What is the recommended diagnostic approach for suspected Cushing syndrome?

Diagnosis of Cushing Syndrome

Exclude Exogenous Glucocorticoid Exposure First

Before any biochemical testing, obtain a comprehensive medication history including oral, inhaled, injectable, topical, and nasal glucocorticoids, because exogenous steroid use is the most common cause of Cushing syndrome and makes further work-up unnecessary. 1

• If the patient is taking exogenous glucocorticoids, stop them if medically feasible before proceeding with diagnostic evaluation 2
• Iatrogenic Cushing syndrome is more prevalent than all endogenous causes combined in clinical practice 3

Initial Biochemical Screening Strategy

For Intermediate-to-High Clinical Suspicion

Perform 2-3 of the following first-line screening tests to confirm hypercortisolism: 2, 1, 4

• Late-night salivary cortisol (LNSC): Collect ≥2 samples around 11 PM-midnight on consecutive days; sensitivity 95%, specificity 93-100% 1, 4
• 24-hour urinary free cortisol (UFC): Collect ≥2 separate 24-hour urine samples to address day-to-day variability; sensitivity 89%, specificity 100% 1, 4
• Overnight 1 mg dexamethasone suppression test (DST): Normal suppression is cortisol <1.8 µg/dL (50 nmol/L); measure simultaneous plasma dexamethasone level to exclude false-positives from malabsorption or drug interactions 1, 4

For Low Clinical Suspicion

• Start with a single screening test (LNSC preferred for ease of collection) 2
• If normal, Cushing syndrome is unlikely unless cyclic disease is suspected 2

Critical Testing Considerations

• CYP3A4-inducing drugs (phenytoin, rifampin, carbamazepine) cause false-positive DST results by accelerating dexamethasone metabolism 1, 3
• Oral estrogens and pregnancy elevate cortisol-binding globulin, raising total cortisol measurements and potentially causing false-positives 1
• False-positive results occur in severe obesity, uncontrolled diabetes, major depression, chronic alcoholism, and polycystic ovary syndrome 2, 1, 3
• If screening results are mildly abnormal with moderate suspicion, consider cyclic Cushing syndrome and repeat testing during symptomatic periods 1

Confirmation Before Localization

• Do not perform imaging or ACTH measurement until biochemical hypercortisolism is confirmed 1
• If a single test is abnormal but clinical suspicion is low-to-moderate, repeat the same test or use an alternative screening modality 1
• When all screening tests are normal but clinical suspicion remains high (progressive classic features like purple striae, proximal myopathy, facial plethora), repeat testing in 3-6 months or refer to endocrinology 1

Determine ACTH-Dependent vs. ACTH-Independent Disease

Measure Morning Plasma ACTH

• Obtain morning (8-9 AM) plasma ACTH after confirming hypercortisolism; fasting is not required 1, 3
• ACTH >5 ng/L (>1.1 pmol/L): Indicates ACTH-dependent Cushing syndrome (pituitary or ectopic source) 1, 3, 4
• ACTH >29 ng/L (>6.4 pmol/L): Provides 70% sensitivity and 100% specificity for Cushing disease (pituitary source) 1, 3
• ACTH <5 ng/L (<1.1 pmol/L): Indicates ACTH-independent Cushing syndrome (adrenal adenoma, carcinoma, or bilateral hyperplasia) 1, 3, 4
• Ensure the patient is not receiving exogenous steroids at the time of ACTH sampling, as this suppresses ACTH and confounds interpretation 1

Localization Based on ACTH Results

ACTH-Independent Disease (Low ACTH)

• Order adrenal CT (preferred for spatial resolution) or MRI to identify adrenal lesions 2, 1, 3
• Proceed directly to imaging without additional dynamic testing 2

ACTH-Dependent Disease (Normal or High ACTH)

Step 1: Pituitary MRI

• Obtain high-quality pituitary MRI with thin slices (3 Tesla preferred with gadolinium) 1, 3, 4
• MRI sensitivity for ACTH-secreting microadenomas is only 63%, so a negative study does not exclude Cushing disease 1, 3

Step 2: Decision Algorithm Based on MRI Findings

• Adenoma ≥10 mm: Strongly suggests Cushing disease; proceed to neurosurgical evaluation without further testing 2, 1
• Adenoma 6-9 mm: Expert consensus is divided; options include CRH/DDAVP stimulation testing or proceeding directly to bilateral inferior petrosal sinus sampling (BIPSS) 2
• Adenoma <6 mm or no visible adenoma: BIPSS is required to differentiate pituitary from ectopic ACTH sources 2, 1

Step 3: Bilateral Inferior Petrosal Sinus Sampling (BIPSS)

• BIPSS has 96-100% sensitivity and approaches 100% specificity for localizing ACTH source 3
• Diagnostic criteria: central-to-peripheral ACTH ratio ≥2 at baseline or ≥3 after CRH/desmopressin stimulation 3
• BIPSS should only be performed at specialized centers with experienced interventional radiologists 1, 3
• Confirm active hypercortisolism on the day of BIPSS, especially critical in cyclic Cushing syndrome 3
• Discontinue steroidogenesis inhibitors before the procedure 3

Evaluation for Ectopic ACTH Source

• If BIPSS suggests ectopic source, perform contrast-enhanced CT from neck to pelvis with thin slices to locate neuroendocrine tumors 3, 5
• If conventional imaging is negative, perform 68Ga-DOTATATE PET to detect occult lesions 3
• Common ectopic sources include small cell lung carcinoma, bronchial and thymic carcinoids, medullary thyroid carcinoma, gastroenteropancreatic neuroendocrine tumors, and pheochromocytoma 5

Special Considerations in Children

• Typical presentation is impaired linear growth (lack of height gain) with concurrent weight gain 2, 3, 4
• Cushing disease is the predominant cause in children >6 years; adrenal lesions dominate in younger children 2, 3
• Microadenomas ≤2 mm cause ~98% of pediatric cases and are often invisible on MRI 3
• Refer all pediatric cases to multidisciplinary centers with dedicated pediatric endocrinology and specialized neurosurgery expertise 2, 4

Common Diagnostic Pitfalls to Avoid

• Never order ACTH measurement or imaging before confirming hypercortisolism biochemically 1
• Never rely on a single abnormal screening test in low-suspicion cases; repeat or use an alternative assay 1
• Failure to measure dexamethasone levels during DST yields false-positives due to malabsorption or rapid metabolism 3
• Performing BIPSS without prior confirmation of active hypercortisolism, particularly in cyclic disease, compromises accuracy 3
• Relying solely on pituitary MRI misses approximately one-third of microadenomas 3
• Not accounting for medications affecting cortisol or dexamethasone metabolism leads to misinterpretation 1, 3

Referral Recommendations

• All patients with biochemically confirmed hypercortisolism should be referred to endocrinology for further evaluation and management 1
• Patients with equivocal screening results but high clinical suspicion should also be referred for specialized testing 1