Hepatology最新文献

{"title":"A novel phosphodiesterase inhibitor for the treatment of chronic liver injury and metabolic diseases.","authors":"Dalton W Staller, Sanjali S Panigrahi, Yahani P Jayasinghe, Yuxiang Dong, Sohan Mahto, Virender Kumar, Donald R Ronning, Ram I Mahato","doi":"10.1097/HEP.0000000000000999","DOIUrl":"10.1097/HEP.0000000000000999","url":null,"abstract":"<p><strong>Background and aims: </strong>Chronic liver disease leads to ~2 million deaths annually. Cyclic AMP (cAMP) signaling has long been studied in liver injury, particularly in the regulation of fatty acid (FA) β-oxidation and pro-inflammatory polarization of tissue-resident lymphocytes. Phosphodiesterase 4B inhibition has been explored as a therapeutic modality, but these drugs have had limited success and are known to cause significant adverse effects. The PDE4 inhibitor 2-(4-([2-(5-Chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl]amino)phenyl)acetic acid) (known as A-33) has yet to be explored for the treatment of metabolic diseases.</p><p><strong>Approach and results: </strong>Herein, we evaluated the efficacy of A-33 in the treatment of animal models of alcohol-associated liver disease and steatotic liver disease. We demonstrated that A-33 effectively ameliorated the signs and symptoms of chronic liver disease, resulting in significant decreases in serum alanine aminotransferase and aspartate aminotransferase levels, decreased overall fat and collagen deposition in the liver, decreased intrahepatic triglyceride concentrations, and normalized expression of genes related to β-oxidation of fatty acids, inflammation, and extracellular matrix deposition. We also designed and synthesized a novel analog of A-33, termed MDL3, which inhibited both phosphodiesterase 4B and PDE5A and was more effective in ameliorating pathophysiological signs and symptoms of liver injury and inflammation. In addition, MDL3 re-sensitized obese mice to glucose and significantly inhibited the pathological remodeling of adipose tissue, which was not observed with A-33 administration.</p><p><strong>Conclusions: </strong>In conclusion, we synthesized and demonstrated that MDL3, a novel phosphodiesterase 4B and PDE5A inhibitor, presents a promising avenue of exploration for treating chronic liver disease.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"1288-1303"},"PeriodicalIF":12.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11922481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141475544","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":"Epidemiological and economical burden of cholestatic liver disease","authors":"Bregje Mol, Ellen Werner, Emma L. Culver, Adriaan J. van der Meer, Johannes A. Bogaards, Cyriel Y. Ponsioen","doi":"10.1097/hep.0000000000001341","DOIUrl":"https://doi.org/10.1097/hep.0000000000001341","url":null,"abstract":"The main cholestatic liver diseases comprise primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and IgG4-related cholangitis (IgG4-C). Despite being classified as rare diseases these are becoming gradually more important in the field of hepatology since their incidence is slowly rising while viral hepatitis burden is declining. Cholestatic liver diseases now rank among the three most frequent indications for liver transplantation in many Western countries. An accurate understanding of the epidemiology and burden of disease on both the individual and society of cholestatic diseases is of great importance. This review aims at providing a comprehensive overview of the current literature on the epidemiology, health related quality of life, and economical burden of PSC, PBC, and IgG4-C.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"3 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757956","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":"Reply: Can pFIB scores reliably exclude significant liver fibrosis in pediatric MASLD?","authors":"Sander Lefere, Antonella Mosca, Christian Hudert, Ellen Dupont, Emer Fitzpatrick, Eirini Kyrana, Anil Dhawan, Laura Kalveram, Andrea Pietrobattista, Anja Geerts, Ruth De Bruyne","doi":"10.1097/HEP.0000000000001069","DOIUrl":"10.1097/HEP.0000000000001069","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"E116-E117"},"PeriodicalIF":12.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078545","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":"Acute kidney injury in severe alcohol-associated hepatitis treated with anakinra plus zinc or prednisone.","authors":"Kavish R Patidar, Wanzhu Tu, Thomas G Cotter, Douglas A Simonetto, Amon Asgharpour, Muhammad Y Jan, Qing Tang, Yunpeng Yu, Yang Li, Moyinoluwa Taiwo, Prashanth Thevkar Nagesh, Srinivasan Dasarathy, Patrick S Kamath, Craig J McClain, Naga Chalasani, Gyongyi Szabo, Ramon Bataller, Mack Mitchell, Wajahat Z Mehal, Laura E Nagy, Vijay H Shah, Samer Gawrieh, Arun J Sanyal","doi":"10.1097/HEP.0000000000001019","DOIUrl":"10.1097/HEP.0000000000001019","url":null,"abstract":"<p><strong>Background and aims: </strong>In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial.</p><p><strong>Approach and results: </strong>Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p =0.001). AKI phenotypes were similar between the 2 treatment arms ( p =0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p =0.035). At baseline, urine-neutrophil-gelatinase-associated lipocalin levels were similar between participants who developed AKI in both treatment arms ( p =0.319). However, day 7 and 14 urine-neutrophil-gelatinase-associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI ( p =0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p =0.005).</p><p><strong>Conclusions: </strong>AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z-treated participants with AKI had higher urine-neutrophil-gelatinase-associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"1256-1268"},"PeriodicalIF":12.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726529","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":"Getting to HBV Cure – will new biomarkers help?","authors":"Jordan J. Feld, Adam J. Gehring, Fabien Zoulim","doi":"10.1097/hep.0000000000001334","DOIUrl":"https://doi.org/10.1097/hep.0000000000001334","url":null,"abstract":"The natural history and response to therapy in chronic hepatitis B (CHB) infection have been defined by a combination of serological and virological biomarkers along with liver biochemistry and/or histology. A number of novel biomarkers including HBV RNA, hepatitis B core-related antigen (HBcrAg), hepatitis B core antigen (HBcAg) and quantitative hepatitis B surface antigen (qHBsAg) have been developed and evaluated in different clinical settings. Novel immunological biomarkers have also been studied but have been less well characterized. In addition to providing insights into HBV biology, these novel biomarkers may significantly aid in the design, development and assessment of novel antiviral strategies aiming for cure of CHB. Biomarkers can be used to confirm the mechanism of action or target engagement of a novel agent but also may be used for patient selection for trials and clinical use. Ideally, biomarkers can be used to more accurately define stages of CHB, particularly degrees of virological control. In this review, the serological, virological and immunological biomarkers are described with a focus on how they can be used to guide development of HBV cure strategies. New terminology is proposed for clinical endpoints, including Sustained Control to replace the concept of partial cure and Resolved Chronic Infection to replace Functional Cure, reserving the term Cure for clearance or silencing of all cccDNA and integrated HBV DNA.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"62 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143757953","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":"Back to phosphodiesterase inhibitors for liver disease: Are we ready for clinical trials?","authors":"Leila Gobejishvili, Craig J McClain","doi":"10.1097/HEP.0000000000001053","DOIUrl":"10.1097/HEP.0000000000001053","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"1126-1128"},"PeriodicalIF":12.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905245","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":"Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC.","authors":"Qingbin Liu, Xiangyu Zhang, Jingjing Qi, Xinchen Tian, Eva Dovjak, Jiaqi Zhang, Honghuan Du, Ni Zhang, Jing Zhao, Yiming Zhang, Lijuan Wang, Yangang Wei, Chenqiao Liu, Ruikun Qian, Longquan Xiang, Weiyang Li, Peng Xiu, Changlin Ma, Yong Yu, Shulong Jiang","doi":"10.1097/HEP.0000000000000962","DOIUrl":"10.1097/HEP.0000000000000962","url":null,"abstract":"<p><strong>Background and aims: </strong>Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature.</p><p><strong>Approach and results: </strong>Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy.</p><p><strong>Conclusions: </strong>In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"1164-1180"},"PeriodicalIF":12.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11902616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141425893","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":"Integrative single-cell and spatial transcriptomic analyses identify a pathogenic cholangiocyte niche and TNFRSF12A as therapeutic target for biliary atresia.","authors":"Man-Huan Xiao, Dong Ma, Sihan Wu, Zaoli Huang, Peishi Liang, Huadong Chen, Zhihai Zhong, Wei Li, Fen Wang, Yanlai Tang, Juncheng Liu, Hong Jiang, Xuyang Feng, Zhenhua Luo","doi":"10.1097/HEP.0000000000001064","DOIUrl":"10.1097/HEP.0000000000001064","url":null,"abstract":"<p><strong>Background and aims: </strong>Biliary atresia (BA) is a devastating fibroinflammatory biliary disease that is the leading indication for pediatric liver transplants worldwide. Although cholangiocytes are the primary target cells, the pathogenic mechanisms involving cholangiocytes remain elusive. Here, we aimed to characterize the pathogenic role of cholangiocytes in BA.</p><p><strong>Approach and results: </strong>Integration of single-cell RNA sequencing of 12 liver tissues (from 9 BA and 3 controls) and the spatial transcriptome of another four liver sections (from 2 BA and 2 controls) provided a comprehensive spatial liver cell atlas of BA. In particular, we identified a cholangiocyte-enriched spatial niche with infiltration of activated HSCs, activated portal fibroblasts, macrovascular endothelial cells, and TREM2 + macrophages that were elevated in the portal triad of BA. This niche was positively correlated with bile duct profiles, liver fibrosis, and poor survival in 2 independent cohorts of patients with BA. Using integrative bioinformatics analyses to mine the cell-cell communication and regulatory network in BA cholangiocytes, we uncovered the fibroinflammatory phenotype of cholangiocytes with TNFSF12-TNFRSF12A as a significant signal. Genetic ablation or blockade of TNFRSF12A suppresses liver injury, inflammation, and bile duct profiles in a mouse model of disease. Using human biliary organoids, we revealed that BA organoids expressed higher levels of CCL2 in response to TNFSF12 stimulation and promoted monocyte chemotaxis via the CCL2-CCR2 axis.</p><p><strong>Conclusions: </strong>Pathogenic cholangiocytes-enriched niche identifies TNFRSF12A as a potential therapeutic target for BA.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"1146-1163"},"PeriodicalIF":12.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043805","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":"Erratum: Theranostical nanosystem-mediated identification of an oncogene and highly effective therapy in hepatocellular carcinoma","authors":"Yu Guo, Jing Wang, Lu Zhang, Shunli Shen, Ruomi Guo, Yang Yang, Wenjie Chen, Yiru Wang, Guihua Chen, Xintao Shuai","doi":"10.1097/hep.0000000000001240","DOIUrl":"https://doi.org/10.1097/hep.0000000000001240","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"35 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723156","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":"Comparative effectiveness of immunotherapy versus lenvatinib in advanced hepatocellular carcinoma: A real-world analysis using target trial emulation.","authors":"Joseph C Ahn, Wee Han Ng, Yee Hui Yeo, Hyun-Seok Kim, Yun Wang, Hirsh Trivedi, Walid S Ayoub, Alexander Kuo, Nicole Rich, Neehar D Parikh, Ghassan K Abou-Alfa, Kevin Sheng-Kai Ma, Amit G Singal, Ju Dong Yang","doi":"10.1097/HEP.0000000000001328","DOIUrl":"10.1097/HEP.0000000000001328","url":null,"abstract":"<p><strong>Background aims: </strong>Immunotherapy has emerged as an effective treatment for advanced hepatocellular carcinoma (HCC). We aimed to investigate the real-world effectiveness of immunotherapy compared to lenvatinib in HCC.</p><p><strong>Approach result: </strong>From the TriNetX database, we used a target trial emulation framework and identified HCC patients who received first-line treatment with immunotherapy (atezolizumab/bevacizumab or tremelimumab/durvalumab) or lenvatinib between or between August 2018 and December 2023. Overall survival (OS) was compared using Kaplan-Meier analysis and Cox proportional hazards regression. After propensity score matching, 1203 patients were included in each group. Immunotherapy was associated with improved OS vs. lenvatinib (median survival: 545 vs. 425 days; hazard ratio [HR]: 0.86, 95% confidence interval [CI]: 0.76-0.97). Regarding treatment type, atezolizumab plus bevacizumab showed improved survival compared to lenvatinib (n=1070 in each group; HR: 0.87, 95% CI: 0.77-0.99), while the point estimate favored durvalumab plus tremelimumab vs. lenvatinib (HR: 0.81, 95% CI: 0.59-1.12), though this difference was not statistically significant, likely due to small sample size. Regarding etiology, immunotherapy had improved OS compared to lenvatinib in viral hepatitis (n=510 in each group; HR: 0.74, 95% CI: 0.61-0.89) and alcoholic liver disease (n=190 in each group; HR: 0.65, 95% CI: 0.49-0.87), but not in metabolic dysfunction-associated steatotic liver diseases (n=156 in each group; HR: 0.96, 95% CI: 0.70-1.31).</p><p><strong>Conclusions: </strong>In this real-world analysis, immunotherapy was associated with improved OS compared to lenvatinib in advanced HCC, with consistent benefit across most subgroups. These findings support the use of immunotherapy as a first-line treatment for advanced HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735573","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}