Hepatology最新文献

{"title":"Distinct immune microenvironment of venous tumor thrombus in hepatocellular carcinoma at single-cell resolution.","authors":"Kai-Qian Zhou, Yu-Chen Zhong, Min-Fang Song, Yun-Fan Sun, Wei Zhu, Jian-Wen Cheng, Yang Xu, Ze-Fan Zhang, Peng-Xiang Wang, Zheng Tang, Jian Zhou, Li-Ye Zhang, Jia Fan, Xin-Rong Yang","doi":"10.1097/HEP.0000000000001182","DOIUrl":"10.1097/HEP.0000000000001182","url":null,"abstract":"<p><strong>Background and aims: </strong>Portal vein tumor thrombus (PVTT) worsens the prognosis of hepatocellular carcinoma by increasing intrahepatic dissemination and inducing portal vein hypertension. However, the immune characteristics of PVTT remain unclear. Therefore, this study aims to explore the immune microenvironment in PVTT.</p><p><strong>Approach and results: </strong>Time-of-flight mass cytometry revealed that macrophages and monocytes were the dominant immune cell type in PVTT, with a higher proportion than in primary tumor and blood (54.1% vs. 26.3% and 9.1%, p<0.05). The differentially enriched clustering of inhibitory and regulatory immune cells in PVTT indicated an immune-suppressive environment. According to the single-cell RNA sequencing, TAM-C5AR1 was characterized by leukocyte chemotaxis and was the most common subpopulation in PVTT (36.7%). Multiplex fluorescent immunohistochemistry staining showed that the C5aR+ TAM/Mφ were enriched in PVTT compared to both the primary tumor and liver and positively correlated with C5a (r=0.559, p<0.001). Notably, THP-1 (monocyte cell line) was recruited by CSQT2 (PVTT cell line) and exhibited up-regulation of CD163, CD206, and PD-L1 upon stimulation. C5aR antagonist could reverse this. C5aR+ TAMs could also inhibit Granzyme B in CD8+ T cells. High infiltration of C5aR+ TAMs in PVTT correlated with poor differentiation (p<0.009) and was a risk factor for overall survival (p=0.003) and for reformation of PVTT after resection (p=0.007).</p><p><strong>Conclusions: </strong>TAMs, especially C5aR+ TAMs, were enriched in PVTT. C5aR+ TAMs contribute to the development of PVTT and poor prognosis by reshaping the immunosuppressive environment.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"82 3","pages":"566-581"},"PeriodicalIF":15.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reappraisal of the conventional hemostasis tests as predictors of perioperative bleeding in the era of rebalanced hemostasis in cirrhosis.","authors":"Armando Tripodi, Massimo Primignani, Roberta D'Ambrosio, Giulia Tosetti, Vincenzo La Mura, Pietro Lampertico, Flora Peyvandi","doi":"10.1097/HEP.0000000000000756","DOIUrl":"10.1097/HEP.0000000000000756","url":null,"abstract":"<p><p>New global laboratory procedures mimicking the in vivo hemostasis process led to the changing paradigm of cirrhosis from the prototype of hemorrhagic diseases to a condition in which hemostasis is normal but fragile, thus justifying the hemorrhagic/thrombotic tendencies that affect these patients. The new paradigm was instrumental to change the management of cirrhosis. For example, international guidelines warn against the entrenched practice of testing patients with conventional hemostasis tests and infusing those with abnormalities with fresh-frozen plasma, coagulation factor concentrates, or platelets, prior to surgery/invasive procedures. These recommendations are, however, largely disattended. The practice of testing patients with the prothrombin time or viscoelastometry and using arbitrary cutoffs to make decisions on perioperative prophylaxis is still common and probably driven by medicolegal issues. There is no doubt that prothrombin time and congeners tests are unable to predict bleeding in cirrhosis. However, it cannot be excluded that some tests may be useful in patients who are severely decompensated. Large prospective collaborative studies are warranted. Enrolled patients should be randomized to receive perioperative prophylaxis based on laboratory testing (eg, viscoelastometry, thrombomodulin-modified thrombin generation) or to usual care. However, for these trials to be useful, a third group of patients who do not receive prophylaxis should be included. In conclusion, until results from these studies are available, physicians attending cirrhosis should refrain from using laboratory tests with arbitrary cutoffs to make decision on perioperative prophylaxis. Decision should be made by considering the clinical history of individual patients and the risk of hemorrhage of specific procedures.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"755-765"},"PeriodicalIF":15.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139424152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multidisciplinary approach to the diagnosis and management of Wilson disease: 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases.","authors":"Michael L Schilsky, Eve A Roberts, Jeff M Bronstein, Anil Dhawan, James P Hamilton, Anne Marie Rivard, Mary Kay Washington, Karl Heinz Weiss, Paula C Zimbrean","doi":"10.1002/hep.32801","DOIUrl":"10.1002/hep.32801","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E41-E90"},"PeriodicalIF":15.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9578290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin 8-CXCR2-mediated neutrophil extracellular trap formation in biliary atresia associated with neutrophil extracellular trap-induced stellate cell activation.","authors":"Yuhuan Luo, Lisa Fraser, Julia Jezykowski, Nitika A Gupta, Alexander G Miethke, Sarah A Taylor, Estella M Alonso, Simon Horslen, Rohit Kohli, Jean P Molleston, Binita M Kamath, Stephen L Guthery, Kathleen M Loomes, John C Magee, Phillip Rosenthal, Pamela Valentino, Ronald J Sokol, Cara L Mack","doi":"10.1097/HEP.0000000000001195","DOIUrl":"10.1097/HEP.0000000000001195","url":null,"abstract":"<p><strong>Background and aims: </strong>Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed that neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and the risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and whether NETs induce stellate cell activation.</p><p><strong>Approach and results: </strong>BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, and IL-8 were quantified by ELISA for plasma and by immunohistochemistry for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by real-time quantitative PCR, ELISA, and FACS. Liver neutrophils and NETs, and plasma elastase, NETs, and IL-8, were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. Immunohistochemistry identified increased NET expression of profibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation based on increased ACTA2 and COL1A1 mRNA, collagen protein, and cell surface expression of actin, collagen1A, and platelet-derived growth factor receptor-beta.</p><p><strong>Conclusions: </strong>Patients with BA have persistent IL-8-CXCR2-mediated NETosis that correlates with biomarkers of injury and fibrosis, and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"552-565"},"PeriodicalIF":15.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining an approach for therapeutic strategies in metabolic dysfunction-associated steatotic liver disease after liver transplantation.","authors":"Mohammad Shadab Siddiqui, Mark Muthiah, Sanjaya K Satapathy, Kavish R Patidar, Mamatha Bhat, Danielle Brandman, Kymberly D Watt, Mary Rinella","doi":"10.1097/HEP.0000000000000720","DOIUrl":"10.1097/HEP.0000000000000720","url":null,"abstract":"<p><p>Occurrence of metabolic dysfunction-associated steatotic liver disease (MASLD) is common following liver transplantation (LT). MASLD can be classified as a recurrent disease when it occurs in patients receiving LT for metabolic dysfunction-associated steatohepatitis (MASH) or as de novo when it occurs in patients undergoing transplantation for non-metabolic dysfunction-associated steatohepatitis etiologies of liver disease. Fibrosis progression in patients with MASLD is accelerated, with progression to cirrhosis occurring more rapidly compared with the general (ie, non-LT) population. Moreover, the metabolic burden in LT recipients with MASLD is high and synergizes with liver disease to negatively affect the clinical course. Despite the oversized clinical burden of MASLD among LT recipients, there is currently a lack of regulatory approach and pathway for therapeutics development in this patient population. The present document, thus, provides guidance for therapeutics development that incorporates nuances of transplant care in patients with post-LT MASLD to facilitate drug development.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"766-776"},"PeriodicalIF":15.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138796770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RIPPLY1 suppresses cancer cell stemness via targeting TBX19 in CTNNB1-mutated hepatocellular carcinoma.","authors":"Guangyan Zhangyuan,Weiwei Yu,Wenfang Tian,Junjie Xie,Jun Wang,Xiayang Ying,Fei Wang,Yufei Shao,Xiuxiang Tan,Hao Qian,Yexuan Deng,Baiyong Shen","doi":"10.1097/hep.0000000000001483","DOIUrl":"https://doi.org/10.1097/hep.0000000000001483","url":null,"abstract":"BACKGROUND AIMSCTNNB1-mutated HCCs exhibit a relatively low stem-like and well-differentiated phenotype. However, the mechanism remains unclear. Ripply transcriptional repressor 1 (RIPPLY1), a transcriptional repressor required for somite segmentation, has hardly been studied in cancer. Here, we aim to unveil the role of RIPPLY1 in the regulation of cancer cell stemness in CTNNB1-mutated HCCs.APPROACH AND RESULTSRIPPLY1 was found to be transactivated by the Wnt/β-Catenin signal pathway. Human sample analysis confirmed that RIPPLY1 was significantly upregulated in CTNNB1-mutated HCC tissues and positively correlated with better prognosis of HCC patients. Hepatocyte-specific deletion of RIPPLY1 promoted tumorigenesis and progression in DEN/PB-induced CTNNB1-mutated HCC mouse model and hydrodynamic tail-vein injection (HDTVi)-induced CTNNB1-mutated HCC mouse model. RIPPLY1 knockout tumor cells displayed upregulated levels of stem cell makers and enhanced cancer stem cell properties. Co-IP and MS identified TBX19 as the target protein of RIPPLY1. RIPPLY1 suppressed the transcriptional activity of TBX19 via recruiting TLE1 and promoting proteasome-dependent degradation of TBX19. TBX19 deficiency abolished the effect of RIPPLY1 loss on cancer cell stemness in CTNNB1-mutated HCCs.CONCLUSIONLoss of RIPPLY1 promotes cancer cell stemness via facilitating the TBX19 transcriptional activity in CTNNB1-mutated HCCs.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"104 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CX3CR1+ macrophages interact with HSCs to promote HCC through CD8+ T-cell suppression.","authors":"Jong-Min Jeong, Sung Eun Choi, Young-Ri Shim, Hee-Hoon Kim, Young-Sun Lee, Keungmo Yang, Kyurae Kim, Min Jeong Kim, Katherine Po Sin Chung, Seok-Hwan Kim, Jin-Seok Byun, Hyuk Soo Eun, Won-Il Jeong","doi":"10.1097/HEP.0000000000001021","DOIUrl":"10.1097/HEP.0000000000001021","url":null,"abstract":"<p><strong>Background and aims: </strong>HSCs contribute to HCC progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to protumorigenic properties in the peritumoral area.</p><p><strong>Approach and results: </strong>In single-cell RNA-sequencing analysis of patients with HCC, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DR- macrophages with CX3CR1 in the HCC adjacent region where α-smooth muscle actin-expressing activated hepatic stellate cells (aHSCs) showed colocalized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro coculture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or coculturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T-cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development.</p><p><strong>Conclusions: </strong>We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"82 3","pages":"655-668"},"PeriodicalIF":15.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2 -/- mice and human cholangiocarcinoma tumorigenesis.","authors":"Lindsey Kennedy, Laura Hargrove, Jennifer Demieville, Walker Karstens, Hannah Jones, Sharon DeMorrow, Fanyin Meng, Pietro Invernizzi, Francesca Bernuzzi, Gianfranco Alpini, Steven Smith, Austin Akers, Vik Meadows, Heather Francis","doi":"10.1097/HEP.0000000000001403","DOIUrl":"10.1097/HEP.0000000000001403","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E114"},"PeriodicalIF":15.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PPARidgm shifts in treatment of metabolic dysfunction associated steatotic liver disease","authors":"Layla Abushamat, Diana Barb","doi":"10.1097/hep.0000000000001511","DOIUrl":"https://doi.org/10.1097/hep.0000000000001511","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"7 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Invasive Tests: Establishing efficacy for metabolic dysfunction associated steatohepatitis beyond the biopsy—current perspectives from the division of hepatology and nutrition, US Food and Drug Administration","authors":"Frank A. Anania, Rebecca Hager, Karen Higgins, George A. Makar, Jeffrey Siegel, Tram T. Tran","doi":"10.1097/hep.0000000000001509","DOIUrl":"https://doi.org/10.1097/hep.0000000000001509","url":null,"abstract":"To support drug development for metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis, multiple stakeholders including patients, clinicians, and investigators have communicated a desire to move away from liver histology. FDA accelerated approval is based on a surrogate endpoint (such as liver histology) that has less definitive evidence tying it to the clinical endpoint (such as death or liver transplant) but nonetheless is considered reasonably likely to predict clinical benefit -- a reasonably likely surrogate endpoint (RLSE). This communication is intended to provide some of the regulatory considerations on adopting non-invasive tests in lieu of liver histology as a RLSE in drug development for MASH. We will also describe FDA mechanisms and the methods by which data can be submitted to the FDA to consider proposals for NIT use in place of liver histology as RLSEs.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"27 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}