Glucosyl hesperidin benefits in primary biliary cholangitis: a multicenter, open-label, randomized controlled study

INTRODUCTION: Primary biliary cholangitis (PBC) has steadily increased in incidence, but its causes remain to be completely elucidated. Moreover, the potential for disease progression is not uncommon, especially when normalization of hepatobiliary enzyme levels is difficult, making the emergence of new treatments highly anticipated. We clarified the therapeutic effects of glucosyl hesperidin (G-Hes), which activates the antioxidant NRF2/KEAP1 pathway, on improving PBC pathophysiology. METHODS: This randomized controlled trial evaluated changes in serum levels of hepatobiliary enzymes, lipids, and heme oxygenase 1, which is an NRF2/KEAP1 pathway target gene protein, after G-Hes administration (500 or 1,000 mg/day) for 24 weeks in 71 patients on maintenance therapy for PBC. RESULTS: Gamma glutamyl transferase (GGT) at week 24, the primary endpoint of this study, decreased significantly by 6.2% only in the high dose group. Among the secondary endpoints, alkaline phosphatase (ALP) increased plausibly due to g-Hes-induced bone metabolism enhancement and bilirubin decreased, both reaching significance only in the standard dose group. There were no significant changes in transaminases in either group. On subgroup analyses of patients with abnormal baseline biochemical levels, significant decrease in GGT at weeks 24 (6.4%) still remained only in the high-dose group. On the other hand, there was no significant change in ALP at any time point in both groups. The blood protein concentration of heme oxygenase 1 increased by 4.8% at week 24, although not significant. There were no G-Hes-related adverse events. DISCUSSION: Inclusion of G-Hes to existing treatment safely provided additional therapeutic effects in patients with PBC. CLINICAL TRIAL REGISTRY WEBSITE AND TRIAL NUMBER: The study was registered at the Japan Registry of Clinical Trials (https://jrct.mhlw.go.jp/en-top) as jRCTs051210210 on Mar.30 2022.