Fluconazole in the treatment of Cushing’s disease
R Ramli, E Hatfield, J Todd, K Meeran, Imperial College Healthcare NHS Trust
We present a 73-year-old woman with a 15-year history of cyclical Cushing’s on a background of hypertension, COPD, dyslipidaemia, thyroidectomy for multinodular goitre and osteoporosis.
She had remissions of Cushing’s every 2 years to begin with, which settled spontaneously. These episodes were associated with candidiasis, facial swelling, hypokalaemia and hair loss, and were biochemically confirmed on Overnight (ODST) and Low Dose Dexamethasone Suppression tests (LDDST). An MRI Pituitary in 2014 showed slight asymmetry but no evidence of an intrinsic adenoma and MRI Adrenals in 2012 were normal. In 2016, she reported Herpes Zoster infection and recurrent respiratory and gastrointestinal viral illnesses. On clinical examination, her BP was normal (126/86 mmHg) and there were no evidence of bruises, striae or proximal myopathy. Biochemistry showed an afternoon cortisol of 461 nmol/L and ACTH of 45.2 ng/L. She failed to suppress on ODST (9 am cortisol 739 nmol/L) and LDDST (0h Cortisol 516 nmol/L; 48h Cortisol 1402 nmol/L and ACTH 103 ng/L). An interval MRI Pituitary did not show any interval changes. An inferior petrosal sinus sampling (IPSS) was initially planned, but as she continued to be asymptomatic and her ACTH fell to 37 ng/L, the procedure was postponed as she seems to have cycled out.
A year later, she presented to hospital with a fall. She reported worsening myopathy and easy bruising. Biochemical investigations showed hypokalaemia (K 2.8 mmol/L), raised 24-hour urinary cortisol (2052, NR 50-270) and she failed to suppress on ODST (9 am 1321 nmol/L). Results from an IPSS unfortunately were inconclusive. An MRI Pituitary showed no interval changes, and a Ga68 DOTATATE whole body PET CT did not show any evidence of DOTATATE avid lesions. She was commenced on Metyrapone but as she was unable to tolerate higher doses of Metyrapone and continued to have raised cortisol levels (365- 610 nmol/L), Fluconazole was added. She continued to feel unwell, and was readmitted to hospital where Metyrapone was stopped and the dose of Fluconazole was increased to 600 mg tds. Her cortisol levels improved (130-140 nmol/L).
Ketoconazole is more commonly used in management of Cushing’s disease. Fluconazole inhibit cortisol production via inhibition of 17-hydroxylase and 11-beta hydroxylase, and potentially with less risk for hepatotoxicity compared to Ketoconazole. This case illustrates the efficacy of Fluconazole as a medical management in Cushing’s disease.