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What Is It?

Cushing’s disease or hyperadrenocorticism is an endocrine disorder in which there is an excess amount of cortisol (a glucocorticoid) in the body. There are three main forms of the disease: pituitary-dependent hyperadrenocorticism, adrenocortical tumor, and iatrogenic hyperadrenocorticism.

Pituitary-dependent hyperadrenocorticism is the most common form of spontaneous disease and accounts for 80-85% of cases in dogs. In this form of the disease, the dog has a functional tumor in the pituitary gland that secretes a compound called adrenocorticotropic hormone or ACTH. This hormone, in turn, acts on both adrenal glands to stimulate the production of cortisol. Normal feedback controls are missing and the excessive secretion of ACTH persists despite having increased levels of cortisol circulating in the body.

The remaining 15-20% of cases of spontaneous hyperadrenocorticism are caused by an adrenocortical tumor, either an adenoma (benign) or adenocarcinoma (malignant). These tumors produce cortisol independently of the pituitary gland or the hypothalamus. The cortisol produced by these tumors suppresses the production of ACTH from the pituitary gland, and without this hormone, the opposite adrenal gland atrophies (becomes smaller).

Animals that have been receiving glucocorticoids orally, topically, or via injection may begin showing signs of hyperadrenocorticism. This is called iatrogenic hyperadrenocorticism. A thorough history and diagnostic testing will determine if this is the cause of your pet’s clinical signs.

Cushing’s disease most often affects dogs 6 years of age or older. Poodles, Dachshunds, Terriers, Schnauzers, German Shepherds, Beagles, Labrador Retrievers, and Boxers are the most commonly affected breeds, though all breeds are capable of developing the disease. The most common clinical signs in dogs with hyperadrenocorticism include increased water consumption, increased urination, increased appetite, panting, abdominal enlargement (“pot belly”), bilateral hair loss, muscle weakness, and lethargy.

Patients with Cushing’s disease may present with secondary complications of the disease. Concurrent diabetes mellitus, pancreatitis (inflammation of the pancreas), urinary tract infections, poor wound healing, bladder stones, high blood pressure, and kidney disease may be present. A more severe complication, pulmonary thromboembolism or the deposition of blood clots within the lungs, causes severe respiratory distress. Some dogs with pituitary-dependent hyperadrenocorticism will begin to show signs of pituitary macrotumor syndrome in which the tumor grows large enough to impinge on surrounding structures in the brain, causing a wide variety of neurological signs. The presence of these secondary complications makes management of the disease even more challenging.

Diagnosis

A thorough evaluation is necessary whenever hyperadrenocorticism is suspected. This will include a thorough medical history, a complete physical examination, a complete blood count (CBC), a serum chemistry profile, and a urinalysis (UA). A urine culture may be necessary if a urinary tract infection is suspected and a thyroid test should be performed to rule out hypothyroidism.

Diagnostic imaging can be useful in the diagnosis of hyperadrenocorticism. Abdominal radiographs and abdominal ultrasonography are used to assess the size of the adrenal glands and ascertain whether there is any involvement of other abdominal organs in the case of a malignant adenocarcinoma. A CT scan is most useful if a pituitary tumor (macroadenoma) is suspected.

Confirmation of the diagnosis of hyperadrenocorticism depends on specific testing. An ACTH stimulation test is the most common screening test performed. A baseline blood cortisol level is measured, an injection of synthetic ACTH is given, and the blood cortisol level is measured 1-2 hours later. If cortisol levels are dramatically elevated, a diagnosis of Cushing’s disease may be made as long as clinical signs and other diagnostics are consistent with the disease. If cortisol levels remain low and unchanged, a diagnosis of iatrogenic hyperadrenocorticism is likely. However, this test only identifies hyperadrenocorticism in 60% of dogs with adrenocortical tumors and in 80-85% of dogs with pituitary-dependent Cushing’s disease, so normal results do not necessarily rule out the disease. Another good screening test for this disease is a urine cortisol : urine creatinine ratio. If this test is normal, your pet is most likely not affected by Cushing’s disease. However, if this test is abnormal, further testing should be performed.

Other tests that are less commonly performed include the low-dose dexamethasone suppression test (LDDST), the high-dose dexamethasone suppression test (HDDST), and the measurement of the endogenous ACTH concentration. These tests are most useful for localizing the tumor (i.e. pituitary vs. adrenal gland). However, they can be difficult to interpret. The results of clinical signs, physical examination findings, routine blood work, and various diagnostic tests must be evaluated together in order to make an appropriate diagnosis.

Treatment

Not all dogs diagnosed with Cushing’s need to be treated. Treatment of this disease is expensive, requires careful monitoring, and can lead to serious side effects. The general rule of thumb is that this disease should be treated if it is causing problems for the pet (lethargy, panting), for the owner (urinating in the house), or for your veterinarian (frequent urinary tract infections, diabetes). Your veterinarian will discuss the pros and cons of treating your particular pet.

Until recently, the treatment of choice for pituitary-dependent hyperadrenocorticism was treatment with a chemotherapeutic agent called mitotane. This medication is designed to destroy the adrenal cortex and prohibit it from producing excessive cortisol. Mitotane therapy involves an initial induction phase, followed by a lifelong maintenance phase. Before beginning therapy, the owner should estimate the amount of food and water being consumed by the pet and the amount of urine produced daily. These parameters can then be used during the induction phase to determine if the medication is working properly. During this phase of therapy, the mitotane is given daily, preferably with a fatty meal to enhance its absorption, until there is a significant decrease in appetite, water consumption, and urination or until there is evidence of hypocortisolism (vomiting, lethargy, inappetence). In 7-10 days, an ACTH stimulation test is performed to evaluate the success of therapy. Most dogs will respond to therapy within the 7-10 days, though a small number may need daily therapy for an extended period of time. If signs of hypocortisolism occur prior to the recheck appointment, mitotane should be discontinued until an ACTH stimulation test can be performed. Once a response to the induction dose of mitotane is seen, the maintenance phase may begin. In this phase, mitotane is given once per week for the lifetime of the pet. An ACTH stimulation test is generally performed 1 and 3 months after the beginning of the maintenance phase, then every 6 months thereafter. The dose and/or frequency of administration may need to be altered depending on the results of ACTH stimulation tests and the clinical status of the pet. Throughout therapy, the pet must be monitored closely for development of adverse effects of mitotane. These may include lethargy, inappetence, vomiting, diarrhea, weakness, or neurological signs (circling, ataxia, stupor, disorientation). If any of these signs occur, the mitotane is discontinued and your pet may be placed on a short course of oral glucocorticoids until clinical improvement is seen. Rarely (in 2-5% of cases), destruction of the adrenal glands can occur necessitating long term therapy for the opposite condition – hypoadrenocorticism (Addison’s disease).

In 2009, a medication called trilostane (Vetoryl) became available in the United States for treatment of canine hyperadrenocorticism. Trilostane is an active steroid analogue that inhibits the synthesis of steroids including cortisol and aldosterone. Side effects are less frequent with this medication, but careful monitoring is still essential. Some patients exhibit lethargy and decreased appetite. Less commonly (in 2-3% of cases), adrenal necrosis and development of hypoadrenocorticism (abnormally low cortisol and aldosterone levels) can occur as with mitotane. In 10-14 days, an ACTH stimulation test is performed to evaluate the success of therapy and the dosage of medication is adjusted accordingly. Once the correct dose is established, an ACTH stimulation test should generally be performed at 30 days, 90 days, and every 6 months thereafter. More frequent monitoring will be necessary if your pet is exhibiting any adverse effects. Trilostane is more expensive than mitotane, though the costs of monitoring are similar.

Various other methods of treatment are available. Mitotane can be used at higher dosages for a prolonged period of time to cause complete destruction of the adrenal cortices (medical adrenalectomy). However, this not only destroys the corticosteroid-producing layer of the adrenal glands, but it destroys other layers as well, causing hypoadrenocorticism (Addison’s disease). As a result, the pet must be given lifelong mineralocorticoid and glucocorticoid supplementation. In addition, relapse of signs of hyperadrenocorticism is common with this therapy. Other medications, including ketoconazole and L-deprenyl (selegiline), have been used for the treatment of pituitary-dependent hyperadrenocorticism. L-deprenyl (selegiline) has been successful in a number of cases and has far fewer side effects than mitotane. Radiation therapy may also prove useful for pituitary macroadenomas.

Surgical adrenalectomy is the treatment of choice for adrenocortical tumors unless the pet is an anesthetic risk, is severely debilitated, or has metastases (spreading of the tumor to other organs). Patients must be treated with oral glucocorticoids and possibly mineralocorticoids following surgery. If only one adrenal gland is removed, oral supplementation can usually be discontinued once the opposite gland becomes functional again.

Any secondary complications of hyperadrenocorticism must also be addressed. Concurrent diabetes mellitus, urinary tract infections, glomerulonephropathies, high blood pressure, pancreatitis, bladder stones, and blood clots must be treated appropriately. Prognosis depends, in part, on the age and overall health of the patient and the development of secondary complications.

Content prepared by St. Francis Animal and Bird Hospital, 1227 Larpenteur Ave. West, Roseville MN. 55113