Boxers, Boston Terriers, and Beagles. Large-breed dogs often have adrenal tumors, and there is a distinct female predilection (3:1).
The most common clinical signs are polydipsia, polyuria, polyphagia, heat intolerance, lethargy, abdominal enlargement or “potbelly,” panting, obesity, muscle weakness, and recurrent urinary tract infections. Dermatologic manifestations of canine hyperadrenocorticism can include alopecia (especially truncal), thin skin, phlebectasias, comedones, bruising, cutaneous hyperpigmentation, calcinosis cutis, pyoderma, dermal atrophy (especially around scars), secondary demodicosis, and seborrhea.
Uncommon clinical manifestations include hypertension, pulmonary thromboembolism, bronchial calcification, congestive heart failure, and neurologic signs, such as polyneuropathy or myopathy, behavior changes, blindness, or pseudomyotonia. Hypercortisolemia may be evident as weakening of collagen manifesting as cranial cruciate rupture (small dog) or corneal ulceration (nonhealing). Reproductive signs of hyperadrenocorticism can include perianal adenoma in a female or castrated male, clitoral hypertrophy in females, testicular atrophy in intact males, or prostatomegaly in castrated male dogs.
In dogs, serum chemistry abnormalities associated with hypercortisolemia include increased serum alkaline phosphatase (ALP), increased ALT, hypercholesterolemia, hyperglycemia, and decreased BUN. The hemogram is characterized by evidence of regeneration (erythrocytosis, nucleated RBC) and a classic stress leukogram (eosinopenia, lymphopenia, and mature leukocytosis). Basophilia is occasionally observed. Many dogs with hyperadrenocorticism show evidence of urinary tract infection without pyuria (positive culture), bacteriuria, and proteinuria resulting from glomerulosclerosis.
There is no single test or combination of tests that is 100% accurate for diagnosing hyperadrenocorticism. The sensitivity and specificity of individual tests or combinations of tests are increased when they are applied to a patient population that is likely to have hyperadrenocorticism. The diagnosis should be based on appropriate clinical signs followed by supporting minimum database abnormalities (eg, high cholesterol, SAP), and confirmed via an appropriate screening test for hyperadrenocorticism. If screening test results are inconclusive, or if laboratory abnormalities associated with hyperadrenocorticism (eg, increased SAP) are noted in a dog without clinical signs, the dog should be retested 3–6 mo later rather than be treated without a definitive diagnosis. In particular, the diagnosis of sex steroid-induced Cushing's disease may be especially difficult.
The urine cortisol to creatinine ratio (UCCR) is a highly sensitive test for separating normal dogs from those with hyperadrenocorticism, but it is not highly specific because dogs with moderate to severe nonadrenal illness also exhibit elevated ratios. UCCR should be determined based on free-catch urine collected at home by the client. The stress of transporting the dog to the veterinarian's office, the stress of cystocentesis, or both, can be enough to cause a falsely elevated UCCR. An elevated UCCR should be confirmed with an ACTH stimulation test, an IV low-dose dexamethasone suppression (LDDS) test, or an oral LDDS test.
The LDDS test is the screening test of choice for canine hyperadrenocorticism when properly used. Only 5–8% of dogs with PDH exhibit suppressed cortisol concentrations at 8 hr (ie, are false negatives). In addition, 30% of dogs with PDH exhibit suppression at 3 or 4 hr followed by “escape” of suppression at 8 hr; this pattern is diagnostic for PDH, making further testing unnecessary. The major disadvantage of the LDDS test is the lack of specificity in dogs with nonadrenal illness: >50% of dogs with nonadrenal illness have a positive LDDS test. In such cases the dog should be allowed to recover from the nonadrenal illness prior to testing for hyperadrenocorticism with an LDDS test.
The ACTH stimulation test is used to diagnose various adrenopathic disorders, including endogenous or iatrogenic hyperadrenocorticism and spontaneous hyperadrenocorticism. As a screening test for the diagnosis of naturally occurring hyperadrenocorticism, it has a diagnostic sensitivity of ~80–85% and a higher specificity than the LDDS test. In one study, only 15% of dogs with nonadrenal disease had an exaggerated response to ACTH stimulation. Adrenal tumors may be particularly difficult to diagnose using an ACTH stimulation test.
Dogs with adrenal sex steroid excess may have negative ACTH stimulation and LDDS tests because serum cortisol concentrations are normal. This may be due to excess cortisol precursors. Increases in progesterone, 17-OH-progesterone, andro-stenedione, testosterone, and estrogens may require dynamic adrenal testing using the ACTH stimulation test and measurement of sex steroids in addition to cortisol.
After the diagnosis of hyperadrenocorticism has been confirmed, differentiation of pituitary- versus adrenal-dependent disease may be necessary. Although most dogs with hyperadrenocorticism have PDH, in atypical cases (eg, the anorectic dog with hyperadrenocorticism), a differentiation test is appropriate. In particular, differentiation of PDH (often macroadenomas) from adrenal tumors is often necessary in large breeds.
The high-dose dexamethasone suppression (HDDS) test works on the principle that autonomous ACTH hypersecretion by the pituitary can be suppressed by supraphysiologic concentrations of steroid. Dogs with autonomous cortisol-producing adrenal tumors have maximally suppressed ACTH production via the normal feedback mechanism; therefore, administration of dexamethasone, no matter how high the dose, cannot suppress serum cortisol concentrations. In dogs with PDH, however, the high dose of dexamethasone is able to suppress ACTH and, hence, cortisol secretion. One important caveat is that dogs with pituitary macroadenomas (15–50% of dogs with PDH) fail to suppress on the HDDS test.
Measurement of endogenous plasma ACTH concentrations is the most reliable method of discriminating between PDH and adrenal tumors. Dogs with adrenal tumors have low to undetectable ACTH concentrations; in contrast, dogs with PDH have normal to elevated ACTH concentrations. Recently, researchers have found that the addition of the protease inhibitor, aprotinin, to whole blood in EDTA tubes inhibits the degradation of ACTH. Samples may be collected, spun in a nonrefrigerated centrifuge, and kept for up to 4 days at <4ºC.
Diagnostic imaging of the pituitary and the adrenal glands can be accomplished via abdominal radiography, ultrasonography, computed tomography, or MRI. Abdominal radiographs should be performed in all dogs that fail to suppress on an HDDS; ~30–50% of dogs with adrenal tumors have a mineralized mass in the area of the adrenal glands. Abdominal ultrasonography is a more sensitive method of identifying adrenal tumors. In addition, liver metastasis or invasion into the vena cava may be demonstrated in dogs with adrenal carcinomas. Computed tomography or MRI of the brain or abdominal cavity in dogs that fail to suppress on the HDDS may demonstrate unilateral adrenal enlargement (50%), pituitary macroadenoma (25%), or pituitary microadenoma (25%).
Treatment and Prognosis
Three treatment options are available for canine hyperadrenocorticism. Medical, surgical, and radiation therapy have all been used with varying degrees of success.
Dogs with PDH may be treated using the adrenolytic agent mitotane (o,p′-DDD), beginning with an induction dose of 25–50 mg/kg/day for 7–10 days. Dogs should be monitored for signs of hypoadrenocorticism, such as anorexia, vomiting, and diarrhea; if such signs occur, mitotane therapy should be discontinued and glucocorticoids administered. Water consumption or appetite may be measured to provide an endpoint for therapy; water consumption should decrease to <60 mL/kg/day (dogs). After 7–10 days of therapy with mitotane or a reduction in water or food consumption, an ACTH response test should be performed to determine if cortisol suppression is adequate. The pre- and post-ACTH cortisols should both be in the normal range. To maintain suppression of cortisol secretion, mitotane is administered at a dosage of 50 mg/kg/wk. Dogs on longterm treatment with mitotane should have an examination and ACTH response test every 3–4 mo. Gradually increasing doses of the drug are often required to maintain adequate clinical remission.
Side effects of mitotane at the recommended dose include GI irritation (vomiting and anorexia), CNS disturbances (ataxia, weakness, seizures), mild hypoglycemia, and a moderate increase in serum alkaline phosphatase. Signs such as depression or ataxia can be alleviated by dividing the daily dose into 2 equal parts administered at 8- to 12-hr intervals. Persistence of CNS signs after mitotane is discontinued suggests an expanding pituitary macroadenoma.
Recent reports have demonstrated the efficacy of the adrenal enzyme inhibitor trilostane in the treatment of PDH in dogs. Studies in dogs with hyperadrenocorticism have shown that trilostane is an effective steroid inhibitor with minimal side effects. Trilostane must be administered daily and often twice daily to achieve a decrease in glucocorticoid secretion from the adrenal glands. Mineralocorticoid insufficiency, which is reversible, can also be observed in patients receiving trilostane; a few cases of adrenal necrosis with permanent adrenal insufficiency have been observed following trilostane administration. Only recently available in the USA, trilostane may prove to be a reasonable alternative to mitotane therapy for PDH in dogs. Dogs with sex steroid imbalance also may benefit from trilostane therapy because the enzyme inhibitor affects precursors of cortisol synthesis in addition to inhibiting cortisol synthesis itself.
Surgical removal of unilateral adrenal adenomas or adenocarcinomas may be indicated in some cases; however, surgical and anesthetic complications (eg, hypotension) may develop secondary to hypoadrenocorticism, which occurs immediately after surgical removal of the tumor. Medical treatment of adrenal tumors is difficult because they tend to be resistant to the effects of mitotane. Finally, if the dog is showing neurologic signs (eg, anorexia, stupor, or seizures) and a large pituitary tumor (macroadenoma) is identified, radiation therapy of the pituitary gland is indicated. However, radiation therapy is expensive and time-consuming (3 wk). Results of radiation therapy in dogs show that this is an effective method of treatment with low morbidity; however, it may take several months for the signs of PDH to subside. These dogs do well in the longterm, however, because the primary disease process (pituitary tumor) has been addressed.
Last full review/revision July 2011 by Deborah S. Greco, DVM, PhD, DACVIM; Janice E. Kritchevsky, 'VMD, MS, DACVIM