Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50 mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.

Efficacy of TIPS plus extrahepatic collateral embolisation in real-world data: a validation study.

OBJECTIVES: The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) plus extrahepatic collateral embolisation (TIPS+E) in reducing rebleeding and hepatic encephalopathy (HE) post-TIPS was recently reported in a meta-analysis, but further validation is essential. This study aims to confirm the effectiveness of TIPS+E using real-world data. METHODS: The multicentre retrospective cohort included 2077 patients with cirrhosis who underwent TIPS±E (TIPS: 631, TIPS+E: 1446) between January 2010 and December 2022. Regression and propensity score matching (PSM) were used to adjust for baseline characteristic differences. After PSM, clinical outcomes, including rebleeding, HE, survival and further decompensation (FDC), were analysed. Baseline data from all patients contributed to the construction of prognostic models. RESULTS: After PSM, 1136 matched patients (TIPS+E: TIPS=568:568) were included. TIPS+E demonstrated a significant reduction in rebleeding (HR 0.77; 95% CI 0.59 to 0.99; p=0.04), HE (HR 0.82; 95% CI 0.68 to 0.99; p=0.04) and FDC (HR 0.85; 95% CI 0.73 to 0.99; p=0.04), comparing to TIPS. Significantly, TIPS+E also reduced rebleeding, HE and FDC in subgroup of using 8 mm diameter stents and embolising of gastric varices+spontaneous portosystemic shunts (GV+SPSS). However, there were no differences in overall or subgroup survival analysis. Additionally, the random forest models showed higher accuracy and AUROC comparing to other models. Controlling post-TIPS portal pressure gradient (pPPG) within 7 mm Hg

Chinese guideline for the diagnosis and treatment of drug-induced liver injury: an update.

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, and antineoplastic drugs), and signal of DILI in clinical trials and its assessment.

Senescence of Hepatic Stellate Cells by Specific Delivery of Manganese for Limiting Liver Fibrosis.

Senescence of activated hepatic stellate cells (HSCs) is crucial for the regression of liver fibrosis. However, impaired immune clearance can result in the accumulation of senescent HSCs, exacerbating liver fibrosis. The activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for both senescence and the innate immune response. Additionally, the specific delivery to activated HSCs is hindered by their inaccessible anatomical location, capillarization of liver sinusoidal endothelial cells (LSECs), and loss of substance exchange. Herein, we propose an antifibrotic strategy that combines prosenescence with enhanced immune clearance through targeted delivery of manganese (a cGAS-STING stimulator) via albumin-mediated transcytosis, specifically aimed at inducing senescence and eliminating activated HSCs in liver fibrosis. Our findings demonstrate that only albumin efficiently transfers manganese to activated HSCs from LSECs via transcytosis compared to liposomes, resulting in significant antifibrotic effects in vivo while exhibiting negligible toxicity.

Development and validation of a prognostic score to identify the optimal candidate for preemptive TIPS in patients with cirrhosis and acute variceal bleeding.

BACKGROUND AND AIM: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining "high-risk" have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. APPROACH AND RESULTS: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). CONCLUSIONS: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.

Primary Budd-Chiari syndrome versus sinusoidal obstruction syndrome: a review.

Budd-Chiari syndrome (BCS) and sinusoidal obstruction syndrome (SOS) are two major vascular disorders of the liver, of which both can cause portal hypertension related complications, but their locations of obstruction are different. BCS refers to the obstruction from the hepatic vein to the junction between the inferior vena cava and right atrium, which is the major etiology of post-sinusoidal portal hypertension; by comparison, SOS is characterized as the obstruction at the level of hepatic sinusoids and terminal venulae, which is a cause of sinusoidal portal hypertension. Both of them can cause hepatic congestion with life-threatening complications, especially acute liver failure and chronic portal hypertension, and share some similar features in terms of imaging and clinical presentations, but they have heterogeneous risk factors, management strategy, and prognosis. Herein, this paper reviews the current evidence and then summarizes the difference between primary BCS and SOS in terms of risk factors, clinical features, diagnosis, and treatment.

Protective and Adverse Roles of DDX3X in Different Cell Types in Nonalcoholic Steatohepatitis Progression.

Persistent hepatic cellular metabolic stress and liver inflammatory stimuli are key signatures of nonalcoholic steatohepatitis (NASH). DDX3X is a vital molecule involved in cell fate decisions in both pro-survival stress granule (SG) and pro-death NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly in response to stress signals. However, the role of DDX3X in NASH remains unclear. We characterized the cell type-specific roles of DDX3X in NASH. Human liver tissues from NASH patients and normal control subjects were collected to assess DDX3X expression and distribution. Nutritional steatohepatitis models were constructed by feeding macrophage-specific DDX3X knockout (DDX3XΔMφ), hepatocyte-specific DDX3X knockout (DDX3XΔhep), and wild-type control (DDX3Xfl/fl) mice a high-fat and high-cholesterol (HFHC) diet, a methionine- and choline-deficient (MCD) diet, and a high-fat/high-iron/high-fructose/high-cholesterol, low-methionine, and choline-deficient (HFHIHFHC-MCD) diet. The study demonstrated that DDX3X was predominantly expressed in macrophages and hepatocytes in control liver tissues, and its expression was down-regulated in patients or mice with NASH. Compared to DDX3Xfl/fl littermates, DDX3XΔMφ mice showed improved liver histology in nutritional steatohepatitis models. Loss of macrophage DDX3X inhibited NLRP3 inflammasome-mediated pyroptosis, causing anti-inflammatory M2 polarization and alleviating hepatocyte steatohepatitic changes. DDX3XΔhep mice developed marked steatohepatitis in multiple nutritional steatohepatitis models compared to DDX3Xfl/fl littermates. DDX3X-deleted hepatocytes showed impaired SG assembly, leading to increased sensitivity and intolerance to metabolic stimulation and resultant steatohepatitis. In conclusion, DDX3X plays opposite roles in different cell types during the progression of NASH. A better understanding of the cell-specific differences in the crosstalk between SG formation and NLRP3 activation is crucial for developing prospective targeted DDX3X inhibitors for the treatment of NASH.

Histological evaluation of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: Correlation with Drum Tower Severity Scoring.

BACKGROUND: Hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids (PA-HSOS) is a complication of drug-induced liver damage. Few studies have examined the relationship between pathological changes and clinical circumstances in PA-HSOS. The Drum Tower Severity Scoring System (DTSS) was developed using prognostic indicators from clinical treatment outcomes. We hypothesized that the severity of pathological damage is consistent with DTSS. AIMS: We aimed to improve our understanding and assessment of vascular liver injury disease histopathology by studying larger sample sizes of human histopathological samples. We also wanted to confirm the link between histopathological findings and DTSS. METHODS: The study included 62 patients with PA-HSOS who underwent transjugular liver biopsy. Their hepatic pathological tissues were evaluated. Analyses of linear regression and Spearman's correlation were employed to examine the relationship between DTSS and pathological characteristics. RESULTS: Clinical performance and the DTSS score were used to determine histopathological severity. The sinusoidal congestion area (SCA), central venous endothelial injury (CVEI), and fibrinoid exudation in congestion foci (FECF) were significant indicators. SCA was linearly related to the DTSS score. CONCLUSION: Our findings show that hepatic pathological characteristics correlate with DTSS scores in PA-HSOS. SCA, CVEI, and FECF may be helpful for determining PA-HSOS severity.

Safety and Effectiveness of a Novel Tips Access Set with Steerable Cannula in a Swine Model.

PURPOSE: This study aimed to assess the safety, effectiveness, and feasibility of the Liverty™ transjugular intrahepatic portosystemic shunt (TIPS) access set, which has an ergonomic handle that allows for in situ cannula tip deflection and a distal steerable cannula angle, versus the COOK® Rosch-Uchida Transjugular Liver Access Set (RUPS-100) in healthy pigs. METHODS: Twelve pigs randomly underwent TIPS with the Liverty™ set or the RUPS-100 set. Three interventionalists performed 4 TIPS procedures, 2 with each set. The primary outcome was procedural success, defined as successful establishment of the intrahepatic portosystemic shunt and stent placement. RESULTS: The shunt was successfully established in 11 pigs. The procedural success was achieved in all 6 pigs in the Liverty™ group and 5 out of 6 pigs for the RUPS-100 group (Fisher exact test, P > 0.999). The mean duration of puncture was shorter in the Liverty™ group versus the RUPS-100 group (12.3 ± 4.5 min vs. 16.2 ± 8.5 min), but without significant statistical difference (two sample t test, P = 0.359). The cannula angle was adjusted 69% of passes in the Liverty™ group, which was significantly higher than that in the RUPS-100 group (12%, P = 0.004). Overall, the TIPS procedural performance was comparable between the groups. Both sets were safe. No intraabdominal hemorrhage, vascular injuries, tissue or organ injuries, porto-biliary fistula, biliary peritonitis, and infection or abscess occurred in either group. CONCLUSION: The Liverty™ set is safe and has similar procedural metrics to the COOK® RUPS-100 set. It allows in situ adjustment of the angle of the stiffening cannula without increasing procedure time and lessens the occurrences of periprocedural complications.

Association of nonmalignant portal vein thrombosis and clinical outcomes in patients with cirrhosis and acute variceal bleeding: a multicenter observational study.

BACKGROUND AND AIM: Baveno VII workshop recommends management of acute variceal bleeding (AVB) in cirrhotic patients with nonmalignant portal vein thrombosis (PVT) should be performed according to the guidelines for patients without PVT. Nevertheless, whether PVT affects the outcome of patients with cirrhosis and AVB remains unclear. The aim of this study was to assess the clinical impact of PVT on the outcomes in the pre-emptive TIPSS eligible patients with cirrhosis and AVB. METHODS: From December 2010 to June 2016, 1219 consecutive cirrhotic patients admitted due to AVB with (n = 151; 12.4%) or without PVT (n = 1068; 87.6%), who received drug plus endoscopic treatment (a combination of vasoactive drugs, antibiotics, and endoscopic ligation for AVB, followed by beta-blockers plus variceal ligation for prevention of rebleeding) were retrospectively included. Fine and Gray competing risk regression models were taken to evaluate the impact of PVT on clinical outcomes after adjusting for potential confounders. RESULTS: During follow-up, 211 patients (17.3%) died, 490 (40.2%) experienced further bleeding, and 78 (6.4%) experienced new or worsening ascites within 1 year. Compared with those without PVT, patients with PVT had a similar risk of mortality (PVT vs no-PVT: 19.9% vs 16.7% at 1 year; adjusted HR 0.88, 95%CI 0.51-1.52, p = 0.653), further bleeding (47.0% vs 39.2% at 1 year, adjusted HR 1.19, 95% CI 0.92-1.53, p = 183), and new or worsening ascites (7.9% vs 9.6%, adjusted HR 0.70, 95% CI 0.39-1.28, p = 0.253) after adjusting for confounders in multivariable models. These findings were consistent across different relevant subgroups and confirmed by propensity score matching analysis. CONCLUSIONS: Our study showed no evidence that the PVT was associated with an improved or worsened outcome among cirrhotic patients with AVB who received standard treatment.

Hepatic Venous Occlusion Type of Budd-Chiari Syndrome versus Pyrrolizidine Alkaloid-Induced Hepatic Sinusoidal Obstructive Syndrome: A Multi-Center Retrospective Study.

(1) Background: Hepatic venous occlusion type of Budd-Chiari syndrome (BCS-HV) and pyrrolizidine alkaloid-induced hepatic sinusoidal obstructive syndrome (PA-HSOS), share similar clinical features, and imaging findings, leading to misdiagnoses; (2) Methods: We retrospectively analyzed 139 patients with BCS-HV and 257 with PA-HSOS admitted to six university-affiliated hospitals. We contrasted the two groups by clinical manifestations, laboratory tests, and imaging features for the most valuable distinguishing indicators.; (3) Results: The mean patient age in BCS-HV is younger than that in PA-HSOS (p < 0.05). In BCS-HV, the prevalence of hepatic vein collateral circulation of hepatic veins, enlarged caudate lobe of the liver, and early liver enhancement nodules were 73.90%, 47.70%, and 8.46%, respectively; none of the PA-HSOS patients exhibited these features (p < 0.05). DUS showed that 86.29% (107/124) of patients with BCS-HV showed occlusion of the hepatic vein, while CT or MRI showed that only 4.55%(5/110) patients had this manifestation (p < 0.001). Collateral circulation of hepatic veins was visible in 70.97% (88/124) of BCS-HV patients on DUS, while only 4.55% (5/110) were visible on CT or MRI (p < 0.001); (4) Conclusions: In addition to an established history of PA-containing plant exposure, local hepatic vein stenosis and the presence of collateral circulation of hepatic veins are the most important differential imaging features of these two diseases. However, these important imaging features may be missed by enhanced CT or MRI, leading to an incorrect diagnosis.

Overweight/Obesity Increases the Risk of Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt in Cirrhotic Patients.

The purpose of this study was to investigate the effect of body mass index (BMI) on the prevalence of overt hepatic encephalopathy (OHE) after the transjugular intrahepatic portosystemic shunt (TIPS) procedure in decompensated cirrhotic patients. A retrospective observational cohort study of 145 cirrhotic patients receiving TIPS was carried out in our department from 2017 to 2020. The relationships between BMI and clinical outcomes including OHE, as well as risk factors of developing post-TIPS OHE, were analyzed. BMI was categorized as normal weight (18.5 ≤ BMI < 23.0 kg/m2), underweight (BMI < 18.5 kg/m2), and overweight/obese (BMI ≥ 23.0 kg/m2). Among the 145 patients, 52 (35.9%) were overweight/obese and 50 (34%) had post-TIPS OHE. Overweight/obese patients more frequently had OHE compared with normal weight patients (OR: 2.754, 95% CI: 1.236-6.140; p = 0.013). Overweight/obesity (p = 0.013) and older age (p = 0.030) were independent risk factors for post-TIPS OHE according to the logistic regression analysis. Kaplan-Meier curve analysis suggested that overweight/obese patients had the highest cumulative incidence of OHE (log-rank p = 0.0118). In conclusion, overweight/obesity and older age may raise the risk of post-TIPS OHE in cirrhotic patients.

Individualized portal pressure gradient threshold based on liver function categories in preventing rebleeding after TIPS.

BACKGROUND: The evidence in Portal pressure gradient (PPG) < 12 mmHg after transjugular intrahepatic portosystemic shunt (TIPS) for preventing rebleeding mostly comes from observations in uncovered stents era. Moreover, association between Child-Pugh classes and post-TIPS hepatic encephalopathy (HE) has indicated that tolerance of PPG reduction depends on liver function. This study aimed to investigate the optimal PPG for covered TIPS and explore the optimal threshold tailored to the Child-Pugh classes to find individualized PPG to balance rebleeding and overt HE. METHODS: This multicenter retrospective study analyzed rebleeding, OHE, and mortality of patients associated with post-TIPS PPGs (8, 10, 12, and 14 mmHg) in the entire cohort and among different Child-Pugh classes. Propensity score matching (PSM) and competing risk analyses were performed for sensitivity analyses. RESULTS: We included 2100 consecutively screened patients undergoing TIPS. In all patients, PPG < 12 mmHg reduced rebleeding after TIPS (p = 0.022). In Child-Pugh class A, none of the PPG thresholds were discriminative of clinical outcomes. In Child-Pugh class B, 12 mmHg (p = 0.022) and 14 mmHg (p = 0.037) discriminated rebleeding, but 12 mmHg showed a higher net benefit. In Child-Pugh class C, PPG < 14 mmHg had a lower rebleeding incidence (p = 0.017), and exhibited more net benefit than 12 mmHg. CONCLUSION: Different PPG standards may be required for patients with different liver function categories. A PPG threshold < 12 mmHg might be suitable for patients in Child-Pugh class B, while < 14 mmHg might be optimal for patients in Child-Pugh class C.

Liver stiffness-spleen diameter to platelet ratio score (LSPS model) predicts variceal rebleeding for cirrhotic patients.

PURPOSE: The liver stiffness- spleen diameter to platelet ratio score (LSPS model) can identify a high risk of decompensated events in cirrhotic patients. We aimed to evaluate the value of the LSPS model as a risk stratification strategy in the secondary prevention for cirrhotic patients with esophageal and gastric variceal bleeding (EGVB). METHODS: Consecutive EGVB patients who underwent liver stiffness measurement by acoustic radiation force impulse, platelet count and ultrasonography were enrolled between January 2013 and December 2019. We calculated the LSPS of all patients and followed up for over 2 years. The primary outcome was rebleeding. Transplant-free survival and overt hepatic encephalopathy (OHE) were the secondary outcomes. RESULTS: A total of 131 patients were analyzed. The median value of the LSPS model is 0.1879. We developed risk stratification based on the LSPS model and divided the patients into two groups: the high-LSPS (LSPS > 0.1879) group and the low-LSPS (LSPS ≤ 0.1879) group. Sixty-two (47.33%) patients suffered rebleeding, in which there were 21 (31.92%) patients with low LSPS and 41 (63.08%) patients with high LSPS (hazard ratio 2.883; 95% confidence interval, 1.723-4.822, P < 0.001). For the whole cohort, the rates of transplant-free survival and OHE were consistently similar between the two groups at 2 years. CONCLUSION: The LSPS is a reliable, noninvasive method for the detection of a high risk of rebleeding for the secondary prevention of EGVB.

Gamma-glutamyl transferase to high-density lipoprotein cholesterol ratio has a non-linear association with non-alcoholic fatty liver disease: A secondary prospective cohort study in non-obese Chinese adults.

Objective: The evidence for a relationship between the ratio of gamma-glutamyl transferase (GGT) to high-density lipoprotein cholesterol (HDL-c) and non-alcoholic fatty liver disease (NAFLD) is currently inadequate. This study aimed to investigate the relationship between the GGT/HDL-c ratio and NAFLD. Materials and methods: This study is a prospective cohort study that recruited a total of 11,891 non-obese volunteers in a Chinese hospital from January 2010 to December 2014 in a non-selective manner. The Cox proportional-hazards regression model was then used to investigate the relationship between baseline GGT/HDL-c ratio and the probability of developing NAFLD. The non-linear link between the GGT/HDL-c ratio and NAFLD was identified using a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (cubic spline smoothing). Furthermore, we conducted several sensitivity and subgroup analyses. Data had been uploaded to the DATADRYAD website. Results: The mean age of study participants was 43.29 ± 14.95 years old, and 6,502 (54.68%) were male. The median (interquartile ranges) of GGT/HDL-c ratio was 15.56 (10.73-23.84). During a median follow-up of 29.35 months, 2028 (17.05%) participants were diagnosed with NAFLD. After adjusting for covariates, the results showed that GGT/HDL-c ratio was positively associated with incident NAFLD (HR = 1.014, 95% CI 1.011-1.017). There was also a non-linear relationship between GGT/HDL-c ratio and NAFLD, and the inflection point of the GGT/HDL-c ratio was 20.35. The effect sizes (HR) on the left and right sides of the inflection point were 1.113 (95% CI 1.096, 1.130) and 1.003 (95% CI 1.000-1.007), respectively. Moreover, the sensitivity analysis demonstrated the robustness of our results. Subgroup analysis showed that GGT/HDL-c ratio was more strongly associated with incident NAFLD in triglyceride (TG) < 1.7 mmol/L participants. In contrast, the weaker association was probed in those with TG ≥ 1.7 mmol/L. Conclusion: The present study reveals a positive and non-linear relationship between the GGT/HDL-c ratio and NAFLD risk in a non-obese Chinese population. GGT/HDL-c ratio is strongly associated with NAFLD when GGT/HDL-c ratio is less than 20.35. Therefore, maintaining the GGT/HDL-c ratio lower than the inflection point is recommended from a treatment perspective.

CLIF-C AD score predicts survival benefit from pre-emptive TIPS in individuals with Child-Pugh B cirrhosis and acute variceal bleeding.

Background & Aims: Among individuals with Child-Pugh B cirrhosis and acute variceal bleeding (AVB), the Baveno VII workshop recommended pre-emptive TIPS in those with a Child-Pugh score of 8-9 and active bleeding at initial endoscopy (Child B8-9 + AB criteria). Nevertheless, whether this criterion is superior to the CLIF-Consortium acute decompensation score (CLIF-C ADs) remains unclear. Methods: Data on 1,021 consecutive individuals with Child-Pugh B cirrhosis and AVB from 13 university hospitals in China who were treated with pre-emptive TIPS (n = 297) or drug plus endoscopic treatment (n = 724) between 2010 to 2019 were retrospectively analysed. A competing risk regression model was used to compare the outcomes between the two groups after adjusting for confounders. The concordance-statistic for benefit (c-for-benefit) was used to evaluate a models' ability to predict treatment benefit (risk difference between treatment groups). Results: Pre-emptive TIPS was associated with reduced mortality compared to drug plus endoscopic treatment (adjusted hazard ratio 0.62, 95% CI 0.44 to 0.88). A higher baseline CLIF-C AD score was associated with greater survival benefit (i.e., larger absolute mortality risk reduction). After adjusting for confounders, a survival benefit was observed in individuals with CLIF-C ADs ≥48 or Child-Pugh B8-9 with active bleeding, but not in those with CILF-C ADs <48, no active bleeding or Child-Pugh B7 with active bleeding. The c-for-benefit of CILF-C ADs for predicting survival benefit was higher than that of Child B8-9+AB criteria. Conclusions: In individuals with Child-Pugh B cirrhosis and AVB, CLIF-C ADs predicts survival benefit from pre-emptive TIPS and outperforms the Child B8-9+AB criteria. Prospective validation should be performed to confirm this result, especially for other aetiologies of cirrhosis. Impact and implications: In this study, among individuals with Child-Pugh B cirrhosis and acute variceal bleeding, the CLIF-Consortium acute decompensation (CLIF-C AD) score could predict the survival benefit from pre-emptive TIPS, with patients with higher CLIF-C AD scores benefiting more from pre-emptive TIPS. Furthermore, the CLIF-C AD score outperformed the Child B8-9 plus active bleeding criteria in terms of discriminating between those who obtained more benefit vs. less benefit from pre-emptive TIPS. Depending on prospective validation, the CLIF-C AD score could be used as the model of choice to determine who should undergo pre-emptive TIPS.

Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis.

Glutamine metabolism plays an essential role in cell growth, and glutamate dehydrogenase (GDH) is a key enzyme. GDH promotes the metabolism of glutamate and glutamine to generate ATP, which is profoundly increased in multiple human cancers. Through in vitro and in vivo experiments, we verified that the small-molecule GDH inhibitor EGCG slowed the progression of fibrosis by inhibiting GDH enzyme activity and glutamine metabolism. SIRT4 is a mitochondrial enzyme with NAD that promotes ADP ribosylation and downregulates GDH activity. The role of SIRT4 in liver fibrosis and the related mechanisms are unknown. In this study, we measured the expression of SIRT4 and found that it was downregulated in liver fibrosis. Modest overexpression of SIRT4 protected the liver from fibrosis by inhibiting the transformation of glutamate to 2-ketoglutaric acid (α-KG) in the tricarboxylic acid cycle (TCA), thereby reducing the proliferative activity of hepatic stellate cells (HSCs). Collectively, our study reveals that SIRT4 controls GDH enzyme activity and expression, targeting glutamine metabolism in HSCs and alleviating liver fibrosis.

Characteristics of myeloproliferative neoplasm-associated portal hypertension and endoscopic management of variceal bleeding.

Background: Myeloproliferative neoplasms (MPNs) are a rare yet important clinical cause of portal hypertension, which may cause recurrent gastroesophageal variceal bleeding (GVB). MPN-associated variceal bleeding lacks specific guidelines and clinical consensus and desiderates cohort studies. We performed a multicenter retrospective study to investigate the efficacy of endoscopic management of bleeding in MPNs. Methods: We included consecutive MPN patients with gastroesophageal varices in eight tertiary university hospitals between January 2007 and March 2020. The clinical characteristics of participants were summarized. MPN patients with a history of GVB were followed up for the rebleeding and death, compared with controls suffering from schistosomiasis-associated portal hypertension who received endoscopic treatment for variceal bleeding at the same period. Results: A total of 62 MPN patients with gastroesophageal varices were identified, and 37 had a history of GVB. Of these, 24 patients received endoscopic variceal ligation and endoscopic injection of cyanoacrylate for the prophylaxis of variceal rebleeding. Endoscopic treatment significantly reduced the rebleeding rate in MPN patients with a history of GVB (28.2% versus 68.3%, p = 0.0269). Multivariable Cox regression indicated that endoscopic treatment (HR = 0.10, 95% CI: 0.02-0.54, p = 0.008) was the independent protective factor for decreasing the 3-year rebleeding rate, while the use of non-selective beta-blockers (NSBB) (HR = 13.41, 95% CI: 2.15-83.42, p = 0.005) was the risk factor for increasing the 3-year rebleeding rate. As for the efficacy of endoscopic management, 3-year rebleeding rate was significantly lower in MPN patients in contrast to 46 controls with schistosomiasis-associated variceal bleeding (32.9% versus 59.0%, p = 0.0346). Conclusion: Endoscopic treatment might be a feasible and potent approach in the management of gastroesophageal variceal rebleeding in MPNs, while NSBB might be ineffective.