What investigations should be sent for a patient with suspected exogenous Cushing's syndrome?

Investigations for Suspected Exogenous Cushing Syndrome

The most critical first step is to obtain a detailed medication history to identify and document all sources of exogenous glucocorticoid exposure, as this is the most common cause of Cushing syndrome and must be ruled out before pursuing any biochemical testing. 1, 2, 3

Initial Clinical Assessment

Medication History Documentation

• Systematically review all routes of glucocorticoid administration: oral tablets, inhalers, nasal sprays, topical creams/ointments, intra-articular injections, epidural injections, and over-the-counter preparations 4, 5
• Document specific drug names, doses, duration of use, and frequency for each glucocorticoid source 4
• Inquire about use of liquorice, nasal drops, cocaine, amphetamines, oral contraceptives, non-steroidal anti-inflammatory drugs, erythropoietin, and cyclosporin, as these can raise blood pressure and mimic or contribute to Cushingoid features 4

Physical Examination Findings

• Look for features of Cushing syndrome: facial plethora, moon facies, dorsocervical fat pad ("buffalo hump"), supraclavicular fat pads, purple striae (>1 cm wide), easy bruising, thin skin, proximal muscle weakness, and central obesity 4, 2, 3
• In children specifically, assess for weight gain with concurrent lack of height gain, as this combination has high sensitivity and specificity for Cushing syndrome 4, 1

Biochemical Investigations (Only After Ruling Out Exogenous Sources)

If exogenous glucocorticoid use is confirmed, no further biochemical testing is needed as the diagnosis is established. However, if there is uncertainty about whether exogenous exposure fully explains the clinical picture, or if you suspect both exogenous and endogenous sources, proceed as follows:

Screening Tests for Hypercortisolism

Perform 2-3 of the following first-line screening tests to confirm hypercortisolism if endogenous Cushing syndrome is suspected despite documented exogenous use: 1, 6, 2

• 24-hour urinary free cortisol (UFC): Collect 2-3 samples to account for variability; abnormal if >193 nmol/24h (>70 μg/m²) with 89% sensitivity and 100% specificity 4, 1, 7
• Late-night salivary cortisol (LNSC): Based on local assay cut-off; 95% sensitivity and 100% specificity; easiest for patient compliance 4, 1, 7
• Overnight 1 mg dexamethasone suppression test (DST): Abnormal if morning serum cortisol >50 nmol/L (>1.8 μg/dL); 95% sensitivity and 90% specificity 4, 1, 7

Important Caveats for Screening Tests

• False positives occur in: severe obesity, uncontrolled diabetes, depression, alcoholism, pregnancy, and with certain medications (CYP3A4 inducers, oral estrogens) 4, 1, 7
• Measuring dexamethasone levels along with cortisol improves DST interpretability and rules out malabsorption or rapid metabolism 1, 8
• If any screening test is abnormal, repeat 1-2 tests to confirm before proceeding 1

Determining ACTH Dependency (If Hypercortisolism Confirmed)

• Measure morning (08:00-09:00h) plasma ACTH level to differentiate ACTH-dependent from ACTH-independent causes 1, 6, 8
• ACTH >5 ng/L indicates ACTH-dependent Cushing syndrome (pituitary or ectopic source) 1, 8
• ACTH <5 ng/L or undetectable indicates ACTH-independent Cushing syndrome (adrenal source) 1, 8
• ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing disease specifically 8

Imaging Studies Based on ACTH Results

For ACTH-dependent Cushing syndrome (elevated ACTH):

• Perform high-quality pituitary MRI with thin slices (3T preferred over 1.5T) to detect pituitary adenoma 1, 6, 8
• If adenoma ≥10 mm detected, Cushing disease is presumed 4, 1, 6
• If no adenoma or lesion <6 mm found, bilateral inferior petrosal sinus sampling (BIPSS) is indicated 1, 6, 8

For ACTH-independent Cushing syndrome (suppressed ACTH):

• Perform adrenal CT or MRI to identify adrenal lesion(s) 1, 8

Special Considerations

Cyclic Cushing Syndrome

• Hypercortisolemia must be confirmed immediately prior to diagnostic procedures like BIPSS to ensure the patient is in an active disease phase 8
• Scalp-hair cortisol/cortisone analysis can help detect transient periods of hypercortisolism 5

Pediatric Patients

• Children with suspected Cushing syndrome should be referred to multidisciplinary centers with pediatric endocrinology expertise 1, 6
• Growth failure (subnormal growth velocity with weight gain) is the most sensitive discriminator between simple obesity and Cushing syndrome in prepubertal children 4

Common Pitfall to Avoid

Never proceed with biochemical testing or imaging before thoroughly documenting and excluding exogenous glucocorticoid exposure, as this wastes resources and can lead to unnecessary interventions. 4, 2, 3, 5 The diagnosis of exogenous Cushing syndrome is clinical, based on medication history and temporal relationship between glucocorticoid use and symptom onset.