Adjunct Fenofibrate Up-regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis.

Abstract

Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator-activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up-regulate BA-glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n\xa0=\xa032) and primary sclerosing cholangitis (PSC, n\xa0=\xa023), who experienced an incomplete response while receiving ursodiol monotherapy (13-15\xa0mg/kg/day), defined as serum alkaline phosphatase (ALP)\xa0≥\xa01.5 times the upper limit of normal, received additional fenofibrate (145-160\xa0mg/day) as standard of care. Serum BA and BA-glucuronide concentrations were measured by liquid chromatography-mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (-76%, P\xa0<\xa00.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (-54%), and increased serum BA-glucuronides (+2.1-fold, P\xa0<\xa00.01) versus ursodiol monotherapy. The major serum BA-glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid-6G (+3.7-fold, P\xa0<\xa00.01), hyocholic acid-6G (+2.6-fold, P\xa0<\xa00.05), chenodeoxycholic acid (CDCA)-3G (-36%), and lithocholic acid (LCA)-3G (-42%) versus ursodiol monotherapy. Fenofibrate also up-regulated the expression of uridine 5 -diphospho-glucuronosyltransferases and multidrug resistance-associated protein 3 messenger RNA in primary human hepatocytes. Pearson s correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA-3G (r2 \xa0=\xa00.62, P\xa0<\xa00.0001), deoxycholic acid (DCA)-3G (r2 \xa0=\xa00.48, P\xa0<\xa00.0001), and LCA-3G (r2 \xa0=\xa00.40, P\xa0<\xa00.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA-glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA-glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα-mediated anti-cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA-glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.