Treating hyperadrenocorticism (Proceedings)

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Hyperadrenocorticism (HAC) 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 appropriate evaluation of clinical signs, selection and interpretation of diagnostic tests, and administration and monitoring of therapy.

Hyperadrenocorticism (HAC) 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 appropriate evaluation of clinical signs, selection and interpretation of diagnostic tests, and administration and monitoring of therapy.

Pituitary dependent hyperadrenocorticism (PDH, Cushing's disease) occurs in 85% of dogs with HAC, while 15% have a functional adrenal tumor (AT). PDH is usually caused by a microadenoma, however some dogs develop a pituitary macroadenoma (>1cm) best treated by radiation therapy or surgery.  Of adrenal tumors, approximately half are benign adenomas, and half are malignant carcinomas. Histopathology does not always predict tumor behavior after surgical removal; some adrenal “adenomas” can re-grow and become locally invasive even following surgical removal. Typically, dogs with PDH are middle-aged (>6 years) to geriatric of either sex. Poodles, dachshunds, beagles, Boston terriers, and German shepherd dogs are more commonly reported with PDH, but any pure- or mixed breed dog can be affected. Adrenal tumors have a mean age of onset 11 years, and females and large-breed dogs predisposed.

The most common historical findings include polyuria, polydipsia, polyphagia, pendulous abdomen, neuromuscular weakness, increased respiratory rate or panting, and truncal alopecia. Importantly, HAC by itself should not cause mental dullness, cardiac changes, dehydration, or severe clinical illness. Evidence of these signs on physical examination indicates concurrent disease even if hyperadrenocorticism is suspected.

Medical database tests include CBC, serum biochemical profile, urinalysis, and urine culture. Thoracic and abdominal radiographs and abdominal ultrasonography should be performed when clinical signs dictate necessity. Findings on these tests are summarized in the following table:

There is no single diagnostic protocol to establish a definitive diagnosis or localization of hyperadrenocorticism. Sometimes the diagnosis can be made relatively quickly with few tests; whereas in other cases multiple tests must be performed to establish diagnosis and localization of disease. Any test for hyperadrenocorticism can have a false negative result since tests primarily measure cortisol, and cortisol can become elevated in non-adrenal illness. Importantly, any dog being tested for hyperadrenocorticism should have clinical signs and historical findings that are supportive of a diagnosis. The table below lists possible screening and localizing tests that can be used.

There are a variety of treatment options for hyperadrenocorticism. The selection of treatment modality for any given patient will be influenced by whether the disease is pituitary or adrenal dependent, severity of the disease, and the owner's ability to monitor for problems during and after therapy. Additionally, the expense and limited availability of certain treatments may influence recommendations.

Pituitary dependent hyperadrenocorticism can be treated with drugs that reduce circulating cortisol levels by limit synthesis of adrenal cortex hormones (e.g. trilostane or ketoconazole), cause partial or complete necrosis of the adrenal cortex (e.g. mitotaine), or limit ACTH production (e.g. Selegiline). Selegiline and ketoconazole are less effective than mitotaine or trilostane. Although dogs seem to tolerate trilostane better than mitotaine, both require regular follow-up monitoring and both have potential negative side effects.

Trilostane is a synthetic steroid analogue that acts as a competitive inhibitor of the 3 beta hydroxysteroid dehydrogenase enzyme, and may interfere with other enzymes responsible for steroid production. By blocking enzymes, production of the end-products of steroid metabolism, primarily cortisol and to a lesser extent aldosterone, is reduced. Starting dose for trilostane should be between 1 and 2.5 mg/kg once daily. Approximately 80% of dogs will be controlled on once daily administration, and the remainder will require twice daily administration. Peak concentration occurs within 2 hours following oral administration, and follow-up ACTH stimulation testing should be performed 4 hours following administration. Although most dogs have minimal complications with trilostane therapy and can be managed long-term with this treatment, some dogs have been reported to develop adrenal gland necrosis with permanent hypocortisolemia and hypoaldosteronism.

Conservative dosing protocols and regular ACTH stimulation monitoring will help to avoid these complications. The owner should monitor for resolution of clinical signs of hyperadrenocorticism, and absence of gastrointestinal signs and weakness. The first ACTH stimulation testing should be performed 10 days after initiation of treatment, and at one month, 3 months, and every 3 months thereafter. Cortisol values between 60 and 200 mmol/L indicate appropriate dosing. Values < 60 mmol/L indicate that trilostane should be discontinued for a month and re-instated as needed, and values > 200 mmol/L indicate that the dose should be increased by 25-50%, or the dose should remain the same and frequency be increased to twice daily administration.

 

Mitotaine is cytotoxic to the adrenal cortex, resulting in selective, progressive atrophy. Treatment includes initiating therapy with a loading dose of the drug over few to several days, and then reducing to a maintenance dose to continue the drug's effect. Response to mitotaine can vary widely between individuals, and between normal dogs and dogs with PDH; therefore, clients and veterinary staff should be counseled on signs associated with hypoadrenocorticism in the event of an exaggerated response.

Initial “loading” dose for mitotaine is 30-50mg/kg/day, either given as one treatment, or divided twice a day, for 7-10 days.  Mitotaine is a fat-soluble drug, and should be administered with food for best absorption. If the dog shows reduced appetite, anorexia, weakness, vomiting, diarrhea, or lethargy, mitotaine should be discontinued, prednisone should be administered at a twice- physiologic maintenance dose (0.5mg/kg/day) and the dog should return for ACTH stimulation testing in 2-3 days, or sooner if the symptoms do not resolve with initiation of glucocorticoid therapy.

Mitotaine may induce stomach upset in some dogs without obvious hypoadrenocorticism. Reasonable treatment strategy in those individuals should include physiologic maintenance prednisone at 0.25mg/kg/day, administered concurrently with mitotaine, and choosing a loading dose at the low end of the treatment range.

Following initial loading with mitotaine, ACTH stimulation testing should be repeated. The goal of loading is to have an ACTH stimulation test within the basal range (60-200 mmol/L) for the post sample. Following the initial 1-month recheck, ACTH stimulation testing should be repeated at least 3 times a year, or more frequently if the owner sees return of clinical signs. Dogs on mitotaine maintenance are subject to change at any time, and often escape maintenance over a long course of therapy. If the cortisol level is gradually increasing in a dog formerly controlled, increasing the maintenance dose by 50% may help to avoid a repeat loading. Repeat loading may be necessary with a dog that is persistently out of the basal range of cortisol post-stimulation.

Adrenal dependent hyperadrenocorticism can be treated surgically or medically. Complete surgical excision of an adrenal mass remains the mainstay of treatment. Local tumor involvement and invasion of vascular structures may prohibit surgical removal. If surgical removal is successful, medical management will be necessary to address hypoadrenocorticism while the opposite adrenal gland resumes normal function. If surgical excision is impossible based upon the location or invasiveness of the tumor, medical management with trilostane or mitotaine may be successful in reducing cortisol secretion from the abnormal gland.

Prognosis varies considerably depending upon the source of HAC, and whether the underlying disease is curable. Concurrent diseases such as glomerulonephritis, diabetes mellitus, or pulmonary hypertension, may significantly shorten expected lifespan. Hyperadrenocorticism cause hypercoagulability and acute thromboembolism may be rapidly fatal. Complications of treatment may be life-threatening. 

Table 1

Complete blood count: Serum biochemical profile:

Mature neutrophilia

Monocytosis

Lymphopenia

Eosinopenia

Increased:  Alkaline phosphatase (ALP)

                  Alanine aminotransferase (ALT)

                  Gamma glutamyl transferase (GGT)

Hypercholesterolemia

Lipemia   

Mild hyperglycemia Urinalysis: Radiographs/ultrasound:

Proteinuria

Isosthenuria

+/- Pyuria, Bactiuria

Adrenal masses

Adrenal mineralization

 

Table 2

Screening tests for hyperadrenocorticism: Localizing tests for hyperadrenocorticism:

Recommended:

ACTH stimulation test

Low Dose dexamethasone suppression test

Urine cortisol: creatinine ratio

Not recommended:

Resting plasma cortisol

Steroid-induced Isoenzyme of Alkaline Phosphatase

  Combination HDDST:ACTH stimulation test

Low dose dexamethasone suppression test

High dose dexamethasone suppression test

Plasma ACTH hormone concentration

Abdominal ultrasonography

Computed tomography

  Magnetic resonance imaging

 

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