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BACKGROUND Several studies have explored the association between the use of proton pump inhibitors (PPIs) and the risk of developing hepatic encephalopathy (HE) in patients with advanced liver disease. However, the evidence-based conclusions are controversial. We hypothesized that using PPIs may increase the risk of HE in patients with advanced liver disease. If confirmed, clinicians must strictly adhere to the indications for PPI treatment in this population. AIM To evaluate the pooled risk of HE in patients with advanced liver disease who use PPIs. METHODS Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from the date of database inception through January 8, 2019 to identify comparative studies evaluating the association between PPI use and the risk of HE. Data from the included studies were extracted. The random-effects model was used for pooling risk estimates and the corresponding 95% confidence intervals (CIs). Subgroup and sensitivity analyses were also performed. RESULTS In total, 4342 patients from five case-control studies and 188053 patients from four cohort studies were included in this analysis. In patients with advanced liver disease, PPI use was associated with an elevated risk of developing HE, with significant heterogeneity. The pooled odds ratio for case-control studies was 2.58 (95%CI: 1.68-3.94, I 2 = 72%). The pooled RR for cohort studies was 1.67 (95%CI: 1.30-2.14, I 2 = 67%). The results of the subgroup analyses suggested that the heterogeneity may be the result of differences in the study designs and the definitions of PPI use. The sensitivity and subgroup analyses did not alter our findings. CONCLUSION In patients with advanced liver disease, PPI use is associated with an elevated risk of HE. Future large prospective studies are needed to confirm this association.

BACKGROUNDAcute variceal bleeding is one of the deadliest complications of cirrhosis, with a high risk of in-hospital rebleeding and mortality. Some risk scoring systems to predict clinical outcomes in patients with upper gastrointestinal bleeding have been developed. However, for cirrhotic patients with variceal bleeding, data regarding the predictive value of these prognostic scores in predicting in-hospital outcomes are limited and controversial.AIMTo validate and compare the overall performance of selected prognostic scoring systems for predicting in-hospital outcomes in cirrhotic patients with variceal bleeding.METHODSFrom March 2017 to June 2019, cirrhotic patients with acute variceal bleeding were retrospectively enrolled at the Second Affiliated Hospital of Xi’an Jiaotong University. The clinical Rockall score (CRS), AIMS65 score (AIMS65), Glasgow-Blatchford score (GBS), modified GBS (mGBS), Canada-United Kingdom-Australia score (CANUKA), Child-Turcotte-Pugh score (CTP), model for end-stage liver disease (MELD) and MELD-Na were calculated. The overall performance of these prognostic scoring systems was evaluated.RESULTSA total of 330 cirrhotic patients with variceal bleeding were enrolled; the rates of in-hospital rebleeding and mortality were 20.3% and 10.6%, respectively. For in-hospital rebleeding, the discriminative ability of the CTP and CRS were clinically acceptable, with area under the receiver operating characteristic curves (AUROCs) of 0.717 (0.648-0.787) and 0.716 (0.638-0.793), respectively. The other tested scoring systems had poor discriminative ability (AUROCs < 0.7). For in-hospital mortality, the CRS, CTP, AIMS65, MELD-Na and MELD showed excellent discriminative ability (AUROCs > 0.8). The AUROCs of the mGBS, CANUKA and GBS were relatively small, but clinically acceptable (AUROCs > 0.7). Furthermore, the calibration of all scoring systems was good for either in-hospital rebleeding or death.CONCLUSIONFor cirrhotic patients with variceal bleeding, in-hospital rebleeding and mortality rates remain high. The CTP and CRS can be used clinically to predict in-hospital rebleeding. The performances of the CRS, CTP, AIMS65, MELD-Na and MELD are excellent at predicting in-hospital mortality.

Lysyl‐oxidase‐like 3 (LOXL3) was reported to be essential in epithelial‐mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this study, we explored clinical significance, biological functions, and regulatory mechanisms of LOXL3 in HCC. Our study found that LOXL3 expression was markedly associated with the tumor size and clinical stage of HCC, and it was highly expressed in tumor tissues of metastatic HCC patients. High expression of LOXL3 predicted a poor prognosis of HCC. TGF‐β1 treatment elevated LOXL3 protein expression and cell invasion, and reduced cell apoptosis in HCC cell lines (SMMC‐7721 and Huh‐7), while downregulation of LOXL3 reversed the promotive effects of TGF‐β1 treatment on LOXL3 protein expression and cell invasion, and the inhibitory effect on cell apoptosis. Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin‐specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co‐IP assays. Overexpression of USP4 reversed the inhibitory effect of LOXL3 silence on EMT in HCC cells through deubiquitinating and stabilizing the expression of Snail1. Moreover, LOXL3‐promoted HCC EMT through Wnt/β‐catenin/Snail1 signaling pathway. In vivo study revealed that silence of LOXL3‐inhibited HCC tumor growth. In conclusion, LOXL3 silence inhibited HCC invasion and EMT through Snail1/USP4‐mediated circulation loop and Wnt/β‐catenin signaling pathway.

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