Prevalence and clinical characteristics of advanced portal vein thrombosis in cirrhotic patients with gastroesophageal variceal hemorrhage.

OBJECTIVES: Portal venous thrombosis (PVT) in cirrhotic patients is usually asymptomatic and diagnosed incidentally. In this study we aimed to investigate the prevalence and characteristics of advanced PVT in cirrhotic patients with a recent episode of gastroesophageal variceal hemorrhage (GVH). METHODS: Cirrhotic patients with recent GVH at one month before their admission for further treatment to prevent rebleeding were retrospectively recruited. Hepatic venous pressure gradient (HVPG) measurements, contrast-enhanced computed tomography (CT) scan of the portal vein system, and endoscopy were performed. PVT was diagnosed by CT examination and classified as none, mild and advanced. RESULTS: Of the 356 patients enrolled, 80 (22.5%) had advanced PVT. Elevated levels of white blood cells (WBC) and serum D-dimer were observed in advanced PVT patients compared with those with no or mild PVT. Moreover, HVPG was lower in patients with advanced PVT, with fewer patients having HVPG exceeding 12 mmHg, while grade III esophageal varices and varices with red signs were more prevalent. Multivariate analysis showed that WBC count (odds ratio [OR] 1.401, 95% confidence interval [CI] 1.171-1.676, P < 0.001), D-dimer level (OR 1.228, 95% CI 1.117-1.361, P < 0.001), HVPG (OR 0.942, 95% CI 0.900-0.987, P = 0.011), and grade III esophageal varices (OR 4.243, 95% CI 1.420-12.684, P = 0.010) were associated with advanced PVT. CONCLUSIONS: Advanced PVT, which is associated with a more severe hypercoagulable and inflammatory status, causes severe prehepatic portal hypertension in cirrhotic patients with GVH.

Risk factors associated with failure of endoscopic combined treatment to prevent varices rebleeding in patients with liver cirrhosis.

BACKGROUND: The aim of this study is to investigate risk factors associated with gastroesophageal variceal rebleeding after endoscopic combined treatment. RESEARCH DESIGN AND METHODS: Patients who had liver cirrhosis and underwent endoscopic treatment to prevent variceal rebleeding were retrospectively recruited. Hepatic venous pressure gradient (HVPG) measurement and CT examination of portal vein system were performed before endoscopic treatment. Endoscopic obturation for gastric varices and ligation for esophageal varices were performed simultaneously at the first treatment. RESULTS: One hundred and sixty-five patients were enrolled, and after the first endoscopic treatment, recurrent hemorrhage occurred in 39 patients (23.6%) during 1-year follow-up. Compared to the non-rebleeding group, HVPG was significantly higher (18 mmHg vs.14 mmHg, P = 0.024) and more patients had HVPG exceeding 18 mmHg (51.3% vs.31.0%, P = 0.021) in the rebleeding group. No significant difference was found in other clinical and laboratory data between two groups (P > 0.05 for all). By a logistic regression analysis, high HVPG was the only risk factor associated with failure of endoscopic combined therapy (OR = 1.071, 95%CI, 1.005-1.141, P = 0.035). CONCLUSIONS: The poor efficacy of endoscopic treatment to prevent variceal rebleeding was associated with high HVPG. Therefore, other therapeutic options should be considered for the rebleeding patients with high HVPG.

Prognostic importance of interleukin 2 receptor for patients with a history of cirrhotic variceal bleeding.

OBJECTIVES: Variceal hemorrhage is a fatal complication of cirrhosis. In this study, we aimed to investigate the role of serum interleukin 2 receptor (sIL-2R) as a predictive indicator in patients with a previous history of cirrhosis-related variceal bleeding. METHODS: A total of 340 cirrhotic patients who had experienced variceal bleeding from December 2016 to December 2018 were enrolled, and were randomly assigned to the modeling group and the validation group. The 3-year variceal rebleeding rate and other outcomes including adverse events were analyzed between patients with different sIL-2R levels. RESULTS: A time-dependent receiver operating characteristic (ROC) curve of variceal rebleeding indicated that sIL-2R had an area under the ROC curve (AUROC] of 0.731 and 0.837 for the modeling and validation groups, respectively, with a cut-off value of 426 U/mL. Kaplan-Meier analysis showed that higher sIL-2R level was related to an increased risk of variceal rebleeding rate (55.33% vs 24.34%, P = 0.024 and 51.28% vs 15.32%, P = 0.049) and decreased 3-year survival rate (91.16% vs 98.92%, P = 0.013 and 90.52% vs 97.50%, P = 0.180) in the modeling and validation groups. Elevated sIL-2R levels were associated with an increased risk of portal vein thrombosis and severe ascites as well as inferior liver function, hypercoagulable state, and increased portal pressure. CONCLUSION: High sIL-2R levels were associated with poor prognosis in cirrhotic patients with previous variceal bleeding.

Practice patterns in endoscopic treatment for gastric varices: A Chinese survey.

OBJECTIVES: Gastric varices (GV), a common complication of liver cirrhosis, often cause serious consequences. However, the management of GV remains debated. In this study we aimed to explore the practice patterns of Chinese practitioners in GV treatment and discuss whether these patterns conform to the guidelines in China and around the world. METHODS: Between October 2020 and January 2021, an online questionnaire was sent to doctors from different regions in China via WeChat. Data on the practice patterns for endoscopic treatment with and without a multidisciplinary discussion team (MDT) clinic for GV were analyzed. RESULTS: Questionnaires were collected from 241 practitioners from 29 provinces in China. Before endoscopic treatment, 100 (41.5%) of the practitioners arranged computed tomography angiography (CTA) examination. In endoscopic tissue adhesive (ETA) treatment, 183 (75.9%) of the practitioners chose ETA combined with lauromacrogol. Approximately one-fourth of all practitioners did not prescribe drugs to reduce portal pressure. Only 75 (31.1%) of physicians preferred using early transjugular intrahepatic portosystemic shunt (TIPS) for patients at a high risk of treatment failure for GV. Compared to those without MDT clinics, practitioners with MDT clinics more often chose early TIPS for high-risk patients (39.0% vs 18.9%, P = 0.001). CONCLUSIONS: Treatment for GV differ across China. Practitioners with MDT clinics can better use assistant strategies such as CTA to evaluate the risk and efficacy. Further clinical studies are needed, and more guidelines and consensuses are warranted to standardize clinical practice for GV.

Effects of dietary nucleotides on growth performance, immune response, intestinal morphology and disease resistance of juvenile largemouth bass, Micropterus salmoides.

An 8 week feeding trial was carried out to investigate the effects of dietary nucleotides on growth performance, intestinal morphology, immune response and disease resistance of juvenile largemouth bass, Micropterus salmoides. Five grades of dietary nucleotide levels were designed as 0, 0.2, 0.4, 0.8 and 1.2 g kg-1 , respectively. Each group had 3 replicates, with 40 fish in each replicate. After the feeding experiment, 15 fish from each tank were infected with Aeromonas hydrophila for 14 days. The results indicated that fish fed the diets containing 0.4, 0.8 and 1.2 g kg-1 nucleotides had higher growth performance and feed utilization than those fed the control diet. Nonetheless, there were no significant differences in survival between all the groups, although fish fed the diets with all-level nucleotides obtained higher survival than those fed the control diet. Dietary nucleotides significantly affected the superoxide dismutase, acid phosphatase and catalase activities in serum but not the malondialdehyde content. Fish fed the 0.4 g kg-1 nucleotide diets had the highest fold height, enterocyte height and muscular layer thickness significantly. The average mortality of largemouth bass infected with A. hydrophila was significantly influenced by dietary nucleotides. The mortality was significantly higher in the control group (91.11%) and 0.02% nucleotide group (73.11%) followed by the other groups and lowest in the 0.8 g kg-1 nucleotide group. In summary, dietary 0.4-0.8 g kg-1 nucleotides promoted growth performance, enhanced immunity and improved intestinal morphology and disease resistance of largemouth bass.

A magnetic resonance imaging modality for non-invasively distinguishing progression of liver fibrosis by visualizing hepatic platelet-derived growth factor receptor-beta expression in mice.

BACKGROUND AND AIM: Activated hepatic stellate cells (HSCs) are the most critical cells responsible for liver fibrosis, and platelet-derived growth factor (PDGF) is the most prominent mitogen for HSCs in fibrogenesis. This study aimed to explore the potential of gadolinium (Gd)-labeled cyclic peptides (pPB) targeting PDGF receptor-ß (PDGFR-ß) as a magnetic resonance imaging (MRI) radiotracer to identify the progression of liver fibrosis by imaging hepatic PDGFR-ß expression. METHODS: Mice treated with carbon tetrachloride (CCl4 ) were used to mimic hepatic fibrosis in vivo. The binding activity of FITC-labeled pPB to PDGFR-ß was assessed in cultured human HSCs (HSC-LX2). MRI was performed to visualize hepatic PDGFR-ß expression in mice with different degrees of liver fibrosis after Gd-labeled pPB was injected. RESULTS: Hepatic PDGFR-ß expression level was correlated with the severity of liver fibrosis, and the majority of cells expressing PDGFR-ß were found to be activated HSCs in fibrotic livers. Culture-activated human HSCs expressed abundant PDGFR-ß, and FITC-labeled pPB could bind to these cells in a concentration-dependent and time-dependent manner. With Gd-labeled pPB as a tracer, an MRI modality demonstrated that the relative hepatic T1-weighted MRI signal value progressively increased with the severity of hepatic fibrosis and reduced with remission. CONCLUSIONS: Hepatic PDGFR-ß expression reflects the progression of hepatic fibrosis, and MRI using Gd-labeled pPB as a tracer exhibits potential for distinguishing liver fibrosis staging in mice.

Increased portal vein diameter is predictive of portal vein thrombosis development in patients with liver cirrhosis.

BACKGROUND: Cirrhotic patients with portal vein thrombosis (PVT) may have a high risk of hepatic decompensation and increased mortality. This study aimed to investigate if increased portal vein diameter is associated with PVT development. METHODS: A total of 174 cirrhotic patients were enrolled between February 1 and August 31, 2017. All participants were divided into PVT (n=62) and non-PVT (n=112) groups based on the thrombus that was detected by ultrasonography and confirmed by computed tomography angiography (CTA). RESULTS: The study participants, aged 54.7±10.5 years (PVT) and 55.8±11.6 years (non-PVT), were included in this analysis. The Child-Pugh score of PVT or non-PVT was 6.6±1.3 and 5.8±0.9, respectively. Hepatitis B virus (HBV) is the primary etiological agent of cirrhosis. Logistic regression, receiver operating characteristic (ROC), and nomograph analysis designated portal diameter as the strongest independent risk factor for predicting PVT development [odds ratio (OR): 3.96, area under the ROC curve (AUC): 0.88; P<0.01], and the cutoff with predictive value for PVT development was >12.5 mm. No differences were observed in the overall survival (OS) in cirrhosis with or without PVT or stratifying on portal diameter based on the cutoff value. CONCLUSIONS: Increased portal diameter is associated with an increased risk of PVT development. Patients with cirrhosis and increased portal diameter are a high-risk subgroup that may need thromboprophylaxis.

LncRNA TUG1 regulates autophagy-mediated endothelial-mesenchymal transition of liver sinusoidal endothelial cells by sponging miR-142-3p.

Accumulating evidence indicates that competing endogenous RNA networks play a critical role in cirrhosis progression. However, their biological role and regulatory mechanisms in liver sinusoidal endothelial cells (LSECs) have not been explored. Here, we exposed LSECs to starvation and lipopolysaccharide (LPS) treatment and assessed changes in TUG1 and miR-142-3p expression, autophagy, and endothelial-mesenchymal transition (EndMT). We confirmed the effects of targeted binding between miR-142-3p and TUG1 or ATG5 by luciferase activity and radio-immunoprecipitation assay. Using an in vivo rat model of cirrhosis, we evaluated autophagy and EndMT in LSECs by immunofluorescence co-localization and immunohistochemical staining. The diagnostic efficiency of miR-142-3p and LPS were determined by receiver-operating characteristic curve analysis. We found that LSECs survived starvation by activating autophagy. LPS treatment enhanced autophagy and promoted EndMT of LSECs by upregulating TUG1. Our rat model of cirrhosis confirmed that serum LPS level, autophagy, and EndMT were increased in LSECs. TUG1 was highly expressed in LSECs, and TUG1 knockdown suppressed ATG5-mediated autophagy and EndMT of LSECs. TUG1 regulated ATG5 via shared miR-142-3p response elements. miR-142-3p was expressed at low levels in LSECs and negatively regulated autophagy and EndMT by reducing ATG5 expression. Our results suggest that TUG1 promotes LPS-induced autophagy and EndMT of LSECs by functioning as an endogenous sponge for miR-142-3p and promoting the expression of ATG5. LPS and miR-142-3p are potential diagnostic and therapeutic targets in cirrhosis.

Candidate lncRNA-miRNA-mRNA network in predicting hepatocarcinogenesis with cirrhosis: an integrated bioinformatics analysis.

PURPOSE: This study aimed to explore the potential competing endogenous RNA (ceRNA) network in forecasting HCC development in patients with cirrhosis through a comprehensive bioinformatic analysis. METHODS: Data mining from GEO and TCGA databases was employed to dig a spectrum of differentially expressed mRNA, lncRNA and miRNA profiles. Their expression was confirmed by RT-PCR in matched HCC cohorts (n = 6/group). The ceRNA network was constructed by co-expression analysis. Their reciprocal regulations and their roles in epithelial-to-mesenchymal transition (EMT) process were validated by gain- and loss-of-function experiments at the cellular level. Kaplan-Meier method was applied to reveal prognostic values. RESULTS: By intersecting differentially expressed genes (DEGs) in GEO and TCGA data sets and Pearson correlation analysis, 20 mRNAs, 24 miRNAs and 41 lncRNAs were identified. Of these, FOXD2-AS1, BLVRA and CYTH2 were markedly upregulated in HCC tissues and HCC cells with high metastatic potential (MHCC97H) compared with their adjacent normal/cirrhotic tissues and L02 and MHCC97L cells. However, dysregulated miR-139-5p exhibited the opposite expression pattern. Using miRanda algorithms, FOXD2-AS1, BLVRA and CYTH2 showed potential binding sites for miR-139-5p. FOXD2-AS1 knockdown induced a marked increase in miR-139-5p and EMT inhibition. The loss of miR-139-5p led to an increase in BLVRA and CYTH2 expression and EMT process. Conversely, miR-139-5p overexpression suppressed BLVRA and CYTH expression and EMT process. FOXD2-AS1, miR-139-5p, BLVRA and CYTH2 highly correlated with prognosis in patients with HCC. CONCLUSION: FOXD2-AS1/miR-139-5p/BLVRA or CYTH2 axis might be the underlying molecular mechanism that dissects HCC development caused by cirrhosis.

Balloon-occluded Retrograde Transvenous Obliteration of Portovenous Shunts During Endoscopic Therapy for the Treatment of Gastric Varices.

INTRODUCTION: To explore the safety and feasibility of balloon-occluded retrograde transvenous obliteration (BRTO) of portovenous shunts during endoscopic cyanoacrylate injection for the treatment gastric varices (E-BRTO) secondary to portal hypertension. PATIENTS AND METHODS: A total of 28 cirrhotic patients with gastroesophageal varices and concurrent gastrorenal or gastrosplenorenal shunt, treated with E-BRTO, were enrolled. Operative details were recorded to evaluate the safety, feasibility, and efficacy of the procedure. Short-term follow-up was conducted to denote any incidence of distant emboli, variceal rebleeding, or mortality (Video, Supplemental Digital Content 1, http://links.lww.com/SLE/A179). RESULTS: All the patients successfully received E-BRTO without intraoperative complications. The average volume of cyanoacrylate was 2.4±1.3 mL. During the 90 days follow-up, none of the patients experienced distant systemic emboli. However, 8 patients suffered from gastrointestinal rebleeding, including one death, while 2 patients were lost to follow-up. The short-term rebleeding rate (intention to treat) was about 36% in E-BRTO for this subset of patients. CONCLUSIONS: BRTO during endoscopic cyanoacrylate injection is an alternative selection for cirrhotic patients with portovenous shunts. The procedure is feasible and procedurally safe, but the associated high rebleeding rate may require a multimodality approach.

Long-term efficacy of endoscopic ligation plus cyanoacrylate injection with or without sclerotherapy for variceal bleeding.

OBJECTIVE: This study aimed to evaluate the long-term outcomes and efficacy of continued ligation plus cyanoacrylate injection compared with those of combined ligation and sclerotherapy plus cyanoacrylate injection for secondary prophylaxis of variceal bleeding in cirrhotic patients with concomitant esophageal and gastric varices. METHODS: Medical records of the patients who were admitted for variceal bleeding due to liver cirrhosis were retrospectively reviewed and their related data was collected. The patients were divided into two groups, including the continued ligation plus cyanoacrylate injection group [the sclerotherapy (-) group] and the combined ligation and sclerotherapy plus cyanoacrylate injection group [the sclerotherapy (+) group]. The Kaplan-Meier survival analysis was conducted and log-rank test was used to compare the differences between the two groups. RESULTS: Altogether 125 patients were enrolled between 1 April 2004 and 31 December 2012. After a median follow-up of 23.4 months, no significant difference was observed between the two groups in regard to variceal rebleeding (29.7% vs 47.5%, P = 0.097) and mortality (12.5% vs 14.8%, P = 0.879). Among patients with ascites the cumulative rebleeding rate was significantly lower in the sclerotherapy (-) group (26.3% vs 59.4%, P = 0.020). A relapse of bleeding after the initial endoscopic therapy was an independent prognostic factor of rebleeding (P = 0.004). Portal thrombosis was an independent prognostic factor for mortality (P = 0.044). CONCLUSION: No superiority of combined ligation and sclerotherapy compared with continued ligation and cyanoacrylate injection for secondary prophylaxis of variceal bleeding is observed.