Makindo Medical Notes

Related Subjects: |Adrenal Physiology |Addisons Disease |Phaeochromocytoma |Adrenal Adenomas |Adrenal Cancer |Cushing Syndrome |Cushing Disease |Cushing's Syndrome due to Ectopic ACTH |Congenital Adrenal hyperplasia |Primary hyperaldosteronism (Conn's syndrome) |ACTH |McCune Albright syndrome

⚡ Rapid onset and progression of Cushingoid features should raise suspicion of an ectopic ACTH source. Unlike pituitary Cushing’s disease, ectopic ACTH often presents with severe metabolic derangements and subtle or atypical Cushing’s features.

📍 About

• Cushing’s syndrome = clinical state of chronic excess cortisol.
• Ectopic ACTH syndrome: cortisol excess due to ACTH production outside the pituitary.
• Accounts for ~10–15% of all cases of ACTH-dependent Cushing’s syndrome.

🧬 Aetiology & Pathophysiology

• Tumours secrete ACTH (and often POMC precursors).
• This drives adrenal hyperplasia → ↑ cortisol → metabolic complications.
• Loss of negative feedback: cortisol fails to suppress ectopic ACTH secretion.

⚠️ Causes (Key Tumour Types)

• 🚬 Small cell lung carcinoma (most common).
• 🌿 Bronchial carcinoid tumours.
• 🍴 Pancreatic carcinoids.
• 🫁 Thymic carcinoids.
• 🦋 Medullary thyroid carcinoma.
• ⚡ Phaeochromocytoma.

🩺 Clinical Features

• Classical Cushing’s signs (moon face, centripetal obesity, striae) may be less pronounced.
• 🌑 Hyperpigmentation (very high ACTH → stimulates melanocytes).
• ⚡ Severe metabolic effects: hypokalaemic metabolic alkalosis, hypertension, hyperglycaemia, muscle weakness.
• ⚠️ Weight loss, cachexia → unlike pituitary Cushing’s (often due to malignancy).
• Symptoms of underlying tumour (e.g. haemoptysis, cough, carcinoid syndrome).

🔬 Investigations

• 🧪 Biochemistry: hypokalaemic metabolic alkalosis, hyperglycaemia.
• 📊 Hormonal tests:
  • PTH suppressed; cortisol ↑.
  • High-dose dexamethasone test (8mg): fails to suppress cortisol in ectopic ACTH (but suppresses partially in pituitary disease).
  • Elevated POMC levels can identify occult ectopic tumours.
• 📸 Imaging: CXR, CT thorax/abdomen/pelvis to identify tumour source.
• 🔍 Histology: tumour typing and staging (metastases influence prognosis).

📉 Mortality and morbidity depend on: 1️⃣ Tumour histology 2️⃣ Presence of metastases 3️⃣ How effectively cortisol excess is controlled

💊 Management

• 🎯 Surgical excision of ACTH-producing tumour if localised and resectable.
• 💧 Acute control: aggressive IV hydration, correction of hypokalaemia.
• 💊 Medical therapies to lower cortisol:
  • Metyrapone (11β-hydroxylase inhibitor).
  • Ketoconazole or fluconazole (block steroidogenesis).
  • Etomidate IV (emergency use, rapid cortisol blockade in ICU).
  • Mifepristone (cortisol receptor antagonist) useful in severe ACTH-associated psychosis.
• 🩺 Bilateral adrenalectomy: last-resort option if tumour cannot be controlled and cortisol excess is life-threatening.

📚 Teaching Pearls

• 🚩 Think ectopic ACTH if: rapid onset, profound hypokalaemia, weight loss, subtle Cushingoid features.
• ACTH-secreting carcinoids may produce indolent Cushing’s; small cell carcinoma → fulminant course.
• High-dose dexamethasone test: key discriminator between pituitary and ectopic ACTH.
• Long-term survival depends far more on the tumour biology than cortisol excess itself.

🔗 References

• The ectopic ACTH syndrome (PubMed)