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Objective Persistent hepatocellular secretory failure (PHSF) is a rare syndrome characterized by sustained hyperbilirubinemia despite successful biliary decompression, typically following endoscopic retrograde cholangiopancreatography (ERCP). This study aimed to define the clinical course, biochemical predictors, and outcomes of post-ERCP PHSF.Methods A multicentre retrospective case series was conducted including 35 adult patients with bilirubin levels >10 mg/dL persisting for at least one week after ERCP biliary decompression. Patients with chronic liver disease, hepatotoxic exposure, or hepatic malignancy were excluded. Data on demographics, liver function tests, procedural details, and clinical outcomes were analyzed using regression models to identify predictors of persistent hyperbilirubinemia.Results The cohort had a mean age of 65.2 years, with biliary obstruction primarily due to pancreatic head mass (71.4%) or choledocholithiasis (28.6%). Mean bilirubin decreased significantly from 27.3 mg/dL pre-index ERCP to 21.1 mg/dL before the second ERCP (p = 0.0003). Pre-index bilirubin, alkaline phosphatase, platelet count, and time from symptom onset to ERCP were significant predictors of persistent hyperbilirubinemia. Patients receiving self-expanding metal stents (SEMS) had higher bilirubin levels pre-second ERCP compared to those undergoing duct clearance alone (25.4 vs. 13.2 mg/dL, p = 0.0008). Additional interventions at second ERCP did not significantly improve bilirubin levels or reduce recovery time, underscoring the importance of reviewing our proposed standardized diagnostic and management pathway for PHSF to optimize clinical ( figure 1).Conclusion Based on our findings, we propose a standardized diagnostic and management pathway for PHSF to guide clinical decision-making, particularly to prevent unnecessary repeat ERCPs in patients lacking biochemical improvement within one week after initial biliary decompression. Further research into its pathophysiology and therapeutic options.References Van Dijk R, Kremer AE, Smit W, et al. Characterization and treatment of persistent hepatocellular secretory failure. Liver Int. 2015;35:1478–1488. doi: 10.1111/liv.12603. (This is the foundational paper defining PHSF).Shi M, Sheng L, Lian M, et al. Efficacy and safety of rifampicin in patients with persistent hepatocellular secretory failure. J Gastroenterol Hepatol. 2021;36:3233–3238. doi: 10.1111/jgh.15629.Abstract P19 Figure 1Proposed standardized diagnostic and management pathway for persistent hepatocellular secretory failure (PHSF) following endoscopic retrograde cholangiopancreatography (ERCP)