Hyperadrenocorticism - The Merck Veterinary Manual

Hyperadrenocorticism
(Cushing’s disease)

Pituitary- Versus Adrenal-Dependent Disease

Functional tumors in the pituitary gland, derived from corticotroph (ACTH-secreting) cells in either the pars distalis or the pars intermedia, result in a clinical syndrome of cortisol excess. This disease is common in dogs but not other species. Miniature Poodles, Dachshunds, Boxers, Boston Terriers, and Beagles are at increased risk of the disease. In ~85% of affected dogs, the hyperadrenocorticism is pituitary dependent (PDH), while ~15% have functional adrenal tumors. Differentiation of PDH from adrenal tumors is necessary for appropriate treatment.

Clinical Findings:

Hyperadrenocorticism, Poodle

Hyperadrenocorticism is a disease of middle-aged to older dogs (7-12 yr). A sex predilection for females is seen in some dogs with hyperadrenocorticism secondary to adrenal tumors. The most common clinical signs are polydipsia (PD), polyuria (PU), polyphagia, heat intolerance, lethargy, abdominal enlargement or “potbelly,” panting, obesity, muscle weakness, and recurrent urinary tract infections. Dermatologic manifestations are numerous and often include truncal alopecia, thin skin, phlebectasias, comedones, bruising, cutaneous hyperpigmentation, calcinosis cutis, pyoderma, dermal atrophy, secondary demodicosis, and seborrhea. Cutaneous mineralization (calcinosis cutis) is a characteristic although infrequent finding in dogs. Although mineral deposition may occur anywhere in the skin, the dorsal midline, ventral abdomen, and inguinal region are affected most frequently. Numerous mineral crystals are deposited along collagen and elastin fibers in the dermis and outer subcutis and may protrude through the atrophic and thinned epidermis. In less severe cases, the epidermis remains intact and appears irregularly elevated by the firm, opaque, white deposits of mineral. A narrow rim of hyperemia and foreign-body granulomatous inflammation often surrounds the areas of mineralization. The mineral deposits occur despite normal blood calcium and phosphorus levels probably because of the gluconeogenic and protein catabolic actions of cortisol. Mineralization may also occur in other tissues of the body, most frequently the airways and blood vessels.

Uncommon clinical manifestations include hypertension, pulmonary thromboembolism, testicular atrophy, polyneuropathy and myopathy, congestive heart failure, prostatomegaly in male castrated dogs, clitoral hypertrophy, bronchial calcification, behavioral changes, corneal ulceration (nonhealing), blindness, neuralgic disease, pseudomyotonia, cranial cruciate rupture (small dogs), and perianal adenoma in female or castrated male dogs.

Adenomas of the adrenal cortex are seen most frequently in old dogs and sporadically in horses, cattle, and sheep. They usually occur as well-demarcated, single nodules in one adrenal gland but may be bilateral. Larger cortical adenomas are yellow to red, distort the external contour of the affected gland, and are partially or completely encapsulated. Adjacent cortical parenchyma is compressed, and the tumor may extend into the medulla.

Carcinomas of the adrenal cortex occur with equal frequency to adenomas and have been reported most often in adult to older cattle and dogs, with no apparent breed or sex predilection. Adrenal carcinomas are larger then adenomas and more likely to be bilateral. In dogs, they are composed of a variegated, yellow-red, friable tissue that incorporates the affected adrenal gland. They often are fixed in location because of extensive invasion of surrounding tissues (posterior vena cava, kidney, and aorta) and may result in a large tumor thrombus. In cattle, carcinomas may attain considerable size (≥10 cm in diameter), have multiple areas of mineralization or ossification, and usually completely obliterate the affected adrenal.

Some carcinomas and adenomas of the adrenal cortex in dogs are functional and secrete excess cortisol, sex steroids, or both. They may compress adjacent organs, invade the aorta or posterior vena cava (which leads to intra-abdominal hemorrhage), and metastasize to distant sites (eg, liver, kidneys, mesenteric lymph nodes, and lungs). Functional cortisol-secreting cortical adenomas and carcinomas are associated with profound atrophy of the contralateral cortex because of inhibition of pituitary ACTH secretion due to increased blood cortisol levels. The adrenal medulla appears expanded and is more conspicuous because of the lack of cortical parenchyma.

Laboratory Abnormalities:

In dogs, serum chemistry abnormalities associated with hypercortisolemia include increased serum alkaline phosphatase and ALT, hypercholesterolemia, hyperglycemia, and decreased BUN. The hemogram is often characterized by evidence of regeneration (erythrocytosis, nucleated red blood cells) and a classic “stress leukogram” (mature neutrophilia, lymphopenia, and eosinopenia). Basophilia is occasionally seen.

Many dogs have evidence of urinary tract infection without pyuria (positive culture), bacteriuria, and proteinuria resulting from glomerulosclerosis. Thyroid status is often affected, as evidenced by decreased basal thyroxine (T₄) and triiodothyronine (T₃), caused by euthyroid sick syndrome and by an attenuated response to TSH stimulation due to the effect of cortisol and overcrowding on pituitary thyrotrophs. Overt diabetes mellitus may result from the insulin antagonism caused by hypercortisolemia in ~10-25% of dogs with hyperadrenocorticism and in an even higher percentage of cats. In addition, hyperadrenocorticism can be a cause of insulin resistance and poor glycemic control in diabetic dogs. A consistent finding is the excretion of large amounts of dilute urine with a low specific gravity (≤1.015).

Diagnosis:

Diagnosis can be challenging; it should be based on clinical signs and laboratory abnormalities and confirmed via an appropriate screening test for hyperadrenocorticism. If results of screening tests are inconclusive or if laboratory abnormalities associated with hyperadrenocorticism are noted in a dog without clinical signs, the dog should be retested 3-6 mo later.

The low-dose dexamethasone suppression (LDDS) test is the screening test of choice for hyperadrenocorticism in dogs. It is sensitive; only 5% of dogs with hyperadrenocorticism exhibit suppressed cortisol concentrations at 8 hr. 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. The major disadvantage of the LDDS test is the lack of specificity in dogs with nonadrenal illness (diabetes mellitus, chronic renal disease, liver disease); these dogs should be treated for the nonadrenal illness and stabilized before the LDDS test is performed.

The ACTH stimulation test is used to diagnose a variety of adrenopathic disorders, including endogenous or iatrogenic hyperadrenocorticism and spontaneous hypoadrenocorticism. As a screening test for the diagnosis of naturally occurring hyperadrenocorticism, the ACTH stimulation test has a diagnostic sensitivity of ~85-90% and a higher specificity than the LDDS test.

The urine cortisol/creatinine ratio (UCCR) is a rapid and easy screening test; however, it is very sensitive and can be associated with false-positive results. Therefore, a normal UCCR can only effectively rule out the diagnosis of hyperadrenocorticism, whereas an increased UCCR requires an LDDS or ACTH stimulation test to confirm the diagnosis. Collection of the first urine sample in the morning may be a better reflection of cortisol production over time than random urine samples obtained throughout the day when the time since the last urination may have been only a few hours.

Measurement of ciALP as a screening test appears to lack both sensitivity and specificity. An increased ciALP is suggestive but not diagnostic.

Pituitary- Versus Adrenal-Dependent Disease:

Once 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 of dogs.

Measurement of endogenous plasma ACTH concentrations is the most reliable method of differentiating between PDH and adrenal tumors. Dogs with adrenal tumors have low to undetectable ACTH concentrations; in contrast, dogs with PDH have normal to increased ACTH concentrations. The high-dose dexamethasone suppression (HDDS) test works on the principle that ACTH secretion has already been suppressed maximally in dogs with functioning adrenal tumors; therefore, administration of dexamethasone, no matter how high the dose, will not suppress serum cortisol concentrations. In dogs with PDH, however, high doses of dexamethasone are able to suppress ACTH and hence cortisol secretion. One caveat is that in dogs with pituitary macroadenomas (15-50% of dogs with PDH) cortisol concentrations do not suppress on the HDDS test.

Diagnostic imaging of the pituitary or adrenal glands can be accomplished via abdominal radiography, ultrasonography, computed tomography (CT), or MRI. Abdominal radiographs should be performed in all dogs that do not suppress on an HDDS; in ~30-50% of dogs with adrenal tumors, a mineralized mass in the area of the adrenal glands can be seen. 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. CT and/or MRI of the abdomen or brain in dogs that do not suppress on the HDDS may show unilateral adrenal enlargement, pituitary macroadenoma, or pituitary microadenoma.

Treatment:

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 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. If signs such as depression or ataxia develop, they can usually 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.

Ketoconazole, which affects steroid biosynthesis, is an alternative therapy for hyperadrenocorticism in dogs. It is given at 5 mg/kg, bid, PO, initially for 7 days. If no problems (such as anorexia or icterus) are noted, the dosage is increased to 10 mg/kg, bid. After 14 days, an ACTH response test is performed. If cortisol secretion is not adequately suppressed, the dosage may be increased to 15 mg/kg, bid. The disadvantages of ketoconazole are its cost, twice daily administration indefinitely, and a failure rate of 20-25%.

l-deprenyl (selegiline hydrochloride) is approved by the FDA for the management of PDH in dogs. In initial studies it was effective in 70−80% of cases of PDH with mild to moderate clinical signs, although other investigators have found it to be less effective. Its use is associated with few side effects. Its mechanism of action is through inhibition of monoamine oxidase, resulting in increased concentrations of dopamine with subsequent inhibition of endogenous ACTH. The initial dosage is 1 mg/kg, sid, and dogs are monitored based on clinical response. If no response is seen after 2 wk, the dosage can be increased to 2 mg/kg, sid. Because l -deprenyl does not cause hypoadrenocorticism, routine endocrine evaluations are not warranted.

Recent reports have demonstrated the efficacy of the adrenal enzyme inhibitor trilostane in the treatment of PDH in dogs. As is the case with ketoconazole, trilostane must be administered daily and results in glucocorticoid insufficiency without effects on aldosterone concentrations.

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.