What are the key features and workup for adrenal Cushing's syndrome?

Adrenal Cushing's Syndrome: Clinical Features and Diagnostic Workup

Key Clinical Features

Adrenal Cushing's syndrome presents with distinctive features that differentiate it from simple obesity, most notably the combination of weight gain with specific physical stigmata and metabolic derangements. 1

Most Specific Clinical Findings

• Abnormal fat distribution in supraclavicular and temporal fossae (highly specific for Cushing's) 2
• Wide purple striae (>1 cm), though absence does not exclude diagnosis 3, 2
• Proximal muscle weakness with difficulty rising from a chair or climbing stairs 2
• Truncal obesity with relatively thin extremities 4
• Facial plethora and moon facies 4

Critical Distinguishing Feature in Children

• Growth deceleration (declining height velocity or decreasing height SDS) combined with weight gain is the most sensitive discriminator from simple obesity in prepubertal children 3, 5
• Not all patients with Cushing's are obese, making growth patterns particularly important in pediatric cases 3

Associated Metabolic Complications

• Hypertension (very common) 4
• Glucose intolerance or diabetes mellitus 4
• Increased susceptibility to infections 4
• Osteoporosis and vertebral fractures 1

Diagnostic Workup Algorithm

Step 1: Exclude Exogenous Glucocorticoid Use

Before any biochemical testing, eliminate all exogenous glucocorticoid exposure, as exogenous steroids are the most common cause of Cushing's syndrome. 3 This includes:

• Oral, inhaled, topical, and injected corticosteroids 1
• Nasal drops, creams, and joint injections 1

Step 2: Initial Biochemical Screening (Perform 2-3 Tests Simultaneously)

The Endocrine Society recommends performing 2-3 first-line screening tests simultaneously rather than relying on a single test, as no test has 100% diagnostic accuracy. 3, 6

Three Essential First-Line Tests:

1. Late-Night Salivary Cortisol (LNSC)

   • Sensitivity: 95%, Specificity: 100% 6, 5
   • Collect at least 2-3 samples on consecutive days 6
   • Most useful screening test due to high accuracy and ease of collection 2, 7
   • Measures loss of normal circadian rhythm 1

2. 24-Hour Urinary Free Cortisol (UFC)

   • Sensitivity: 89-95%, Specificity: 98-100% 3, 6
   • Collect at least 2-3 samples to account for 50% intra-patient variability 1
   • Measures total cortisol production independent of cortisol-binding globulin changes 1
   • Less useful in renal impairment (CrCl <60 mL/min) or polyuria (>5 L/24h) 1

3. Overnight 1-mg Dexamethasone Suppression Test (DST)

   • Sensitivity: 95%, Specificity: 80-90% 3, 5
   • Normal response: serum cortisol <1.8 μg/dL (50 nmol/L) at 8 AM after 1 mg dexamethasone at midnight 6
   • Measures impaired glucocorticoid feedback 1

Critical Interpretation Pitfalls:

False positives can occur with: 1

• CYP3A4 inducers (phenobarbital, carbamazepine, St. John's wort) causing rapid dexamethasone metabolism
• Increased cortisol-binding globulin from oral estrogens, pregnancy, or chronic hepatitis
• Pseudo-Cushing's states (severe obesity, uncontrolled diabetes, depression, alcoholism) 6

False negatives can occur with: 1

• CYP3A4 inhibitors (fluoxetine, cimetidine, diltiazem) causing higher dexamethasone levels
• Decreased cortisol-binding globulin (nephrotic syndrome)

Measuring dexamethasone levels concomitantly with cortisol improves test interpretability and reduces false-positive results. 1, 6

Step 3: Confirm Hypercortisolism

• If any screening test is abnormal, repeat 1-2 screening tests to confirm 6
• If all tests are normal, Cushing's syndrome is unlikely 6
• Values in pseudo-Cushing's tend to be mildly elevated; UFC is almost always within 3-fold of normal 1

Step 4: Determine ACTH-Dependent vs. ACTH-Independent (Adrenal) Cushing's

Measure morning (8 AM) plasma ACTH level to differentiate the etiology: 6, 5

• Low or undetectable ACTH (<5 ng/L or <1.1 pmol/L) = ACTH-independent (adrenal) Cushing's syndrome 6, 5

  • Sensitivity: 68%, Specificity: 100% 5
  • This confirms adrenal source of cortisol excess

• Normal or elevated ACTH (>5 ng/L or >1.1 pmol/L) = ACTH-dependent Cushing's (pituitary or ectopic) 6, 5

Step 5: Adrenal Imaging for ACTH-Independent Cushing's

Once low ACTH confirms adrenal Cushing's, proceed with adrenal imaging: 6

• Non-contrast CT of adrenal glands is the primary imaging modality 1
• Measure Hounsfield units (HU) to characterize lesions 1
• Lesions with >10 HU require further evaluation 1

Additional Hormonal Testing for Adrenal Lesions:

Screen for excess androgen production when adrenocortical carcinoma (ACC) is suspected or virilization is present: 1

• DHEA-S, testosterone, 17β-estradiol 1
• 17-OH progesterone, androstenedione 1
• ACC is responsible for >50% of androgen hypersecretion cases 1

Step 6: Management Based on Findings

For unilateral cortisol-secreting adrenal masses with clinically apparent Cushing's syndrome, perform unilateral adrenalectomy of the affected gland, preferably via minimally invasive surgery. 1

For mild autonomous cortisol secretion (MACS, formerly subclinical Cushing's): 1

• Younger patients with progressive metabolic comorbidities attributable to cortisol excess can be considered for adrenalectomy after shared decision-making 1
• Patients managed non-surgically require annual clinical screening for new or worsening comorbidities 1
• MACS has low risk of progression to overt Cushing's but contributes to medical comorbidity 1

Special Considerations

Cyclic Cushing's Syndrome

• Consider cyclic Cushing's in cases with inconsistent test results 6
• Scalp-hair cortisol/cortisone analysis helps assess long-term glucocorticoid exposure and detect transient hypercortisolism 8

Pediatric Patients

• Screen children only when unexplained weight gain is combined with declining height velocity or decreasing height SDS 3, 5
• Male predominance in pediatric cases (63% overall, 71% prepubertal) versus female predominance in adults 3
• Refer all children with suspected endogenous Cushing's to tertiary care centers with experienced pediatric endocrinology specialists 3

Perioperative Considerations

• All patients require education on stress dosing and medical alert bracelets for adrenal insufficiency 1
• Start stress-dose corticosteroids (hydrocortisone 100 mg IV or dexamethasone 4 mg) for acute adrenal crisis 1
• Taper stress-dose corticosteroids to maintenance over 7-14 days post-operatively 1