Escape from medical therapy in a severely ill patient with Cushing’s disease
TM Tan, N Mendoza, F. Roncaroli, NM Martin
Metyrapone or ketoconazole may be used to control the hypercortisolaemia of Cushing’s syndrome (CS) prior to definitive treatment with surgery. However, escape from control with medical therapies presents particular challenges in the severely ill patient.
We present a 57 year old female with severe CS, characterised by new onset type 2 diabetes mellitus, hypertension, weight gain, bruising, proximal myopathy, severe depression and cellulitic ulcers on both legs which were slow to heal.
Investigations revealed hypokalemia and confirmed ACTH-dependent CS. An LDDST (0.5mg every 6h for 48h) was performed: baseline ACTH 85ng/L, baseline cortisol 907nmol/L, T=48h cortisol 807nmol/L (n <50nmol/L). An HDDST (2mg every 6h for 48h) showed failure to suppress cortisol to less than 50% baseline: T=0h cortisol 1372nmol/L, T=48h cortisol 825nmol/L. MRI pituitary revealed a left sided microadenoma. CT chest, abdomen and pelvis did not reveal any potential ectopic source of ACTH. The patient was too unwell to undergo petrosal sinus sampling.
Combined therapy was initiated with ketoconazole and metyrapone. Repeated escape from control necessitated increases in the dose of both drugs to 750mg three times daily and 600mg twice daily respectively. However, cortisol levels remained >1000nmol/L (target approximately 250-300nmol/L) and she required continuous intravenous potassium replacement.
A subhypnotic infusion of etomidate, starting at a dose of 2.5mg/h, was therefore commenced. Initially serum cortisol fell to approximately 200nmol/L. However, within 2 weeks serum cortisol again escaped control despite increases in the dose to 5mg/h. The options of bilateral adrenalectomy, which would cure the patient regardless of the cause, and pituitary surgery were discussed at numerous MDTs. The patient proceeded to an uncomplicated trans-sphenoidal hypophysectomy. Histology confirmed a corticotroph adenoma and post-operatively, serum cortisol fell to 168 nmol/L (09:00h, off replacement hydrocortisone). She has recovered well from many of her manifestations of Cushing’s apart from depression.
This case illustrates two points: (1) corticotroph adenomas of the pituitary are theoretically more likely to escape control with medical therapy than CS due to ectopic ACTH production. This is thought to be due to reduced negative feedback from falling serum cortisol levels resulting in greater ACTH drive, sufficient to overcome pharmacological blockade of cortisol production; (2) the misleading results from an HDDST test. There is thus no indication for a HDDST, which should be abolished.