Hypercortisolism

• Cushing’s Syndrome 🦬 : central obesity, moon facies, anasarca, buffalo hump, thin skin & bruising, abdominal striae, hirsutism & oligomenorrhea, proximal myopathy, hypertension, polycythemia, hyperglycemia, hypokalemia, & osteopenia +/- hyperpigmentation (if ACTH-dependent)

• Cushing’s vs. Metabolic Syndrome (i.e. base rate) ❓ : the probability of Cushing’s is >90% in an obese patient with the triad of thin skin, osteoporosis, & ecchymosis

• Normal hormonal cycle of HPA axis 🧠 : hypothalamus produces CRH, which stimulates pituitary to secrete ACTH, which stimulates adrenals to secrete cortisol, which then provides ⊖ feedback. In healthy adults, secretion of cortisol is pulsatile & highest in the early A.M.

• Diagnostic confirmation 🟡 : the most reliable confirmatory test is the 24-hour Urine Free Cortisol, which should be repeated 2x. UpToDate recommends corroborating this w/ the bedtime salivary cortisol test, which should also be repeated 2x. (The basis for repeat testing in patients with high pre-test probability is that cortisol levels in Cushing’s patients can be quite variable & therefore not captured on 1x testing.)

• Diagnostic stratification 🩸 : after confirmation, the next step is to stratify the disease into ACTH-dependent (”inappropriate normal” / ↑) vs. independent (↓).

🔍 Clues 🔍 The absence of hypertension in patient who otherwise has the Cushing’s signature should prompt consideration of exogenous glucocorticoids.

1. If the disease is ACTH-dependent, the next step is comparison of ACTH concentration from the inferior petrosal sinus to the concentration of ACTH peripherally: if the central-to-peripheral ratio is > 3, this suggests central release of ACTH. If the ratio is < 3, this suggests ectopic release. For the latter, the next step is to screen the chest via CT for small cell lung cancer, & then proceed with MRI of the abdomen to screen for intra-abdominal tumors.

🔍 Clues 🔍 Since ectopic ACTH production generally leads to the highest cortisol levels, the presence of hypokalemia may suggest an ectopic ACTH source. (Rationale: the cortisol concentration is so high that cortisol’s breakdown enzyme, 11β-hydroxysteroid dehydrogenase type 2, becomes completely saturated, & resultant leftover cortisol binds to the mineralocorticoid receptor, simulating aldosterone’s effect)

❓What about the High-dose Dex Suppression Test❓ In theory, an 8 mg dexamethasone dose should suppress ACTH secretion from pituitary tumors, which generally retain some responsiveness to ⊖-feedback inhibition, which differs from many ectopic tumors that do not contain active glucocorticoid receptors & therefore are typically not responsive to this feedback. However, there are pituitary adenomas that do not suppress, & also ectopic tumors that do suppress, making this a very imperfect test … (If used, this test should be interpreted with great caution & in conjunction with the pituitary MRI & clinical features.)

2. If the disease is ACTH-independent, the next step is to scan the abdomen to assess for focal vs. diffuse disease.

🔍 Clues 🔍 Adrenal carcinoma is associated with larger size (> 5 cm) & secretion of additional adrenal hormones (e.g. androgen)

• @AndreMansoor’s Frameworks for Internal Medicine

• Dexamethasone suppression tests

Presenting Labs of Ectopic Hypercortisolism

VMRs