Ectopic ACTH Syndrome and Nelson Syndrome
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Direct answer
Ectopic ACTH syndrome is Cushing syndrome caused by a tumour outside the pituitary that secretes ACTH, most often small cell lung carcinoma. It usually produces rapid, severe hypercortisolism with marked hypokalaemia, often without the gradual features seen in pituitary disease. Nelson syndrome is a later complication of bilateral adrenalectomy for pituitary Cushing disease, in which a residual corticotroph tumour enlarges and drives very high ACTH levels.
What you must remember
- Commonest source: small cell lung carcinoma; bronchial and thymic carcinoids, pancreatic neuroendocrine tumours and medullary thyroid carcinoma are other sources.
- Presentation: rapid onset with hypokalaemic metabolic alkalosis, marked hyperpigmentation and proximal weakness.
- Hormone pattern: raised or inappropriately normal ACTH with high cortisol confirms ACTH-dependent Cushing syndrome.
- Suppression tests: high-dose dexamethasone usually fails to suppress cortisol in ectopic disease, although some tumours behave differently.
- Localisation: inferior petrosal sinus sampling after CRH; a central to peripheral ACTH ratio of 2 or more at baseline, or 3 or more after CRH, favours a pituitary source.
- Nelson syndrome: enlargement of a residual corticotroph adenoma after bilateral adrenalectomy, causing marked pigmentation and sometimes visual field loss.
- Bridging treatment: metyrapone, ketoconazole or osilodrostat lower cortisol production when surgery is delayed or not possible.
A stepwise approach to hypercortisolism with high ACTH
A rapidly progressing Cushing picture with low potassium points towards a high-grade source. The workup separates ectopic from pituitary disease in a fixed sequence.
- Confirm cortisol excess: late-night salivary cortisol or 24-hour urinary free cortisol is raised, and cortisol fails to suppress after overnight 1 mg dexamethasone.
- Measure ACTH: a raised or inappropriately normal plasma ACTH confirms that the cortisol excess is ACTH-dependent.
- Image the chest and abdomen: CT looks for a small cell carcinoma, carcinoid or pancreatic primary.
- Image the pituitary: MRI of the sella may show a microadenoma, but a negative scan does not exclude pituitary disease.
- Localise when unclear: bilateral inferior petrosal sinus sampling with CRH stimulation decides whether the source is pituitary or ectopic.
- Treat the source and correct potassium: resect the tumour where possible, replace potassium, and start a cortisol synthesis inhibitor if control is needed before surgery.
- Monitor after adrenalectomy: in pituitary disease, ACTH, pigmentation and pituitary MRI are followed for Nelson syndrome.
Where students lose marks
Examiners return to the same few traps around localisation and complications.
- Trap: reading a suppressed dexamethasone test as proof of a pituitary source. Correct: suppression is unreliable for localisation, because some ectopic tumours also suppress, so petrosal sampling decides.
- Trap: calling every ACTH-dependent Cushing syndrome Cushing disease. Correct: raised ACTH shows ACTH dependence only, and the source must still be located before the diagnosis is made.
- Trap: expecting Nelson syndrome after unilateral adrenalectomy. Correct: Nelson syndrome follows bilateral adrenalectomy for pituitary disease, because loss of cortisol feedback allows the corticotroph tumour to grow.
- Trap: dismissing a severely hypokalaemic patient as having mild disease. Correct: rapid onset with marked hypokalaemia points to a high-grade ectopic source, often small cell carcinoma.
Frequently asked questions
Which tumour most commonly causes ectopic ACTH syndrome?
Small cell lung carcinoma is the most common cause of ectopic ACTH syndrome. Bronchial and thymic carcinoids, pancreatic neuroendocrine tumours and medullary thyroid carcinoma are other recognised sources. The presentation is usually rapid, with severe hypokalaemia and hyperpigmentation.
What does inferior petrosal sinus sampling show in ectopic ACTH syndrome?
Inferior petrosal sinus sampling compares ACTH levels in blood draining the pituitary with peripheral blood, usually after CRH. A central to peripheral gradient favours a pituitary source, while no gradient points towards an ectopic tumour. The test is used when imaging does not locate the source.
How does Nelson syndrome differ from Cushing disease?
Nelson syndrome is an enlarging corticotroph tumour that develops after bilateral adrenalectomy performed for Cushing disease. Cushing disease is cortisol excess from a pituitary adenoma without prior adrenal removal. Nelson syndrome causes very high ACTH, skin pigmentation and sometimes visual field loss from mass effect.
Which drugs control cortisol excess before definitive treatment?
Metyrapone, ketoconazole and osilodrostat lower cortisol production when surgery is delayed or not possible in ectopic ACTH syndrome. Mifepristone, a glucocorticoid receptor blocker, is also used in selected cases. Potassium replacement and blood pressure control are needed alongside these drugs.