Cushing's syndrome Study Guide

📖 Core Concepts Cushing’s syndrome – clinical picture from chronic excess glucocorticoids (endogenous or exogenous). Cushing’s disease – subset of endogenous Cushing’s caused by a pituitary ACTH‑secreting adenoma (≈ 70 % of endogenous cases). ACTH‑dependent vs. ACTH‑independent – high ACTH = pituitary or ectopic source; low ACTH = adrenal source or exogenous steroids. Negative feedback loop – cortisol normally suppresses CRH (hypothalamus) and ACTH (pituitary); excess cortisol can bypass or override this loop. Mineralocorticoid spillover – very high cortisol binds mineralocorticoid receptors → hypertension, hypokalemia, hypernatremia. --- 📌 Must Remember Key labs: 24‑h urinary free cortisol ↑ Low‑dose dexamethasone suppression test: cortisol > 50 nmol/L (1.81 µg/dL) = positive. Midnight plasma or salivary cortisol ↑. Plasma ACTH: high → ACTH‑dependent; low → ACTH‑independent. Classic physical signs: moon face, buffalo hump, central obesity with thin limbs, purple striae, easy bruising, proximal muscle weakness. Most common cause: prolonged exogenous glucocorticoid therapy. First‑line treatment for Cushing’s disease: transsphenoidal pituitary surgery. Nelson’s syndrome: hyperpigmentation & pituitary tumor growth after bilateral adrenalectomy. --- 🔄 Key Processes Normal HPA axis Hypothalamus → CRH → anterior pituitary → ACTH → adrenal zona fasciculata → cortisol → negative feedback on CRH & ACTH. Diagnostic algorithm ① Review meds → rule out exogenous steroids. ② Screen: 24‑h urinary cortisol, low‑dose dexamethasone suppression, late‑night cortisol. ③ Measure ACTH → determine dependence. ④ Imaging: pituitary MRI (if ACTH‑high) or adrenal CT (if ACTH‑low). ⑤ If pituitary MRI negative but ACTH high → inferior petrosal sinus sampling. Treatment pathway Exogenous → taper/replace. ACTH‑dependent (pituitary) → transsphenoidal surgery → consider medical inhibitors (ketoconazole, metyrapone, mifepristone, osilodrostat). ACTH‑independent (adrenal) → adrenalectomy → steroid replacement. --- 🔍 Key Comparisons Exogenous vs. Endogenous Exogenous: history of glucocorticoid use, suppressed ACTH, no adrenal/pituitary tumor. Endogenous: no steroid exposure, ACTH may be high (pituitary/ectopic) or low (adrenal). Pituitary (Cushing’s disease) vs. Ectopic ACTH Pituitary: gradual onset, may have mild hyperpigmentation, CRH‑stimulated ACTH rise, MRI pituitary adenoma. Ectopic: rapid, severe hyperglycemia/hypokalemia, often associated with small‑cell lung cancer, very high ACTH, no CRH response. ACTH‑dependent vs. ACTH‑independent Dependent: ACTH ↑, cortisol ↑, adrenal glands may be bilateral hyperplasia. Independent: ACTH ↓ (suppressed), cortisol ↑, adrenal mass or hyperplasia. --- ⚠️ Common Misunderstandings “All Cushing’s patients have purple striae.” – Striae are classic but may be absent in mild cases. “Normal blood pressure rules out Cushing’s.” – Hypertension is common but not universal; early disease can have normal BP. “Low‑dose dexamethasone suppression always rules out Cushing’s.” – Some patients have partial suppression; confirm with additional tests. “Exogenous steroids cannot cause ACTH suppression.” – They do suppress ACTH; the syndrome persists while the drug is present. --- 🧠 Mental Models / Intuition “Feedback Bypass” – Imagine the HPA axis as a thermostat. Exogenous steroids turn the thermostat off, but the heater (cortisol) keeps running because the thermostat is ignored. “ACTH level as a traffic light” Green (high) → look upstream (pituitary/ectopic). Red (low) → look downstream (adrenal or exogenous). --- 🚩 Exceptions & Edge Cases Partial suppression on low‑dose dexamethasone may occur in mild Cushing’s or in pseudo‑Cushing states (e.g., severe depression, alcoholism). Nelson’s syndrome only after bilateral adrenalectomy; not seen after unilateral adrenal removal. Mild endogenous hypercortisolism can be asymptomatic, discovered incidentally on imaging or lab screening. --- 📍 When to Use Which Screening test: low‑dose dexamethasone suppression is first‑line; use 24‑h urinary cortisol or late‑night salivary cortisol if dexamethasone test unavailable or contraindicated. ACTH measurement: order immediately after a positive screening test to differentiate dependent vs. independent disease. Imaging: pituitary MRI when ACTH high; adrenal CT when ACTH low. Inferior petrosal sinus sampling: reserved for ACTH‑high patients with negative or equivocal pituitary MRI. Medical therapy: ketoconazole/​metyrapone for pre‑operative control or when surgery contraindicated; mifepristone for cortisol‑induced hyperglycemia; osilodrostat for patients unsuitable for surgery. --- 👀 Patterns to Recognize “Central obesity + thin limbs + purple striae” → think Cushing’s. High cortisol + low ACTH → exogenous or adrenal tumor. High cortisol + high ACTH + rapid symptom onset → ectopic ACTH source. Hypertension + hypokalemia + metabolic alkalosis → mineralocorticoid effect of excess cortisol. --- 🗂️ Exam Traps Choosing the wrong ACTH‑dependent source – distractors may list “pituitary adenoma” and “small‑cell lung cancer” together; remember rapid severe disease points to ectopic source. Dexamethasone dose confusion – low‑dose (1 mg) vs. high‑dose (8 mg) suppression; low‑dose is for screening, high‑dose can differentiate pituitary from ectopic (not in outline but common). Stick to low‑dose criteria given. Assuming all patients need surgery – some cases (exogenous, mild adrenal hyperplasia) are managed medically or with tapering. Misreading cortisol units – the cutoff is 50 nmol/L (1.81 µg/dL); answer choices using mg/dL are wrong. Nelson’s syndrome misattribution – only after bilateral adrenalectomy, not after unilateral. ---