Definitions for the quality of the evidence (+OOO, ++OO, +++O, and ++++); the strength of the recommendation (1 or 2); and for the difference between a "recommendation" and a "suggestion" are provided at the end of the "Major Recommendations" field.
Diagnosis
Who Should Be Tested?
The Task Force recommends obtaining a thorough drug history to exclude excessive exogenous glucocorticoid exposure leading to iatrogenic Cushing's syndrome before conducting biochemical testing (1 | ++++).
The Task Force recommends testing for Cushing's syndrome in the following groups:
- Patients with unusual features for age (e.g., osteoporosis, hypertension) (1 | ++OO)
- Patients with multiple and progressive features, particularly those who are more predictive of Cushing's syndrome (1 | ++OO)
- Children with decreasing height percentile and increasing weight (1 | +OOO)
- Patients with adrenal incidentaloma compatible with adenoma (1 | +OOO)
The Task Force recommends against widespread testing for Cushing's syndrome in any other patient group (1 | +OOO).
Initial Testing
For the initial testing for Cushing's syndrome, the Task Force recommends one of the following tests based on its suitability for a given patient (1 | +OOO):
- Urine free cortisol (UFC; at least two measurements)
- Late-night salivary cortisol (two measurements)
- 1-mg overnight dexamethasone suppression test (DST)
- Longer low-dose DST (2 mg/d for 48 h)
The Task Force recommends against the use of the following to test for Cushing's syndrome
(1 | +OOO):
- Random serum cortisol or plasma adrenocorticotropic hormone (ACTH) levels
- Urinary 17-ketosteroids
- Insulin tolerance test
- Loperamide test
- Tests designed to determine the cause of Cushing's syndrome (e.g., pituitary and adrenal imaging, 8 mg DST)
In individuals with normal test results in whom the pretest probability is high (patients with clinical features suggestive of Cushing's syndrome and adrenal incidentaloma or suspected cyclic hypercortisolism), the Task Force recommends further evaluation by an endocrinologist to confirm or exclude the diagnosis (1 | +OOO).
In other individuals with normal test results (in whom Cushing's syndrome is very unlikely), the Task Force suggests reevaluation in 6 months if signs or symptoms progress (2 | +OOO).
In individuals with at least one abnormal test result (for whom the results could be falsely positive or indicate Cushing's syndrome), the Task Force recommends further evaluation by an endocrinologist to confirm or exclude the diagnosis (1 | +OOO).
Subsequent Evaluation
For the subsequent evaluation of abnormal initial test results, the Task Force recommends performing another recommended test (1 | +OOO).
The Task Force suggests the additional use of the dexamethasone-corticotropin-releasing hormone (CRH) test or the midnight serum cortisol test in specific situations (2 | +OOO).
The Task Force suggests against the use of the desmopressin test, except in research studies, until additional data validate its utility (2 | +OOO).
The Task Force recommends against any further testing for Cushing's syndrome in individuals with concordantly negative results on two different tests (except in patients suspected of having the very rare case of cyclical disease) (1 | +OOO).
The Task Force recommends tests to establish the cause of Cushing's syndrome in patients with concordantly positive results from two different tests, provided there is no concern regarding possible non-Cushing's hypercortisolism (1 | ++OO).
The Task Force suggests further evaluation and follow-up for the few patients with concordantly negative results who are suspected of having cyclical disease and also for patients with discordant results, especially if the pretest probability of Cushing's syndrome is high (2 | +OOO).
Special Populations/Considerations
Pregnancy: The Task Force recommends the use of urine free cortisol (UFC) and against the use of dexamethasone testing in the initial evaluation of pregnant women (1 | +++O).
Epilepsy: The Task Force recommends against the use of dexamethasone testing in patients receiving antiepileptic drugs known to enhance dexamethasone clearance and recommend instead measurements of nonsuppressed cortisol in blood, saliva, or urine (1 | +++O).
Renal failure: The Task Force suggests using the 1-mg overnight DST rather than UFC for initial testing for Cushing's syndrome in patients with severe renal failure (2 | +OOO).
Cyclic Cushing's syndrome: The Task Force suggests use of UFC or midnight salivary cortisol tests rather than DSTs in patients suspected of having cyclic Cushing's syndrome (2 | +OOO).
Adrenal incidentaloma: The Task Force suggests use of the 1-mg DST or late-night cortisol test, rather than UFC, in patients suspected of having mild Cushing's syndrome (2 | ++OO).
Definitions:
Strength of Recommendations
1 - Indicates a strong recommendation and is associated with the phrase "The Task Force recommends."
2 - Denotes a weak recommendation and is associated with the phrase "The Task Force suggests."
Quality of the Evidence
+OOO Denotes very low quality evidence
++OO Denotes low quality evidence
+++O Denotes moderate quality evidence
++++ Denotes high quality evidence
