Cushing syndrome

⚠️ Important: Hypokalaemia is more likely when the source of ACTH is malignant. 🧠 A normal pituitary MRI does not exclude Cushing’s disease – up to 50% (especially children) may have normal imaging. 👉 In such cases, inferior petrosal sinus sampling is crucial.

📖 About

• Cushing's Syndrome = chronic exposure to excessive cortisol.
• Disrupts hypothalamic–pituitary–adrenal (HPA) axis feedback 🔄.
• Loss of normal circadian cortisol rhythm 🌙☀️.
• Cushing’s Disease = pituitary adenoma secreting ACTH.

🧬 Aetiology

• 🌟 ACTH-dependent:
  • 🧠 Pituitary adenoma (Cushing’s disease).
  • 🫁 Ectopic ACTH from tumours (e.g. lung, pancreas).
• 🌟 ACTH-independent:
  • 🟤 Adrenal adenomas/carcinomas.
  • 💊 Exogenous glucocorticoids (most common overall cause).

⚡ Causes

• 🧠 Pituitary Adenoma (Cushing’s Disease) (~70% endogenous)
  • Microadenomas → ↑ACTH → bilateral adrenal hyperplasia.
  • Key: not suppressed by low-dose dex, partially suppressed by high-dose; ↑ACTH & cortisol; responds to CRH.
• 🟤 Adrenal Tumours
  • Autonomous cortisol secretion → suppressed ACTH.
  • No suppression on low or high-dose dex.
• 🫁 Ectopic ACTH Production
  • Sources: small cell lung carcinoma, bronchial carcinoid, pancreatic NET.
  • ACTH high, no suppression on high-dose dex.
  • Often severe hypokalaemia ⚠️ due to mineralocorticoid activity.
• 💊 Iatrogenic – long-term glucocorticoid therapy (asthma, RA, PMR, UC, post-transplant).
• 🎭 Pseudo-Cushing’s – alcohol excess, severe obesity, depression (reversible).
• 🤰 Pregnancy – ↑ cortisol-binding globulin → raised total cortisol (rarely true Cushing’s).

👀 Clinical Features

• Appearance 🌙:
  • Centripetal obesity.
  • Moon face, facial plethora, acne.
  • Dorsocervical fat pad (“buffalo hump”).
  • Muscle wasting → thin extremities.
  • Purple striae (abdomen, thighs, breasts).
• Skin 🩹:
  • Thin fragile skin, easy bruising.
  • Slow wound healing.
  • Hirsutism in women.
  • Hyperpigmentation (if ACTH-driven).
• MSK 💪:
  • Proximal myopathy (difficulty standing/climbing stairs).
  • Osteoporosis → fractures.
  • Avascular necrosis of femoral head.
• Metabolic 🧪:
  • Glucose intolerance / diabetes.
  • Hyperlipidaemia.
  • Hypertension.
  • Hypokalaemia & metabolic alkalosis.
• Neuropsychiatric 🧠:
  • Mood swings, depression, psychosis.
  • Cognitive impairment.
• Reproductive ❤️:
  • Women: amenorrhoea, infertility.
  • Men: ↓ libido, impotence.
• Growth 📏:
  • Stunted growth in children.
• Immune 🛡️:
  • Infections, reactivation of TB.
  • Poor wound healing.

🧪 Diagnostic Tests

🌙 Overnight Dexamethasone Suppression (screen)

• 1 mg dex at midnight → cortisol at 08:00.
• Normal < 50 nmol/L;> 50 → suspect Cushing’s.
• ⚠️ False positives: depression, obesity, alcohol, phenytoin.

🧪 24h Urinary Free Cortisol (screen)

• Normal < 280 nmol/24h; elevated = abnormal.

💉 Low-Dose 48h Dex Test (confirm)

• 0.5 mg dex 6-hourly × 48h (total 4 mg).
• Cortisol undetectable = excludes; detectable = Cushing’s confirmed.

📊 High-Dose 48h Dex Test (localise)

• 2 mg dex 6-hourly × 48h (total 16 mg).
• Pituitary: >50% suppression.
• Ectopic/adrenal: no suppression.

🧬 Plasma ACTH

• ⬇️ Undetectable → adrenal tumour.
• ⬆️ High → pituitary vs ectopic.
• CRH test: rise = pituitary; no rise = ectopic.

📚 Exam Tip: Think stepwise → Overnight (screen) → Low-dose (confirm) → High-dose/ACTH (localise). Pituitary = suppressible, ectopic/adrenal = resistant.

🖼️ Imaging

• 🧠 Pituitary MRI (but 50% normal!) → may need inferior petrosal sinus sampling.
• 🟤 Adrenal CT/MRI → adenoma or carcinoma.
• 🫁 Chest/abdomen CT → ectopic ACTH tumours.
• 📡 Octreotide scans for ectopic localisation.

💊 Management

• 🧠 Pituitary adenoma: transsphenoidal resection; radiotherapy if unsuccessful; pasireotide or ketoconazole if refractory.
• 🟤 Adrenal tumours: adrenalectomy ± mitotane if carcinoma.
• 🫁 Ectopic ACTH: treat primary tumour if resectable; otherwise medical control of cortisol.
• 💊 Iatrogenic: gradual steroid taper, switch to steroid-sparing alternatives.

🧪 Medical Therapy (for inoperable / pre-surgery)

• Metyrapone (11β-hydroxylase inhibitor).
• Ketoconazole (blocks steroidogenesis).
• Aminoglutethimide (cholesterol → pregnenolone block).
• Mitotane (adrenolytic, carcinomas).
• Etomidate (IV emergency use).

📌 Key Points

• Early recognition prevents morbidity & mortality.
• Diagnosis = stepwise biochemical + imaging + sometimes petrosal sampling.
• Management is cause-directed (surgery first-line where possible).
• 🏥 Long-term follow-up essential: recurrence, metabolic complications, bone health, psychological support.

Cases - Cushing’s Syndrome

• Case 1 - Iatrogenic steroid use 💊: A 55-year-old woman with rheumatoid arthritis on long-term prednisolone presents with weight gain, easy bruising, proximal muscle weakness, and thin skin. Exam: moon facies, buffalo hump, purple abdominal striae. Diagnosis: exogenous Cushing’s syndrome due to chronic glucocorticoid therapy. Managed by gradual tapering of steroids and use of steroid-sparing agents.
• Case 2 - Pituitary-dependent (Cushing’s disease) 🧠: A 36-year-old woman presents with irregular menses, hirsutism, and worsening acne. Exam: central obesity, hypertension, and skin thinning. Bloods: elevated cortisol not suppressed by low-dose dexamethasone, but suppressed with high-dose dexamethasone. MRI: pituitary microadenoma. Diagnosis: Cushing’s disease (ACTH-secreting pituitary adenoma). Managed with trans-sphenoidal pituitary surgery.
• Case 3 - Adrenal tumour ⚠️: A 42-year-old man presents with new-onset diabetes, hypertension, and muscle wasting. No exogenous steroid use. Bloods: raised cortisol with suppressed ACTH. CT abdomen: adrenal mass. Diagnosis: ACTH-independent Cushing’s syndrome due to adrenal adenoma. Managed with adrenalectomy.

Teaching Point 🩺: Cushing’s syndrome = chronic glucocorticoid excess. Common causes: exogenous steroids, pituitary adenoma (Cushing’s disease), adrenal adenoma/carcinoma, ectopic ACTH (e.g. small-cell lung cancer). Clinical clues: central obesity, moon facies, striae, proximal weakness, hypertension, diabetes, mood changes. Diagnosis: screen with 24h urinary cortisol, overnight dexamethasone suppression, late-night salivary cortisol. Management: treat underlying cause (taper steroids, pituitary surgery, adrenalectomy).