Cushing's Disease in Dogs

Hyperadrenocorticism (HAC), also known as Cushing's disease, is a common endocrine syndrome that affects middle-aged and geriatric dogs. HAC is generally caused by tumors of either the pituitary or adrenal glands; however, long-term administration of exogenous glucocorticoids can also cause HAC. Regardless of the etiology, the cause of the clinical signs typically seen in this syndrome is an abnormally elevated serum cortisol level.

Etiology

Normally, the amount of cortisol in the blood is carefully regulated. When a pituitary or adrenal gland is affected by a tumor, it stops responding to the signals of the feedback loop. Pituitary gland tumors account for 85% of naturally occurring cases (pituitary-dependent hyper­adrenocorticism [PDH]); the remaining 15% of cases are caused by adrenal gland tumors. Secondary, or iatrogenic, HAC caused by administration of high doses of exogenous cortisol creates a physiologic situation similar to that of an adrenal tumor.

These pituitary tumors usually have complications limited to the clinical signs of HAC (e.g., polyuria, polydipsia). Large pituitary adenomas can result in neurologic signs, such as stupor or confusion.

Signalment

The median age of dogs with PDH is 10 years.

Clinical Signs

Physical Abnormalities

The most frequently reported and recognized clinical signs of canine HAC are polyuria and polydipsia (increased thirst and urination) These signs are reported in 80% to 85% of cases. Owners often bring affected dogs to their veterinarian because of increased urination or the loss of housetraining habits. Other common clinical signs include lethargy, increased appetite, and a "potbellied" appearance. Although a patient with HAC can gain weight as a result of a hearty appetite, abdominal enlargement is attributable to cortisol's promotion of muscle weakness, hepatomegaly, and increased abdominal fat stores. High cortisol levels also induce hair follicle atrophy and cause several dermatologic problems. Patients with HAC often develop alopecia, which can be limited to pressure points, such as elbows and hocks, or can be bilaterally symmetric and of variable severity. HAC should be suspected in geriatric canine patients with poor hair regrowth after clipping. Additional dermatologic changes associated with hypercortisolemia include thin, transparent skin; seborrhea; and pyoderma.

Respiratory effects of HAC can be mild, such as panting or tachypnea, or severe, such as pulmonary thromboembolism. Several factors contribute to the development of these problems. Panting and tachypnea at rest are attributable to increased abdominal fat, weakened respiratory muscles, and hepatomegaly. The formation of pulmonary thromboemboli is thought to be the result of a hyper­coagulable state caused by diminished levels of antithrombin III and increased levels of several clotting factors, fibrinogen, and plasminogen. The predisposition to develop pulmonary thromboemboli poses the greatest threat to patients with HAC.

Diagnostic Imaging

Abdominal ultrasonography can be useful in differentiating PDH from adrenal tumor, but it has limitations and it is not a diagnostic test only a differentiating test. Even well-trained radiologists cannot always discern changes in the size, shape, and architecture of the adrenal glands. In general, bilaterally enlarged adrenal glands are suggestive of PDH, and unilateral changes are suggestive of adrenal tumor. In a study that evaluated 71 dogs with adrenal tumor, 86% of cases were correctly diagnosed. Ultrasonography is not useful for distinguishing benign adrenal adenomas from carcinomas.

Abdominal computed tomography is a better differentiating test than abdominal ultrasonography. False-negative results are possible because not all dogs with HAC have enlarged adrenal glands. Dogs with unilateral adrenal hyperplasia can have computed tomography results identical to those of dogs with adrenal tumor.

Pituitary tumors can also be elusive. These masses are often less than 1 cm in diameter and are not always detected on imaging studies. Magnetic resonance imaging is more commonly used to evaluate diagnosed pituitary tumors than to differentiate pituitary disease from adrenal disease.

Treatment and Prognosis

The course of treatment for HAC is contingent on the diagnosis of PDH, adrenal tumor, or iatrogenic HAC. If pharmaceutical therapy is instituted, the goal is to ameliorate the clinical problems of HAC by indirectly suppressing the pituitary gland's release of ACTH or directly suppressing the adrenal glands' production of cortisol. Unless a tumor is deemed nonresectable, the preferred treatment for an adrenal tumor is adrenalectomy (surgical removal). Dogs with PDH are more commonly treated with drug therapy than with radiation or surgery. If a pituitary mass results in neurologic problems, then surgical removal should be considered.

Three treatment main options are available for Cushing disease in dogs. Medical, surgical, and radiation therapy have all been used with varying degrees of success.

Medical

Mitotane is a chemotherapeutic agent and is directly toxic to adrenal tissue; the dose must therefore be carefully titrated to avoid complete adrenal necrosis. Although mitotane can provide excellent control of HAC, practitioners should familiarize themselves with published protocols or consult with an internist when using this drug. It is not licensed for use in dogs, and owners should be provided with appropriate written guidelines regarding handling and use. Treatment with mitotane (o,p′-DDD), beginning with an induction dosage for 7-10 days before transitioning to a maintenance dose. 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 Dogs on long-term treatment with mitotane should have an examination and ACTH response test every 3–4 months. Gradually increasing dosages of the drug are often required to maintain adequate clinical remission. Persistence of CNS signs after mitotane is discontinued suggests an expanding pituitary macroadenoma.

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 adverse effects. Trilostane should be administered one to twice daily to achieve a decrease in glucocorticoid secretion from the adrenal glands. A few cases of adrenal necrosis with permanent adrenal insufficiency have been seen after trilostane administration. Monitoring of trilostane treatment can be tricky; however, most people use the ACTH stimulation test to maintain post ACTH cortisol levels in the normal range. Once-daily therapy with trilostane can be associated with transient hypoadrenocorticism, which may be difficult to identify with routine testing. Another option for monitoring is to determine pre-trilostane or 3-hour post trilostane cortisol concentrations. Pre-trilostane and 3-hour post trilostane cortisol concentrations ≤ 138 nmol/L or 62 nmol/L, respectively, were associated with excellent control based on clinical signs observed by the owner.

Radiation

Radiation therapy of pituitary tumors is associated with a high rate of response; however, most dogs and cats require ancillary trilostane or mitotane therapy for several months after radiation treatment because of residual ACTH secretion. In dogs with PDH undergoing hypophysectomy, 80% achieved remission, with an 11% recurrence; thyroid and glucocorticoid support may be needed after surgery, and animals may lose the ability to secrete vasopressin, leading to diabetes insipidus as well. Selegiline is an irreversible monoamine oxidase (type B) inhibitor that increases dopamine levels. Dopamine inhibits ACTH release from the pituitary gland. However, only 20% of cases with PDH can be expected to respond; no significant changes in serum cortisol or creatinine, ACTH stimulation, or LDDS have been noted with selegiline therapy.

Surgical

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. Median survival for dogs with carcinomas treated with surgical excision was 778 days. The metastatic rate was 5% at time of surgery and 14% longterm. With unilateral adrenalectomies, mortality within 1 month after surgery was 14%–60%; overall rate for cure for adrenal tumors was ~50%. Medical treatment of adrenal tumors is difficult because they tend to be resistant to the effects of mitotane. Adrenal tumors are relatively resistant to mitotane; dogs require as much as four times the dose of mitotane to respond, and clinical response tends to be less favorable.

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. Newer types of radiation therapy (cyberknife, gamma knife) may prove to be superior to previously available modalities and can treat pituitary tumors in <3 days with minimal adverse effects. 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 longterm, however, because the primary disease process (pituitary tumor) has been addressed. Hypophysectomy is available on a limited basis and has many advantages over conventional therapies, such as rapid reversal of clinical signs and excellent prognosis. Side effects of hypophysectomy can include transient diabetes insipidus, infection, and complications arising from rapid reversal of the hyperadrenocorticism.

Prognosis of dogs with PDH has been estimated to be about 2 years with or without medical therapy. Radiation treatment of pituitary tumors causing PDH or hypophysectomies is associated with a relatively good long-term prognosis (2–5 years). Prognosis of dogs with unilateral adrenalectomy was 18 months.