What are the guidelines for diagnosing Cushing syndrome?

Guidelines for Diagnosing Cushing's Syndrome

The diagnosis of Cushing's syndrome requires a systematic approach using multiple screening tests, including late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and/or overnight 1-mg dexamethasone suppression test (DST), followed by tests to determine the etiology of hypercortisolism. 1

Initial Clinical Suspicion

• Look for specific clinical features:

  • Central obesity with thin extremities
  • Facial plethora (redness)
  • Proximal muscle weakness
  • Wide purple striae
  • Easy bruising
  • Unexplained osteoporosis 1
  • In children: unexplained weight gain combined with growth rate deceleration or height centile decrement 2

• Rule out exogenous glucocorticoid use (oral, injections, inhalers, topical) before proceeding with testing 2

First-Line Screening Tests

1. Late-night salivary cortisol (LNSC)

   • Sensitivity >90%, specificity 100% 1
   • Reflects free (active) cortisol
   • Non-invasive collection at home
   • Multiple collections recommended (≥2 tests)
   • Less specific in patients with severe obesity or PCOS 1

2. 24-hour urinary free cortisol (UFC)

   • Sensitivity 97%, specificity 91% when measured by LC-MS/MS 3
   • Reflects integrated tissue exposure to cortisol over 24h
   • Collect 2-3 specimens to improve accuracy
   • Ensure complete urine collections with appropriate total volumes 1, 4

3. Overnight 1-mg dexamethasone suppression test (DST)

   • Serum cortisol cutoff of <50 nmol/L (<1.8 μg/dl) to exclude Cushing's syndrome 2, 1
   • Higher specificity (97%) at cutoff of 138 nmol/L 3
   • Preferred for patients with disrupted circadian rhythms, severe obesity, or PCOS 1

Testing Strategy

• For patients with low clinical suspicion: Use a single screening test (LNSC, UFC, or DST) 1
• For patients with intermediate to high clinical suspicion: Use 2-3 screening tests 1
• Start with either UFC and/or LNSC; DST is an alternative if LNSC not feasible 2, 1
• Multiple LNSC collections may be easier for patient compliance 1
• UFC measured by liquid chromatography tandem-mass spectrometry achieves the best accuracy among screening tests 3

Confirming Cushing's Syndrome

• Abnormal results should be repeated to confirm diagnosis
• Consider cyclic Cushing's syndrome if initial tests are normal but clinical suspicion remains high 5
• Be aware of pseudo-Cushing's states (depression, alcoholism, poorly controlled diabetes) that can cause hypercortisolism 1

Determining Etiology

Once Cushing's syndrome is confirmed:

1. Measure plasma ACTH:

   • Low ACTH: ACTH-independent Cushing's syndrome (adrenal cause)
   • Normal or high ACTH: ACTH-dependent Cushing's syndrome (pituitary or ectopic source) 2, 1

2. For ACTH-independent Cushing's syndrome:

   • Perform adrenal CT or MRI to identify adrenal tumors 1

3. For ACTH-dependent Cushing's syndrome:

   • Perform pituitary MRI to identify pituitary adenomas
   • Consider bilateral inferior petrosal sinus sampling (IPSS) for:
     • Adenomas <6mm
     • No visible adenoma on MRI
     • Inconclusive results 2, 1

Special Considerations

• Children: Cushing's disease accounts for 75-80% of pediatric Cushing's syndrome cases 2

  • Microadenomas are the most common cause (98% of cases)
  • Male predominance in prepubertal children (71%)
  • Growth failure with weight gain is a key distinguishing feature from simple obesity 2

• False positives can occur with:

  • Severe obesity
  • Pregnancy
  • Uncontrolled diabetes mellitus
  • Medications (oral estrogens, anticonvulsants)
  • Substances (grapefruit juice, licorice) 1

• Pitfalls to avoid:

  • Relying on a single test (multiple tests improve diagnostic accuracy)
  • Ignoring medication effects on cortisol metabolism
  • Failing to recognize pseudo-Cushing's states
  • Inadequate sample collection (especially for UFC and LNSC) 1, 4
  • Not considering cyclic Cushing's syndrome when initial tests are normal 5

By following this systematic approach, clinicians can effectively diagnose Cushing's syndrome and determine its etiology, leading to appropriate treatment decisions.