Cushing syndrome

Clinical syndrome of chronic cortisol excess (hypercortisolism); Cushing disease refers specifically to an ACTH-secreting pituitary adenoma (a subset cause of the syndrome).

• Uncontrolled Cushing's causes serious complications (diabetes, infections, hypertension, osteoporosis). It's often tricky to diagnose because features (obesity, HTN, depression) are common in the general population, so distinguishing true Cushing's from look-alikes is a classic exam challenge.

• Classic appearance: progressive central obesity (round "moon" face, buffalo hump fat pad) with thin limbs, purple striae (>1 cm wide), easy bruising, acne, and proximal muscle weakness. Often accompanied by hypertension, weight gain, and hyperglycemia (new-onset diabetes); women may have hirsutism or irregular menses.
• Clues to suspect Cushing's: multiple progressive cushingoid features (e.g. rapid unexplained weight gain with wide striae and muscle weakness) or any unusual combination like early osteoporosis or refractory hypertension in a young adult. Patients 20-50 years old are most commonly affected.
• Etiologies: Exogenous steroids (iatrogenic) are most common overall. Endogenous Cushing's is rare; ~70% is Cushing disease (pituitary ACTH adenoma, usually microadenoma in women). The rest are either ectopic ACTH production (paraneoplastic, e.g. small cell lung cancer) or an adrenal tumor (adenoma or carcinoma). Only ACTH-dependent causes (pituitary or ectopic) cause skin hyperpigmentation (due to high ACTH).

1. Always first exclude exogenous glucocorticoid use (most common cause of Cushing's).
2. Confirm true Cushing syndrome with an initial screening test for cortisol excess. Options (choose one or two): the 1 mg overnight dexamethasone suppression test, 24‑hour urinary free cortisol (UFC, ≥2 collections), or late-night salivary cortisol (two nights). If the first test is abnormal, confirm with a second method. Note: random cortisol or ACTH levels are not useful for initial screening.
3. If hypercortisolism is confirmed, measure plasma ACTH to classify the cause. Low ACTH (<5 pg/mL) indicates an ACTH-independent source (likely an adrenal tumor or exogenous steroid). Normal or high ACTH points to ACTH-dependent Cushing's (either pituitary or ectopic ACTH).
4. For ACTH-dependent cases, do tests to distinguish a pituitary source (Cushing disease) from ectopic ACTH. The classic approach is a high-dose dexamethasone suppression test: give 8 mg dexamethasone overnight (or 2 mg q6h for 48h) and re-measure cortisol. Pituitary adenomas typically show significant cortisol suppression (>50% drop from baseline), whereas an ectopic ACTH source will not suppress. A CRH stimulation test is another tool: pituitary adenomas respond with a rise in ACTH/cortisol, but ectopic ACTH tumors show no response.
5. Once lab results suggest a source, use imaging to find it. If ACTH is high and tests indicate pituitary: get a pituitary MRI to look for an adenoma (most are microadenomas <10 mm). If MRI is negative but labs strongly suggest pituitary, consider inferior petrosal sinus sampling (IPSS) for ACTH to confirm a hidden pituitary source. If ACTH is high but suggests ectopic source: scan the chest/abdomen (CT/MRI) to find a tumor (e.g. lung mass). If ACTH is low: image the adrenal glands (CT or MRI) for an adenoma or carcinoma.

1. Exogenous (iatrogenic) Cushing's: Gradually taper off the glucocorticoid if medically feasible. This allows the HPA axis to recover and the Cushingoid features will resolve.
2. Pituitary Cushing disease: Transsphenoidal resection of the pituitary adenoma is first-line (≈90% cure for small microadenomas). If not cured, options include a second surgery, radiation therapy, or medical therapies to lower cortisol (e.g., ketoconazole, metyrapone, mitotane, osilodrostat, or pasireotide; and mifepristone to block cortisol effects). Bilateral adrenalectomy is a last resort in refractory cases (but necessitates lifelong steroid replacement).
3. Adrenal tumor: surgical adrenalectomy (laparoscopic for benign adenomas; open surgery if large or malignant). Ectopic ACTH syndrome: treat the underlying tumor (e.g., surgical removal or chemo for a lung cancer). If the source can't be immediately eliminated, use medical adrenal-blocking drugs to control cortisol. Always manage co-morbidities (diabetes, infections, osteoporosis) alongside definitive treatment.

• Mnemonic (causes): CAPE – Cushing disease (pituitary ACTH adenoma), Adrenal tumor, Paraneoplastic ACTH (ectopic), Exogenous steroids.
• Mnemonic (features): CUSHINGOID – Cataracts, Ulcers (peptic), Skin changes (thin skin, striae, bruising), Hypertension/Hirsutism/Hyperglycemia, Infections (immunosuppression), Necrosis (avascular necrosis of femoral head), Glycosuria, Osteoporosis/Obesity (central), Iatrogenic (cause)/Immunosuppression, Diabetes.
• High ACTH levels can cause skin hyperpigmentation (ACTH stimulates melanocytes). Thus, ACTH-dependent Cushing's (pituitary or ectopic) often has darker skin, whereas adrenal tumor or steroid-induced Cushing's does not.

• Profound immunosuppression – patients with severe Cushing's can develop opportunistic infections or sepsis; a sudden worsening (fever, confusion) in a Cushingoid patient requires urgent evaluation and treatment for infection.
• Thromboembolism risk – Cushing's creates a hypercoagulable state, so be vigilant for DVT, pulmonary embolism, or stroke (new-onset chest pain or neurologic deficits = emergency).
• Abrupt steroid withdrawal can precipitate adrenal crisis (acute adrenal failure) – always taper steroids slowly and consider stress-dose steroids if a Cushing's patient undergoes surgery or trauma.

1. Suspicious features (moon facies, striae, etc.) or an adrenal incidentaloma → suspect Cushing syndrome.
2. Check for exogenous steroid use (most common cause) and discontinue/taper if possible.
3. Screen for cortisol excess: 1 mg overnight DST, 24h urine free cortisol, or late-night salivary cortisol (any positive test → proceed to confirm with a second test).
4. If cortisol excess is confirmed → measure plasma ACTH.
5. ACTH <5 pg/mL → ACTH-independent (likely adrenal) → adrenal CT/MRI to find tumor. ACTH normal/high → ACTH-dependent Cushing's.
6. For ACTH-dependent: perform high-dose DST (± CRH test). Suppression (or CRH-responsive) → pituitary source (Cushing disease); no suppression → ectopic ACTH source.
7. Pituitary source confirmed → pituitary MRI to localize adenoma (if none seen and labs strongly suggest pituitary, do IPSS sampling). Ectopic suspected → imaging (CT chest/abdomen) to find the ACTH-secreting tumor.

• Young woman with central obesity, facial rounding (moon facies), dorsocervical fat pad, and wide purple striae; labs show elevated cortisol with suppression on high-dose DST → Cushing disease (pituitary adenoma).
• Middle-aged smoker with a lung mass, diffuse skin hyperpigmentation, severe proximal muscle weakness, and very high cortisol that does not suppress with high-dose dexamethasone → ectopic ACTH (paraneoplastic Cushing syndrome, e.g. small cell lung cancer).