Parkland MR: Cushing’s Disease

Yesterday, we had a great case of Cushing’s Disease at Parkland Morning Report that brought up a number of questions regarding how to diagnose and work up the etiology!

Case:

A 22-year-old man with no medical history presented with fatigue, generalized weakness, polyuria/polydipsia, and increasing central and facial adiposity with abdominal striae.  He was found to have 24-hour urinary free cortisol of 1600 mcg (normal <45 mcg), ACTH level of 177 (normal < ~50 pg/ml but variable throughout day), and 8AM cortisol of 23 mcg/dL after 1-mg dexamethasone suppression test.  An MRI of the pituitary showed a small (5-6 mm) hypo-intense lesion concerning for adenoma.  He then underwent inferior petrosal sinus sampling, which confirmed ACTH-producing adenoma.  ENT and NSGY are performing a trans-sphenoidal resection today!

How should I screen for hypercortisolism?

  • The following are appropriate screening tests:
    • Urinary free cortisol (2 measurements)
    • Late-night salivary cortisol (2 measurements)
    • 1-mg overnight dexamethasone suppression test (DST)
    • 48-hour low-dose DST (2 mg/day for 48 hours)
  • The following tests should NOT be used to screen for hypercortisolism:
    • Random cortisol levels
    • Plasma ACTH levels
  • What do I do if a screening test is positive?
    • Repeat the same or another first-line test to rule out false-positives.
    • Refer to an endocrinologist.

How do I perform a DST and interpret the results?

  • Start with a standard low-dose DST.  Give 1 mg dexamethasone between 11PM and midnight.  Check cortisol levels at 8AM (normal <1.8 mcg/dL).
    • Normal suppression = Normal.  In general, you can stop here!
    • All causes of Cushing’s syndrome (except exogenous steroids) show failure of cortisol suppression (8 AM cortisol >1.8 mcg/dL).
  • If low-dose DST is positive and confirmed, check ACTH to differentiate ACTH-independent (i.e. adrenal adenoma) vs. ACTH-dependent disease (i.e. pituitary adenomas, ectopic ACTH).

Okay, the ACTH is high…but from where is it coming?

  • There are 3 tests to differentiate between pituitary and ectopic ACTH production.
    • High-dose (8 mg) DST:  Pituitary adenomas have 8AM cortisol <5 mcg/dL due to negative feedback with high dose steroids.
    • CRH stimulation test:  ACTH levels increase if pituitary source.
    • Desmopressin stimulation test:  ACTH levels increase if pituitary source.
  • High-dose DST + CRH stim test suggesting pituitary source are very specific, but much less sensitive!  If only one is positive, inferior petrosal sinus sampling may be needed to determine ACTH source.

I think this is Cushing’s Disease from a pituitary adenoma…what do I do next?

  • Obtain Pituitary MRI.  Unfortunately, these are only 50% sensitive for pituitary adenomas.
  • If MRI does not identify any lesions or identifies a pituitary adenoma <6 mm, inferior petrosal venous sinus sampling for ACTH verifies pituitary source before attempting surgery.
  • Before and after surgery, check other pituitary hormone levels to determine need for replacement.  Post-op hormonal deficiencies occur in up to 25% of those with Cushing’s disease, more than with other pituitary adenomas.

For more information, check out the Endocrine Society Guidelines.