AKT · Endocrine/Paraneoplastic & neuroendocrine

Ectopic ACTH syndrome

Paraneoplastic ACTH secretion (small-cell lung cancer, carcinoid) → Cushing's

Overview

Paraneoplastic Cushing's syndrome from ectopic ACTH secretion by a non-pituitary tumour — classically small-cell lung cancer (rapid, severe) or a bronchial carcinoid (more indolent). Distinguished from pituitary Cushing's disease by very high ACTH, failure to suppress on high-dose dexamethasone, rapid onset with weight loss, marked hypokalaemic alkalosis and pigmentation.

Recognise

Rapid-onset cortisol excess often with WEIGHT LOSS (the tumour) rather than the classic Cushingoid weight gain
Marked HYPOKALAEMIC metabolic alkalosis, hyperglycaemia, hypertension, proximal myopathy, hyperpigmentation (high ACTH)
Very high ACTH; fails to suppress on high-dose dexamethasone (unlike pituitary disease)

Red flags

Underlying malignancy (small-cell lung) → investigate/stage urgently
Severe hypokalaemia/hyperglycaemia from extreme cortisol

Differentials & how to tell them apart

Pituitary Cushing's diseaseACTH high but SUPPRESSES on high-dose dexamethasone; slower, classic weight gain; pituitary MRI

Adrenal Cushing'sACTH SUPPRESSED (adrenal tumour autonomously making cortisol)

Exogenous steroidshistory; ACTH and cortisol both low

Investigations

Confirm cortisol excess (dexamethasone/urinary cortisol), then ACTH (very high) and high-dose dexamethasone suppression (no suppression in ectopic). CT chest/abdomen, somatostatin scan; inferior petrosal sinus sampling distinguishes pituitary vs ectopic. Potassium (low), glucose.

Management

Treat the tumour + medical cortisol control (metyrapone) + correct potassium

1Confirm cortisol excess, then ACTH (very high) and high-dose dexamethasone (no suppression). Localise the tumour (chest/abdomen imaging; IPSS to confirm ectopic). Control cortisol medically and treat the source.Gate: High-dose dexamethasone SUPPRESSES pituitary Cushing's disease but NOT ectopic ACTH — that, plus rapid onset with weight loss, hypokalaemia and pigmentation, points to a tumour (often small-cell lung)
2Resect/treat the tumour; metyrapone/ketoconazole for cortisol control; correct electrolytes/glucose; bilateral adrenalectomy in refractory cases.

Treat the tumour — resect/oncological treatment of the source (e.g. carcinoid resection)

Steroidogenesis inhibitors (metyrapone/ketoconazole) — control cortisol while treating the tumour

Correct hypokalaemia (spironolactone) — for the mineralocorticoid effect of very high cortisol

Key points

Rapid Cushingoid + weight LOSS + marked hypokalaemia + pigmentation + ACTH that won't suppress on high-dose dexamethasone = ectopic ACTH (small-cell lung). It's paraneoplastic Cushing's — find the tumour.

Monitor & prognosis

Cortisol/potassium; tumour response.

Depends on the malignancy.

Source: Endocrine Society; StatPearls