Kendra D. Conzen

Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis

OBJECTIVE The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival. METHODS A retrospective, single-institution analysis of outcomes in patients submitted to primary adult orthotopic liver transplantation was conducted using data for the period from 1 January 2002 to 31 December 2012. Recipients were divided into six groups by pre-transplant body mass index (BMI), comprising those with BMIs of <18.0 kg/m(2) , 18.0-24.9 kg/m(2) , 25.0-29.9 kg/m(2) , 30.0-35.0 kg/m(2) , 35.1-40.0 kg/m(2) and >40 kg/m(2) , respectively. Pre- and post-transplant parameters were compared. A P-value of <0.05 was considered to indicate statistical significance. Independent predictors of patient and graft survival were determined using multivariate analysis. RESULTS A total of 785 patients met the study inclusion criteria. A BMI of >35 kg/m(2) was associated with non-alcoholic steatohepatitis (NASH) cirrhosis (P < 0.0001), higher Model for End-stage Liver Disease (MELD) score, and longer wait times for transplant (P = 0.002). There were no differences in operative time, intensive care unit or hospital length of stay, or perioperative complications. Graft and patient survival at intervals up to 3 years were similar between groups. Compared with non-obese recipients, recipients with a BMI of >40 kg/m(2) showed significantly reduced 5-year graft (49.0% versus 75.8%; P < 0.02) and patient (51.3% versus 78.8%; P < 0.01) survival. CONCLUSIONS Obesity increasingly impacts outcomes in liver transplantation. Although the present data are limited by the fact that they were sourced from a single institution, they suggest that morbid obesity adversely affects longterm outcomes despite providing similar short-term results. Further analysis is indicated to identify risk factors for poor outcomes in morbidly obese patients.

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 increased susceptibility to cold ischemia/reperfusion (CIR) injury in comparison with 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 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 after liver transplantation into strain‐matched lean recipients. ER stress response components were reduced by the chemical chaperone taurine‐conjugated ursodeoxycholic acid (TUDCA), and this resulted in an improvement in the allograft injury. TUDCA treatment decreased nuclear factor kappa B activation and the proinflammatory cytokines interleukin‐6 and interleukin‐1β. However, the predominant response was decreased expression of the ER stress cell death mediator [CCAAT/enhancer‐binding protein homologous protein (CHOP)]. Furthermore, activation of inflammation‐associated caspase‐11 was decreased, and this linked ER stress/CHOP to proinflammatory cytokine production after 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. Liver Transpl 17:189–200, 2011.

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

BackgroundThe 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.ResultsThe 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.ConclusionDown-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.

Liver Transplant in Patients with Portal Vein Thrombosis: Medical and Surgical Requirements

1. Pretransplant portal vein thrombosis is associated with increased postliver transplant morbidity and mortality. 2. Preoperative imaging with CT and ultrasound is essential to determine extent of portal vein thrombus and to identify a site of mesenteric inflow for the liver allograft. 3. Options for management of PVT in the pretransplant patient include anticoagulation, TIPS, and frequent monitoring with serial imaging studies. 4. Eversion thrombectomy or thrombendvenectomy, with or without ligation of spontaneous portosystemic shunts, may be used to re-establish portal venous flow during liver transplant in patients with PVT. 5. In patients with cavernous transformation of the portal vein or occlusive PVT involving the splenic-SMV confluence, venous inflow to the liver allograft can be established through a pericholedochal varix or enlarged coronary vein, SMV-PV jump graft, renoportal anastomosis, or cavoportal hemitransposition.