The role of molecular chaperonins in warm ischemia and reperfusion injury in the steatotic liver: A proteomic study

BACKGROUND: The molecular basis of the increased susceptibility of steatotic livers to warm ischemia/reperfusion (I/R) injury during transplantation remains undefined. Animal model for warm I/R injury was induced in obese Zucker rats. Lean Zucker rats provided controls. Two dimensional differential gel electrophoresis was performed with liver protein extracts. Protein features with significant abundance ratios (p < 0.01) between the two cohorts were selected and analyzed with HPLC/MS. Proteins were identified by Uniprot database. Interactive protein networks were generated using Ingenuity Pathway Analysis and GRANITE software. RESULTS: The relative abundance of 105 proteins was observed in warm I/R injury. Functional grouping revealed four categories of importance: molecular chaperones/endoplasmic reticulum (ER) stress, oxidative stress, metabolism, and cell structure. Hypoxia up-regulated 1, calcium binding protein 1, calreticulin, heat shock protein (HSP) 60, HSP-90, and protein disulfide isomerase 3 were chaperonins significantly (p < 0.01) down-regulated and only one chaperonin, HSP-1was significantly upregulated in steatotic liver following I/R. CONCLUSION: Down-regulation of the chaperones identified in this analysis may contribute to the increased ER stress and, consequently, apoptosis and necrosis. This study provides an initial platform for future investigation of the role of chaperones and therapeutic targets for increasing the viability of steatotic liver allografts

Dabigatran Reversal With Idarucizumab in 2 Patients With Portal Vein Thrombosis Undergoing Orthotopic Liver Transplantation

There are limited data to guide the use of anticoagulation in cirrhotic patients prior to liver transplantation especially when using direct oral anticoagulants. In this article, we present 2 cases. The first is a 42-year-old male with cirrhosis complicated by portal vein thrombosis (PVT) treated with dabigatran who underwent orthotopic liver transplantation without complication. The second case is a 65-year-old man with alcoholic cirrhosis complicated by PVT treated with dabigatran who underwent orthotopic liver transplantation and required reoperation for surgical bleeding. Both patients were treated with dabigatran’s reversal agent idarucizumab prior to incision. In this case series, we discuss the treatment of cirrhotic patients with various anticoagulants, considerations for anticoagulant selection and reversal prior to liver transplant, and questions for future investigation. </jats:p

Novel three-dimensional imaging technique improves the accuracy of hepatic volumetric assessment

AbstractBackgroundWith pre-operative prediction of liver volume becoming increasingly important to safely carry out complex hepatic resections, the aim of the present study was to validate the accuracy of a three-dimensional (3-D) liver surgery operative planning software in performing hepatic volumetry.MethodsBetween 1999 and 2007, we performed 29 live donor liver resections for transplantation. Eleven patients had pre-operative volumetry performed by radiologists from either computed tomography (CT) or magnetic resonance (MR) imaging with documentation of the corresponding specimen weight. Retrospectively, images were uploaded into Scout™ where 3-D models of each case were generated to perform volumetry. A correlational analysis was performed followed by an accuracy comparison.ResultsEstimations by both radiologists and Scout™ were significantly correlated with the specimen weights, P≤ 0.0001. Compared with radiologists' volumetry, Scout™ significantly improved overall accuracy [per cent error (PE) 20.0% ± 5.3 vs. 32.9% ± 5.7, P= 0.005], accuracy of CT-based estimations (PE 23.2% ± 6.7 vs. 37.2% ± 6.9, P= 0.023) and accuracy of the left lateral section (PE 11.1% ± 3.9 vs. 26.6% ± 6.8, P= 0.027).DiscussionThis 3-D planning software is a valid tool for use in volumetry. Significance is greatest for CT-based models of the left lateral section. This approach gives surgeons the ability to assess volumetrics and actively plan resections

Management of excluded bile ducts in paediatric orthotopic liver transplant recipients of technical variant allografts

AbstractBackgroundA strategy to increase the number of size- and weight-appropriate organs and decrease the paediatric waiting list mortality is wider application of sectional orthotopic liver transplantation (OLT). These technical variants consist of living donor, deceased donor reduced and split allografts. However, these grafts have an increased risk of biliary complications. An unusual and complex biliary complication which can lead to graft loss is inadvertent exclusion of a major segmental bile duct. We present four cases and describe an algorithm to correct these complications.MethodsA retrospective review of the paediatric orthotopic liver transplantation database (2000–2010) at Washington University in St. Louis/St. Louis Children's Hospital was conducted.ResultsSixty-eight patients (55%) received technical variant allografts. Four complications of excluded segmental bile ducts were identified. Percutaneous cholangiography provided diagnostic confirmation and stabilization with external biliary drainage. All patients required interval surgical revision of their hepaticojejunostomy for definitive drainage. Indwelling biliary stents aided intra-operative localization of the excluded ducts. All allografts were salvaged.DiscussionAggressive diagnosis, percutaneous decompression and interval revision hepaticojejunostomy are the main tenets of management of an excluded bile duct. Careful revision hepaticojejunostomy over a percutaneous biliary stent can result in restoration of biliary continuity and allograft survival

Endoplasmic reticulum stress is a mediator of posttransplant injury in severely steatotic liver allografts

Hepatic steatosis continues to present a major challenge in liver transplantation. These organs have been shown to have an increased susceptibility to cold ischemia and reperfusion (CIR) injury compared to otherwise comparable lean livers; the mechanisms governing this increased susceptibility to CIR injury are not fully understood. Endoplasmic reticulum (ER) stress is an important link between hepatic steatosis, insulin resistance and the metabolic syndrome. In this study, we investigated ER stress signaling and blockade in the mediation of CIR injury in severely steatotic rodent allografts. Steatotic allografts from genetically leptin-resistant rodents had increased ER stress responses and increased markers of hepatocellular injury following liver transplantation into strain-matched lean recipients. ER stress response components were decreased by the chemical chaperone, TUDCA, resulting in improvement of the allograft injury. TUDCA treatment decreased NF-κB activation, and the pro-inflammatory cytokines IL-6 and IL-1β. However, the predominant response was decreased expression of the ER stress cell death mediator, CHOP. Further, activation of the inflammation-associated caspase 11 was decreased linking ER Stress/CHOP to pro-inflammatory cytokine production following steatotic liver transplantation. These data confirm ER stress in steatotic allografts, and implicate this as a mediating mechanism of inflammation and hepatocyte death in the steatotic liver allograft