Ectopic ACTH Syndrome

Ectopic ACTH syndrome is ACTH-dependent hypercortisolism caused by a non-pituitary tumour secreting ACTH or corticotrophin releasing hormone. It accounts for 10 to 20% of ACTH-dependent Cushing syndrome.

Causes are bronchial and thymic carcinoid tumours, small cell lung cancer, pancreatic and other neuroendocrine tumours, medullary thyroid carcinoma and phaeochromocytoma. The source is not found in 10 to 15% of patients.

Indolent carcinoids can mimic Cushing disease. Aggressive tumours cause rapid, severe hypercortisolism with a high mortality.

Pathophysiology.

Tumour cells express proopiomelanocortin and process it to ACTH without feedback inhibition. Very high cortisol overwhelms renal 11-beta hydroxysteroid dehydrogenase type 2, so cortisol acts on the mineralocorticoid receptor and causes hypokalaemia, alkalosis and hypertension.

• Rapid onset hypertension, hypokalaemia, hyperglycaemia, proximal weakness, oedema and weight loss rather than classic Cushingoid appearance.
• Skin hyperpigmentation, psychosis, infection, venous thromboembolism and osteoporotic fracture.
• Features of the primary tumour: cough, haemoptysis, flushing or diarrhoea.

Red flags.

• Potassium under 3.0 mmol/L, sepsis (including Pneumocystis jirovecii) or psychosis.
• Venous thromboembolism or gastrointestinal perforation.

• Biochemical confirmation of hypercortisolism: 24-hour urinary free cortisol (often over four times the upper limit), late night salivary cortisol, and failure of 1 mg overnight dexamethasone suppression.
• Plasma ACTH raised (often over 100 ng/L, 22 pmol/L, but it may be lower in carcinoid). Low potassium and raised bicarbonate.
• High dose dexamethasone does not suppress cortisol by over 50% in most. Inferior petrosal sinus sampling shows no central gradient (ratio under 2 at baseline and under 3 after corticotrophin releasing hormone or desmopressin) if the source is unclear.
• Imaging: CT of chest, abdomen and pelvis, then MRI, somatostatin receptor PET-CT and fluorodeoxyglucose PET-CT. A pituitary incidentaloma is common and does not prove Cushing disease. Repeat imaging if negative.

Differential diagnosis.

• Cushing disease (pituitary ACTH source).
• Pseudo-Cushing states and exogenous glucocorticoid.
• Adrenal causes (ACTH suppressed).

• Tumour resection is curative when the source is found.
• Urgent control of cortisol before and after investigation: metyrapone 250 mg three times daily up to 6 g daily; osilodrostat 2 mg twice daily up to 30 mg twice daily; ketoconazole 200 mg twice daily up to 1200 mg daily with liver tests; mifepristone 300 mg daily up to 1200 mg daily.
• If oral drugs are not possible: etomidate by infusion in critical care, starting 0.03 mg/kg as a bolus then 0.02 to 0.08 mg/kg/h, with hydrocortisone replacement titrated to cortisol of 150 to 300 nmol/L.
• Bilateral adrenalectomy for occult or unresectable disease, with lifelong hydrocortisone and fludrocortisone.
• Correct hypokalaemia to over 4.0 mmol/L with potassium and spironolactone 50 to 100 mg daily. Control glucose with insulin. Give low molecular weight heparin and pneumocystis prophylaxis (co-trimoxazole). Treat infection promptly.
• Oncological treatment for metastatic neuroendocrine disease (somatostatin analogues, chemotherapy or peptide receptor radionuclide therapy).

Special groups. Pregnancy: rare; metyrapone is the usual drug.

Monitoring. Cortisol (or urinary free cortisol), potassium, glucose and liver tests every 1 to 2 weeks until stable. Annual imaging for recurrence for at least 5 years.

Referral and escalation. Specialist endocrine centre with oncology and endocrine surgery; critical care for sepsis, psychosis or severe hypokalaemia.