What is the differential diagnosis for Cushing's syndrome?

Differential Diagnosis of Cushing's Syndrome

The differential diagnosis of Cushing's syndrome is fundamentally determined by plasma ACTH levels, which classify the condition into ACTH-dependent (elevated ACTH) or ACTH-independent (low/undetectable ACTH) causes. 1

Primary Classification Based on ACTH Levels

ACTH-Dependent Cushing's Syndrome (ACTH >5 ng/L)

Any ACTH level >5 ng/L indicates ACTH-dependent disease, with ACTH >29 ng/L having 70% sensitivity and 100% specificity for Cushing's disease. 1

The ACTH-dependent causes include:

• Cushing's disease (pituitary adenoma) - accounts for 75-80% of Cushing's syndrome in children/adolescents and is the most common ACTH-dependent cause in adults 2
• Ectopic ACTH syndrome - from non-pituitary tumors secreting ACTH, typically presenting with very high urinary free cortisol and profound hypokalemia 1
• Ectopic CRH secretion - rare cause from non-hypothalamic tumors secreting CRH 3

ACTH-Independent Cushing's Syndrome (ACTH low or undetectable)

Low or undetectable ACTH levels definitively indicate an adrenal source of cortisol excess. 1

The ACTH-independent causes include:

• Adrenal adenoma - benign cortisol-secreting tumor, most common adrenal cause 1, 4
• Adrenal carcinoma - malignant cortisol-secreting tumor 1, 4
• Primary pigmented nodular adrenocortical disease (PPNAD) 3
• Massive adrenal hyperplasia (MAH) 3
• Bilateral adrenal hyperplasia - can be managed with unilateral adrenalectomy or medical therapy 1

Special Variants and Mimics

Unclassified Variants

• Cyclic Cushing's syndrome - characterized by unpredictable fluctuating cortisol levels requiring documentation of active phase before diagnostic testing 2, 3
• Subclinical Cushing's syndrome - abnormal dexamethasone suppression without overt clinical signs of cortisol excess 1
• Pituitary hyperplasia - rare variant of ACTH-dependent disease 3

Pseudo-Cushing's States (Must Be Excluded)

Pseudo-Cushing's states can mimic true Cushing's syndrome biochemically but resolve with treatment of the underlying condition. 2

These include:

• Severe obesity - causes false positive screening tests 2, 5
• Depression - can cause mild hypercortisolism 2, 5
• Alcoholism - produces false positive results 2, 5
• Uncontrolled diabetes mellitus - may cause false positive dexamethasone suppression 1
• Disrupted sleep-wake cycles - affects circadian cortisol rhythm 5

Diagnostic Algorithm for Differential Diagnosis

Step 1: Confirm Hypercortisolism

Use any combination of: 24-hour urinary free cortisol, low-dose dexamethasone suppression test (LDST), or late-night salivary cortisol 2, 5

Step 2: Measure Morning (09:00h) Plasma ACTH

This single measurement determines the fundamental classification and directs all subsequent testing. 1, 5

Step 3A: If ACTH-Dependent (ACTH >5 ng/L)

• Obtain pituitary MRI with thin slices (3T preferred) to identify adenoma 1, 5
• If adenoma ≥10 mm: presume Cushing's disease 1
• If adenoma 6-9 mm: consider CRH stimulation test 1
• If no adenoma or <6 mm lesion: perform bilateral inferior petrosal sinus sampling (BIPSS) with CRH or desmopressin stimulation 2, 1, 5
  • Central-to-peripheral ACTH ratio ≥2:1 baseline or ≥3:1 post-stimulation confirms pituitary source 1, 5
• If ectopic ACTH suspected (very high cortisol, profound hypokalemia): perform neck-to-pelvis CT scan and consider 68Ga-DOTATATE PET imaging 1

Step 3B: If ACTH-Independent (ACTH low/undetectable)

• Perform adrenal CT or MRI to identify and characterize adrenal lesion(s) 1, 5
• Distinguish between adenoma, carcinoma, or bilateral hyperplasia based on imaging characteristics 1

Critical Pitfalls to Avoid

• Never rely on a single test - no test reaches 100% specificity, and results may be discordant in up to one-third of patients 1
• Always exclude exogenous glucocorticoid use before any biochemical testing 5
• Document active hypercortisolism immediately before BIPSS in cyclic Cushing's syndrome to avoid false negatives 2, 1
• Stop steroidogenesis inhibitors before BIPSS to enable accurate interpretation 1
• Measure dexamethasone levels if false-positive LDST suspected due to malabsorption or drug interactions with CYP3A4 inducers 2, 1
• Consider pseudo-Cushing's states in patients with mild hypercortisolism - monitor 3-6 months and treat underlying conditions before pursuing invasive testing 2

Age-Specific Considerations

In children and adolescents, unexplained weight gain combined with growth deceleration (declining height velocity or height SDS) has high sensitivity and specificity for Cushing's syndrome. 2

• Microadenomas (≤2 mm) account for 98% of pediatric Cushing's disease 2
• Prepubertal males show 71% predominance, while post-pubertal females predominate 2
• Growth failure reliably discriminates simple obesity from Cushing's syndrome in prepubertal children but not in post-pubertal adolescents 2