Cushing Disease

Cushing disease is ACTH-dependent hypercortisolism caused by a corticotroph pituitary adenoma. It accounts for about 70% of endogenous Cushing syndrome.

The incidence is about 1 to 2 for each million people each year. Women are affected 3 to 8 times more often than men, with onset usually between 25 and 45 years. Most tumours are microadenomas, often under 5 mm.

USP8 variants are found in a large share of tumours. Without treatment, mortality from cardiovascular disease, infection and thromboembolism is high.

Pathophysiology.

Tumour corticotrophs secrete ACTH autonomously with partial resistance to glucocorticoid feedback. Sustained cortisol excess causes catabolic, metabolic and immune effects.

Excess cortisol can be cyclical in some patients, so a single normal test does not exclude disease.

• Central weight gain, plethora, thin skin, easy bruising, wide violaceous striae, proximal myopathy, hypertension, diabetes, osteoporosis, depression and menstrual disturbance.
• Hirsutism, recurrent infection, venous thromboembolism and kidney stones. Children: growth failure with weight gain.

Red flags.

• Severe hypokalaemia, psychosis, sepsis or venous thromboembolism.
• Rapid onset with marked hypokalaemia and pigmentation (suggests ectopic ACTH).

• Confirm hypercortisolism with at least two of: late night salivary cortisol (two samples), 24-hour urinary free cortisol (two collections), and 1 mg overnight dexamethasone suppression with 8 am cortisol over 50 nmol/L (1.8 micrograms/dL).
• ACTH-dependent if morning plasma ACTH is 10 ng/L (2 pmol/L) or more.
• Pituitary MRI with contrast (positive in about 60%). If MRI is normal or the lesion is under 6 mm, perform bilateral inferior petrosal sinus sampling: central to peripheral ACTH ratio of 2 or more at baseline or 3 or more after corticotrophin releasing hormone or desmopressin.
• A high dose (8 mg) dexamethasone test suppressing cortisol by over 50% supports a pituitary source.

Differential diagnosis.

• Ectopic ACTH syndrome (bronchial or thymic carcinoid, small cell lung cancer, pancreatic neuroendocrine tumour).
• Pseudo-Cushing states (depression, heavy alcohol use, severe obesity, poorly controlled diabetes).
• Exogenous glucocorticoid exposure and adrenal causes (ACTH suppressed).

• Transsphenoidal selective adenomectomy in an experienced centre. Remission is suggested by morning cortisol under 138 nmol/L (5 micrograms/dL) within 7 days of surgery (under 50 nmol/L, 1.8 micrograms/dL, is stronger), measured before glucocorticoid cover.
• After surgery give hydrocortisone replacement until the axis recovers (6 to 18 months), with periodic morning cortisol testing. Give low molecular weight heparin perioperatively.
• Drug control when surgery fails or is awaited: osilodrostat 2 mg twice daily up to 30 mg twice daily; metyrapone 250 mg three times daily up to 6 g daily; ketoconazole 200 mg twice daily up to 1200 mg daily with liver tests; pasireotide 0.6 mg subcutaneously twice daily up to 0.9 mg twice daily (raises glucose); cabergoline 0.5 to 3 mg weekly; mifepristone 300 mg daily up to 1200 mg daily (cortisol cannot be used to monitor).
• Repeat surgery, stereotactic radiotherapy or bilateral adrenalectomy for persistent disease. After adrenalectomy watch for corticotroph tumour progression.
• Treat hypertension, diabetes, osteoporosis and thromboembolic risk. Consider pneumocystis prophylaxis with co-trimoxazole in severe hypercortisolism.

Special groups. Pregnancy: metyrapone is the usual drug, and surgery is preferred in the second trimester. Avoid ketoconazole and osilodrostat. Children: growth hormone deficiency may follow, so monitor growth and pubertal progress.

Monitoring. Cortisol and ACTH response after surgery, then annual late night salivary or urinary cortisol for life because late recurrence occurs. Drug treatment: cortisol, potassium, liver tests, glucose and QT interval.

Referral and escalation. Specialist pituitary centre; urgent review for sepsis, psychosis, severe hypokalaemia or thromboembolism.