What is the recommended workup for Cushing's syndrome?

From the Guidelines

The workup for Cushing's syndrome should begin with screening tests to establish hypercortisolism, followed by tests to determine its cause, as recommended by the most recent guidelines 1. The initial screening should include a 24-hour urinary free cortisol test, late-night salivary cortisol measurement, and an overnight dexamethasone suppression test (1 mg dexamethasone given at 11 PM with cortisol measured at 8 AM the next day; normal response is cortisol <1.8 μg/dL) 1. If screening tests are positive, proceed with confirmatory testing such as a low-dose dexamethasone suppression test (0.5 mg every 6 hours for 48 hours) or a midnight serum cortisol level 1. Once hypercortisolism is confirmed, determine the cause with an ACTH level, as ACTH-independent Cushing syndrome can be caused by a benign adrenal tumor or a malignant adrenal tumor, neither of which produce ACTH 1. If ACTH is elevated, obtain pituitary MRI to look for an adenoma and consider inferior petrosal sinus sampling to confirm a pituitary source, as recommended by the guidelines 1. If ACTH is suppressed, order an adrenal CT scan to identify adrenal tumors, and for suspected ectopic ACTH syndrome, chest and abdominal imaging is necessary 1. Additional tests may include CRH stimulation test and high-dose dexamethasone suppression test to differentiate between pituitary and ectopic sources, as these tests can help guide appropriate treatment, whether surgical removal of a tumor or medical management 1.

Some key points to consider in the workup of Cushing's syndrome include:

• The importance of using a combination of screening tests to establish hypercortisolism, as no single test is 100% sensitive or specific 1
• The need to determine the cause of hypercortisolism, as this guides treatment and management 1
• The role of imaging studies, such as pituitary MRI and adrenal CT, in identifying the source of excess cortisol production 1
• The use of additional tests, such as CRH stimulation and high-dose dexamethasone suppression, to differentiate between pituitary and ectopic sources of ACTH 1

Overall, a stepwise approach to the workup of Cushing's syndrome is essential to ensure accurate diagnosis and effective management, and to minimize morbidity and mortality associated with this condition.

From the FDA Drug Label

2.2 Recommendations Prior to Initiation of SIGNIFOR Prior to the start of SIGNIFOR, patients should have baseline levels of the following: fasting plasma glucose (FPG) hemoglobin A1c (HbA1c) liver tests serum potassium and magnesium levels Patients should also have a baseline electrocardiogram (ECG) and gallbladder ultrasound

The recommended workup for Cushing's syndrome prior to initiation of pasireotide (SIGNIFOR) includes:

• Baseline levels of fasting plasma glucose (FPG)
• Baseline levels of hemoglobin A1c (HbA1c)
• Baseline liver tests
• Baseline serum potassium and magnesium levels
• Baseline electrocardiogram (ECG)
• Baseline gallbladder ultrasound 2

From the Research

Diagnostic Approach

The recommended workup for Cushing's syndrome involves a combination of screening tests, including:

• 1-mg dexamethasone suppression test (DST) 3, 4, 5, 6
• 24-hour urinary free cortisol (UFC) measurement 7, 3, 4, 5, 6
• Late-night salivary cortisol (LNSC) measurement 3, 4, 5, 6

Screening Test Characteristics

The characteristics of each screening test are:

• 1-mg DST: high specificity, but may have false positives due to drug interference 6
• LNSC: easy to measure, but may have false positives or negatives due to inadequate device soaking or cyclic Cushing's syndrome 6
• UFC: reflects integrated tissue exposure to free cortisol, but requires complete urine collections and may have false positives due to cross-reactivity with other metabolites 6

Diagnostic Algorithm

The diagnostic algorithm for Cushing's syndrome involves:

• Initial screening with one of the recommended tests (1-mg DST, UFC, or LNSC) 3, 4, 5, 6
• If screening test is positive, measure plasma ACTH concentrations to differentiate between ACTH-dependent and ACTH-independent causes 3, 4
• Further assessment with imaging modalities (e.g. MRI, CT scan) and dynamic biochemical testing (e.g. bilateral inferior petrosal sinus sampling) to pinpoint the cause of Cushing's syndrome 3, 4

Test Performance

The performance of each test is:

• UFC: high sensitivity and specificity, with a combined higher positive and lower negative likelihood ratio among first-line tests 5
• 1-mg DST: high specificity, but may have lower sensitivity 5
• LNSC: moderate sensitivity and specificity, with potential for false positives or negatives 5