The value of gadobenate dimeglumine-enhanced biliary imaging from the hepatobiliary phase for predicting post-hepatectomy liver failure in HCC patients.

OBJECTIVES: To determine the value of gadobenate dimeglumine-enhanced biliary imaging from the hepatobiliary phase for predicting post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). METHODS: Patients with HCC who underwent gadobenate dimeglumine-enhanced hepatobiliary magnetic resonance imaging prior to hepatectomy were collected in two centers. The relative enhancement ratio of the biliary system (REB) and the liver to muscle ratio (LMR) were measured at the hepatobiliary phase. Potential risk factors for PHLF were analyzed by logistic regression. The capacity of the REB and LMR to predict PHLF was analyzed via receiver operating characteristic curve. RESULTS: Of the 221 patients, post-hepatectomy liver failure occurred in 60 patients (27.1%). The REB was an independent risk factor for PHLF (odds ratio [OR] = 0.127 [0.047-0.348], p < 0.001). Although the LMR tended to be associated with PHLF (p = 0.063), it was not an independent risk factor in the multivariable analysis (OR = 0.624 [0.023-16.709], p = 0.779). Moreover, the area under the receiver operating characteristic curve of the REB and LMR was 0.87 and 0.60. The most appropriate cutoff value for the REB was 2.21. The HCC patients with the REB ≤ 2.21 had a higher incidence of post-hepatectomy liver failure than those with the REB > 2.21 (60.0% versus 8.5%, p < 0.001). CONCLUSIONS: Gadobenate dimeglumine-enhanced biliary imaging from the hepatobiliary phase was valuable in predicting post-hepatectomy liver failure in HCC patients. KEY POINTS: • The relative enhancement ratio of the biliary system (REB) was an independent risk factor for post-hepatectomy liver failure in HCC patients. • HCC patients with the REB ≤ 2.21 had significantly higher incidence of post-hepatectomy liver failure than those with the REB > 2.21 (60.0% versus 8.5%).

CT-Based Radiomics Score Can Accurately Predict Esophageal Variceal Rebleeding in Cirrhotic Patients.

Purpose: This study aimed to develop a radiomics score (Rad-score) extracted from liver and spleen CT images in cirrhotic patients to predict the probability of esophageal variceal rebleeding. Methods: In total, 173 cirrhotic patients were enrolled in this retrospective study. A total of 2,264 radiomics features of the liver and spleen were extracted from CT images. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select features and generate the Rad-score. Then, the Rad-score was evaluated by the concordance index (C-index), calibration curves, and decision curve analysis (DCA). Kaplan-Meier analysis was used to assess the risk stratification ability of the Rad-score. Results: Rad-scoreLiver, Rad-scoreSpleen, and Rad-scoreLiver-Spleen were independent risk factors for EV rebleeding. The Rad-scoreLiver-Spleen, which consisted of ten features, showed good discriminative performance, with C-indexes of 0.853 [95% confidence interval (CI), 0.776-0.904] and 0.822 (95% CI, 0.749-0.875) in the training and validation cohorts, respectively. The calibration curve showed that the predicted probability of rebleeding was very close to the actual probability. DCA verified the usefulness of the Rad-scoreLiver-Spleen in clinical practice. The Rad-scoreLiver-Spleen showed good performance in stratifying patients into high-, intermediate- and low-risk groups in both the training and validation cohorts. The C-index of the Rad-scoreLiver-Spleen in the hepatitis B virus (HBV) cohort was higher than that in the non-HBV cohort. Conclusion: The radiomics score extracted from liver and spleen CT images can predict the risk of esophageal variceal rebleeding and stratify cirrhotic patients accordingly.

Carvedilol attenuates carbon tetrachloride-induced liver fibrosis and hepatic sinusoidal capillarization in mice.

AIM: To investigate the effect of carvedilol on liver fibrosis and hepatic sinusoidal capillarization in mice with carbon tetrachloride (CCl4)-induced fibrosis. METHODS: A liver fibrosis mouse model was induced by intraperitoneal CCl4 injection for 8 weeks. The mice were divided into five experimental groups: the normal group, the oil group, the CCl4 group, the CCl4+carvedilol (5 mg/kg/d) group, and the CCl4+carvedilol (10 mg/kg/d) group. The extent of liver fibrosis was evaluated by histopathological staining, and the changes in fenestrations of hepatic sinus endothelial cells were observed by scanning electron microscope (SEM). The expression of α-smooth muscle actin (α-SMA) and vascular endothelial markers was detected by immunohistochemistry and Western blot assays. The effect of carvedilol on cell apoptosis was studied via Terminal deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL) assay, and the serum levels of matrix metalloproteinase-8 (MMP-8), vascular endothelial growth factor (VEGF), and angiopoietin-2 were detected through a Luminex assay. RESULTS: Liver fibrosis in CCl4-treated mice was attenuated by reduced accumulation of collagen and the reaction of inflammation with carvedilol treatment. Carvedilol reduced the activation of hepatic stellate cells (HSCs) and increased the number of apoptotic cells. The expression of α-SMA, CD31, CD34 and VWF (von Willebrand factor) was significantly decreased after carvedilol treatment. In addition, the number of fenestrae in the hepatic sinusoid showed notable differences between the groups, and the serum levels of MMP-8, VEGF and angiopoietin-2 were increased in the mice with liver fibrosis and reduced by carvedilol treatment. CONCLUSION: The study demonstrated that carvedilol could prevent further development of liver fibrosis and hepatic sinusoidal capillarization in mice with CCl4-induced fibrosis.

Carvedilol improves liver cirrhosis in rats by inhibiting hepatic stellate cell activation, proliferation, invasion and collagen synthesis.

Portal hypertension (PHT) is one of the most severe consequences of liver cirrhosis. Carvedilol is a first­line pharmacological treatment of PHT. However, the antifibrogenic effects of carvedilol on liver cirrhosis and the intrinsic mechanisms underlying these effects have not been thoroughly investigated. The present study aimed to investigate the antifibrogenic effects of carvedilol on liver cirrhosis in vivo and in vitro. Liver cirrhosis was induced in rats by carbon tetrachloride (CCl4) administration for 9 weeks; carvedilol was administered simultaneously in the experimental group. Blood samples were collected for serum biochemistry. Liver tissues were used for fibrosis evaluation, histological examination, immunohistochemistry and western blot analysis. The human hepatic stellate cell (HSC) line LX­2 was used for in vitro studies. The effects of carvedilol on LX­2 cell proliferation and invasion were evaluated by Cell Counting Kit­8 assay and Transwell invasion assays, respectively. The effect of carvedilol on transforming growth factor ß1 (TGFß1)­induced collagen synthesis in LX­2 cells and the molecular mechanisms were examined by western blot analysis. The results demonstrated that carvedilol improved CCl4­induced structural distortion and fibrosis in the liver. Carvedilol inhibited HSC activation, proliferation and invasion. Carvedilol inhibited HSC collagen synthesis through the TGFß1/SMAD pathway. In conclusion, carvedilol may alleviate liver cirrhosis in rats by inhibiting HSC activation, proliferation, invasion and collagen synthesis. Carvedilol may be a potential treatment of early­stage liver cirrhosis.

Balloon-Assisted Percutaneous Transhepatic Antegrade Embolization with 2-Octyl Cyanoacrylate for the Treatment of Isolated Gastric Varices with Large Gastrorenal Shunts.

AIMS: To evaluate the safety and effectiveness of percutaneous transhepatic antegrade embolization (PTAE) with 2-octyl cyanoacrylate assisted with balloon occlusion of the left renal vein or gastrorenal shunts (GRSs) for the treatment of isolated gastric varices (IGVs) with large GRSs. METHODS: Thirty patients with IGVs associated with large GRSs who had underwent PTAE assisted with a balloon to block the opening of the GRS in the left renal vein were retrospectively evaluated and followed up. Clinical and laboratory data were collected to evaluate the technical success of the procedure, complications, changes in the liver function using Child-Pugh scores, worsening of the esophageal varices, the rebleeding rate, and survival. Laboratory data obtained before and after PTAE were compared (paired-sample t-test). RESULTS: PTAE was technically successful in all 30 patients. No serious complications were observed except for one nonsymptomatic pulmonary embolism. During a mean follow-up of 30 months, rebleeding was observed in 4/30 (13.3%) patients, worsening of esophageal varices was observed in 4/30 (13.3%) patients, and newly developed or aggravated ascites were observed on CT in 3/30 (10%) patients. Significant improvement was observed in Child-Pugh scores (p=0.009) and the international normalized ratio (INR) (p=0.004) at 3 months after PTAE. The cumulative survival rates at 1, 2, 3, and 5 years were 96.3%, 96.3%, 79.9%, and 79.9%, respectively. CONCLUSION: Balloon-assisted PTAE with 2-octyl cyanoacrylate is technically feasible, safe, and effective for the treatment of IGV associated with a large GRS.

Carvedilol Ameliorates Intrahepatic Angiogenesis, Sinusoidal Remodeling and Portal Pressure in Cirrhotic Rats.

BACKGROUND Carvedilol is the first-line drug for the primary prophylaxis of variceal bleeding due to portal hypertension (PHT) in liver cirrhosis. This study aimed to investigate the effects of carvedilol on intrahepatic angiogenesis and sinusoidal remodeling in cirrhotic rats and explore the underlying mechanisms of carvedilol in PHT. MATERIAL AND METHODS For in vivo experiments, carbon tetrachloride was used to induce liver cirrhosis in rats, and carvedilol was simultaneously administered by gavage. The portal pressure was measured in rats, and liver tissues were examined by immunohistochemistry. Sinusoidal remodeling was observed by transmission electron microscopy. For in vitro experiments, the effects of carvedilol on fibronectin (FN) synthesis in human umbilical vein endothelial cells (HUVECs) were explored by quantitative real-time polymerase chain reaction and western blot analysis. RESULTS Portal vein pressure measurements showed that carvedilol reduced portal pressure in cirrhotic rats. Immunohistochemistry assays indicated that carvedilol ameliorated intrahepatic angiogenesis. Transmission electron microscopy examination demonstrated that carvedilol improved sinusoidal remodeling. In the in vitro experiments, carvedilol suppressed transforming growth factor ß1 (TGFß1)-induced FN synthesis in HUVECs by inhibition of the TGFß1/Smads pathway. CONCLUSIONS Carvedilol ameliorated intrahepatic angiogenesis, sinusoidal remodeling and portal pressure in cirrhotic rats. Carvedilol improved sinusoidal remodeling by suppressing FN synthesis in endothelial cells. Carvedilol has potential utility for treating early-stage liver cirrhosis.

Carvedilol attenuates liver fibrosis by suppressing autophagy and promoting apoptosis in hepatic stellate cells.

Carvedilol has been identified as a promising agent for the treatment of liver fibrosis. Meanwhile, autophagy and apoptosis have been reported to play key roles in the activation of hepatic stellate cells (HSCs), which can contribute to the progression of liver fibrosis. However, the effects of carvedilol on autophagy and apoptosis in HSCs remain unclear. Our study aimed to detect these effects and identify the underlying mechanisms by which carvedilol mediates HSC autophagy and apoptosis. For this purpose, the LX-2 cell line was used in this study, and the cells were exposed to various concentrations of carvedilol for specific times. First, we found that carvedilol increased autophagic marker levels, the number of GFP-LC3-containing puncta and LC3B-II levels in LX-2 cells. Interestingly, the addition of chloroquine (CQ) failed to enhance the effects on GFP-LC3 puncta and LC3B-II levels, and carvedilol treatment resulted in a significant increase in p62 protein levels. Moreover, carvedilol treatment led to the accumulation of yellow dots only in GFP-RFP-LC3-LX-2 cells, similar to the results following CQ treatment, indicating that carvedilol inhibited autophagic flux. Next, we found evidence that carvedilol inhibited autophagic flux by increasing lysosomal pH and not by impairing the fusion of autophagosomes with lysosomes. Moreover, carvedilol substantially reduced the viability of LX-2 cells and noticeably induced cell apoptosis, as observed by flow cytometry. In addition, increased levels of cleaved caspase-3, cleaved caspase-8 and cleaved PARP, increased Bax activity and decreased Bcl-2 expression were detected in LX-2 cells. Finally, the carvedilol treatment inhibited autophagy and subsequently induced apoptosis in vitro. In conclusion, carvedilol suppresses autophagy and promotes apoptosis in HSCs and the late-stage inhibition of autophagy preceded the induction of apoptosis.

Metformin attenuates motility, contraction, and fibrogenic response of hepatic stellate cells in vivo and in vitro by activating AMP-activated protein kinase.

AIM: To investigate the effect of metformin on activated hepatic stellate cells (HSCs) and the possible signaling pathways involved. METHODS: A fibrotic mouse model was generated by intraperitoneal injection of carbon tetrachloride (CCl4) and subsequent treatment with or without metformin. The level of fibrosis was detected by hematoxylin-eosin staining, Sirius Red staining, and immunohistochemistry. The HSC cell line LX-2 was used for in vitro studies. The effect of metformin on cell proliferation (CCK8 assay), motility (scratch test and Transwell assay), contraction (collagen gel contraction assay), extracellular matrix (ECM) secretion (Western blot), and angiogenesis (ELISA and tube formation assay) was investigated. We also analyzed the possible signaling pathways involved by Western blot analysis. RESULTS: Mice developed marked liver fibrosis after intraperitoneal injection with CCl4 for 6 wk. Metformin decreased the activation of HSCs, reduced the deposition of ECM, and inhibited angiogenesis in CCl4-treated mice. Platelet-derived growth factor (PDGF) promoted the fibrogenic response of HSCs in vitro, while metformin inhibited the activation, proliferation, migration, and contraction of HSCs, and reduced the secretion of ECM. Metformin decreased the expression of vascular endothelial growth factor (VEGF) in HSCs through inhibition of hypoxia inducible factor (HIF)-1α in both PDGF-BB treatment and hypoxic conditions, and it down-regulated VEGF secretion by HSCs and inhibited HSC-based angiogenesis in hypoxic conditions in vitro. The inhibitory effects of metformin on activated HSCs were mediated by inhibiting the Akt/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) pathways via the activation of adenosine monophosphate-activated protein kinase (AMPK). CONCLUSION: Metformin attenuates the fibrogenic response of HSCs in vivo and in vitro, and may therefore be useful for the treatment of chronic liver diseases.