Diagnosis of Spontaneous Canine Hyperadrenocorticism: 2012 ACVIM Consensus Statement (Small Animal)- Part 1 of 3

Part 2 of Cushing's Consensus Statement

Part 3 of Cushing's Consensus Statement

...and more liver information

Clinical Presentation: Indications For Diagnostic Testing

The possibility that a patient has hyperadrenocorticism (HAC) is based on the history and physical examination. Endocrine tests should be performed only when clinical signs consistent with HAC are present. The Panel believes that because of heightened awareness of HAC, dogs are currently evaluated at much earlier stages of disease development. Consequently, clinical manifestations are more subtle, and the prevalence of clinical signs and physical examination findings in individual dogs is less than that published several decades ago.

The primary indication for pursuing a diagnosis of HAC is the presence of one or more of the common clinical signs and physical examination findings (Table 1).1-10 If only 1 clinical sign is present, it is usually polyuria and polydipsia, or alopecia and skin changes suggestive of an endocrine disease.11 Cases seen by dermatologists may have a different constellation of findings than those seen by internists. Failure to identify multiple indicators for HAC does not rule out the disease. However, the more abnormalities identified, the stronger the indication to pursue testing. Less common clinical signs and physical examination findings add further support for diagnostic testing.

• HAC, hyperadrenocorticism.

Less common clinical presentations of HAC include anestrus and testicular atrophy; ligament laxity that may lead to tearing and lameness12; facial palsy; and pseudomyotonia.13, 14 Severe polyuria, urinary tract infection or both may lead to urine leaking, especially when the dog is asleep, and owner‐perceived urinary incontinence. Hypercoagulability may result in spontaneous thromboembolism, typically involving pulmonary vessels and causing acute respiratory distress.15, 16 Cortisol‐induced insulin resistance may promote diabetes mellitus and impair exogenous insulin response.17, 18 If less common clinical presentations are identified first, a thorough review of the history, physical examination findings, and routine laboratory test results often provides additional evidence for the disease. Failure to identify abnormalities listed in Tables 1 and 2 is a major negative indicator for the presence of HAC.

• HAC, hyperadrenocorticism; CBC, complete blood count.

Clinical manifestations may develop secondary to mass‐occupying effects of a pituitary or adrenal tumor (AT). A large pituitary tumor may cause neurologic signs (pituitary macrotumor syndrome), including inappetence, anorexia, stupor, circling, aimless wandering, pacing, ataxia, and behavioral alterations. Although pituitary macrotumor syndrome develops in 10–25% of dogs months to years after HAC diagnosis, some have pituitary macrotumor syndrome, albeit subtle, at initial presentation. Documenting a large pituitary mass on computed tomography (CT) or magnetic resonance imaging (MRI) during the evaluation of neurologic signs supports testing for HAC. Adrenocortical carcinomas may invade the phrenicoabdominal vein, caudal vena cava, or both, causing retroperitoneal hemorrhage, blood‐loss anemia and abdominal pain, or incite formation of a tumor thrombus that leads to ascites or rear limb paresis.19, 20

Testing for HAC is recommended after unexpected identification of an adrenal mass on imaging performed for another problem such as vomiting. A review of the history, physical examination findings, and results of routine blood and urine tests will usually, but not always, provide evidence for HAC, if present, and prompt additional testing. Because the presence of an AT dictates perioperative management, testing for HAC should be recommended before adrenalectomy.

Results of a complete blood count (CBC), biochemistry panel, urinalysis, urine protein : creatinine ratio, and blood pressure measurement may further support HAC (Table 2). No abnormality listed in Table 2 is pathognomonic for HAC. Laboratory test results and a blood pressure measurement must be interpreted within the context of the history and physical examination findings. An absence of common abnormalities noted in Table 1 should strongly decrease the suspicion of HAC. Conversely, failure to identify abnormalities listed in Table 2 does not, by itself, rule out HAC. If measured, bile acid concentrations may be mildly increased. A cause and effect relationship between HAC and formation of gall bladder mucoceles has yet to be clarified. Identification of bilateral adrenomegaly or an AT on abdominal ultrasound examination provides additional evidence to pursue the diagnosis of HAC in dogs with common abnormalities listed in Table 1. However, the presence of ultrasonographically normal‐sized adrenal glands does not rule out HAC.

Ideally, testing for HAC should be avoided if serious illness exists. Many illnesses affect results of HAC screening tests.21, 22 Testing for HAC is not mandatory at the time suspicion arises. Postponing testing until concurrent illness is resolved or controlled is recommended, but the concurrent illness must be considered.

• Compatible history and physical examination findings. The greater the number of findings, the stronger the suspicion. Biochemical panel, CBC, urinalysis, and urine protein : creatinine ratio results and blood pressure measurement by themselves are not indications to test.
• A pituitary macrotumor.
• A diabetic dog with persistently poor response to high dosages of insulin not attributed to another cause, including owner issues.
• An adrenal mass.
• Persistent hypertension. (The Panel did not reach consensus on this point. Some would not test if hypertension was the only abnormality present.)

Screening Tests

No test has 100% diagnostic accuracy. Positive and negative predictive values are dependent upon disease prevalence. In a population appropriately screened so that disease prevalence is high, all diagnostic tests will be more accurate.

Diagnosis of HAC depends on demonstration of either: (1) increased cortisol production or (2) decreased sensitivity of the hypothalamic‐pituitary‐adrenal axis (HPAA) to negative glucocorticoid feedback. Measurement of a single basal cortisol concentration has no diagnostic value. Pulsatile adrenocorticotrophic hormone (ACTH) secretion results in variable cortisol concentrations23, 24 which may at times be within the reference range. Dogs with nonadrenal illness (NAI) can have increased baseline cortisol concentrations.22, 25

The tests used most often include the low‐dose dexamethasone suppression test (LDDST), urinary corticoid : creatinine ratio (UCCR), and ACTH stimulation test. Because all were introduced into veterinary medicine in the 1970s and 1980s, the Panel believes current reference ranges and cut‐off values should be re‐evaluated. First, measured cortisol concentrations differ among assays. Thus, values generally cannot be used interchangeably. Second, methods and assays have changed over previous decades, but new reference ranges were not usually generated. Third, studies from which reference ranges were derived had various shortcomings, namely comparison of dogs with HAC to healthy dogs rather than those suspected of having HAC; inclusion of groups with small numbers of dogs; and, use of controls with NAI that were not suspected of having HAC. Furthermore, trials to evaluate screening tests were performed in referral settings with a high disease prevalence, but the tests often are now used in primary care settings with a low disease prevalence. Fourth, the incidence of mild cases of HAC has appeared to increase over time, possibly because of heightened awareness and earlier patient presentation. Milder cases will have a lower degree of cortisol hypersecretion, and cut‐off values previously established may not apply.

Any screening test may be negative in a patient with HAC. If a test is negative but suspicion for HAC remains, another test should be performed. If more than 1 test is negative, the possibility that the patient does not have HAC must be considered. Alternatively, the patient may have mild HAC and the tests have not yet become positive. It may be worthwhile to retest in 3–6 months if clinical signs progress.