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!
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.