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Veterinarian Technician June 2007 (Vol 28, No 6) Focus: Endocrine Disorders

Overview of Hyperadrenocorticism

by Mindy Cohan, VMD

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    Key Points

    • Of dogs with naturally occurring hyperadrenocorticism (HAC), 85% have pituitary gland tumors and 15% have adrenal gland tumors.
    • A diagnosis of HAC is based on clinical signs, laboratory tests, and diagnostic imaging.
    • Treatment for HAC depends on the etiology and clinical signs.

    Hy­per­adre­no­­cor­ti­cism (HAC), also known as Cushing's disease, is a common endocrine syndrome that affects middle-aged and geriatric dogs and, occasionally, cats. HAC is generally caused by tumors of either the pituitary or adrenal glands; however, long-term administration of exogenous glucocorticoids can also cause HAC. Regardless of the etiology, the cause of the clinical signs typically seen in this syndrome is an abnormally elevated serum cortisol level.

    Etiology

    Normally, the amount of cortisol in the blood is controlled by interaction between the adrenal glands, the pituitary gland, and the hypothalamus. When cortisol is needed (e.g., to respond to a stressful situation), the hypothalamus signals the pituitary gland to release adrenocorticotropic hormone (ACTH), which prompts the adrenal glands to produce cortisol. In turn, high levels of cortisol in the blood cause the hypothalamus to decrease its signal to the pituitary gland, which in turn produces less ACTH, thereby reducing the demand for cortisol. This relationship is known as a negative feedback loop.1

    When a pituitary or adrenal gland is affected by a tumor, it stops responding to the signals of the feedback loop. Pituitary tumors cause the pituitary gland to produce ACTH regardless of cortisol levels, leading to increased production of cortisol, and adrenal tumors continue to secrete excessive amounts of cortisol despite diminished quantities of plasma ACTH.1 Pituitary gland tumors account for 85% of naturally occurring cases (pituitary-dependent hyper­adrenocorticism [PDH]); the remaining 15% of cases are caused by adrenal gland tumors.2 Secondary, or iatrogenic, HAC caused by administration of high doses of exogenous cortisol creates a physiologic situation similar to that of an adrenal tumor. The exogenous cortisol has a negative feedback effect on the hypothalamus and suppresses the release of ACTH from the pituitary gland. The diminished ACTH level can lead to atrophy of the adrenal glands. However, continued administration of cortisol perpetuates HAC.

    Necropsy of canine patients with PDH commonly reveals adenomas of the pars distalis.1 These pituitary tumors usually have complications limited to the clinical signs of HAC (e.g., polyuria, polydipsia). Large pituitary adenomas can result in neurologic signs, such as stupor or confusion.2

    Tumors affecting the adrenal glands tend to be unilateral, with benign adenomas comprising half of all cases and the other half being malignant carcinomas.2 The resulting persistent negative feedback of diminished ACTH on the nonneoplastic adrenal gland leads to its atrophy.1

    Other than problems caused by the size and location of the tumor, the clinical signs of PDH and adrenal tumor are identical.2 Patients with iatrogenic HAC share the same clinical signs as patients with naturally occurring disease. A definitive diagnosis of HAC is contingent on laboratory and radiographic tests. Technicians familiar with the diagnostic procedures, current therapies, and monitoring protocols for canine patients with HAC can play a vital role in the management of this disease.

    Signalment

    The median age of dogs with PDH is 10 years. Dogs with adrenal tumors tend to be older, with a median age of 11.3 years at the time of diagnosis. Females are slightly more predisposed than males and account for approximately 60% of all dogs with HAC.1 Poodles, dachshunds, beagles, German shepherds, and many terrier breeds are commonly affected. Although there are no established correlations between weight and adrenal tumor development, 75% of dogs with diagnosed PDH weigh less than 9 lb (20 kg).1

    Clinical Signs

    Physical Abnormalities

    The most frequently reported and recognized clinical signs of canine HAC are polyuria and polydipsia. These signs are reported in 80% to 85% of cases.1 Owners often bring affected dogs to their veterinarian because of increased urination or the loss of housetraining habits.

    Other common clinical signs include lethargy, increased appetite, and a "potbellied" appearance. Although a patient with HAC can gain weight as a result of a hearty appetite, abdominal enlargement is attributable to cortisol's promotion of muscle weakness, hepatomegaly, and increased abdominal fat stores.1

    High cortisol levels also induce hair follicle atrophy and cause several dermatologic problems.1 Patients with HAC often develop alopecia, which can be limited to pressure points, such as elbows and hocks, or can be bilaterally symmetric and of variable severity.1 HAC should be suspected in geriatric canine patients with poor hair regrowth after clipping. Additional dermatologic changes associated with hypercortisolemia include thin, transparent skin; seborrhea; and pyoderma.1

    Respiratory effects of HAC can be mild, such as panting or tachypnea, or severe, such as pulmonary thromboembolism. Several factors contribute to the development of these problems. Panting and tachypnea at rest are attributable to increased abdominal fat, weakened respiratory muscles, and hepatomegaly.1 The formation of pulmonary thromboemboli is thought to be the result of a hyper­coagulable state caused by diminished levels of antithrombin III and increased levels of several clotting factors, fibrinogen, and plasminogen.1 The predisposition to develop pulmonary thromboemboli poses the greatest threat to patients with HAC.

    Technicians presented with an older canine patient with a history of urinary accidents should inquire about the dog's water consumption, appetite, and breathing pattern. Changes in a dog's appearance can be subtle; therefore, it is important to ask the owner if he or she has noticed a change in the pet's coat or general appearance.

    Hematologic Abnormalities

    Cortisol is associated with the "fight or flight" stress response; therefore, it is logical that patients with HAC exhibit hematologic changes consistent with a stress leukogram. These changes include neutrophilia, monocytosis, lymphopenia, and eosinopenia. Hematocrit values tend to be normal or slightly elevated.1

    Serum Biochemistry Abnormalities

    HAC can cause several changes in serum biochemistry. Excessive cortisol induces lipolysis, which increases levels of serum cholesterol and triglycerides.1 Cortisol also plays a role in promoting glucose production and has antagonizing effects on insulin, which may lead to a mild increase in serum blood glucose.1 The diuresis that is a frequent reason for presentation can result in loss of blood urea nitrogen and phosphorus.

    An elevation in serum alkaline phosphatase (ALP) is the most common abnormality that can raise suspicion for HAC. Cortisol's direct effect on hepatocytes results in ALP and alanine aminotransferase production.1 Despite the large percentage of dogs with HAC and elevated ALP, the finding of elevated ALP lacks specificity and is not diagnostic for HAC.

    Urine Abnormalities

    In addition to a complete blood count and serum biochemical profile, a urinalysis should be conducted for all dogs suspected of having HAC. Urinalysis is useful as a screening test and helps to diagnose secondary problems, such as diabetes mellitus and urinary tract infections. Dogs with HAC are predisposed to urinary tract infections because of the immunosuppressive effects of cortisol. The most common urine abnormality seen in dogs with HAC is a reduced urine specific gravity. The exact cause of dilute urine is uncertain, but it is speculated to be related to cortisol's effects on antidiuretic hormone.1

    Screening Tests for HAC

    (see box)

    Urine Cortisol: Creatinine Ratio

    Although developed for use in humans, the urine cortisol:creatinine ratio (UC:CR) has been found to be useful as a screening test for dogs suspected of having HAC. The test is convenient because it requires only a free-catch urine sample and does not involve hospitalization or venipuncture. Because stress has been speculated to cause false elevations in urine cortisol levels, it is recommended that the sample be collected at home in a stress-free environment.2

    A study to assess the diagnostic value of the UC:CR was conducted using healthy dogs, dogs that had a history of polyuria/polydipsia, and dogs with a confirmed diagnosis of HAC.3 The sensitivity, or probability that a dog with HAC would have a positive test result, was 100%. However, many dogs with polyuria/polydipsia caused by conditions other than HAC also had elevated UC:CR results. Therefore, the specificity of the test (i.e., the probability that a dog without HAC would have a negative test result) was low (22%).3 Because of the high sensitivity and low specificity of the UC:CR, a negative result is very helpful in ruling out HAC, but an elevated UC:CR result requires further testing to confirm a diagnosis.

    Low-Dose Dexamethasone Suppression Test

    The low-dose dexamethasone suppression test (LDDST) is based on the negative feedback system between the pituitary and adrenal glands. In a dog without HAC, the administration of exogenous dexamethasone causes the pituitary gland to decrease its secretion of ACTH, which, in turn, decreases the adrenal glands' release of cortisol. However, canine patients with pituitary-dependent HAC (PDH) are minimally affected by the administration of a low dose of exogenous dexamethasone. The diseased pituitary gland continues to secrete ACTH, thus maintaining excessive release of cortisol from the typically hypertrophied adrenal glands. Analysis of blood samples taken before and 4 and 8 hours after dexamethasone administration reveals whether cortisol levels are affected by this test.

    Adenomas and adenocarcinomas of the adrenal glands also function autonomously despite the administration of exogenous dexamethasone. During an LDDST, ACTH levels drop in patients with a normal pituitary gland and a diseased adrenal gland, but the abnormal adrenal gland continues its excessive production of cortisol.

    The sensitivity of the LDDST is estimated to be between 85% and 100%. Because illnesses other than HAC can contribute to false-positive results, the specificity of the LDDST has been estimated to be between 44% and 73%.2

    ACTH Stimulation Test

    The ACTH stimulation test relies on the fact that dogs with HAC have an increased capacity to produce cortisol from either PDH-induced adrenal hypertrophy or a functioning adrenal tumor. In this test, exogenous ACTH is administered and the patient's cortisol response measured. Dogs with naturally occurring HAC are expected to have exaggerated cortisol production.4 Because the adrenal glands are atrophied in dogs with iatrogenic HAC, in­creased cortisol production is not seen in these patients. The advantages of this test are the short time it requires and its ability to distinguish naturally occurring HAC from iatrogenic HAC.5

    Studies including dogs with either PDH or adrenal tumor revealed the sensitivity of the ACTH stimulation test to be between 73% and 95%.2 Sensitivity levels decrease when the two individual forms of HAC are evaluated separately.2 Dogs with early-onset PDH may not have adrenal hypertrophy and therefore may fail to have an exaggerated response to ACTH administration. Also, not all adrenal tumor cells produce excessive cortisol when challenged with ACTH.

    Differentiating Tests for PDH versus Adrenal Tumor

    Following the confirmation of naturally occurring HAC via screening tests, it is important to differentiate pituitary disease from adrenal disease. Determining the cause of disease enables the veterinarian to formulate the most appropriate treatment protocol and determine an accurate prognosis. The LDDST is sometimes useful in differentiating PDH from adrenal tumor; however, the ACTH stimulation test is not.

    High-Dose Dexamethasone Suppression Test

    The high-dose dexamethasone suppression test (HDDST), similar to the LDDST, is based on the feedback system between the pituitary and adrenal glands. Using a higher dose of dexamethasone can overcome a pituitary tumor's resistance to negative feedback and cause a decrease in serum cortisol. In contrast, adrenal tumors tend to be immune to the administration of high doses of exogenous dexamethasone and continue to produce excessive amounts of cortisol.2 Unfortunately, the HDDST is not very sensitive. Approximately 25% to 30% of dogs with PDH do not show suppressed cortisol levels during the HDDST.2,4

    Endogenous ACTH Concentration

    The measurement of endogenous ACTH concentration cannot be used as a screening test because many dogs with HAC have values within the normal range. However, this test does have merit in differentiating patients with PDH from those with adrenal tumor or iatrogenic HAC. Dogs with iatrogenic HAC or adrenal tumor have diminished levels of endogenous ACTH compared with dogs with PDH.1

    The endogenous ACTH concentration test has significant drawbacks. Results can fall into a nondiagnostic range, and the sample requires very careful and specific handling by veterinary technicians and laboratory personnel.

    Diagnostic Imaging

    Abdominal ultrasonography can be useful in differentiating PDH from adrenal tumor, but it has limitations. For optimal accuracy, the test should be conducted by an experienced veterinary radiologist. Even well-trained radiologists cannot always discern changes in the size, shape, and architecture of the adrenal glands. In general, bilaterally enlarged adrenal glands are suggestive of PDH, and unilateral changes are suggestive of adrenal tumor.2 In a study that evaluated 71 dogs with adrenal tumor, 86% of cases were correctly diagnosed.2 Ultrasonography is not useful for distinguishing adrenal adenomas from carcinomas.

    Abdominal computed tomography is a better differentiating test than abdominal ultrasonography.2 False-negative results are possible because not all dogs with HAC have enlarged adrenal glands. Dogs with unilateral adrenal hyperplasia can have computed tomography results identical to those of dogs with adrenal tumor.2

    Pituitary tumors can also be elusive. These masses are often less than 1 cm in diameter and are not always detected on imaging studies.2 Magnetic resonance imaging is more commonly used to evaluate diagnosed pituitary tumors than to differentiate pituitary disease from adrenal disease.2

    Treatment

    The course of treatment for HAC is contingent on the diagnosis of PDH, adrenal tumor, or iatrogenic HAC. If pharmaceutical therapy is instituted, the goal is to ameliorate the clinical problems of HAC by indirectly suppressing the pituitary gland's release of ACTH or directly suppressing the adrenal glands' production of cortisol. Unless a tumor is deemed nonresectable, the preferred treatment for adrenal tumor is adrenalectomy. Dogs with PDH are more commonly treated with drug therapy than with radiation or surgery.6 If a pituitary mass results in neurologic problems, then surgical removal should be considered. Dogs with iatrogenic HAC should be slowly weaned off of exogenous steroids to allow the adrenal glands to resume normal production of glucocorticoids.

    Medical Therapy

    Mitotane

    Mitotane, a derivative of the insecticide dichloro­diphenyl­dichloroethane, causes cell necrosis in two of the three layers of the adrenal glands — the zona fasciculata and zona reticularis.7 The areas affected are responsible for the production of glucocorticoids. The zona glomerulosa is typically spared from necrosis; therefore, it continues to produce the mineralocorticoid aldosterone.7 Maintenance of aldosterone production is important because this hormone regulates the body's sodium and potassium balance. Mitotane can be used to treat PDH or adrenal tumor. The initial induction phase of therapy involves a daily mitotane dose of 40 to 50 mg/kg PO with food. This "knockdown" dose is typically given for 7 to 10 days to promote necrosis and atrophy of the adrenal zona fasciculata and zona reticularis.6

    Concurrent prednisone or prednisolone (0.15 to 0.25 mg/kg/day PO) can help alleviate the potential side effects following mitotane administration.8 The development of anorexia, vomiting, diarrhea, lethargy, and weakness is not directly caused by mitotane but rather is the result of a rapid drop in the serum cortisol level, known as an addisonian (hypoadrenocorticism) crisis. Technicians should carefully advise owners about these potential problems associated with mitotane dosing.

    At the end of the induction phase, an ACTH stimulation test is conducted to assess the success of therapy. It is important to instruct owners to discontinue oral steroid supplementation on the day of the ACTH stimulation test. Owners should also be instructed to give mitotane with a meal for enhanced absorption and to wear gloves when handing fragments of the pills.

    Once clinical signs have improved and desired results of an ACTH stimulation test are reported, maintenance mitotane therapy is started. The dose is usually 25 to 50 mg/kg PO divided over 2 or 3 days of the week indefinitely.8 Technicians must stress the importance of conducting ACTH stimulation tests every few months to ensure control of HAC and the avoidance of iatrogenic hypoadrenocorticism.

    Ketoconazole

    Ketoconazole is an antifungal agent that decreases cortisol production by inhibiting the enzymes necessary for glucocorticoid synthesis.7 Its side effects are similar to those of mitotane and are the result of rapidly diminished serum cortisol levels. Unlike mitotane, ketoconazole has the potential to cause a change in coat color, elevated liver enzymes, and hepatotoxicity.7,8

    Further studies are needed to establish the efficacy of ketoconazole in treating HAC. Current estimates, based on a survey of veterinary internists and dermatologists, indicate that at least 20% to 25% of dogs with PDH will not respond to ketoconazole.7 Ketoconazole is dosed at 5 to 30 mg/kg/day PO.8 Because of its expense, requirement for twice-daily dosing, and lower efficacy rating in the survey, it is not the primary choice for treatment of PDH. It is most useful in patients with mitotane intolerance or a mitotane-resistant adrenal tumor.8 An ACTH stimulation test should be conducted after 3 weeks of therapy. The test should commence 3 to 6 hours after the administration of ketoconazole on the day of the test.8 Unless adverse effects are observed, or ketoconazole is deemed ineffective, it is administered indefinitely.

    Trilostane

    Trilostane is a synthetic, hormonally inactive steroid that inhibits the production of cortisol, aldosterone, and sex hormones.7,8 Trilostane has not been associated with severe side effects. As it resolves hypercortisolemia, patients may experience lethargy and a decrease in appetite.8

    The efficacy of trilostane is comparable to that of mitotane. Because trilostane does not induce adrenal necrosis, its effects are largely reversible,8 and it poses less risk than mitotane for causing permanent hypoadrenocorticism (Addison's disease). The greatest drawbacks of trilostane are its cost and requirement for daily dosing. Trilostane was previously only available to international pharmacies. It has become more accessible in the United States, but only through compounding pharmacies. Many patients require higher dosages to remain in remission. Gradual dose increases are recommended to help minimize adverse effects. Patients should be monitored with an ACTH stimulation test 2 weeks, 1 month, and then every 3 months after beginning trilostane therapy. This test, along with measurement of serum electrolyte concentrations, should be conducted 4 to 6 hours after the administration of trilostane on the day of testing.8 If well tolerated and effective, trilostane is administered indefinitely.

    l-Deprenyl

    l-Deprenyl increases central dopamine concentration by selectively and irreversibly inhibiting monoamine oxidase type B. The benefits of elevated dopamine levels are postulated to be a decrease in ACTH secretion and the inhibition of pituitary adenoma growth.8 The drug's efficacy in the treatment of HAC is limited. Because of l-deprenyl's wide margin of safety, its use can be considered for patients intolerant of mitotane, trilostane, or ketoconazole or for patients with mild clinical signs of PDH. l-Deprenyl has been found to help alleviate problems associated with canine cognitive dysfunction.8

    Surgical Therapy

    In the absence of predetermined complicating factors (e.g., uncontrolled diabetes mellitus, hypercoagulability), patients with adrenal tumors are usually managed with adrenalectomy. All canine candidates for adrenalectomy should have a preoperative workup that includes a complete blood count, chemistry profile, urinalysis, and chest radiography. Abdominal ultrasonography can be helpful in identifying complicating circumstances, such as tumor invasion of the caudal vena cava or the renal vein. Medical therapy with ketoconazole or mitotane can be used before surgery to help control the signs of HAC.9 For dogs undergoing unilateral adrenalectomy, corticosteroids should be administered before and after surgery. If bilateral adrenalectomy is to be performed, glucocorticoids and mineralocorticoids should be given before surgery, and both will need to be continued indefinitely.9

    Postoperatively, technicians must closely monitor respiratory rate, heart rate, blood pressure, mucous membrane color, and capillary refill time. Electrolyte levels should be checked with close attention to decreasing sodium and increasing potassium levels.9

    Adrenal adenomas tend to be well delineated and less invasive than adenocarcinomas.10 Dogs with invasive tumors that cannot be resected completely require medical therapy following surgery. The long-term prognosis for adrenalectomy patients is good; however, several serious perioperative complications, such as thromboembolism, hypoadrenocorticism, pancreatitis, and cardiac arrest, can occur. Veterinary technicians play a vital role in patient monitoring following surgery.

    Role of the Technician

    HAC is a complex syndrome, but its successful management is rewarding for the pet, the client, and the veterinary team. Familiarity with the hypothalamus-pituitary-adrenal axis is important for veterinary technicians to gain an understanding of the tests and treatments associated with HAC. Technicians play an important role in diagnosing HAC and are crucial in maintaining the correct protocol for screening tests. Technicians also can help in differentiating PDH from adrenal tumor by assisting with imaging tests, conducting the HDDST, and overseeing the proper handling of endogenous ACTH samples.

    The numerous steps involved in diagnosing HAC and the potential for serious adverse complications of therapy make client communication a priority. Technicians must be familiar with the requirements of the ACTH stimulation test in particular. Clients must be properly instructed on when to discontinue medications (e.g., prednisone) before testing as well as the appropriate time frame for testing during medical treatment (e.g., 4 to 6 hours following ketaconazole or trilostane administration).

    1. Feldman EC, Nelson RW: Hyperadrenocorticism (Cushing's syndrome), in Canine and Feline Endocrinology and Reproduction, ed. 2. Philadelphia, Saunders, 1996, pp 187-265.

    2. Behrend EN, Kemppainen RJ: Diagnosis of canine hyper­adrenocorticism. Vet Clin North Am Small Anim Pract 31(5): 985-1003, 2001.

    3. Feldman EC, Mack RE: Urine cortisol:creatinine ratio as a screening test for hyperadrenocorticism in dogs. JAVMA 200(11):1637-1641, 1992.

    4. Braddock JA: Diagnosis of hyperadrenocorticism in the dog. Aust Vet J 81(1-2):25-27, 2003.

    5. Mack RE: Screening tests used in the diagnosis of canine hyperadrenocorticism. Semin Vet Med Surg (Small Anim) 9(3):118-122, 1994.

    6. Peterson ME, Kintzer PP: Medical treatment of pituitary-dependent hyperadrenocorticism in dogs. Semin Vet Med Surg (Small Anim) 9(3):127-131, 1994.

    7. Braddock JA: Medical treatment of hyperadrenocorticism in the dog. Aust Vet J 81(1-2):31-33, 2003.

    8. DeClue AE, Cohn LA, Kerl ME: Medical therapies for canine pituitary-dependent hyperadrenocorticism. Vet Med 99(6): 519-527, 2004.

    9. Axlund TW, Behrend EN, Winkler JT: Surgical treatment of canine hyperadrenocorticism. Compend Contin Educ Pract Vet 25(5):334-346, 2003.

    10. Anderson CR, Birchard SA, Powers BE: Surgical treatment of adrenocortical tumors: 21 cases (1990-1996). JAAHA 37:93-97, 2001.

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