MON-413 First Reported Case of Combined High-Dose Mifepristone Therapy and Oral Contraceptive in Inducing Reversible Cholestatic Hepatitis in a Patient with Cushing Disease

Background: Cushing syndrome is predisposed to hepatocellular disease due to increased visceral fat resulting in NAFLD, and direct effects of medical therapy, notably ketoconazole. Mifepristone (MIFE) (a competitive glucocorticoid receptor antagonist) is a CYP3A4 inhibitor, whereas loestrin (an oral contraceptive) is a CYP3A4 substrate. Recently, MIFE has been shown to improve liver enzymes in a patient with NAFLD and cortisol-secreting adrenal adenoma (Ragucci E, et al. Case Rep Endocrinol. 2017). Herein, we present a case of high-dose MIFE with loestrin in inducing cholestatic hepatitis that resolved spontaneously upon drug discontinuation. Case: A 35 year-old woman with Cushing disease (CD) underwent transsphenoidal surgery (TSS) twice (April 2014 and November 2017). Upon re-testing in January 2018, persistent hypercortisolemia was confirmed with 24-hr UFCs x 2 and late-night salivary cortisols x 2 that were > 2 ULN, and nonsuppressed AM cortisol after a 1 mg overnight dexamethasone suppression test. The patient declined pasireotide and ketoconazole due concerns of hyperglycemia and potential liver toxicity, respectively. After her first TSS, she developed secondary hypothyroidism, secondary hypogonadism and DI, and was placed on levothyroxine, loestrin and DDAVP. She agreed to consider MIFE therapy in February 2018. Baseline serum potassium and LFTs were normal, and she was initiated on MIFE 300 mg/d. Her dose was escalated to 600 mg/d in March 2018, 900 mg/d in May 2018, and alternating 900 mg/d and 1200 mg/d in June 2018. Fourteen days after being on alternating high-dose MIFE therapy, the patient presented to the ER with abdominal pains, nausea, vomiting, pruritus, jaundice and dark urine, and abnormal LFTs (hyperbilirubinemia, and mild increases in AST and ALP). She was hospitalized, and ultrasound of her abdomen revealed normal liver architecture, whereas liver biopsy confirmed diffuse canalicular and cytoplasmic bile stasis without zonal predilection consistent with acute drug-induced cholestasis. She had not taken any new medications or supplements after MIFE was initiated. Other causes of liver dysfunction were excluded including normal anti-ANA, anti-Sm and anti-mitochondrial antibodies, and normal viral hepatitis screen. She was treated symptomatically for her pruritus, MIFE and loestrin were discontinued, and she was discharged from hospital after 3 days. Her pruritus resolved and LFTs normalized 5 and 11 weeks, respectively, post-discharge. Conclusion: We report the first case of high-dose MIFE with loestrin in inducing reversible cholestatic hepatitis in CD, which contrasts to the direct hepatocellular toxicity induced by ketoconazole. Our case highlights the importance of knowledge of drugs that behave as CYP3A4 substrates or inhibitors, and close monitoring of LFTs, especially when MIFE dosing is escalated in combination with oral contraceptives.