Role of FXR Agonist in Cholestasis Following Live Donor Liver Transplantation: A Randomized Open-Label Trial

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BACKGROUND: Intrahepatic cholestasis is a frequent postoperative issue in living donor liver transplantation (LDLT), typically stemming from causes such as reperfusion-related damage, infections, biliovascular issues, or rejection. Prompt intervention is key to preserving graft viability and promoting long-term recovery. OBJECTIVE: To evaluate the safety and efficacy of obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, versus ursodeoxycholic acid (UDCA) in post-liver transplant patients to ameliorate cholestatic injury and reduce biopsy-proven rejection. METHODOLOGY: In this randomized, open-label trial, adult LDLT recipients received OCA (5 mg/day) or UDCA (300 mg thrice daily) from postoperative day 3 for one year. The primary endpoint was ≥15% reduction in alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) from one-month postoperative baseline assessed at three, six, and 12 months. Secondary outcomes included changes in relevant biochemical tests and molecular parameters like plasma bile acids, transforming growth factor-beta (TGF-β), cytokeratin-18 (CK-18), serum autotaxin, fibroblast growth factor-19 (FGF-19), and bile salt export pump (BSEP), as well as the incidence of rejection, early allograft dysfunction (EAD), biliary complications, mortality, adverse events, and quality of life (QoL). RESULTS: In the interim analysis of 83 patients, more than a 15% reduction in ALP between six and 12 months was observed in a higher proportion of patients in the OCA group (43%) than in the UDCA group (21%) (p=0.036). More than a 15% reduction in GGT between one and three months was observed in 80% of patients in the OCA group compared to 62% in the UDCA group (p=0.062). Plasma bile acids were lower in the OCA group at one month (170 vs. 226 µmol/L; p=0.012). Low-density lipoprotein (LDL)-cholesterol was higher in the OCA group at three (OCA 121 vs UDCA 107, p=0.027) and six months (OCA 130 vs UDCA 117, p=0.043). UDCA therapy resulted in a significantly greater improvement in overall QoL, with higher gains in both total mean and domain scores compared to OCA. No differences were detected in rejection, biliary complications, mortality, or other secondary endpoints. CONCLUSION: OCA led to greater biochemical improvement, while better QoL was achieved with UDCA in LDLT recipients, with a comparable safety profile.

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