What is the next step in management for a patient with an elevated dexamethasone suppression test (DST) result?

Management of Elevated Dexamethasone Suppression Test Results

For patients with an elevated dexamethasone suppression test (DST) result, the next step should be additional confirmatory testing with 24-hour urinary free cortisol (UFC) measurements and/or late-night salivary cortisol (LNSC) tests to establish or rule out Cushing's syndrome, followed by ACTH measurement to determine the source of hypercortisolism. 1, 2

Confirmatory Testing Algorithm

1. Confirm true positive result:

   • Check for potential false positives:
     • Medication interactions (especially CYP3A4 inducers like carbamazepine, phenobarbital, St. John's wort) 1, 3
     • Estrogen therapy or pregnancy (increases CBG levels) 1, 2
     • Renal or hepatic impairment 1

2. Perform additional confirmatory tests:

   • Collect at least 2-3 24-hour urine samples for UFC measurement 1
   • Obtain 2-3 late-night salivary cortisol samples 2
   • Consider measuring dexamethasone levels concomitantly with cortisol to verify adequate absorption and metabolism 1

3. If confirmatory tests are positive:

   • Measure plasma ACTH to differentiate ACTH-dependent from ACTH-independent Cushing's syndrome 2
     • Elevated ACTH: Suggests pituitary Cushing's disease or ectopic ACTH syndrome
     • Low/suppressed ACTH: Suggests adrenal source (adenoma, carcinoma, or hyperplasia)

4. For ACTH-dependent Cushing's syndrome:

   • Perform high-dose DST (8 mg overnight) to help differentiate pituitary from ectopic source 4, 5
   • Consider CRH stimulation test (higher sensitivity than DST) 1, 2
   • Obtain pituitary MRI if Cushing's disease is suspected 2
   • Consider inferior petrosal sinus sampling if imaging is negative or equivocal 6

5. For ACTH-independent Cushing's syndrome:

   • Obtain adrenal imaging (CT or MRI) 2

Special Considerations

• Pseudo-Cushing's states: Consider conditions that can mimic Cushing's syndrome and cause mild hypercortisolism:

  • Psychiatric disorders
  • Alcohol use disorder
  • Polycystic ovary syndrome
  • Obesity 1

• Test selection based on patient factors:

  • For shift workers or those with disrupted circadian rhythm: DST may be preferred 1
  • For patients with renal impairment: LNSC may be preferred over UFC 1
  • For patients on medications affecting dexamethasone metabolism: Consider 2 mg DST instead of 1 mg DST 7

• Diagnostic pitfalls:

  • False positive rates in obesity can be as high as 15% with 1 mg DST 7
  • Combined tests (e.g., DST-CRH or desmopressin test) may help distinguish true Cushing's syndrome from pseudo-Cushing's states 1
  • Single abnormal test results are insufficient for diagnosis; multiple positive tests increase diagnostic confidence 2

Management Based on Diagnosis

Once the source is identified, appropriate management includes:

• Cushing's disease: Transsphenoidal surgery is first-line treatment 2
• Adrenal adenoma/carcinoma: Laparoscopic adrenalectomy for benign tumors; open adrenalectomy for suspected malignancy 2
• Ectopic ACTH syndrome: Surgical resection of the tumor when possible 2
• Medical therapy: Consider adrenostatic agents (ketoconazole, mitotane) to control cortisol production when surgery is delayed or contraindicated 2

The management of elevated DST results requires a systematic approach to confirm the diagnosis of Cushing's syndrome and determine its etiology, as misdiagnosis can lead to unnecessary interventions or delayed treatment of a potentially serious condition.