Hyperadrenocorticism offers obstacles in diagnosis, treatment

Hyperadrenocorticism, increased functional activity of the adrenal cortex, is the primary endocrine disease of older dogs. Hyperadrenocorticism may be caused by the presence of an adrenocortical tumor or from excessive production of adrenocorticotropic hormone (ACTH) from the pituitary gland that results in bilateral adrenal gland hyperplasia. Exogenous administration of glucocorticoids may also result in comparable clinical signs of hyperadrenocorticism. In most cases, adrenocortical tumors of dogs are associated with excessive adrenal secretion of cortisol, but excessive secretion of other adrenal hormones may also occur.

A patient with Cushing's diease with restart of hair growth on Lysoderm therapy.

The clinical signs associated with most cases of canine hyperadrenocorticism are the result of high circulating concentrations of glucocorticoids. Clinical signs include polydipsia, polyuria, polyphagia, abdominal enlargement, hepatomegaly, cutaneous changes (alopecia, cutaneous atrophy, calcinosis cutis, hyperpigmentation, pruritus), muscle weakness, decreased exercise tolerance, excessive panting, truncal obesity, lethargy, weight gain, insulin resistance and decreased sexual function.

About 15 percent of dogs with hyperadrenocorticism have adrenocortical tumors, either the right or left adrenal gland is affected with equal frequency. About 50 percent of adrenocortical tumors are adenomas, whereas 50 percent are carcinomas. Bilateral adrenal neoplasia does uncommonly occur in dogs; concurrent pituitary and adrenal tumors may also occur. Adrenocortical tumors occur most often in middle-aged to older dogs and in those dogs larger than 20 kg in body weight. Dog breeds most commonly affected include Poodles, German Shepherd, Dachshunds, Labrador Retrievers and various Terriers.

Adrenocortical tumors

Adrenocortical tumors arise spontaneously and are not associated with long-term ACTH stimulation as in pituitary-dependent hyperadrenocorticism. Adrenocortical tumors are usually unilateral and may be adenomas or carcinomas. Most adrenocortical tumors secrete excessive amounts of cortisol that suppresses ACTH concentrations by negative feedback on the pituitary gland and hypothalamus. The unaffected adrenal gland and normal cells in the affected adrenal gland are atrophic from the insufficient stimulation by ACTH. Cortisol secretion from adrenocortical tumors is not a continuous activity but is episodic. In most cases, ACTH receptors are preserved and adrenocortical tumors respond to exogenous administration of ACTH. Cortisol secretion from adrenocortical tumors is not affected by administration of exogenous dexamethasone.

Identifying markers

Diagnosis of hyperadrenocorticism in dogs is based on historical and physical examination findings, blood and urine test results (CBC, serum chemistry profile, urinalysis, and urine cortisol-to-creatinine ratio), and specific endocrine function test results (ACTH stimulation test, low-dose dexamethasone suppression test, and possibly high-dose dexamethasone suppression test). The ACTH stimulation test is less sensitive for the diagnosis of adrenocortical tumors and pituitary-dependent hyperadrenocorticism. I prefer the urine cortisol-to-creatinine ratio as an effective screening test and the low-dose dexamethasone suppression test to confirm hyperadrenocorticism. The low-dose dexamethasone suppression test and urine cortisol-to-creatinine ratio are also not able to differentiate between adrenocortical tumors and pituitary-dependent hyperadrenocorticism.

Diagnosis of most adrenocortical tumors is usually based on survey radiography, abdominal ultrasonography and/or computed tomography. About 50 percent of adrenocortical tumors are mineralized and identifiable on survey abdominal radiography. In those adrenocortical tumors in which mineralization is not seen, the tumors may be seen by abdominal ultrasonography. Computed tomography may also be used to identify possible adrenal and pituitary masses. In addition, ultrasonography and computed tomography may be useful to identify metastatic disease and indicate the extent of tumor invasion. Specific endocrine function tests such as the high-dose and low-dose dexamethasone suppression tests are useful in distinguishing between adrenocortical tumors and pituitary-dependent hyperadrenocorticism.

Truncal alopecia and hyperpigmentation in a Yorkshire Terrier with Cushing's disease.

The dog's history, physical examination findings and laboratory test results are not useful in differentiating malignant adrenal tumors from benign adrenal tumors. In general, large adrenocortical tumors that are greater than 50 percent of the size of the adjacent kidney are most likely to be malignant tumors and evidence of vascular or capsular invasion, local extension, or metastasis are also positive predictors of malignancy. Adrenocortical carcinomas usually invade local structures such as kidney, liver, vena cava, aorta, and retroperitoneum and metastasize to the liver and lung.

Ultrasonography of the abdomen serves three useful purposes in suspected cases of hyperadrenocorticism. First, ultrasonography is a part of the complete evaluation of the abdomen for any unexpected abnormalities in older dogs. Second, if an adrenocortical mass (tumor) is identified, ultrasonography is helpful in screening for liver and/or other organ metastasis, tumor invasion of the vena cava or other structures, and compression of adjacent tissues by a tumor. Third, ultrasonography evaluates the size and shape of the adrenal glands. If both adrenal glands are visualized and are relatively equal in size, this is considered strong evidence of adrenal hyperplasia due to pituitary-dependent hyperadrenocorticism. A unilateral abnormally enlarged adrenal mass with an abnormally small to nonvisible contralateral adrenal gland is supportive evidence of an adrenocortical tumor.

Treatment

Dogs that have pituitary-dependent hyperadrenocorticism, inoperable adrenocortical tumors or metastatic disease, or have owners who will not allow adrenal tumor removal often respond to medical treatment with mitotane, starting initially at a minimum dosage of 50 mg/kg per day orally for seven to 10 days, perform the ACTH stimulation test, and then start the dog on a maintenance dose of mitotane if the ACTH stimulation test results are decreased (<5 mg/dl). The daily loading dose of mitotane is continued until the ACTH stimulation test results done every seven to 10 days are decreased. Mitotane is usually successful in controlling the clinical signs and, in some cases, may also result in adrenal tumor shrinkage. The effectiveness of mitotane therapy is best monitored using recurrence of previous clinical signs and the ACTH stimulation test. Other therapeutic approaches may be tried for the treatment and control of adrenal-dependent hyperadrenocorticism, but unfortunately they just do not work as well as mitotane therapy.

Successful treatment of adrenocortical tumors involves surgical removal of the adrenal mass (tumor) or use of medical therapy with mitotane. Adrenalectomy should be reserved for those dogs without extensive tumor invasion of local structures or evidence of metastasis. The surgical approach may be done by way of a midline or paracostal approach. The midline approach allows good visualization of both adrenal glands and other abdominal structures; however, the paracostal approach allows better exposure of the affected adrenal gland, less hemorrhage involved, and avoids the risk associated with poor healing of a midline incision. After unilateral adrenalectomy, normal adrenal gland tissue is atrophic and, therefore, supplemental glucocorticoid and sometimes mineralocorticoid therapy is necessary during the perioperative and postoperative period. The glucocorticoid support could include the addition of a rapid acting glucocorticoid in the intravenous fluids that is administered over six hours as soon as the adrenocortical tumor is identified. The mineralocorticoid support may include fludrocortisone or deoxycorticosterone pivalate administered 12 to 24 hours before surgery. Blood pressure, serum electrolyte concentrations, and blood glucose levels should be monitored before, during, and after surgery. After surgery, parenteral glucocorticoids could be continued for 48 to 72 hours or until the dog is bright, alert, and eating. Oral supplementation with prednisone can then replace the parenteral therapy. Supplementation with mineralocorticoids if administered initially should be discontinued after two doses and the dog monitored for the development of hyperkalemia or hyponatremia. The prognosis for those dogs without metastatic disease that survive the initial postoperative period is excellent.

Prognosis

The long-term prognosis is always guarded in affected dogs because of the many complications associated with mitotane therapy or adrenal surgery. Frequent complications from hyperadrenocorticism in older dogs are mitotane toxicosis; poor wound healing; pulmonary thromboembolism; infection; hypertension; diabetes mellitus; pancreatitis; progressive heart, liver, and/or kidney failure; and metastatic disease. The ACTH stimulation tests should be done every three to six months to assess adrenal gland function throughout mitotane therapy, as well as the dog should be re-evaluated on how it is doing at home - attitude, appetite, weight loss/gain, and other observations.

Summary

Hyperadrenocorticism may be caused by the presence of an adrenocortical tumor or from excessive production of adrenocorticotropic hormone from the pituitary gland that results in bilateral adrenal gland hyperplasia. Exogenous administration of glucocorticoids may also result in clinical signs of hyperadrenocorticism. Dogs that have pituitary-dependent hyperadrenocorticism, adrenocortical tumors or metastatic disease, or have owners who will not allow adrenal tumor removal often respond to medical treatment with mitotane. Successful treatment of adrenocortical tumors involves surgical removal of the adrenal mass (tumor) or use of medical therapy with mitotane. The long-term prognosis is always guarded in affected dogs because of the many complications associated with mitotane therapy or adrenal surgery.

Suggested Reading

• Behrend EN, Kemppainen RJ, Clark TP, et al: Diagnosis of hyperadrenocorticism in dogs: a survey of internists and dermatologists. JAVMA 220:1643, 2002.

• Feldman EC, Feldman MS, Nelson RW: Use of low- and high-dose dexamethasone suppression tests for distinguishing pituitary-dependent from adrenal tumor hyperadrenocorticism in dogs. JAVMA 209:772, 1996.

• Ristic JME, Ramsey IK, Heath FM, et al: The use of 17-hydroxyprogesterone in the diagnosis of canine hyperadrenocorticism. J Vet Intern Med 16:433, 2002.