Background and Aims:Extrahepatic cancers have been recognized as a significant outcome of metabolic dysfunction-associated steatotic liver disease (MASLD), which involves five cardiometabolic risk factors, including hypertension, and is associated with the tumorigenesis of several cancers or with anti-cancer treatment. We aimed to investigate the association between hypertension, liver fibrosis, and extrahepatic cancers in the MASLD population. Methods:This multicenter cross-sectional study was based on a MASLD population from hospital-based databases across 11 centers nationwide in China, according to MASLD diagnostic criteria identified using keywords and ICD-10 codes. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between risk factors and extrahepatic cancers. Results:A total of 103,652 individuals with MASLD were identified, among whom 6,605 were diagnosed with extrahepatic cancers. The primary outcome revealed that hypertension was significantly associated with extrahepatic cancers (OR 1.14, 95% CI: 1.08-1.21), and its combination with hyperglycemia further increased this association (OR 1.36, 95% CI: 1.22-1.51). Risk factors for extrahepatic cancers included being over 40 years of age and female sex. Conversely, certain metabolism-based treatments were found to have potentially protective effects, including angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, fibrates, GLP-1 receptor agonists, and thiazolidinediones. After adjusting for confounding factors, the fibrosis-4 (FIB-4) score was associated with extrahepatic cancers. In the hypertension subgroup, FIB-4 scores of 1.30-2.66, 2.67-3.47, and ≥ 3.48 were associated with extrahepatic cancers in individuals aged 35-64 years, consistent with findings in those aged ≥ 65 years of age with FIB-4 ≥ 2. Conclusions:Hypertension combined with liver fibrosis is associated with extrahepatic cancers in patients with MASLD.

The incidence of acute-onset autoimmune hepatitis (A-AIH) is increasing, yet diagnosis remains challenging, especially in patients with recent hepatotoxic drug exposure. The clinical presentations of A-AIH and drug-induced autoimmune-like hepatitis (DI-ALH) at onset are often indistinguishable, complicating timely diagnosis. We conducted a three-center retrospective study in China, screening patients with acute liver injury, hepatotoxic drug exposure, and autoimmune features. Patients were ultimately classified as DI-ALH if they achieved sustained remission after culprit drug cessation, or as A-AIH if they relapsed. We compared baseline demographics, laboratory indices, immunological profiles, liver histology, and established AIH diagnostic criteria. We developed and independently validated a multivariable logistic regression model to improve discrimination between A-AIH and DI-ALH. Of 458 patients screened, 238 met inclusion criteria and constituted the final cohort (94 A-AIH and 144 DI-ALH). Compared to DI-ALH, A-AIH showed significantly higher IgG levels, lower platelet counts, and higher autoantibody titers. Histologically, A-AIH exhibited more severe portal inflammation, interface hepatitis, fibrosis, and rosette formation. The discriminatory capacity of the 2022 and 2008 histological criteria was limited and comparable (AUC 0.62 vs. 0.59, p = 0.616). The Dx-AID score, incorporating platelet count, IgG, autoantibodies, and histological features, achieved high diagnostic accuracy in both the derivation cohort (AUC 0.84, 95

Objectives Decompensated cirrhosis represents the end-stage of chronic liver diseases and is characterized by cirrhosis-associated immune dysfunction (CAID). Our goal was to characterize the peritoneal immune landscape, focusing on monocytic myeloid-derived suppressor cells (M-MDSCs), and elucidate their association with clinical outcomes and potential regulatory mechanisms involving ascites metabolites in decompensated cirrhosis. Methods Fifty-five patients with decompensated cirrhosis were prospectively recruited, and subsequently classified as survivors (n = 24) and non-survivors (n = 31). Immune cell compartments in ascites and peripheral blood were analyzed by flow cytometry. Targeted metabolomics of ascites supernatant was performed using targeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Human peritoneal M-MDSCs were differentiated in vitro in the presence of glycoursodeoxycholic acid (GUDCA), followed by transcriptomic, metabolic (mitochondria stress test), and functional (coculture with T cells) analyses. Results Survivors had significantly higher frequencies of peritoneal M-MDSCs with an active immunosuppressive phenotype and elevated expression of chemotactic markers. GUDCA levels in ascites were significantly elevated in survivors and positively correlated with peritoneal M-MDSC levels. In vitro, GUDCA induced the expansion and enhanced the suppressive capacity of peritoneal M-MDSCs via the TGR5-TREM2-oxidative phosphorylation axis. Furthermore, TREM2 expression on peritoneal M-MDSCs was associated with improved survival, serving as a potential prognostic marker. Conclusions Peritoneal M-MDSCs play a critical protective role in immune dysfunction associated with decompensated cirrhosis. GUDCA and TREM2 emerge as key regulators of M-MDSC function, providing a conceptual framework for future investigation into immunomodulatory strategies aimed at restoring immune balance in decompensated cirrhosis.

Background: Porto-sinusoidal vascular disorder (PSVD) is often misdiagnosed as liver cirrhosis due to overlapping clinical presentations and imaging features. This study conducted a blinded, independent imaging review to identify and compare the distinct imaging features between the two diseases, and to develop and validate a predictive model for differentiating PSVD from cirrhosis. Methods: Patients with histologically and clinically confirmed PSVD or cirrhosis and available contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans were retrospectively enrolled in the study. Imaging features were independently and systematically analyzed by two abdominal radiologists, who were blinded to the case grouping. Inter-reader discrepancies were resolved by consensus. The key features for analysis included liver surface nodularity (LSN), regenerative nodules (RNs), signs of portal hypertension (PH), and reticular delayed enhancement of the hepatic parenchyma. CT, MRI, and combined predictive models were developed to identify the top performing model, which was then selected and validated on an independent test cohort. Model performance was evaluated based on the area under the curve (AUC), sensitivity, and specificity. Results: In total, 106 patients with PSVD and 104 patients with cirrhosis were included for imaging evaluation and model development. The data of an additional 36 patients with PSVD and 51 patients with cirrhosis were collected for independent model testing. PSVD exhibited the same pronounced PH imaging features as cirrhosis, including grade 1-3 splenomegaly (77/106, 72.6% vs. 67/104, 64.4%; P>0.05), collateral vessels (103/106, 97.2% vs. 94/104, 90.4%; P>0.05), and ascites (35/106, 33.0% vs. 32/104, 30.8%; P>0.05). In addition, PSVD showed more increased small branches of intrahepatic blood vessels than cirrhosis (79/106, 74.5% vs. 41/104, 39.4%; P<0.001). Conversely, PSVD exhibited fewer cirrhosis-specific imaging features, such as reticular delayed enhancement of the hepatic parenchyma (10/48, 20.8% vs. 50/53, 94.3%; P<0.001), RNs (3/48, 6.3% vs. 29/53, 54.7%; P<0.001), and LSN (27/106, 25.5% vs. 75/104, 72.1%; P<0.001). In the validation set, the MRI model [AUC: 0.970, 95% confidence interval (CI): 0.912-1.0], which incorporated four imaging features (reticular delayed enhancement, RNs, LSN and increased small intrahepatic vascular branches), showed superior discriminatory performance compared to the CT model (AUC: 0.825, 95% CI: 0.646-1.0), with a sensitivity of 0.818 and a specificity of 0.889. While the combined model (AUC: 0.97, 95% CI: 0.912-1.0) did not improve upon the performance of the MRI model alone, with sensitivity of 0.821 and specificity of 0.889. Thus, we recommend the MRI model as the preferred modality for diagnosing PSVD. The MRI model also achieved optimal performance in the independent test set, with an AUC of 0.988 (95% CI: 0.967-1), sensitivity of 0.972, and specificity of 0.826. Conclusions: Patients presenting with severe PH imaging features but lacking typical cirrhosis imaging features should be thoroughly evaluated for PSVD. MRI is the preferred imaging modality. Our MRI-based predictive model reliably differentiates PSVD from cirrhosis, offering a non-invasive method for enhancing the suspicion of PSVD.

Bile acid and steroid hormone homeostasis are critical for human health, with disruptions linked to metabolic and endocrine disorders1,2. The organic solute transporter Ostα/β, essential for bile acid efflux in enterohepatic circulation3, has long defied mechanistic elucidation. Here we present cryogenic electron microscopy structures of human Ostα/β in apo and substrate-bound states at 2.6-3.1 Å resolution, revealing a distinctive membrane protein architecture that defines a new transporter class. Ostα/β forms a symmetric tetramer of heterodimers, with each Ostα subunit showing a new seven-transmembrane fold, augmented by a single transmembrane helix of Ostβ. This architecture is stabilized by extensive lipid modifications, including a palmitoylated cysteine-rich motif that forms a lateral substrate-binding groove. The structures uncover a unique transport pathway featuring two substrate-binding sites connected by an amphipathic helix-gated conduit. This design, conserved in the evolutionarily related TMEM184 family, suggests an ancient mechanism for substrate translocation. Electrophysiological studies demonstrate voltage-sensitive, bidirectional transport driven by electrochemical gradients, elucidating the efflux role of Ostα/β in vivo. Lipid interactions, notably palmitoylation-dependent trafficking, emerge as critical for stability and function. These findings clarify the molecular mechanism of Ostα/β, provide a structural basis for disease-associated mutations4,5 and establish a paradigm for lipid-modified membrane transport.

A subset of autoimmune hepatitis (AIH) patients fail to respond to standard treatments or experience frequent relapses. This study evaluates the efficacy and safety of telitacicept, a BAFF/APRIL dual inhibitor, as a rescue therapy. Two AIH patients treated with telitacicept were included. The first, steroid-dependent and refractory to multiple immunosuppressants, showed significant reductions in transaminases and immunoglobulin G, enabling steroid tapering. The second, with comorbid systemic lupus erythematosus, maintained remission and reduced steroid and mycophenolate mofetil doses. No severe adverse events were reported. Telitacicept shows promise as a safe therapy for refractory AIH.

Background Kupffer cells and monocyte-derived macrophages (MoMs) are difficult to study in human primary biliary cholangitis (PBC) even though they reflect a dynamic hepatic immune population. Objective We aim to investigate the role of hepatic macrophage and its therapeutic potential in human PBC and murine autoimmune cholangitis. Design Phenotypic analysis of hepatic macrophages in patients with PBC and dnTGFβRII mice model was performed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Depletion of hepatic macrophages and inhibition of MoMs were performed in murine autoimmune cholangitis. Lyz2-Cre -mediated Atg5 knockout mice and co-culture experiments were applied to explore the role and mechanism of macrophage autophagy in autoimmune cholangitis. Therapeutic intervention was performed using nanoparticle-capsuled small interfering RNA against Atg5 . Results Kupffer cells from patients with PBC and dnTGFβRII mice upregulate genes associated with inflammatory responses and exhibit increased autophagy. Further, macrophage-specific knockout of Atg5 leads to reduction of inflammation and bile duct damage. We propose that the mechanism of this modulation is secondary to decreased activation of pathogenic CD8 + T cells. Indeed, Kupffer cells maintain CD8 + T cell tolerance through expression of inducible nitric oxide synthase (iNOS) and generation of NO. Increased autophagy resulted in degradation of iNOS in Kupffer cells and abrogated their suppressive activity against CD8 + T cells. Finally, we report that targeted downregulation of Kupffer cell autophagy in vivo using cationic lipid-assisted nanoparticles encapsulating siRNA against Atg5 leads to reduction of liver inflammation and bile duct damage. Conclusion Macrophage autophagy promotes autoimmune cholangitis and strongly supports this pathway as a potential therapeutic target.

Large-language models (LLMs) have demonstrated increasing potential in healthcare, including applications in clinical information retrieval, medical reasoning, and decision support. Autoimmune liver diseases (AILDs), including autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related liver disease, are rare and heterogeneous conditions that often present with nonspecific features and require specialized expertise for accurate diagnosis and management. In resource-limited settings, limited access to hepatology subspecialists may contribute to delayed diagnoses and suboptimal care. Although reasoning-oriented LLMs are designed to support structured clinical inference, their performance on AILD-related tasks has not been systematically evaluated. To evaluate and compare the accuracy, safety, readability, comprehensiveness, and diagnostic performance of six large language models for addressing AILD-related clinical questions and real-world cases. We developed 26 clinically relevant questions spanning the key domains of AILDs, including pathogenesis, risk factors, clinical presentation, diagnosis, treatment, and prognosis. Six publicly available LLMs (o1-preview, Claude-3.5-Sonnet, GPT-4o, GPT-4o-mini, GPT-3.5-Turbo, and LLaMA-3.1-405B) generated responses that were independently evaluated by 11 board-certified hepatologists with more than 10 years of specialty experience. Accuracy, safety, readability, comprehensiveness, and clinical helpfulness were assessed by using predefined rating scales. Diagnostic performance was further evaluated in three models (o1-preview, GPT-4o, and GPT-3.5-Turbo) using 21 confirmed real-world AILD cases, with accuracy determined by comparison with gold-standard clinical diagnoses. Among the six models, the o1-preview demonstrated the highest overall performance. It achieved the greatest proportion of accurate responses (78.3

Primary biliary cholangitis (PBC) is a chronic cholestatic disease that if left untreated can progress to cirrhosis, end-stage liver disease, liver transplantation and, ultimately, death. PBC occurs worldwide, with rising prevalence in the North American, European, and Asia-Pacific regions. Ursodeoxycholic acid (UDCA) is the globally recommended first-line treatment, but up to half of UDCA-treated patients do not respond adequately. Fortunately, the PBC treatment landscape has evolved, and new treatments with novel mechanisms of action are available for patients with inadequate response to UDCA, but questions remain. Different treatment strategies have emerged in recent years from major societies across the globe regarding treatment targets, timing of treatment response assessment, management of hepatic and extrahepatic manifestations, and choice of second-line therapies. Drug availability also has global variation. Nine international PBC experts, representing the United States, Canada, Europe, Asia, Africa, and Central/South America, collaborated to formulate opinions about the unanswered questions related to treatment targets in PBC. The result of this expert review is a global perspective on terminology related to the definition of responses to treatment, risk stratification, and treatment targets that can guide clinicians to optimize PBC treatment worldwide.