Cushing’s Disease

Liaison: Melissa Howell

In Cushing’s Disease, also known as hyperadrenocorticism, there is an excess of cortisol or related corticosteroids in the body. Cortisol and other corticosteroid hormones are produced by the cortex, or outer portion, of the adrenal glands. Cortisol is released by the adrenals in response to various types of “stress” (e.g., food intake, exercise, pain, fear). It has numerous functions in the body, including affecting the metabolism of protein, carbohydrates and fat, and reducing inflammation.

In a normal dog, the pituitary gland “senses” the level of cortisol in the body. If more is needed, it releases adrenocorticotropic hormone, or ACTH. This hormone then signals the adrenal glands to release more cortisol. Cushing’s is caused by a defect somewhere in this process.

Signs and Symptoms

Cushing’s Disease is most commonly found in older dogs and many of the symptoms may be confused with the normal aging process. Some of the symptoms are increased appetite, increased drinking and urination, urinary incontinence in females, and pets waking up in the middle of the night to ask to go outside. Other symptoms include panting/shortness of breath, high blood pressure, skin lumps, patterned hair loss without itching, hair that doesn’t grow back after grooming, persistent or recurring skin infections, muscle weakness and extreme lethargy. Excess cortisol relaxes the ligaments of the abdomen and causes liver enlargement leading to the symptom of a potbelly.

In addition to these symptoms, Cushing’s Disease may also be suspected due to abnormal findings during routine bloodwork/urinalysis. These findings might include higher than normal levels of the liver enzymes Alkaline Phosphatase (ALP) or Alanine aminotransferase (ALT), abnormal white cell differential count, or increased urinary cortisol:creatinine ratio.

Causes

Cushing’s disease can be triggered by tumors of the adrenal or pituitary glands. Adrenal tumors can overproduce cortisol. Pituitary tumors can overproduce ACTH (adrenocorticotropic hormone), which then signals the adrenal gland to make and release too much cortisol. About 85% of the cases of Cushing’s disease in dogs are believed to be caused by pituitary tumors.

Cushing’s disease can also be caused by a dog receiving too much corticosteroid for the treatment of another illness. This is “iatrogenic” – inadvertently caused by medical treatment. Some of the drugs that can cause iatrogenic Cushing’s disease are prednisone, prednisolone, dexamethasone, depomedrol, and betamethasone.

Diagnostic Tests

If Cushing’s disease is suspected due to symptoms and results of routine blood/urine analysis, the veterinarian will run additional blood tests which can confirm the presence of Cushing’s and help to determine the cause. Two of the most common tests are described below.

Dexamethasone Suppression Test - Dexamethasone is a synthetic corticosteroid. In a normal dog, a low dose of dexamethasone will signal the pituitary to stop releasing ACTH (adrenocorticotropic hormone), the message that tells the adrenals to release cortisol. The blood cortisol level will then decrease. If a pituitary tumor is present, the pituitary will continue to release ACTH after dexamethasone is given, and the cortisol level will stay the same. The test is run by taking a baseline blood sample, giving a tiny intravenous dose of dexamethasone, then taking additional blood samples at 4 and 8 hours. This test can often distinguish between Cushing’s caused by adrenal vs pituitary tumors.

ACTH Stimulation Test - ACTH normally stimulates the adrenal glands to release cortisol. In a normal dog, a dose of ACTH will cause a normal increase in the level of cortisol in the blood. In Cushing’s disease caused by tumors, the adrenal glands have large amounts of stored cortisol and a dose of ACTH will cause a larger than normal increase in cortisol blood levels. In iatrogenic Cushing’s, the adrenals produce/store little cortisol because it is being supplied to the body by a corticosteroid drug. The dog will have a lower than normal cortisol response to ACTH. After overnight fasting, the test is run by taking a baseline blood sample, giving a dose of ACTH (intramuscular or intravenous), and taking an additional blood sample one to two hours later.

Treatment Guidelines

Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol.

Many adrenal gland tumors can be surgically removed, although surgery in this area (near the kidney and aorta) is considered major and usually requires a specialist. Imaging studies (x-rays, ultrasound, and/or CT) are used prior to surgery to determine the size of the tumor. Drug therapy with cortisol is usually needed post-surgery until the other adrenal gland, which has probably atrophied, recovers its ability to produce it. If surgery isn’t possible, drugs, as described for treatment of pituitary tumors, may also be used.

The following link gives more information about adrenal surgery and complications:

http://www.marvistavet.com/treatment-pituitary-cushings-syndrome.pml 2 bones

Surgery on the pituitary, located at the base of the brain, is very risky in dogs, requires a neurosurgeon, and is rarely performed. Pituitary Cushing’s is treated with drugs that either destroy part of the adrenal gland or suppress cortisol production/release directly (at the adrenal) or indirectly (at the pituitary).

Lysodren (also called mitotane or o,p'-DDD) destroys adrenal tissue that produces cortisol. Monitoring blood tests are required to make sure that the correct amount of adrenal tissue is destroyed.

Ketoconazole (also called nizoral) is an antifungal drug, with a side effect of suppressing production of cortisol. This drug doesn’t require monitoring tests like lysodren, but it’s very expensive and takes longer to work.

L-deprenyl (also called Anipryl or [Selegiline) acts by a very different mechanism, suppressing ACTH release by the pituitary. It doesn’t require monitoring tests, but is expensive, and not all dogs respond to it. ]

Trilostane (also called Vetoryl ) inhibits the production of cortisol. It typically has fewer side effects than lysodren. Note: The FDA approved the use of Trilostane on May 11, 2009 and this should help with availability. Per a letter to veterinarians from the FDA, “Now that VETORYL is approved and available for veterinary use in the U.S., trilostane should not be imported from other countries or compounded from bulk.”

The following website has an excellent discussion of the pros and cons of these different drug treatments:

http://www.marvistavet.com/treatment-pituitary-cushings-syndrome.pml 2 bones

If the cause of Cushing’s is iatrogenic the treatment is to withdraw the drug that caused it. This must be done gradually, because the drugs causing iatrogenic Cushing’s reduce adrenal production of cortisol. The adrenals must be given time to recover and produce cortisol again.

If left untreated, a dog with Cushing’s can develop additional complications including diabetes, high blood pressure, congestive heart failure, hypothyroidism, and liver and kidney failure. It can also lead to increased infections since excess cortisol suppresses the immune system.