Hepatology Communications最新文献

{"title":"Two transcriptionally and functionally distinct waves of neutrophils during mouse acute liver injury.","authors":"Yousef Maali, Manuel Flores Molina, Omar Khedr, Mohamed N Abdelnabi, Jessica Dion, Ghada S Hassan, Naglaa H Shoukry","doi":"10.1097/HC9.0000000000000459","DOIUrl":"10.1097/HC9.0000000000000459","url":null,"abstract":"<p><strong>Background: </strong>Neutrophils are key mediators of inflammation during acute liver injury (ALI). Emerging evidence suggests that they also contribute to injury resolution and tissue repair. However, the different neutrophil subsets involved in these processes and their kinetics are undefined. Herein, we characterized neutrophil kinetics and heterogeneity during ALI.</p><p><strong>Methods: </strong>We used the carbon tetrachloride model of ALI and employed flow cytometry, tissue imaging, and quantitative RT-PCR to characterize intrahepatic neutrophils during the necroinflammatory early and late repair phases of the wound healing response to ALI. We FACS sorted intrahepatic neutrophils at key time points and examined their transcriptional profiles using RNA-sequencing. Finally, we evaluated neutrophil protein translation, mitochondrial function and metabolism, reactive oxygen species content, and neutrophil extracellular traps generation.</p><p><strong>Results: </strong>We detected 2 temporarily distinct waves of neutrophils during (1) necroinflammation (at 24 hours after injury) and (2) late repair (at 72 hours). Early neutrophils were proinflammatory, characterized by: (1) upregulation of inflammatory cytokines, (2) activation of the noncanonical NF-κB pathway, (3) reduction of protein translation, (4) decreased oxidative phosphorylation, and (5) higher propensity to generate reactive oxygen species and neutrophil extracellular traps. In contrast, late neutrophils were prorepair and enriched in genes and pathways associated with tissue repair and angiogenesis. Finally, early proinflammatory neutrophils were characterized by the expression of a short isoform of C-X-C chemokine receptor 5, while the late prorepair neutrophils were characterized by the expression of C-X-C chemokine receptor 4.</p><p><strong>Conclusions: </strong>This study underscores the phenotypic and functional heterogeneity of neutrophils and their dual role in inflammation and tissue repair during ALI.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPED study: Protocol for a randomized controlled trial of different doses of aerobic exercise training.","authors":"Jonathan G Stine, Breianna Hummer, Nataliya Smith, Heather Tressler, J Westley Heinle, Kyra VanKirk, Sara Harris, Matthew Moeller, Gavin Luzier, Kara DiJoseph, Zeba Hussaini, Ryan Jackson, Brandon Rodgers, Ian Schreibman, Elizabeth Stonesifer, Justin Tondt, Chris Sica, Prashant Nighot, Vernon M Chinchilli, Rohit Loomba, Christopher Sciamanna, Kathryn H Schmitz, Scot R Kimball","doi":"10.1097/HC9.0000000000000464","DOIUrl":"10.1097/HC9.0000000000000464","url":null,"abstract":"<p><p>Recently renamed, metabolic dysfunction-associated steatotic liver disease remains a leading cause of chronic liver disease worldwide. Regular physical activity is recommended as a treatment for all with this condition because it is highly efficacious, especially when exercise training is undertaken with a specific goal in mind. Despite decades of research demonstrating exercise's efficacy, key questions remain about the mechanism of benefit and most efficacious dose, as well as the independent impact on liver histology. To answer these questions, we present the design of a 16-week randomized controlled clinical trial of 45 adults aged 18-69 years with metabolic dysfunction-associated steatohepatitis. The primary aim of this study is to better understand the dose required and mechanisms to explain how exercise impacts multiple clinical end points in metabolic dysfunction-associated steatohepatitis. The primary outcome is MRI-measured liver fat. Secondary outcomes include other biomarkers of liver fibroinflammation, liver histology, and mechanistic pathways, as well as cardiometabolic risk and quality of life. This is the first study to compare different doses of exercise training to determine if there is a differential impact on imaging and serum biomarkers as well as liver histology.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a biomarker index for HCC treatment response.","authors":"Jeff Liang, Po-Yi Li, Joshua Norman, Marie Lauzon, Yee Hui Yeo, Hirsh Trivedi, Walid S Ayoub, Alexander Kuo, Marc L Friedman, Kamya Sankar, Jun Gong, Arsen Osipov, Andrew Hendifar, Tsuyoshi Todo, Irene Kim, Georgios Voidonikolas, Todd V Brennan, Steven A Wisel, Justin Steggarda, Kambiz Kosari, Rola Saouaf, Nicholas Nissen, Francis Yao, Neil Mehta, Ju Dong Yang","doi":"10.1097/HC9.0000000000000466","DOIUrl":"10.1097/HC9.0000000000000466","url":null,"abstract":"<p><strong>Background: </strong>Serum AFP-L3%, AFP, and DCP are useful biomarkers for HCC detection, but their utility in assessing treatment response remains unknown. We aim to evaluate the accuracy of a biomarker model in the detection of posttreatment viable tumors.</p><p><strong>Methods: </strong>For model derivation, recipients with HCC undergoing liver transplant from 2018 to 2022 who had biomarkers collected within 3 months before transplant were included. We developed a generalized linear model for detecting posttreatment viable tumors with the 3 biomarkers as covariates, which we termed the \"LAD Score.\" An independent cohort of 117 patients with HCC was used for external validation.</p><p><strong>Results: </strong>Among 205 recipients of transplant, 70.2% had evidence of viable tumor on explant. The median LAD score was higher among patients with viable versus nonviable tumors (1.06 vs. 0.465, p < 0.001). The LAD score had a sensitivity of 55.6% and a specificity of 85.1% at the cutoff of 0.927, which was more accurate than imaging for detecting posttreatment viable tumors (AUROC 0.736 vs. 0.643, respectively; p = 0.045). The superior performance of the LAD score over imaging is primarily driven by its greater accuracy in detecting tumors <2 cm in diameter (AUROC of the LAD score 0.721 vs. imaging 0.595, p = 0.02). In the validation data set, the LAD score had an AUROC of 0.832 (95% CI: 0.753, 0.911) with a sensitivity of 72.5% and a specificity of 89.4% at the cutoff of 0.927.</p><p><strong>Conclusions: </strong>Our findings suggest the utility of LAD score in treatment response assessment after locoregional therapy for HCC, particularly in detecting small tumors. A larger prospective study is in progress to validate its accuracy and evaluate its performance in recurrence monitoring.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Landmark analysis of the risk of recurrence after resection or ablation for HCC: A nationwide study.","authors":"Frederik Kraglund, Nikolaj Skou, Gerda Elisabeth Villadsen, Peter Jepsen","doi":"10.1097/HC9.0000000000000472","DOIUrl":"10.1097/HC9.0000000000000472","url":null,"abstract":"<p><strong>Background: </strong>The risk of HCC recurrence at particular landmarks since the initial treatment is unknown. With this registry-based study, we aimed to provide a nuanced description of the prognosis following resection or ablation for HCC, including landmark analyses.</p><p><strong>Methods: </strong>Using the Danish nationwide health care registries, we identified all patients who received resection or ablation in 2000-2018 as the first HCC treatment. HCC recurrence was defined as a new HCC treatment > 90 days after the first treatment. We conducted competing risk landmark analyses of the cumulative risk of recurrence and death.</p><p><strong>Results: </strong>Among 4801 patients with HCC, we identified 426 patients who received resection and 544 who received ablation. The 2 treatment cohorts differed in cirrhosis prevalence and tumor stage. The 5-year recurrence risk was 40.7% (95% CI 35.5%-45.8%) following resection and 60.7% (95% CI: 55.9%-65.1%) following ablation. The 1-year recurrence risk decreased over the landmarks from 20.4% (95% CI: 16.6%-24.6%) at the time of resection to 4.7% (95% CI: 0.9%-13.9%) at the 5-year landmark. For ablation, the risk decreased from 36.1% (95% CI: 31.9%-40.4%) at the time of treatment to 5.3% (95% CI: 0.4%-21.4%) at the 5-year landmark. The risk of death without recurrence was stable over the landmarks following both resection and ablation.</p><p><strong>Conclusions: </strong>In conclusion, the risk of recurrence or death following resection or ablation for HCC is high from the treatment date, but the risk of recurrence decreases greatly over the survival landmarks. This information is valuable for clinicians and their patients.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validating new coding algorithms to improve identification of alcohol-associated and nonalcohol-associated cirrhosis hospitalizations in administrative databases.","authors":"Liam A Swain, Jenny Godley, Mayur Brahmania, Juan G Abraldes, Karen L Tang, Jennifer Flemming, Abdel Aziz Shaheen","doi":"10.1097/HC9.0000000000000469","DOIUrl":"10.1097/HC9.0000000000000469","url":null,"abstract":"<p><strong>Background: </strong>Alcohol (AC) and nonalcohol-associated cirrhosis (NAC) epidemiology studies are limited by available case definitions. We compared the diagnostic accuracy of previous and newly developed case definitions to identify AC and NAC hospitalizations.</p><p><strong>Methods: </strong>We randomly selected 700 hospitalizations from the 2008 to 2022 Canadian Discharge Abstract Database with alcohol-associated and cirrhosis-related International Classification of Diseases 10th revision codes. We compared standard approaches for AC (ie, AC code alone and alcohol use disorder and nonspecific cirrhosis codes together) and NAC (ie, NAC codes alone) case identification to newly developed approaches that combine standard approaches with new code combinations. Using electronic medical record review as the reference standard, we calculated case definition positive and negative predictive values, sensitivity, specificity, and AUROC.</p><p><strong>Results: </strong>Electronic medical records were available for 671 admissions; 252 had confirmed AC and 195 NAC. Compared to previous AC definitions, the newly developed algorithm selecting for the AC code, alcohol-associated hepatic failure code, or alcohol use disorder code with a decompensated cirrhosis-related condition or NAC code provided the best overall positive predictive value (91%, 95% CI: 87-95), negative predictive value (89%, CI: 86-92), sensitivity (81%, CI: 76-86), specificity (96%, CI: 93-97), and AUROC (0.88, CI: 0.85-0.91). Comparing all evaluated NAC definitions, high sensitivity (92%, CI: 87-95), specificity (82%, CI: 79-86), negative predictive value (96%, CI: 94-98), AUROC (0.87, CI: 0.84-0.90), but relatively low positive predictive value (68%, CI: 62-74) were obtained by excluding alcohol use disorder codes and using either a NAC code in any diagnostic position or a primary diagnostic code for HCC, unspecified/chronic hepatic failure, esophageal varices without bleeding, or hepatorenal syndrome.</p><p><strong>Conclusions: </strong>New case definitions show enhanced accuracy for identifying hospitalizations for AC and NAC compared to previously used approaches.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of hepatic steatosis among persons with and without HIV using natural language processing.","authors":"Jessie Torgersen, Melissa Skanderson, Farah Kidwai-Khan, Dena M Carbonari, Janet P Tate, Lesley S Park, Debika Bhattacharya, Joseph K Lim, Tamar H Taddei, Amy C Justice, Vincent Lo Re","doi":"10.1097/HC9.0000000000000468","DOIUrl":"10.1097/HC9.0000000000000468","url":null,"abstract":"<p><strong>Background: </strong>Steatotic liver disease (SLD) is a growing phenomenon, and our understanding of its determinants has been limited by our ability to identify it clinically. Natural language processing (NLP) can potentially identify hepatic steatosis systematically within large clinical repositories of imaging reports. We validated the performance of an NLP algorithm for the identification of SLD in clinical imaging reports and applied this tool to a large population of people with and without HIV.</p><p><strong>Methods: </strong>Patients were included in the analysis if they enrolled in the Veterans Aging Cohort Study between 2001 and 2017, had an imaging report inclusive of the liver, and had ≥2 years of observation before the imaging study. SLD was considered present when reports contained the terms \"fatty,\" \"steatosis,\" \"steatotic,\" or \"steatohepatitis.\" The performance of the SLD NLP algorithm was compared to a clinical review of 800 reports. We then applied the NLP algorithm to the first eligible imaging study and compared patient characteristics by SLD and HIV status.</p><p><strong>Results: </strong>NLP achieved 100% sensitivity and 88.5% positive predictive value for the identification of SLD. When applied to 26,706 eligible Veterans Aging Cohort Study patient imaging reports, SLD was identified in 72.2% and did not significantly differ by HIV status. SLD was associated with a higher prevalence of metabolic comorbidities, alcohol use disorder, and hepatitis B and C, but not HIV infection.</p><p><strong>Conclusions: </strong>While limited to those undergoing radiologic study, the NLP algorithm accurately identified SLD in people with and without HIV and offers a valuable tool to evaluate the determinants and consequences of hepatic steatosis.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver disease and transplantation in telomere biology disorders: An international multicenter cohort.","authors":"YunZu Michele Wang, Batul Kaj-Carbaidwala, Adam Lane, Suneet Agarwal, Fabian Beier, Alison Bertuch, Kristin A Borovsky, Steven K Brennan, Rodrigo T Calado, Luiz Fernando B Catto, Carlo Dufour, Christen L Ebens, Francesca Fioredda, Neelam Giri, Nicholas Gloude, Frederick Goldman, Paula M Hertel, Ryan Himes, Sioban B Keel, Divya T Koura, Christian P Kratz, Sakil Kulkarni, Iris Liou, Taizo A Nakano, Silvia Nastasio, Marena R Niewisch, Daniel D Penrice, Ghadir S Sasa, Sharon A Savage, Douglas A Simonetto, David S Ziegler, Alexander G Miethke, Kasiani C Myers","doi":"10.1097/HC9.0000000000000462","DOIUrl":"10.1097/HC9.0000000000000462","url":null,"abstract":"<p><strong>Background: </strong>Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes.</p><p><strong>Methods: </strong>Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study.</p><p><strong>Results: </strong>Group A (\"Advanced\") included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M (\"Mild\") included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant.</p><p><strong>Conclusions: </strong>LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel experimental model of MetALD in male mice recapitulates key features of severe alcohol-associated hepatitis.","authors":"Mrigya Babuta, Caroline Morel, Marcelle de Carvalho Ribeiro, Aditi Ashish Datta, Charles Calenda, Christopher Copeland, Imad Nasser, Gyongyi Szabo","doi":"10.1097/HC9.0000000000000450","DOIUrl":"10.1097/HC9.0000000000000450","url":null,"abstract":"<p><strong>Background: </strong>The recent increase in the incidence of alcohol-associated hepatitis (AH) coincides with the obesity epidemic in the United States. However, current mouse models do not fully replicate the combined insults of obesity, metabolic dysfunction-associated steatohepatitis, and alcohol. The aim of this study was to develop a new mouse model that recapitulates the robust inflammatory and fibrotic phenotype characteristic of human MetALD.</p><p><strong>Methods: </strong>Eight- to 10-week-old male C57BL/6 mice were fed chow or high fat-cholesterol-sugar diet (metabolic dysfunction-associated steatohepatitis diet) and in each group, some received alcohol in drinking water (ad libitum) and weekly alcohol binges (EtOH) for 3 months. The liver was assessed for features of AH.</p><p><strong>Results: </strong>MetALD mice displayed increased liver damage indicated by highly elevated ALT and bilirubin levels compared to all other groups. Liver steatosis was significantly greater in the MetALD mice compared to all other experimental groups. The inflammatory phenotype of MetALD was also recapitulated, including increased IL-6 and IL-1β protein levels as well as increased CD68+ macrophages and Ly6G+ neutrophils in the liver. Sirius red staining and expression of collagen 1, alpha-smooth muscle actin indicated advanced fibrosis in the livers of MetALD mice. In addition, indicators of epithelial-to-mesenchymal transition markers were increased in MetALD mice compared to all other groups. Furthermore, we found increased ductular reaction, dysregulated hedgehog signaling, and decreased liver synthetic functions, consistent with severe AH.</p><p><strong>Conclusions: </strong>Alcohol administration in mice combined with metabolic dysfunction-associated steatohepatitis diet recapitulates key characteristics of human AH including liver damage, steatosis, robust systemic inflammation, and liver immune cell infiltration. This model results in advanced liver fibrosis, ductular reaction, decreased synthetic function, and hepatocyte dedifferentiation, suggesting a robust model of MetALD in mice.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating bacterial peptides and linked metabolomic signatures are indicative of early mortality in pediatric cirrhosis.","authors":"Babu Mathew, Gaurav Tripathi, Vipul Gautam, Vasundhra Bindal, Nupur Sharma, Manisha Yadav, Sushmita Pandey, Neha Sharma, Abhishak C Gupta, Sadam H Bhat, Akhilesh K Saini, Vikrant Sood, Bikrant Bihari Lal, Seema Alam, Rajeev Khanna, Jaswinder Singh Maras","doi":"10.1097/HC9.0000000000000440","DOIUrl":"10.1097/HC9.0000000000000440","url":null,"abstract":"<p><strong>Background: </strong>Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the deterioration of patients with PC-S to early mortality are unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating patients with PC-S predisposed to early mortality in plasma, and we further validated the selected metabolite panel in paired 1-drop blood samples using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using machine-learning algorithms.</p><p><strong>Methods: </strong>We enrolled 160 patients with liver diseases (cirrhosis-sepsis/nonsepsis [n=110] and noncirrhosis [n=50]) and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis, n=70 and noncirrhosis, n=40). The candidate predictors were validated on 2 test cohorts-T1 (plasma test cohort) and T2 (1-drop blood test cohort). Both T1 and T2 had 120 patients each, of which 70 were from the training cohort.</p><p><strong>Results: </strong>Increased levels of tryptophan metabolites and Salmonella enterica and Escherichia coli-associated peptides segregated patients with cirrhosis. Increased levels of deoxyribose-1-phosphate, N5-citryl-d-ornithine, and Herbinix hemicellulolytic and Leifsonia xyli segregated patients with PC-S. MMCN-based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S nonsurvivors. Increased Indican, Staphylobillin, glucose-6-phosphate, 2-octenoylcarnitine, palmitic acid, and guanidoacetic acid along with L. xyli, Mycoplasma genitalium, and Hungateiclostridium thermocellum segregated PC-S nonsurvivors and superseded the liver disease severity indices with high accuracy, sensitivity, and specificity for mortality prediction using random forest machine-learning algorithm.</p><p><strong>Conclusions: </strong>Our study reveals a novel metabolite signature panel capable of segregating patients with PC-S predisposed to early mortality using as low as 1-drop blood.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BTLA deficiency promotes HSC activation and protects against hepatic ischemia-reperfusion injury.","authors":"Xiaoyun Shen, Rongyun Mai, Xiao Han, Qi Wang, Yifan Wang, Tong Ji, Yifan Tong, Ping Chen, Jia Zhao, Xiaoyan He, Tong Wen, Rong Liang, Yan Lin, Xiaoling Luo, Xiujun Cai","doi":"10.1097/HC9.0000000000000449","DOIUrl":"10.1097/HC9.0000000000000449","url":null,"abstract":"<p><strong>Background and aims: </strong>Hepatic ischemia-reperfusion injury (IRI) is unavoidable even despite the development of more effective surgical approaches. During hepatic IRI, activated HSC (aHSC) are involved in liver injury and recovery.</p><p><strong>Approach and result: </strong>A proportion of aHSC increased significantly both in the mouse liver tissues with IRI and in the primary mouse HSCs and LX-2 cells during hypoxia-reoxygenation. \"Loss-of-function\" experiments revealed that depleting aHSC with gliotoxin exacerbated liver damage in IRI mice. Subsequently, we found that the transcription of mRNA and the expression of B and T lymphocyte attenuator (BTLA) protein were lower in aHSC compared with quiescent HSCs. Interestingly, overexpression or knockdown of BTLA resulted in opposite changes in the activation of specific markers for HSCs such as collagen type I alpha 1, α-smooth muscle actin, and Vimentin. Moreover, the upregulation of these markers was also observed in the liver tissues of global BLTA-deficient (BTLA-/-) mice and was higher after hepatic IRI. Compared with wild-type mice, aHSC were higher, and liver injury was lower in BTLA-/- mice following IRI. However, the depletion of aHSC reversed these effects. In addition, the depletion of aHSC significantly exacerbated liver damage in BTLA-/- mice with hepatic IRI. Furthermore, the TGF-β1 signaling pathway was identified as a potential mechanism for BTLA to negatively regulate the activation of HSCs in vivo and in vitro.</p><p><strong>Conclusions: </strong>These novel findings revealed a critical role of BTLA. Particularly, the receptor inhibits HSC-activated signaling in acute IRI, implying that it is a potential immunotherapeutic target for decreasing the IRI risk.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11155569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}