Nonalcoholic fatty liver disease (NAFLD) has become a major public health concern. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor transcription factors. PPARs are categorized into three subtypes: PPARα, β/δ, and γ. Three subtypes of PPARs play crucial roles in lipid and glucose metabolism, inflammation and fibrosis. This review summarizes randomized controlled trials on the use of PPAR agonists in the treatment of NAFLD. PPARα and PPARβ/δ agonists control circulatory lipids well, but they do not yield enough liver benefits. PPARγ agonists, particularly pioglitazone, are recommended for NAFLD treatment. PPARα/γ agonists and PPARα/β/γ agonists are plausible in the treatment of NAFLD. More clinical studies are still in need to properly unveil the efficacy of PPAR agonists in the treatment of NAFLD.

Aim:Porto-sinusoidal vascular disorder (PSVD) is a rare vascular liver disease that has similar manifestations to liver cirrhosis. However, limited information is available on the prevalence and clinical impacts of sarcopenia in patients with PSVD in China. Methods:We enrolled 92 patients with PSVD from West China Hospital between January 2019 to June 2024 to analyze and characterize the burden of sarcopenia. The psoas muscle mass index (PMI), measured at the third lumbar vertebra (L3-PMI, cm2/m2), was used for quantitative analysis of skeletal muscle mass. Age- and sex- specific cut-off values, optimized for the Chinese population, were endorsed for the diagnosis of sarcopenia. Results:Sarcopenia was observed in 17 out of the 92 PSVD patients (18.5%). The sarcopenia group had a higher proportion of patients with a history of esophagogastric variceal bleeding (EGVB) compared to the non-sarcopenia group (88.24% vs. 60.0%, p = 0.046). Transjugular intrahepatic portosystemic shunt (TIPS) creation significantly increased L3-PMI [4.84 (3.70-5.44) vs. 5.10 (4.40-6.10), p = 0.0153]. During the 1-year follow-up after endoscopic treatment, the cumulative incidence of rebleeding was significantly higher in the sarcopenia group than in the non-sarcopenia group [HR 4.39, 95% CI 1.01-19.10, log-rank p = 0.0485]. Multivariate Cox regression analysis showed that sarcopenia was an independent predictor of 1-year variceal rebleeding. Conclusion:Sarcopenia is common in patients with PSVD, particularly among those with a history of EGVB. TIPS placement may potentially enhance the muscle mass of PSVD patients. Importantly, sarcopenia appears to negatively impact clinical outcomes in PSVD patients undergoing endoscopic therapy for variceal bleeding.

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4-dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation-dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

A 56-year-old female suffered from recurrent esophagogastric varices bleeding for 2 years due to cavernous transformation of the portal vein caused by hepatic hydatidosis. Multiple esophageal variceal ligations failed to prevent rebleeding. Transmesenteric vein extrahepatic portosystemic shunt was performed to decrease portal pressure gradient and prevent rebleeding.

INTRODUCTION:Hepatic encephalopathy (HE) is a major complication following transjugular intrahepatic portosystemic shunt (TIPS) placement, significantly affecting patients' quality of life and long-term prognosis. This study aims to compare the efficacy of underdilated TIPS versus standard TIPS in preventing variceal rebleeding in patients with cirrhosis and portal hypertension and to evaluate the incidence of post-procedural HE. METHODS AND ANALYSIS:This multicentre randomised controlled trial will be conducted across five Grade A tertiary hospitals in China. A total of 648 patients with portal hypertension-related oesophagogastric variceal bleeding undergoing TIPS will be enrolled and randomly assigned in a 1:1 ratio to either the experimental or control group. In the experimental group, underdilated TIPS will be performed using 6 mm balloon for stent expansion. In the control group, standard TIPS will be performed using progressive balloon dilation, starting at 8 mm and increasing stepwise as needed until the portosystemic pressure gradient is reduced to <12 mm Hg. The primary endpoint is the rebleeding rate over the entire follow-up period after TIPS. Secondary endpoints include the incidence of HE and liver function impairment. All statistical analyses will be performed using SPSS V.27.0 (IBM, Armonk, New York, USA), with a significance level set at p<0.05. ETHICS AND DISSEMINATION:The study protocol (V.2, 1 July 2025) has been approved by the Medical Ethics Committee of the First Affiliated Hospital of Air Force Medical University (Approval No.: KY20252233-F-2). Written informed consent will be obtained from all participants prior to enrolment. Findings will be presented at academic conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER:ChiCTR2500110490; NCT07253389.

Background:Hepatic encephalopathy (HE), especially overt HE (OHE), is the most common transjugular intrahepatic portosystemic shunt (TIPS) complication, affecting quality of life. Existing noninvasive models have suboptimal predictive performance. Aim:To develop a novel model integrating preoperative and intraoperative indicators to predict post-TIPS OHE. Methods:We included 455 TIPS patients from three centers (Army Medical Center, Xinqiao Hospital, and West China Hospital) between March 2018 and September 2024, randomly allocated into 7:3 development and validation cohorts. LASSO and multivariate logistic regression identified independent risk factors, with model discrimination/calibration evaluated against traditional models (Child-Pugh, model for end-stage liver disease [MELD], albumin-bilirubin [ALBI], and Freiburg index of post-TIPS survival [FIPS]). Results:A total of 455 patients were included. During follow-up, 91 patients (28.4%) in the development cohort and 41 (30.4%) patients in the validation cohort developed OHE. The analysis identified the following independent risk factors: peripheral blood monocyte count (odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.22-1.63, P < 0.001), thrombin time (TT; OR = 1.35, 95% CI: 1.15-1.59, P < 0.001), age (OR = 1.08, 95% CI: 1.05-1.12, P < 0.001), history of diabetes (OR = 7.64, 95% CI: 3.50-17.55, P < 0.001), ascites grade [mild-moderate ascites (OR = 2.35, 95% CI: 1.19-4.77, P = 0.02), severe ascites (OR = 3.76, 95% CI: 1.15-12.64, P = 0.03)]. Stent underdilated (8-mm stent dilated to 6-mm) was a strong independent protective factor (OR = 0.12, 95% CI: 0.05-0.26, P < 0.001). The six-factor prediction model achieved area under the curve values of 0.864 (development cohort) and 0.812 (validation cohort), significantly outperforming Child-Pugh (0.617/0.656), MELD (0.551/0.569), ALBI (0.607/0.662), and FIPS (0.667/0.608) scores (all P < 0.05). Conclusion:The prediction model incorporating stent dilatation status, peripheral blood monocyte count, TT, age, ascites severity, and history of diabetes demonstrates high predictive accuracy for assessing OHE risk after TIPS. Notably, the model was derived in a mainly hepatitis B virus-cirrhosis Asian population, which may limit generalizability to alcoholic/nonalcoholic steatohepatitis-dominant western populations.

BACKGROUND The effect of post-transjugular intrahepatic portosystemic shunt (TIPS) rebleeding on liver-related mortality remains uninvestigated. AIM To investigate the relationship between post-TIPS rebleeding and liver-related mortality in patients with cirrhosis and to conduct subgroup analyses based on liver function. METHODS This study included 1782 patients who underwent covered TIPS at seven medical centers to prevent rebleeding. The primary endpoints were liver-related death and all-cause rebleeding. Propensity score matching, adjusted survival curves, and competing risk analyses based on liver transplantation and non-liver death were performed to ensure the robustness of the results. RESULTS During a median follow-up period of 32.25 months, 346 patients (19.4%) developed post-TIPS rebleeding, and 429 (24.1%) died from liver-related causes. Chronic HBV infection was the predominant cirrhosis etiology. Multivariable analysis identified older age, higher Child-Pugh and model for end-stage liver disease-Na scores, and post-TIPS rebleeding as independent predictive factors for liver-related mortality. Liver-related mortality increased by approximately 49.4% in the rebleeding group compared with the no-bleeding group. These findings remained consistent after propensity score matching, survival curve adjustment, and competing risk assessment. Similar findings were observed across different liver function subgroups. CONCLUSION Post-TIPS rebleeding was significantly associated with higher mortality in patients with cirrhosis and variceal bleeding irrespective of liver function category.

ObjectiveTransjugular intrahepatic portosystemic shunt (TIPS) is a high-bleeding-risk vascular intervention. The association between TIPS-related hemorrhage and preprocedural platelet (PLT) count remains unclear.MethodsThis was a retrospective cohort study including patients receiving TIPS procedures for complications related to portal hypertension due to liver cirrhosis between 2011 and 2022. Logistic regression and subgroup analyses were performed to evaluate the relationship between TIPS-related hemorrhage and preprocedural PLT count. Patients were divided into two groups based on a PLT threshold of 50 × 109/L. Furthermore, patients with PLT count < 50 × 109/L were stratified into two subgroups based on a threshold of 20 × 109/L. The primary endpoint was TIPS procedure-related hemorrhage.ResultsA total of 632 patients with liver cirrhosis who underwent TIPS were categorized into two groups based on their PLT counts of 50 × 109/L. The incidence of TIPS-related hemorrhage was 2.8% in the PLT < 50 × 109/L group (n = 417) and 1.9% in the PLT ≥ 50 × 109/L group (n = 215) (95% CI: 0.23–1.97; P = 0.480). In subgroup analysis, the bleeding rate was 0% in PLT < 20 × 109/L group (n = 10) and 2.9% in PLT 20–50 × 109/L group (n = 205). No statistically significant intergroup differences in bleeding rates were found (95% CI: 0–9.7; P = 0.501). In the univariate and multivariate analysis, advanced age is the independent risk factor for TIPS-related bleeding (OR = 1.054, 95% CI: 1.006–1.105, P = 0.028).ConclusionThis study revealed that preoperative PLT count is not associated with TIPS procedure-related hemorrhage in patients with cirrhosis. Patient age should be carefully considered in the preoperative assessment.

Portal hypertension (PHT), a critical complication of liver disease, is primarily assessed via invasive procedures that carry inherent risks and discomfort. Recent advancements in deep learning have demonstrated potential for non-invasive diagnostic assistance based on computed tomography (CT) images. However, the small sample size and notable imbalance in PHT clinical data severely restrict the performance of deep learning methods, while the bias introduced by label discretization further compromises model robustness. To address these challenges, we propose a Regression-assisted Classification (RAC) method for noninvasive PHT diagnosis. Firstly, we propose the RAC method instead of direct classification, enabling fine-grained estimation of hepatic venous pressure gradient (HVPG) values before making categorical decisions, thereby reducing the bias caused by discrete label assignment. Moreover, the boundary-aware weighted learning method is proposed to jointly optimize model parameters and the loss function by dynamically assigning online bucket-based weights and enforcing gradient balance across decision boundaries. We show that this approach can significantly reduce the impact of data imbalance and help handle the challenges of smallsample learning in PHT diagnosis. Experiments on our collected clinical CT dataset achieve 83.28% accuracy and 82.69% for the area under the receiver operating characteristic curve in the three-class classification task of PHT, outperforming the cross-entropy baseline by +1.01% and +2.38%, respectively. These results demonstrate leading performance in PHT multi-class classification diagnostic tasks and offer an effective solution for the direct diagnosis of PHT based on CT images.

BACKGROUND:Transjugular intrahepatic portosystemic shunt (TIPS) is an established procedure for managing portal hypertension in cirrhotic patients, but the impact of post-TIPS overt hepatic encephalopathy (OHE) on survival remains controversial. While its effect on short-term survival is well-documented, its long-term implications remain unclear. AIMS:This study aims to investigate the long-term impact of post-TIPS OHE on mortality in cirrhotic patients for variceal bleeding, focusing on the timing and predictive value of OHE beyond the first year post-TIPS. METHODS:A multicenter, retrospective cohort study was conducted involving 3262 cirrhotic patients who underwent TIPS for variceal bleeding at seven Chinese tertiary centers between January 2010 and June 2020. Clinical data, including demographics, procedure details, post-TIPS complications and survival outcomes, were collected. The primary endpoints were all-cause mortality and OHE, with follow-up until death, liver transplantation or 60 months. Propensity score matching minimised confounding effects, and multivariate Fine-Grey competing risk models identified independent mortality predictors. RESULTS:During a median follow-up of 1077 days, 33.2% developed post-TIPS OHE, associated with higher MELD and Child-Pugh scores. Among these, 19.3% died, with a median time from OHE onset to death of 947 days. Post-TIPS OHE was not linked to early survival (within 12 months) but emerged as an independent predictor of long-term mortality beyond 24 months, consistent across various clinical scenarios. CONCLUSION:Post-TIPS OHE does not affect short-term survival but significantly increases long-term mortality risk. These findings highlight the need for continuous monitoring and tailored interventions to improve long-term outcomes in post-TIPS patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder globally, affecting 30% of the population and causing a significant healthcare burden due to its increasing incidence and limited therapeutic options. Arachidonic acid (AA) is a key bioactive lipid precursor that generates eicosanoids, such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acids, via 3 distinct enzymatic pathways: cyclooxygenase, lipoxygenase, and cytochrome P450. Emerging evidence indicates that AA-derived metabolites and pathway factors contribute to the progression and severity of MASLD and liver fibrosis. This review systematically summarizes the pathophysiological roles of AA metabolism in MASLD and liver fibrosis, focusing on mechanisms involving lipid accumulation, liver inflammation, fibrogenesis, and related cellular processes. In addition, we discuss potential therapeutic targets within the AA metabolic pathway in MASLD and liver fibrosis, highlighting emerging clinical advances targeting AA metabolites and pathway factors to improve these pathological conditions.

BACKGROUND AND AIMS:Hepatic encephalopathy (HE) is the most common complication of cirrhosis after transjugular intrahepatic portosystemic shunt (TIPS) and is closely related to intestinal dysbiosis. The efficacy of probiotics in improving minimal HE (MHE) has been well studied, while the role of probiotics for the primary prophylaxis of overt HE (OHE) after TIPS has not been established. We aimed to determine whether Live Combined Bifidobacterium and Lactobacillus Tablets, a commonly used probiotic preparation in China, reduced the risk of post-TIPS HE. METHOD:We conducted an open-label, randomised, blank-controlled trial of 142 patients with cirrhosis receiving TIPS. Patients were randomly assigned to receive probiotics (2 g three times daily) or not. The primary outcome was the incidence of OHE within 24 weeks after TIPS. The secondary outcomes were improvement in cognitive function [defined by the number connection test-A (NCT-A) and digit symbol test (DST)] and the incidence of other cirrhosis-related complications at 24 weeks. RESULTS:The incidence of post-TIPS OHE was 51.4% in the control group (n = 70), which was significantly lower in the probiotics group (n = 72, 36.1%, Fine-Grey p = 0.043). In the subgroup of patients without post-TIPS OHE, liver transplantation or death, there was no significant difference in DST and NCT-A tests at 24 weeks compared with baseline in the control group. By contrast, both DST [31.5 (26.4-39.3) vs. 34.5 (29.8-43.0), p < 0.0001] and NCT-A [53.8 (43.3-71.2) vs. 46.6 (40.2-64.4), p = 0.0045] significantly improved at 24 weeks in the probiotics group. There was no significant difference in other cirrhosis-related complications between the two groups. CONCLUSION:Live Combined Bifidobacterium and Lactobacillus Tablets might reduce the risk of OHE and improve cognitive function in cirrhosis patients receiving TIPS for variceal bleeding without previous OHE. Multicenter studies should be performed to provide further evidence. TRIAL REGISTRATION:Chictr.org: ChiCTR2200062996.