Understanding Cushing syndrome and cortisol: From lab work to rechecks

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Hyperadrenocorticism (HAC), or Cushing syndrome, can result from prolonged exposure to excessive amounts of glucocorticoids. The 2 most common forms of canine HAC are pituitary-dependent hyperadrenocorticism (PDH) and adrenal-dependent hyperadrenocorticism (ADH). PDH occurs when the inappropriate secretion of adrenocorticotropic hormone (ACTH) stimulates the adrenal glands to produce excessive cortisol. Adrenal-dependent hyperadrenocorticism occurs when adrenocortical adenoma or carcinoma autonomously secretes excessive cortisol. Cushing syndrome typically affects middle-aged and older dogs of any breed.

Clinical signs of Cushing syndrome can vary and reflect the myriad effects of cortisol on the body. The most common clinical signs associated with this condition include polyuria and polydipsia, polyphagia, a pendulous abdomen, panting, muscle wasting, and dermatologic changes including alopecia, pyoderma, and thin skin. Routine laboratory evaluation typically identifies several abnormalities resulting from excess cortisol, including increased alkaline phosphatase, hyperlipidemia, mild hyperglycemia, stress leukogram, thrombocytosis, low urine specific gravity, and mild to moderate proteinuria. Additionally, many dogs with Cushing syndrome will have systemic hypertension.

A closer look at cortisol and diagnosis

Blood cortisol measurements are vital for diagnosing and monitoring dogs with Cushing syndrome. When clinical signs and examination findings are suspicious for Cushing, 1 or more screening tests are typically performed to confirm diagnosis.

The low-dose dexamethasone suppression test (LDDST) is typically recommended when screening for Cushing syndrome because of its high sensitivity. It also differentiates between PDH and ADH in many cases. The LDDST is performed by measuring a baseline blood cortisol (time 0) followed by administration of 0.01 mg/kg dexamethasone IV. Additional blood cortisol samples are drawn 4 hours and 8 hours after dexamethasone administration. Dogs with Cushing syndrome will demonstrate decreased sensitivity to negative feedback inhibition of exogenous glucocorticoids to the hypothalamic pituitary adrenal axis, with an 8-hour cortisol above the laboratory reference interval consistent with a diagnosis of Cushing syndrome.

The ACTH stimulation test, another currently available screening test, can be completed more quickly than the LDDST and is less affected by non-adrenal illness. However, this test is more expensive and less sensitive than the LDDST and cannot be used to differentiate between PDH and ADH. The ACTH stimulation test is performed by measuring a baseline blood cortisol, administering a synthetic form of ACTH such as cosyntropin, and measuring a second blood cortisol level 1 hour following ACTH administration. A high cortisol following ACTH administration indicates an exaggerated response to ACTH stimulation of the adrenal glands and is consistent with hyperadrenocorticism.

If the screening test used to confirm Cushing does not also differentiate between PDH and ADH, additional tests may be needed. Differentiating tests are necessary if the owner is considering surgery as treatment. This is typically adrenalectomy for ADH, although in some areas, hypophysectomy is performed for PDH. Although surgery is potentially curative, it is expensive, requires an experienced surgeon, and carries significant risk. That’s why many dogs with PDH or ADH are treated medically. Because of ease of use and product availability, trilostane is currently prescribed most as treatment for dogs with Cushing syndrome.

Dogs treated with trilostane will require lifelong monitoring to ensure adequate control of clinical signs and to allow for early recognition of overcontrol. While most dogs do well on trilostane, 15% of dogs will develop iatrogenic hypocortisolemia and associated clinical signs. This can be permanent and potentially fatal if unrecognized and untreated. For this reason, cortisol should be measured in dogs treated with trilostane that display clinical signs of hypocortisolemia (vomiting, loss of appetite, lethargy, diarrhea). If the baseline cortisol measurement is low, an ACTH stimulation test should be performed. A severely blunted response to ACTH stimulation (post-ACTH cortisol less than 1-1.5 μg/dL) with associated clinical signs confirms hypocortisolemia and indicates that trilostane should be stopped and supplemental exogenous glucocorticoids should be given to effect.

While periodic ACTH stimulation tests are classically recommended in dogs treated with trilostane regardless of clinical signs, the role of this test in dogs without clinical signs suggestive of hypocortisolemia is less clear. The test has been shown in multiple studies to be poorly correlated with clinical signs, and the results are highly dependent on timing relative to trilostane dose administration. Because of these concerns as well as the expense and availability of synthetic ACTH, monitoring techniques using single cortisol measurements have also been described and are a promising alternative.

Pre-trilostane and post-trilostane cortisol

Measuring cortisol from blood collected before the patient is due for trilostane administration (pre-trilostane cortisol) has been shown to be a more reliable indicator of good clinical control than the ACTH stimulation test, although this test is still subject to variability from the influence of stress.

Numerous protocols involving timed sampling of blood cortisol several hours after trilostane administration (post-trilostane cortisol) have been investigated with varying results. This test appears to be helpful in ruling out iatrogenic hypocortisolism and, in some cases, may correlate with clinical control.

Ultimately, the most important information received during monitoring appointments should be the patient’s clinical signs, and cortisol measurements and/or ACTH stimulation test results should be interpreted in this context.

The TRUFORMA difference

Cushing is a common disease seen in small animal practice and, for those treated medically, care can often be managed by the primary care practitioner alone. Unfortunately, appropriate monitoring of these patients is intensive and costly and requires regular evaluation of adrenal function. Until recently, an accurate point-of-care (POC) cortisol assay has not been available.

The TRUFORMA diagnostic platform, introduced by Zomedica earlier this year, is the first veterinary diagnostic device to utilize innovative bulk acoustic wave (BAW) technology to achieve highly accurate results at the point of care.

TRUFORMA canine and feline assays were evaluated and correlated with those of the predicate industry gold standard. The assays provide a wide dynamic range that improves a practitioner’s ability to quickly and confidently discriminate between healthy and diseased patients.

The takeaway

Dogs with Cushing syndrome require numerous tests of adrenal function both for diagnosis and for monitoring during medical treatment. Dogs treated medically without frequent monitoring are at risk of serious and potentially fatal complications from iatrogenic hypocortisolemia. For these reasons, an accurate POC cortisol assay will facilitate improved monitoring of these patients under the continued care of their primary care veterinarian, optimizing quality of life and owner satisfaction for patients with Cushing syndrome.