How is adrenal hypercortisolism diagnosed?

Diagnosing Adrenal Hypercortisolism (Cushing's Syndrome)

Start with dexamethasone suppression test (DST), 24-hour urinary free cortisol (UFC), and/or late-night salivary cortisol (LNSC) depending on local availability—there is no single preferred diagnostic test, and clinical judgment determines which test to use based on the specific scenario. 1

Initial Screening Tests

Choose your initial screening test based on patient characteristics:

• For most patients: Begin with 1 mg overnight DST (dexamethasone taken at 11 PM, cortisol measured at 8 AM) 1

  • Cortisol <50 nmol/L excludes hypercortisolism 1
  • Cortisol 51-138 nmol/L suggests possible autonomous cortisol secretion 1
  • Cortisol >138 nmol/L indicates cortisol hypersecretion 1

• For shift workers or patients with disrupted sleep schedules: DST is preferred over LNSC due to unreliable circadian rhythm 1

• For women on oral estrogen: DST may be unreliable due to increased corticosteroid binding globulin (CBG); consider LNSC if cortisone levels can also be reported 1

• For patients with renal impairment (CrCl <60 mL/min) or polyuria (>5 L/24h): LNSC is preferred over UFC 1

• If adrenal tumor is suspected: Start with DST and only use LNSC if cortisone levels can be reported 1

Multiple Testing is Essential

Obtain 2-3 measurements of whichever test you choose to account for variability—this is a high-quality, strong recommendation: 1

• If using UFC: Collect 2-3 separate 24-hour urine samples 1
• If using LNSC: Obtain at least 2-3 tests 1
• Random variability in UFC can be as high as 50% 1

Confirmatory Testing After Positive Screening

If initial screening is abnormal, confirm the diagnosis before proceeding to localization studies:

Distinguishing True Cushing's Syndrome from Pseudo-Cushing's

Pseudo-Cushing's (non-neoplastic hypercortisolism from psychiatric disorders, alcohol use, obesity, PCOS) can cause mildly elevated DST, LNSC, and UFC results 1. UFC is almost always within 3-fold of normal in pseudo-Cushing's, whereas it is markedly elevated in true Cushing's syndrome. 1

Use the desmopressin test or Dex-CRH test to distinguish Cushing's syndrome from pseudo-Cushing's: 1

• Desmopressin test: ACTH-secreting adenomas express vasopressin V1b (V3) receptors and produce a rise in plasma ACTH after desmopressin injection; this test has high specificity for Cushing's disease, is less complex and less expensive than Dex-CRH 1
• Dex-CRH test: Only patients with ACTH-dependent Cushing's syndrome show a cortisol response to CRH after dexamethasone suppression; use at an expert center with dexamethasone level measurement is advised, with cortisol cut-off adjustments in very obese patients 1
• Both tests show excellent agreement when performed together 1

For Patients with Mild Hypercortisolism and Uncertain Diagnosis

Monitor for 3-6 months to see if symptoms resolve; treatment of underlying conditions (such as depression) can restore normal HPA axis function 1. Repeat low-dose dexamethasone test (LDDT) or serial LNSCs over time, correlating with clinical picture 1.

Determining the Source of Hypercortisolism

Once Cushing's syndrome is confirmed, measure plasma ACTH to determine the source: 1, 2

ACTH-Dependent Cushing's Syndrome (Elevated ACTH)

• Pituitary source (Cushing's disease, ~70%): Perform high-dose dexamethasone suppression test (8 mg or more) and CRH stimulation test 2
• Ectopic ACTH production (~10%): Non-pituitary tumors (commonly small cell lung cancer or bronchial carcinoid) 1, 2
• Do NOT use bilateral inferior petrosal sinus sampling (IPSS) to diagnose hypercortisolism itself—the central-to-peripheral ACTH gradient in healthy controls and pseudo-Cushing's overlaps with Cushing's disease 1

ACTH-Independent Cushing's Syndrome (Low/Suppressed ACTH)

• Adrenal source (~20%): Adrenal adenoma or adrenocortical carcinoma 1, 2
• Confirm ACTH independency by measuring plasma ACTH in all patients considering intervention 1

Important Pitfalls and Caveats

False-positive DST results can occur from: 1

• CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) accelerating dexamethasone metabolism
• Increased CBG from oral estrogens, pregnancy, or chronic active hepatitis
• Measure dexamethasone levels concomitantly with cortisol using laboratory-specific ranges to reduce false-positives 1

False-negative DST results can occur from: 1

• Medications inhibiting dexamethasone metabolism (fluoxetine, cimetidine, diltiazem)
• Decreased CBG and albumin (nephrotic syndrome)

Factors affecting UFC interpretation: 1

• Sex, BMI, age, urinary volume, and sodium intake all influence UFC levels
• Requires accurate 24-hour collection by the patient

For cyclic Cushing's disease or unpredictable fluctuating cortisol: Dynamic testing and localization should be preceded by confirmatory LNSC, DST, or UFC to document active phase 1

Special Clinical Scenarios

In patients with lung cancer (especially small cell lung cancer or bronchial carcinoid): 1

• Diagnose paraneoplastic Cushing's syndrome during initial evaluation
• Hypercortisolism increases mortality after chemotherapy due to opportunistic infections and increased VTE risk (2% without surgery, 4% after surgery) 1
• Treat hypercortisolism before chemotherapy or surgery using metyrapone, ketoconazole, etomidate, mitotane, mifepristone, or laparoscopic bilateral adrenalectomy 1

In patients with adrenal incidentalomas: 1

• Screen all patients for autonomous cortisol secretion regardless of imaging characteristics 1
• The probability of subclinical hypercortisolism correlates positively with tumor size and inversely with attenuation on CT 3
• Lipid-poor adenomas can overlap with malignant masses and pheochromocytomas on imaging 1