What is the diagnostic and treatment algorithm for hypercortisolism?

Diagnostic and Treatment Algorithm for Hypercortisolism

The diagnosis of hypercortisolism requires a stepwise approach starting with screening tests, followed by confirmation tests, and then determination of etiology through ACTH measurement and appropriate imaging studies. 1

Initial Screening for Hypercortisolism

• First, rule out exogenous glucocorticoid use (oral, injections, inhalers, topical) as this is a common cause of hypercortisolism 1

• Perform at least one of these screening tests (preferably two tests if clinical suspicion is intermediate or high) 1:

  • Late night salivary cortisol (LNSC) - collect at least two samples
  • 24-hour urinary free cortisol (UFC) - collect 2-3 specimens
  • Overnight 1mg dexamethasone suppression test (DST)

• Consider the following when selecting initial tests 1:

  • For suspected Cushing's disease: Start with UFC and/or LNSC; DST is also an option
  • For suspected adrenal tumor: Start with DST (LNSC has lower specificity)
  • For shift workers or disrupted circadian rhythm: DST may be preferred
  • For patients on estrogen-containing medications: Avoid DST (false positives)

Interpretation of Screening Tests

• Normal results with low clinical suspicion: Cushing's syndrome (CS) is unlikely 1
• Abnormal results: Proceed to confirmation and exclude non-neoplastic hypercortisolism 1
• Mildly abnormal results with normal repeat testing: Consider cyclic CS or re-evaluate periodically 1

Excluding Non-neoplastic Hypercortisolism (Pseudo-CS)

• Consider these conditions that can cause false positive results 1, 2:

  • Severe obesity
  • Uncontrolled diabetes
  • Pregnancy
  • Alcoholism
  • Depression/psychiatric disorders
  • Chronic kidney disease

• Additional tests to distinguish CS from pseudo-CS 1:

  • Combined low-dose dexamethasone-CRH test (Dex-CRH)
  • Desmopressin test
  • Midnight serum cortisol

Determining the Etiology of Confirmed Hypercortisolism

• Measure plasma ACTH levels 1, 3:

  • Low ACTH: ACTH-independent CS (adrenal source)
  • Normal or high ACTH: ACTH-dependent CS (pituitary or ectopic source)

• For ACTH-independent CS 1:

  • Perform adrenal CT or MRI to identify adrenal adenoma, carcinoma, or bilateral disease

• For ACTH-dependent CS 1, 3:

  • Perform pituitary MRI with contrast
  • Lesions ≥10mm strongly suggest Cushing's disease (CD)
  • Lesions <6mm or no visible lesion: Perform inferior petrosal sinus sampling (IPSS)
  • Lesions 6-9mm: Consider CRH and DDAVP stimulation tests; if inconclusive, proceed to IPSS

Treatment Algorithm

For Cushing's Disease (ACTH-dependent, pituitary source)

1. First-line: Transsphenoidal surgery (TSS) 1, 4

2. For persistent/recurrent disease after TSS 1:

   • Second TSS
   • Radiation therapy
   • Medical therapy
   • Bilateral adrenalectomy

3. Medical therapy options 1, 5:

   • For mild disease: Ketoconazole (400-1200 mg/day), osilodrostat, or metyrapone
   • For moderate disease: Consider medications with tumor-shrinking potential (cabergoline, pasireotide)
   • For severe disease: Rapid cortisol normalization with osilodrostat, metyrapone, ketoconazole, or etomidate; consider combination therapy

For Ectopic ACTH Syndrome

1. First-line: Surgical removal of the ACTH-producing tumor 4
2. If surgery not possible 1, 4:
   • Medical therapy with steroidogenesis inhibitors
   • Bilateral adrenalectomy if medical control fails

For ACTH-independent CS (Adrenal Source)

1. Unilateral adrenal adenoma/carcinoma: Surgical resection 1, 6
2. Bilateral adrenal disease: Bilateral adrenalectomy 1, 6
3. Medical therapy if surgery contraindicated 5, 7:
   • Ketoconazole, metyrapone, osilodrostat, or mitotane

Monitoring Treatment Response

• Use multiple serial tests of both UFC and LNSC 5
• Monitor for resolution of clinical features 8
• For patients on medical therapy, monitor for specific adverse effects:
  • Ketoconazole: Liver function tests, drug interactions 1, 5
  • Osilodrostat: Androgenic effects, hypokalemia 1
  • Metyrapone: Hirsutism, hypertension 9

Special Considerations

• Children with CS should be referred to multidisciplinary centers with pediatric endocrinology expertise 1
• Genetic testing should be considered, especially in children and young adults 1
• Paraneoplastic CS (especially with SCLC) requires urgent treatment of hypercortisolism before cancer therapy to reduce complications 1
• Cyclic CS may require repeated testing during symptomatic periods 1, 10

Common Pitfalls to Avoid

• Not ruling out exogenous glucocorticoid use before testing 1, 3
• Relying on a single test for diagnosis (due to variability in cortisol secretion) 1
• Not considering drug interactions that affect dexamethasone metabolism 1
• Failing to recognize pseudo-CS, especially in patients with obesity, alcoholism, or psychiatric disorders 1, 2
• Not measuring dexamethasone levels during DST (to ensure adequate absorption) 1