What are the characteristic signs, symptoms, and laboratory findings of hypercortisolism (Cushing’s syndrome) in adults?

Hypercortisolism: Signs, Symptoms, and Laboratory Findings

Clinical Features

The most discriminating physical signs of hypercortisolism are central obesity with supraclavicular and dorsocervical fat pads, wide (≥1 cm) violaceous striae, proximal muscle weakness, and thin fragile skin with easy bruising. 1, 2

Cardinal Physical Findings

• Central obesity with characteristic fat redistribution to face ("moon facies"), supraclavicular fossae, and dorsocervical region ("buffalo hump") distinguishes true Cushing's syndrome from simple obesity 1, 3, 2
• Wide purple striae (≥1 cm) on abdomen, thighs, or arms—the violaceous color and width are key discriminators from normal striae 1, 3, 2
• Proximal muscle weakness affecting hip flexors and shoulder girdle, manifesting as difficulty rising from a chair or lifting objects overhead 1, 2, 4
• Thin, fragile skin with easy bruising from minor trauma 1, 2, 4

Additional Clinical Manifestations

• Facial plethora and rounded facial appearance 2, 4
• Hirsutism and menstrual irregularities in women 1, 3
• Hypertension present in 70-90% of cases 1, 3
• Psychiatric symptoms including depression, anxiety, and cognitive deficits 2, 4
• Metabolic complications: hyperglycemia/diabetes (>80% of patients), dyslipidemia 3, 4
• Osteoporosis and increased fracture risk 4
• Increased susceptibility to infections due to immunosuppression 2, 4

Pediatric-Specific Features

• Growth failure with weight gain—the combination of declining height velocity with increasing weight is highly sensitive and specific for Cushing's syndrome in prepubertal children 1
• Height standard deviation score (SDS) below the mean while BMI SDS is above the mean for age and sex 1
• This growth pattern reliably discriminates Cushing's syndrome from simple obesity in prepubertal children but is unreliable in post-pubertal adolescents 1

Laboratory Findings

Initial Screening Tests

Three first-line screening tests should be used, with at least two abnormal results required for diagnosis: 1, 3, 5

• Late-night salivary cortisol (≥2-3 measurements): 95% sensitivity, 100% specificity—the most accurate single screening test 1, 3, 6
• 24-hour urinary free cortisol (UFC): diagnostic cut-off >193 nmol/24h (sensitivity 89%, specificity 100%); perform 2-3 collections to assess variability 1, 3, 5
• 1-mg overnight dexamethasone suppression test (DST): morning serum cortisol >50 nmol/L (>1.8 μg/dL) indicates failed suppression; false-negative rate only 1.9% 1, 3, 5

Confirmatory Testing

• Plasma ACTH measurement (morning, 08:00-09:00h) to distinguish ACTH-dependent from ACTH-independent disease 1, 7, 8, 5:
  • ACTH >5 ng/L (>1.1 pmol/L) indicates ACTH-dependent Cushing's syndrome 7, 8
  • ACTH >29 ng/L (>6.4 pmol/L) provides 70% sensitivity and 100% specificity for Cushing's disease specifically 7, 8
  • ACTH <5 ng/L or undetectable indicates ACTH-independent (adrenal) disease 7, 8

Additional Biochemical Abnormalities

• Hypokalemia with metabolic alkalosis, particularly marked in ectopic ACTH syndrome 1, 8
• Hyperglycemia or impaired glucose tolerance 1, 3
• Dyslipidemia 4
• Loss of normal cortisol circadian rhythm—midnight cortisol levels fail to suppress to normal nadir 1, 9, 6

Diagnostic Algorithm

Step 1: Confirm Hypercortisolism

Perform at least two different screening tests (late-night salivary cortisol, 24-hour UFC, or 1-mg DST); repeat abnormal results for confirmation 1, 8, 5

Step 2: Exclude Pseudo-Cushing States

Rule out physiologic hypercortisolism from severe obesity, uncontrolled diabetes, major depression, chronic alcoholism, or exogenous glucocorticoid use 1, 8, 9. Consider Dex-CRH test (cortisol rise >38 nmol/L at 15 minutes indicates true Cushing's) or serial monitoring over 3-6 months if mild hypercortisolism is present 1, 7.

Step 3: Measure Morning Plasma ACTH

Obtain morning (08:00-09:00h) ACTH to classify as ACTH-dependent (>5 ng/L) or ACTH-independent (<5 ng/L) 7, 8, 5

Step 4: Localize the Source

For ACTH-dependent disease: 1, 7, 8

• Obtain high-resolution 3-Tesla pituitary MRI with 1-mm slices and gadolinium (sensitivity 63%, specificity 92%)
• If adenoma ≥10 mm: presume Cushing's disease, proceed to surgery
• If adenoma 6-9 mm: perform CRH or desmopressin stimulation test
• If no adenoma or <6 mm lesion: perform bilateral inferior petrosal sinus sampling (BIPSS)—the gold standard with 96-100% sensitivity and near-100% specificity

For ACTH-independent disease: 7, 8

• Obtain adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral hyperplasia

Critical Pitfalls to Avoid

• Do not rely on a single screening test—false positives occur with severe obesity, uncontrolled diabetes, depression, and alcoholism 1, 8, 9
• Measure dexamethasone levels if DST results are equivocal to exclude malabsorption or rapid metabolism 1, 7
• Account for medications: CYP3A4 inducers (phenytoin, rifampin) accelerate dexamethasone metabolism; oral estrogens increase cortisol-binding globulin, elevating total cortisol 1, 8
• Confirm active hypercortisolism immediately before BIPSS in patients with cyclic Cushing's disease using late-night salivary cortisol, DST, or UFC 1, 7, 8
• Discontinue steroidogenesis inhibitors before BIPSS to ensure accurate interpretation 1, 7, 8
• Recognize that pituitary MRI misses approximately one-third of microadenomas (≤2 mm), necessitating BIPSS when clinical suspicion is high despite negative imaging 1, 7, 8