What diagnosis is indicated by a positive dexamethasone suppression test with a normal ACTH level, and what are the appropriate next steps?

Positive Dexamethasone Suppression Test with Normal ACTH: Diagnosis and Management

A positive dexamethasone suppression test (failure to suppress cortisol) combined with normal ACTH levels most strongly suggests ACTH-independent Cushing's syndrome from an adrenal source, typically an adrenal adenoma or adrenocortical carcinoma. 1

Understanding the Biochemical Pattern

The combination of autonomous cortisol secretion (positive DST) with normal—rather than suppressed—ACTH creates a diagnostic challenge:

• Classic ACTH-independent disease (adrenal adenoma or carcinoma) typically presents with low or undetectable ACTH (<5 ng/L or <1.1 pmol/L) because autonomous cortisol production suppresses pituitary ACTH secretion 2
• Normal ACTH levels in the setting of failed cortisol suppression suggest either:
  • Early or mild adrenal disease where ACTH has not yet been fully suppressed 1
  • Pseudo-Cushing's state (physiologic hypercortisolism from obesity, depression, alcoholism, or uncontrolled diabetes) 1, 2
  • Technical issues with the DST (inadequate dexamethasone absorption, drug interactions) 3, 4

Immediate Next Steps

1. Confirm True Hypercortisolism

Repeat 1-2 additional first-line screening tests to exclude false-positive results and confirm genuine cortisol excess 3, 2:

• Late-night salivary cortisol (LNSC): Collect 2-3 samples on consecutive evenings at usual bedtime; contraindicated in shift workers 2
• 24-hour urinary free cortisol (UFC): Obtain 2-3 separate collections to account for day-to-day variability 2
• Measure dexamethasone level from the original DST if serum was saved; levels <1.8 ng/mL indicate inadequate drug exposure and invalidate the test 3, 4

2. Exclude Pseudo-Cushing's States

Evaluate for conditions that activate the HPA axis without true neoplastic disease 1:

• Psychiatric disorders (major depression, anxiety)
• Alcohol use disorder
• Severe obesity (BMI >35)
• Uncontrolled diabetes mellitus
• Polycystic ovary syndrome

If pseudo-Cushing's is suspected, treat the underlying condition and repeat biochemical testing after 3-6 months 3, 2. The Dex-CRH test or desmopressin test may help distinguish ACTH-dependent Cushing's from pseudo-Cushing's, though these are complex and should be performed by endocrinology 1.

3. Obtain Adrenal Imaging

If repeat testing confirms hypercortisolism, proceed immediately to adrenal CT or MRI 1:

• CT is first-line for suspected adrenal pathology (less expensive, widely available) 1
• Look for features suggesting malignancy: size >4 cm, irregular margins, inhomogeneous enhancement, Hounsfield units >10 on unenhanced CT 1
• Adrenocortical carcinoma (ACC) must be considered, especially if the mass is large or has suspicious imaging features 1

4. Comprehensive Hormonal Evaluation for Adrenal Masses

Perform complete steroid profiling as recommended by ESMO guidelines for any adrenal mass with cortisol excess 1:

• DHEA-S, 17-OH-progesterone, androstenedione, testosterone (serum)
• 17-beta-estradiol (in men and postmenopausal women)
• 24-hour urine steroid metabolite examination if available
• Plasma and urine metanephrines to exclude pheochromocytoma (can be skipped if ACC is clearly established) 1

This "hormonal fingerprint" is critical for follow-up monitoring and helps differentiate benign adenomas from ACC, which often shows immature steroidogenesis patterns 1.

Critical Diagnostic Pitfalls

False-Positive DST Results

Common causes that must be excluded 3, 4:

• CYP3A4 inducers: Phenobarbital, carbamazepine, phenytoin, rifampin, St. John's wort accelerate dexamethasone metabolism 3
• Oral estrogen therapy: Increases cortisol-binding globulin, reducing free cortisol suppression 1, 3
• Rapid gut transit or malabsorption: Inadequate dexamethasone absorption 3

When ACTH is "Normal" Rather Than Suppressed

This intermediate pattern warrants careful interpretation:

• In early adrenal disease, ACTH may not yet be fully suppressed despite autonomous cortisol production 1
• Cyclic Cushing's syndrome can produce variable ACTH levels; consider extended monitoring with multiple sequential LNSC measurements 1, 2
• Bilateral adrenal macronodular hyperplasia occasionally shows partial ACTH suppression 5

When to Refer to Endocrinology

Immediate referral is indicated for 2:

• Persistently abnormal screening tests (≥2 different modalities)
• Any adrenal mass >4 cm or with suspicious imaging features
• Discordant biochemical results (e.g., normal ACTH with failed DST suppression)
• Clinical features strongly suggesting Cushing's syndrome (proximal myopathy, wide purple striae, easy bruising, facial plethora)

Algorithmic Approach Summary

1. Verify the DST was performed correctly: Check for drug interactions, measure dexamethasone level if possible 3, 4
2. Repeat screening: Obtain 2-3 LNSC and/or 24-hour UFC to confirm hypercortisolism 3, 2
3. Exclude pseudo-Cushing's: Assess for obesity, depression, alcoholism, diabetes 1, 2
4. If hypercortisolism confirmed: Obtain adrenal CT/MRI regardless of ACTH level 1
5. Complete steroid profiling: DHEA-S, precursors, sex steroids, urine metabolites 1
6. Surgical evaluation: If imaging shows adenoma or suspected ACC, refer to experienced adrenal surgeon 1

The key principle: normal ACTH does not exclude adrenal disease—imaging is mandatory when cortisol autonomy is confirmed, and adrenocortical carcinoma must always be considered in this clinical scenario. 1