From the Guidelines
To confirm Cushing's disease after a positive low-dose dexamethasone suppression test, a corticotrophin-releasing hormone (CRH) test or measurement of plasma ACTH levels should be performed, as these tests can help differentiate between pituitary and non-pituitary sources of hypercortisolism. The CRH test involves administering 1.0 μg/kg of CRH intravenously and measuring the increase in cortisol levels, with an increase of >=20% suggesting Cushing's disease 1. Alternatively, measuring plasma ACTH levels can also be useful, as a level >1.1 pmol/l (>5 ng/l) is indicative of Cushing's disease 1.
If the results of these tests are still inconclusive, bilateral inferior petrosal sinus sampling (BIPSS) for ACTH should be considered, as it can provide a definitive diagnosis of Cushing's disease by demonstrating a central-to-peripheral ACTH ratio >=3 after CRH or desmopressin stimulation 1. BIPSS is a more invasive procedure, but it is highly accurate and can help confirm the diagnosis of Cushing's disease.
It is also important to note that a pituitary MRI scan should be performed to locate a potential adenoma, as this can help guide treatment decisions 1. The goal of these additional tests is to precisely identify the source of excess cortisol production, which is essential for guiding appropriate treatment and improving patient outcomes.
Some key points to consider when interpreting the results of these tests include:
- A positive CRH test or elevated plasma ACTH levels suggest Cushing's disease
- A central-to-peripheral ACTH ratio >=3 after CRH or desmopressin stimulation during BIPSS confirms a pituitary source of hypercortisolism
- The presence of an adenoma on pituitary MRI can help guide treatment decisions
- The diagnosis of Cushing's disease should be made based on a combination of clinical, biochemical, and imaging findings 1.
From the Research
Confirming Cushing's Disease
If the low-dose dexamethasone suppression test is positive, it indicates endogenous hypercortisolaemia, which is a key feature of Cushing's syndrome 2. To confirm Cushing's disease, the following steps can be taken:
- Plasma ACTH measurement at 9 am to check for elevated levels 2
- MRI scan of the pituitary to identify any adenomas 2
- Corticotrophin releasing hormone (CRH) test to distinguish pituitary from ectopic ACTH-dependent Cushing's syndrome 2, 3
- Bilateral petrosal sinus sampling, which is the gold standard for differentiating between pituitary and ectopic ACTH-dependent Cushing's syndrome 2, 4
Diagnostic Tests
The low-dose dexamethasone suppression test is a useful tool for confirming the diagnosis of Cushing's syndrome, but it may not be sufficient to differentiate between Cushing's disease and other forms of Cushing's syndrome 5, 6. The test may produce false-negative results, and the criterion for normal suppression of cortisol after dexamethasone is controversial 5.
- The area under the curve (AUC) of the low-dose dexamethasone suppression test using urine free cortisol was higher than that using serum cortisol 4
- The AUC of the low-dose dexamethasone suppression test was higher than that of the high-dose dexamethasone suppression test 4
- A very high dose dexamethasone suppression test (32 mg) may be more effective in suppressing cortisol secretion in patients with Cushing's disease who are refractory to the standard high-dose test 3
Differential Diagnosis
The differential diagnosis of Cushing's syndrome involves distinguishing between ACTH-dependent and non-ACTH dependent causes, as well as between pituitary and ectopic ACTH-dependent Cushing's syndrome 6.
- Measurement of ACTH can help discriminate between ACTH-dependent and non-ACTH dependent causes of Cushing's syndrome 6
- Adrenal imaging can provide clues for the aetiology of non-ACTH dependent forms 6
- Pituitary MRI imaging, the high-dose dexamethasone suppression test, the CRH test, and bilateral inferior petrosal sinus sampling can help differentiate between pituitary and ectopic ACTH-dependent Cushing's syndrome 6