What are the next steps for a patient with a history of Paroxysmal Supraventricular Tachycardia (PSVT) and elevated morning cortisol levels, with normal Dehydroepiandrosterone (DHEA) and a cancelled Adrenocorticotropic Hormone (ACTH) serum test?

Next Steps for Elevated Morning Cortisol with Normal DHEA

Repeat the ACTH test and obtain a 24-hour urinary free cortisol (UFC) to confirm hypercortisolism before proceeding with further diagnostic workup. 1

Immediate Diagnostic Steps

Confirm Hypercortisolism

• Obtain 24-hour urinary free cortisol (UFC) - at least two or three collections are needed to account for intra-patient variability, as random variability can be as high as 50% 1
• Perform late night salivary cortisol (LNSC) - collect at least two or three samples at usual bedtime (not necessarily midnight) to assess loss of normal circadian rhythm 1
• Consider overnight 1-mg dexamethasone suppression test (DST) - a serum cortisol <1.8 μg/dL (50 nmol/L) at 0800h after 1 mg dexamethasone given at 2300h excludes dysregulated cortisol production 1

Repeat ACTH Measurement

• Redraw ACTH with proper handling - ACTH has a short half-life and requires immediate processing on ice 1
• Obtain paired morning cortisol and ACTH - this is the diagnostic test for primary adrenal insufficiency, but in your case with elevated cortisol, it will help differentiate ACTH-dependent from ACTH-independent causes 1

Critical Interpretation Points

If ACTH is Detectable or Elevated (ACTH-Dependent)

• This indicates ACTH-dependent Cushing syndrome - most likely sources are pituitary adenomas (Cushing disease) or ectopic ACTH production from lung, thyroid, pancreas, or bowel tumors 2
• Perform CRH stimulation test - a >20% increase in cortisol from baseline suggests pituitary origin rather than ectopic source 2
• Order pituitary MRI - though adenomas are detected in only about 63% of cases 2
• If MRI is negative or equivocal, proceed to bilateral inferior petrosal sinus sampling (BIPSS) - this is the gold standard to confirm pituitary source, with a central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin and ≥3:1 after stimulation confirming pituitary origin 2

If ACTH is Suppressed (ACTH-Independent)

• This suggests primary adrenal pathology - proceed with adrenal imaging (CT or MRI) to identify adenoma or carcinoma 2

Important Caveats

Rule Out Physiologic Causes First

• Morning cortisol naturally peaks after awakening - the cortisol awakening response is a distinct phasic increase that occurs specifically with the sleep-wake transition, separate from the circadian rise 3
• Verify the patient is not on estrogen-containing medications - oral contraceptives increase cortisol-binding globulin (CBG), which can cause extreme elevations in total cortisol (up to 50-61 mcg/dL) while free cortisol remains normal 4
• Check if patient takes any medications affecting cortisol measurement - exogenous steroids (oral prednisolone, dexamethasone, inhaled fluticasone) can confound interpretation 1

Consider Pseudo-Cushing States

• Depression, alcoholism, and obesity can mimic biochemical hypercortisolism 2
• Stress, illness, or anxiety at time of blood draw can transiently elevate cortisol 1

Why Normal DHEA Matters

• Normal DHEA-S with elevated cortisol is unusual in ACTH-dependent Cushing syndrome - typically both are elevated together, though dissociation can occur 5
• This pattern suggests either early/mild disease, cyclic Cushing syndrome, or a non-ACTH mediated process 5

Monitoring During Workup

• Do not delay treatment if patient develops signs of severe hypercortisolism - hypertension, hyperglycemia, hypokalemia, and muscle atrophy require urgent intervention 2
• Consider medical therapy if waiting time for definitive treatment is prolonged - ketoconazole (400-1200 mg/day) is most commonly used due to relatively tolerable side effects 2