Cortisol is a normal hormone produced by the adrenal glands. It is produced rapidly in times of stress to prepare the body to conserve sodium and water. Cortisol triggers the metabolism of fat stores in the body as well. A small gland at the base of the brain called the pituitary gland produces ACTH when cortisol levels fall. ACTH signals the adrenals to pump out more cortisol.
There are three origins of Cushing’s disease: pituitary-dependent, adrenal-dependent, and iatrogenic Cushing’s. Pituitary-dependent suggests that the pituitary gland is responsible for the disease. This type of Cushing’s accounts for 85% of the cases in dogs and is caused by a small, generally benign tumor of the pituitary. The tumor itself overproduces ACTH, causing the adrenal glands to enlarge and constantly make cortisol. The other 15% of Cushing’s cases are due to a tumor of the adrenal glands. The tumor produces excess cortisol despite ACTH levels being normal. These cases are referred to as adrenal-dependent, and the tumor is sometimes malignant. Iatrogenic Cushing’s is caused by the overuse of synthetic cortisol – cortisone, which is the active chemical found in prednisone, dexamethasone, triamcinalone, and other commonly prescribed corticosteroid drugs. The overuse of these medications, while unintentional or even necessary to produce quality of life in very ill patients, causes equally serious side effects. Tapering off of the drugs can reverse the disease in some cases, but suddenly stopping the cortisone can be life threatening.
Symptoms of Cushing’s disease may be vague, mild, and multi-systemic at first, progressing into a classical appearance as the disease becomes more advanced. Symptoms may be attributed to old-age or senility. Increased thirst and urination, accidents in the house, and urinary tract infections occur in almost all Cushing’s patients. A well behaved indoor dog may begin to knock over trash cans and beg for food as they develop an insatiable appetite. Skin infections and hair-loss (alopecia) become more frequent or severe, and wounds may not heal. A bizarre condition called calcinosis cutis causes calcium to deposit in the skin leaving raised, rock-like formations anywhere on the body. Also, muscle will atrophy (shrink) and fat will accumulate in the abdomen giving the dog a pot-bellied appearance. Diabetic patients’ blood glucose will become impossible to regulate despite insulin therapy. More than 80% of cats with Cushing’s develop concurrent diabetes mellitus.
Testing for Cushing’s disease is not always straight forward. A number of laboratory tests may be run and re-run to diagnose the disease. Treatment is never begun on a pet until hyperadrenocorticism has been confirmed, as the treatment would be harmful to a non-Cushinoid animal. The type of Cushing’s must be known as well, because treatment is entirely different for each type. In most dogs, a liver enzyme called serum-alkaline phosphatase (SAP) will be elevated in the presence of high cortisol levels. Recent dosing of drugs containing cortisone will also cause this liver function test to rise, and a high SAP is not diagnostic by itself. A screening test called a urine cortisol creatinine ratio can rule out Cushing’s but cannot confirm the disease.
A low-dose dexamethasone suppression cortisol assay is usually the first disease-specific test performed on an animal suspected of having Cushing’s. A very small dose of cortisone given IV should suppress the pituitary gland’s ACTH production within 8 hours. If a pituitary tumor exists, then ACTH levels will remain elevated, causing the adrenals to continue to over-produce cortisol. Pituitary-dependent disease would be confirmed in this scenario. If this test returns equivocal or gray-zone results, an ACTH stimulation test is run. When a calculated dose of ACTH is given to the patient, an expected rise in cortisol occurs. If the cortisol elevates above a predicted level, then Cushing’s disease is diagnosed, but the type of Cushing’s is not determined. A high-dose dexamethasone suppression test can then be performed to classify the location of the tumor. A large dose of dexamethasone will suppress the pituitary’s ACTH production despite the existence of a pituitary tumor; however, adrenal tumors will continue to pump out cortisol since they are not ACTH dependent.
Once a diagnosis is made and the disease is classified, treatment can be instituted. The traditional drug for pituitary-dependent Cushing’s disease is Mitotane (Lysodren). This drug would be very harmful to a non-Cushinoid animal, as it selectively destroys the cortisol secreting cells of the adrenal glands reducing their ability to produce the hormone. Cortisol levels must be monitored closely during the induction phase of treatment with Lysodren. The main concern is that too much of the adrenal gland will be destroyed causing the opposite disease to Cushing’s: Addison’s Disease (hypoadrenocorticism). Usually antidotal prednisone is prescribed to the patient in case of a reaction to Lysodren. A maintenance dosing of Lysodren is typically once or twice a week, and the drug is inexpensive.
Ketaconazole is a safer but less effective alternative treatment to Lysodren. It inhibits enzymes necessary for cortisol synthesis rather than destroying the adrenal gland. It is not possible to cause Addison’s disease with Ketaconazole. This drug may be expensive, and it must be given twice a day; however, compared to the cost of ongoing testing with Lysodren treatment, the increased cost of Ketoconazole may be inconsequential. Some dogs do not respond effectively to treatment with this drug, and side effects include vomiting and diarrhea.
L-Deprenyl (Anipryl) is another safe alternative treatment for pituitary-dependent Cushing’s Disease. However, its effectiveness is up for debate. It is expensive, and is dosed daily. At best, improvement in symptoms is seen in some patients, but because of its mode of activity, blood tests do not confirm resolution of the disease.
Treatment for adrenal-dependent Cushing’s disease depends on whether the adrenal tumor is benign or malignant. Surgery is the treatment of choice to remove the adrenal tumor, but should be performed by a specialist as this surgery is especially risky. High doses of Lysodren can be used to treat adrenal tumors, but the incidence of serious side effects can be much higher. An Addisonian crisis can be fatal.