Diagnosing and treating Cushing's disease (Proceedings)

Hyperadrenocorticism (HAC) (commonly called Cushing's disease) is a commonly diagnosed endocrinopathy in dogs which is caused by persistently high cortisol levels in circulation. Diagnosis and treatment may not be straightforward, and successful management depends upon evaluation of clinical signs, performance of diagnostic tests, and administration and monitoring of therapy.

Cortisol is a hormone produced by the adrenal glands, which are paired glands located near each kidney. The anterior pituitary gland in the brain produces a hormone called adrenocorticotropic hormone (ACTH) that is released into circulation in response to the body's need for cortisol. ACTH stimulates release of cortisol, and cortisol, in turn, shuts off release of ACTH. Cortisol has a variety of beneficial functions in the body that are mainly centered around helping cells and tissues remain healthy, maintaining blood glucose, and helping the body to combat stress. Excessive amounts of cortisol can cause muscle weakness, panting, increased urination and drinking, thinning of skin, loss of hair, and increased susceptibility to infections and to diabetes mellitus. Too little cortisol causes weakness, low blood sugar, loss of appetite, vomiting, diarrhea, and shaking.

The adrenal glands also make aldosterone, a hormone that helps the kidneys maintain sodium and excrete potassium. Without aldosterone, low sodium and high potassium can cause severe dehydration, mental dullness, shock, and cardiac arrhythmias.

Cushing's disease occurs commonly in older dogs, has symptoms that occur slowly and gradually over time, and affects quality and length of life. A series of tests is required to diagnose, and a coordinated long-term treatment effort is important for treatment success. The most common disorder causing hyperadrenocorticism is a malfunctioning pituitary gland that releases ACTH despite elevated cortisol levels in circulation. A few dogs (up to 15% of those diagnosed) may have an adrenal gland tumor that hyper-functions and does not respond to signals from the pituitary gland. As a result of these changes, too much cortisol is released from the adrenal glands and has harmful effects within the body.

Dogs are usually middle-aged to geriatric (>7 years) at diagnosis, may be any breed or mixed breed, and either sex. Cats are rarely affected, and always have concurrent diabetes mellitus at the time of diagnosis. The most common client observations include increased appetite, drinking and urinating, weight gain with a pot-bellied appearance, and loss of hair, especially on the abdomen and sides, but not on the head or legs. Hyperadrenocorticism should not cause the animal to act “sick” unless there is another disease process going on at the same time.

Testing for Hyperadrenocorticism:

In addition to routine blood testing for patients with illness (CBC, serum chemistry profile, urinalysis), the veterinarian may order tests that specifically evaluate function of the pituitary-adrenal axis. These tests must be performed following specific protocol, and may be adversely affected by stress or nervousness. Patients should be maintained in a stress-free environment for that reason. In the diabetic patient, blood glucose must not become below normal throughout testing since low blood sugar is a form of stress. When hyperadrenocorticism is suspected, the disease must first be diagnosed with one or more tests. If diagnosis is confirmed, then additional tests are necessary to identify the cause of hyperadrenocorticism prior to starting treatment.

Common tests to diagnose hyperadrenocorticism:

Urine cortisol: creatinine ratio (UCCR)

• Rationale: Cortisol is excreted in the urine. Diagnosis of hyperadrenocorticism in people involves calculating urine cortisol excretion over a 24-hour period. Evaluating ratio of creatinine to cortisol in veterinary patients eliminates need to do timed urine collection since cortisol should be present in urine in proportion to creatinine at steady state

• Protocol:

• Obtain a free-catch urine sample from a dog in a relaxed environment (best plan: have the owner collect urine at home)

• Submit for laboratory measure of urine cortisol and creatinine

• UCCR < 20 x 10-6 is normal

• Bottom line: Good choice for a one-time test to exclude diagnosis of hyperadrenocorticism. False positive tests common.

ACTH stimulation test

• Rationale: ACTH is released from the pituitary gland, stimulates release of cortisol from adrenal gland. Injectable ACTH hormone is administered in excess of the body's need to maximally stimulate cortisol release. With hyperadrenocorticism, cortisol is released at greater than normal levels.

• Protocol:

• Paired serum cortisol samples at 0 and 1-hour post synthetic ACTH

• Administer synthetic ACTH at 250ug/dog IV or IM, or at a dose of 5ug/kg IV or IM. ACTH can be reconstituted, diluted, and frozen: maintains potency when frozen for 4 months.

• Interpretation of post-sample

• 550 mmol/L, consistent with hyperadrenocorticism

• 200-550 mmol/L, normal

• 60-200 mmol/L, goal for post-treatment with trilostane

• < 60 mmol/L = hypoadrenocorticism

• Bottom line: Extremely useful test for pituitary-dependent hyperadrenocorticism, iatrogenic hyperadrenocorticism, and hypoadrenocorticism. May be normal if an adrenal tumor is causing the disease.

Low dose dexamethasone suppression test

• Rationale: Normal pituitary will stay suppressed for at least 8 hours following dexamethasone administration, and dexamethasone will not be measured on the cortisol assay

• Protocol:

• Measure cortisol before dexamethasone administration

• Administer 0.015mg/kg dexamethasone IV or IM

• Measure cortisol at 4 and 8-hours post dexamethasone

• Interpretation:

• Suppression  by 8 hours < 40 mmol/L, normal

• No suppression by 8 hours, hyperadrenocorticism

• Suppression by 4 hours, escape by 8 hours, consistent with pituitary-dependent hyperadrenocorticism

• Bottom line: Mainstay of diagnosing hyperadrenocorticism if stress can be minimized. Can diagnose and localize disease with one test in 30% of dogs.

Tests to localize hyperadrenocorticism:

High dose dexamethasone suppression test (HDDST)

• Rationale: With enough cortisol, any pituitary disease should suppress for > 8 hours, but adrenal disease should not

• Protocol: Measure cortisol at 0, 4, and 8 hours. Administer dexamethasone at 0.15mg/kg IV or IM (modified high dose) or 1mg/kg/hr (true high dose). Suppression of < 45 mmol/l is consistent with pituitary disease or a normal dog. No suppression is consistent with adrenal-dependent disease 60% of the time. True high dose can cause more pituitary-dependent dogs to suppress.

• Bottom line: Is the right test to localize, but may not localize in all cases

ACTH level

• Rationale: In hyperadrenocorticism, adrenal-dependent dogs should have minimal circulating ACTH, while pituitary dependent dogs should have excessive ACTH

• Protocol: Discuss protocol with your diagnostic lab – procedures vary. Typically just a one-time blood draw.

• Bottom line: Very useful test, but not particularly easy to locate a lab doing clinical testing. Must have diagnosed dog with hyperadrenocorticism first.

Imaging studies: Radiographs, ultrasound, CT scan

• Rationale: With pituitary-dependent hyperadrenocorticism, adrenal glands should be bilaterally symmetrical and non-calcified. Asymmetry or calcification is seen with adrenal dependent disease.

• Protocol: Take imaging studies and look for unilateral or bilateral adrenal enlargement, as well as screening for other disease

• Bottom line: Evaluate all studies for presence of adrenal glands, even if you were taking imaging studies to look for other disease

Treatments for hyperadrenocorticism:

Pituitary-dependent hyperadrenocorticism is usually treated with oral medications. Two oral medications are used in the United States: mitotaine (Lysodren) and Trilostane. Mitotaine treats hyperadrenocorticism by causing necrosis of the section of the adrenal gland that produces cortisol. When using this medication, a higher dose is used initially to cause adrenal gland necrosis, and then reduced to a maintenance dose to maintain the gland function at a limited level. The biggest side effect of this medication is that necrosis can also occur in the section of the adrenal gland that produces aldosterone which controls sodium and potassium levels. Regular ACTH stimulation testing is used to monitor response to mitotaine. Clients should be instructed to plan on post-treatment ACTH stimulation testing 3 days after the high dose phase of mitotaine, and every 3 months thereafter. Testing must occur at 4 hours post-pill administration.

Trilostane limits enzyme function in the adrenal glands so that less cortisol is produced. The biggest side effect of this medication is excessive reduction of cortisol causing weakness, loss of appetite, and intestinal upset from excessively rapid reduction of cortisol (iatrogenic hypoadrenocorticism). Any complaint of these symptoms in dogs receiving treatment deserves to be evaluated. Symptoms may happen at any time during a course of treatment. Pituitary-dependent hypoadrenocorticism is not cured, but is merely treated and controlled. Regular ACTH stimulation testing is used to monitor response to trilostane. Clients should be instructed to plan on post-treatment ACTH stimulation testing 10 days after initiation of the medication, and every 3 months thereafter. Testing must occur at 4 hours post-pill administration.

Adrenal dependent hyperadrenocorticism is best treated and may be cured with surgery. Removing the abnormal adrenal gland may resolve symptoms. Removal may not be possible since adrenal tumors sometimes grow into nearby vital structures like the caudal vena cava. 50% of adrenal tumors are malignant and may re-grow after removal, and 50% are benign. Postoperative care following adrenal removal requires particular attention to monitor for sudden hypoadrenocorticism since the adrenal tumor that was removed will have caused suppression of the opposite adrenal gland. Prednisone will need to be administered to cover maintenance needs of the body for the weeks following surgery until the remaining adrenal gland function returns.