Work

Effects of hypothermic oxygenated machine perfusion on bile composition after liver transplantation – Findings from a randomized controlled trial

Year: 2025

Type: article

Abstract: Background In liver transplantation, bile acid (BA) toxicity contributes to injury of both hepatocytes and cholangiocytes. While hypothermic oxygenated machine perfusion (HOPE) reduces ischemia–reperfusion injury (IRI) and improves clinical outcomes, its impact on bile composition remains unclear due to the lack of bile samples available after LT. Methods Bile, blood and liver tissue were collected within a multicentric randomized controlled trial (NCT03124641), from 26 patients receiving extended criteria donation (ECD) allografts from donors after brain death (DBD). Fourteen donor livers were static cold stored (SCS group), while 12 livers underwent end-ischemic HOPE. Grafts were randomly assigned. BA levels and metabolic parameters were analyzed across samples with mass spectrometry. Expression of bile transporters and enzymes was assessed in liver biopsies before and after transplantation. Results Serum and biliary levels of hydrophobic BAs were positively correlated with IRI severity, such as serum AST and ALT, and decreased across postoperative days (POD) for all allografts (Bile: POD-1 vs. POD-2/-3, p<0.001; Blood: Admission vs. POD-1–3, p<0.001). Expression of the hepatocyte bile transporters ABCB4 and ABCG8 decreased post-reperfusion (p=0.045; p<0.001). In the SCS group, intrahepatic BA levels increased post-reperfusion (8.71 to 10.77 pmol/mg, p0.023), while biliary BA levels decreased postoperatively (POD-1 vs POD-3, p0.06). The HOPE-group showed higher biliary BA and phosphatidylcholine (PC) levels on POD-3 compared to the SCS-group (Total BAs: 2.30 × 10 9 vs. 2.03×10 9 Peak area [PA], p0.047; PC: 6.49 × 10 8 vs. 4.48 × 10 8 PA, p0.031), and a decline in biliary BA/PC ratio. Conclusion This is the first randomized study demonstrating effects of HOPE treatment on bile composition following ECD-DBD liver transplantation. Protection from bile acid toxicity may represent a novel mechanism underlying the effects of HOPE. Clinical trial number NCT03124641 IMPACT AND IMPLICATIONS Worldwide liver allograft scarcity has led to the implementation of hypothermic oxygenated machine perfusion (HOPE) to enhance the safety of liver transplantation (LT) using extended criteria donors. However, its protective mechanisms remain incompletely understood, largely due to limited human data. In this study, we provide evidence that HOPE improves biliary lipid secretion after LT, limits intrahepatic bile acid accumulation upon allograft reperfusion, reduces biliary bile-acid-to-phosphatidylcholine ratio and promotes normalization of serum bile acids levels post LT. Our findings suggest that protection from bile acid toxicity may constitute a novel mechanism underlying the effects of HOPE.

Source: JHEP Reports

DOI: 10.1016/j.jhepr.2025.101647