Hyperadrenocorticism

Hyperadrenocorticism (HAC) is common in middle-aged to older dogs and is uncommon in other domestic species. About 85% of dogs with HAC have pituitary tumors, usually microadenomas. Chronic overproduction of ACTH by the tumor(s) results in bilateral adrenocortical hyperplasia, involving the ZF and ZR, but sparing the ZG. The remaining 15% of dogs with HAC have adrenal tumors; adenomas and adenocarcinomas are equally represented. The neoplastic cells produce cortisol which suppresses ACTH release from the pituitary gland. Common effects of excess cortisol release from the adrenal glands are polydipsia, polyuria, polyphagia, hepatic enlargement, muscle atrophy and weakness, lethargy, dermatologic disorders (alopecia, hyperpigmentation, thinning of the epidermis, calcium deposition, pyoderma), urinary tract infection, and panting. Less common manifestations are hypertension, cardiac disease, pulmonary thromboembolism, neuropathies, myopathies, and behavioural changes. Dogs with adrenal tumors, particularly adenocarcinomas, may have additional signs related to local and metastatic tumor growth, and signs may be more acute than with pituitary dependent hyperadrenocorticism (PDH).

CBC findings

Lymphopenia is the most consistent finding on the CBC; however, a more classic stress leukogram with neutrophilia, monocytosis, eosinopenia, and lymphopenia may be seen. HAC, perhaps due to increased androgen secretion, has a positive effect on erythropoiesis which can be manifested as elevations in the red blood cell count, hematocrit, and hemoglobin.

Biochemical panel findings

Mild fasting hyperglycemia results from increased gluconeogenesis and insulin antagonism leading to decreased peripheral utilization of glucose. A low proportion of dogs with HAC are predisposed to development of concurrent diabetes mellitus. Serum urea and creatinine are often decreased due to diuresis. Affected dogs are polyuric due to decreased ADH secretion, antagonism of the effect of ADH in the renal collecting ducts, and increased GFR. Polydipsia is secondary to polyuria. Fasting hypercholesterolemia and hypertriglyceridemia may occur due to abnormal lipid metabolism. Hepatic enzyme activities are commonly elevated. ALP is affected most consistently and to the greatest degree; however, ALT, GLDH, and GGT activities may be mildly to moderately elevated as well. Most of the ALP is the corticosteroid-induced isoform of the enzyme; however, many other conditions also increase this form of the enzyme and there is little advantage in measuring corticosteroid-induced ALP compared to the total ALP. Corticosteroids may increase ALP, ALT, GGT, and GLDH activities indirectly by causing hepatocellular glycogen accumulation and vacuolization (glucocorticoid hepatopathy); evidence for true enzyme induction is not established for ALT, GGT and GLDH.

Urinalysis findings

Polyuria is usually associated with a USG of <1.020, although dogs often change their behaviour in the veterinary hospital and urine may become more concentrated if water consumption is reduced. About 40-50% of dogs with HAC have urinary tract infections, many without an appreciable leukocyte response on urine sediment examination. Therefore, bacterial culture of cystocentesis-collected urine is recommended in all dogs with HAC. Mild proteinuria is also common and may relate to hypertension and glomerulosclerosis.

Pituitary-adrenal axis testing

The history, physical examination findings, routine laboratory test results, and pituitary-adrenal axis test results are all taken into consideration when diagnosing HAC. Pituitary-adrenal axis testing should not be done unless there is a high suspicion of HAC based on these historical, physical, and preliminary laboratory findings.

The ACTH stimulation test and the low dose dexamethasone suppression test (LDDST) are the 2 laboratory tests designed to differentiate normal dogs from those with HAC, regardless of pituitary or adrenal origin. Measurement of baseline plasma cortisol, in itself, is of no diagnostic value because fluctuations throughout the day create a wide RI and there is tremendous overlap between normal dogs and those with HAC. However, baseline plasma cortisol is required to provide a reference point for interpretation of these challenge tests.

ACTH stimulation test

For the ACTH stimulation test (see Protocol Manual), plasma cortisol is measured before and after administration of exogenous ACTH. The adrenals of dogs with HAC have a heightened ability to synthesize and secrete cortisol, which is further enhanced by ACTH administration. Therefore, cortisol concentration following ACTH administration is exaggerated in dogs with HAC compared to the response in normal dogs. In addition to using the ACTH stimulation test to diagnose HAC, this test is used to monitor the efficacy of medical therapy after the diagnosis is made. The ACTH stimulation test is also the only test which identifies iatrogenic HAC; dogs with this condition have low normal baseline cortisol concentrations and fail to respond to exogenous ACTH. Obviously, these animals must have a history and clinical findings consistent with the diagnosis of iatrogenic HAC since hypoadrenocorticism could also explain a failure to respond to exogenous ACTH (see section on hypoadrenocorticism below).

Low dose dexamethasone suppression test

The LDDST involves measuring plasma cortisol before, 3 (or 4), and 8 hours after dexamethasone administration. In normal dogs, the low dose of dexamethasone inhibits pituitary secretion of ACTH, decreasing plasma cortisol concentrations within 2 to 3 hours of administration and maintaining this suppression of endogenous cortisol for up to 48 hours. An 8 hour sample is used as the reference point to evaluate the degree of suppression. Dogs with HAC do not show adequate suppression of cortisol concentrations at 8 hours post dexamethasone administration. The 3 (or 4) hour plasma cortisol is measured because some dogs with PDH exhibit suppression at this time, which disappears by 8 hours. In this case, the test supports the diagnosis of HAC and differentiates between PDH and HAC caused by an adrenal tumor. All adrenal tumors and 25% of PDH cases generally do not adequately suppress cortisol secretion at either time point. Suppression is defined as a decrease to <50% of the baseline cortisol at either 3(or 4) or 8 hours, or 3(or 4) hour concentration > 40 nmol/L.

Urine cortisol to creatinine ratio (UC:CR)

A UC:CR is occasionally requested to evaluate cortisol production by dogs or cats suspected to have HAC. Dogs and cats with ratios below the reference value are unlikely to have HAC; however, dogs and cats with many diseases besides HAC can have ratios above the reference value. Therefore, this test only helps to rule out, not support, the diagnosis of HAC, and it is seldom recommended.

Differentiating tests

In addition to the LDDST discussed earlier, the high dose dexamethasone suppression test (HDDST) and endogenous ACTH determination help differentiate pituitary and adrenal-dependent HAC. Differentiation is important because treatment and prognosis differ. The HDDST is based on the principle that a high dose of dexamethasone will suppress ACTH production by the pituitary adenoma(s) and consequently suppress cortisol release, but will have no effect on cortisol production by an adrenal tumor, which is acting more autonomously.

Endogenous ACTH determination, though available only at specialized referral laboratories, is very useful for determining if HAC exists due to excess ACTH production by a pituitary tumor or excess cortisol production by an adrenal tumor. Endogenous ACTH concentrations are expected to be high with PDH and low with adrenal dependent disease. Measurement of endogenous ACTH concentration is not performed routinely due to the specific, strict guidelines for sample-handling that must be followed due its labile nature and the limited number of laboratories offering this test (consult your reference laboratory for specific handling requirements).

Unfortunately, despite myriad tests available to assess dogs for the presence of HAC and to differentiate between PDH and adrenal tumor, equivocal results are sometimes obtained due to overlapping results between normal and affected dogs. Nonadrenal illnesses may be associated with abnormal test results likely due to the effects of concurrent stress, therefore pituitary-adrenal axis testing should only performed when there is a high index of suspicion of HAC. The collective information from the history, physical examination, and laboratory findings must be considered when diagnosing the disease and making treatment decisions. The use of imaging studies adds to the array of tools which assist in making a correct diagnosis.

Hyperadrenocorticism in cats

HAC is uncommon, but does occur, in cats. Cats are thought to be relatively resistant to the clinical effects of cortisol that are seen in dogs, therefore, signs are more variable and may be subtle. The distribution of pituitary versus adrenal disease and malignant versus benign adrenal tumors is similar to the situation in dogs. Many cats diagnosed with HAC also have diabetes mellitus which is difficult to regulate due to insulin antagonism by cortisol. Cats may experience polyuria, polydipsia, polyphagia, weight loss, lethargy, dermatologic disorders, and skin fragility resulting in tearing. Physical findings may include abdominal enlargement, muscle atrophy, thin skin, unkempt appearance, hepatic enlargement, and weakness. CBC results are inconsistent although a stress leukogram is seen in a proportion of affected cats. Serum hepatic enzyme and cholesterol changes are also variable. The polyuria and polydipsia seen in a proportion of cats with HAC may be due to concurrent diabetes mellitus, chronic renal failure, or both, since high serum cortisol concentrations do not directly cause polyuria in cats. The preliminary tests for HAC in cats and tests to differentiate between pituitary and adrenal dependent disease are similar to those used for dogs. Similar problems exist with RI and interpretation of equivocal results.