Predictors of patient survival following liver transplant in non-alcoholic steatohepatitis: A systematic review and meta-analysis.

Background: Non-alcoholic steatohepatitis (NASH) is the second-leading indication for liver transplantation (LT) worldwide and is projected to become the leading indication. Our study aimed to determine clinical variables that predict post-LT survival in NASH. Methods: A systematic review and meta-analysis was performed. On June 18, 2020 and April 28, 2022, Ovid MEDLINE ALL, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were searched. No date limits were applied. Inclusion criteria specified the type of study and our study's population/comparison and outcome/timepoints. Pediatric, animal, retransplantation-only, and studies classifying cryptogenic cirrhosis patients with body mass index (BMI) <30 as NASH were excluded. Studies with duplicate cohorts and missing information were excluded from the meta-analysis. Studies were appraised using the Newcastle-Ottawa Scale. This study was preregistered in PROSPERO (CRD42020196915). Findings: Out of 8583 studies identified, 25 studies were included in the systematic review, while 5 studies were included in the meta-analysis. Our quantitative review suggested that the following variables were predictive of post-LT NASH patient survival: recipient age, functional status, pre-LT hepatoma, model for end-stage liver disease (MELD) score, diabetes mellitus (DM), pre-LT dialysis, hepatic encephalopathy, portal vein thrombosis, hospitalization/ICU at LT, and year of LT. Predictors of graft survival included recipient age, BMI, pre-LT dialysis, and DM. Our pooled meta-analyses included five predictors of patient survival. Increased patient mortality was associated with older recipient age (HR=2·07, 95%CI: 1·71-2·50, I2=0, τ2=0, p=0·40) and pretransplant DM (HR=1·18, 95%CI: 1·08-1·28, I2=0, τ2=0, p=0·76). Interpretation: Our systematic review and meta-analysis aimed to synthesise predictive variables of mortality in LT NASH patients. Clinically, this might help to identify modifiable risk factors that can be optimized in the post-transplant setting to improve patient outcomes and optimises decision making in the resource-limited LT setting. Funding: Toronto General and Western Hospital Foundation.

Impaired Wnt/ß-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by acute intestinal injury. Intestinal stem cell (ISC) renewal is required for gut regeneration in response to acute injury. The Wnt/ß-catenin pathway is essential for intestinal renewal and ISC maintenance. We found that ISC expression, Wnt activity and intestinal regeneration were all decreased in both mice with experimental NEC and in infants with acute active NEC. Moreover, intestinal organoids derived from NEC-injured intestine of both mice and humans failed to maintain proliferation and presented more differentiation. Administration of Wnt7b reversed these changes and promoted growth of intestinal organoids. Additionally, administration of exogenous Wnt7b rescued intestinal injury, restored ISC, and reestablished intestinal epithelial homeostasis in mice with NEC. Our findings demonstrate that during NEC, Wnt/ß-catenin signaling is decreased, ISC activity is impaired, and intestinal regeneration is defective. Administration of Wnt resulted in the maintenance of intestinal epithelial homeostasis and avoidance of NEC intestinal injury.

Influence of stress factors on intestinal epithelial injury and regeneration.

PURPOSE: Lgr5+ intestinal epithelial stem cells (ISCs) crucial for intestinal epithelial regeneration are impaired during necrotizing enterocolitis. This study aims to investigate the influence of different stressors on intestinal epithelial injury and regeneration in vitro. METHODS: Intestinal epithelial cells (IEC-18) were exposed to stressors such as lipopolysaccharide, hydrogen peroxide, and serum. Cell viability was assessed using MTT assay at 18 and 24 h. IL-6 and Lgr5 gene expressions were measured using qPCR. RESULTS: IEC-18 cell viability decreased 18 h following administration of lipopolysaccharide, hydrogen peroxide, and low serum concentration. However, after 24 h, the decrease in cell viability was observed only in higher, but not in lower concentrations of lipopolysaccharide and hydrogen peroxide. IL-6 expression increased in all groups compared to control. Lgr5 expression was up-regulated in cells exposed to a single stressor, but down-regulated when multiple stressors were administered. CONCLUSION: Lipopolysaccharide, hydrogen peroxide, or low serum induced IEC-18 injury. The upregulation of Lgr5 expression after exposure to a single stressor suggests that minor injury to IEC-18 induces Lgr5+ ISCs to stimulate repair. Conversely, when IEC-18 cells were exposed to multiple stressors, Lgr5 expression was reduced. We speculate that this finding is similar to what happens in NEC when multiple stressors cause impairment of intestinal epithelium regeneration.