Pub Date : 2024-09-13DOI: 10.1097/hep.0000000000001087
Xueying Lyu, Karen Man-Fong Sze, Joyce Man-Fong Lee, Abdullah Husain, Lu Tian, Sandrine Imbeaud, Jessica Zucman-Rossi, Irene Oi-Lin Ng, Daniel Wai-Hung Ho
Oncoviruses can integrate into the host genome and cause tumorigenesis. In particular, hepatitis B virus (HBV) infection accounts for more than 50% of hepatocellular carcinoma (HCC) worldwide. We revealed the global geographical disparity of HBV integration that the landscape of HBV integration between HCC tumor and non-tumorous liver varied in regional cohorts, suggesting the different degrees of clonal enrichment. Most HBV integrations were positionally enriched at telomeres and centromeres (T&C) and they highlighted the novel co-involvement of HBV integration, which likely introduces genomic instability in HCC development. This was confirmed by phospho-H2AX staining. We constructed a large meta-cohort of multiple ethnicities to refine the landscape of HBV integration. This enables the gene set/family level exploration. As TERT is the most frequently integrated gene, we further investigated the underlying mechanistic modulation of TERT transcription activation and revealed the concurrent influence by the orientation and relative distance of HBV integration. Additionally, clonal disparity of HBV integration was observed among patients and the higher level of clonal disparity score can indicate poor patients’ prognostication. Taken together, our study uncovered the different levels of clonal enrichment of HBV integration, mechanistic insights, and prognostic biomarker signature, to strengthen our understanding in HBV-associated hepatocarcinogenesis.
{"title":"Disparity landscapes of viral-induced structural variations in hepatocellular carcinoma: Mechanistic characterization and functional implications","authors":"Xueying Lyu, Karen Man-Fong Sze, Joyce Man-Fong Lee, Abdullah Husain, Lu Tian, Sandrine Imbeaud, Jessica Zucman-Rossi, Irene Oi-Lin Ng, Daniel Wai-Hung Ho","doi":"10.1097/hep.0000000000001087","DOIUrl":"https://doi.org/10.1097/hep.0000000000001087","url":null,"abstract":"Oncoviruses can integrate into the host genome and cause tumorigenesis. In particular, hepatitis B virus (HBV) infection accounts for more than 50% of hepatocellular carcinoma (HCC) worldwide. We revealed the global geographical disparity of HBV integration that the landscape of HBV integration between HCC tumor and non-tumorous liver varied in regional cohorts, suggesting the different degrees of clonal enrichment. Most HBV integrations were positionally enriched at telomeres and centromeres (T&C) and they highlighted the novel co-involvement of HBV integration, which likely introduces genomic instability in HCC development. This was confirmed by phospho-H2AX staining. We constructed a large meta-cohort of multiple ethnicities to refine the landscape of HBV integration. This enables the gene set/family level exploration. As <jats:italic toggle=\"yes\">TERT</jats:italic> is the most frequently integrated gene, we further investigated the underlying mechanistic modulation of <jats:italic toggle=\"yes\">TERT</jats:italic> transcription activation and revealed the concurrent influence by the orientation and relative distance of HBV integration. Additionally, clonal disparity of HBV integration was observed among patients and the higher level of clonal disparity score can indicate poor patients’ prognostication. Taken together, our study uncovered the different levels of clonal enrichment of HBV integration, mechanistic insights, and prognostic biomarker signature, to strengthen our understanding in HBV-associated hepatocarcinogenesis.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231453","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}
Pub Date : 2024-09-12DOI: 10.1097/hep.0000000000001086
Patricia P. Bloom, Caitlyn J. Fisher, Nicholas Tedesco, Neil Kamdar, Luis Garrido-Trevino, Jessica Robin, Sumeet K. Asrani, Anna S. Lok
Background & Aims: Hepatic encephalopathy (HE) is a major cause of poor quality of life in patients with cirrhosis. A simple diagnostic test to identify minimal HE (MHE) and predict future overt HE (OHE) is lacking. We aimed to evaluate if analysis of speech patterns using a modern speech platform: 1) correlates with validated HE tests, 2) correlates with MHE, and 3) predicts future OHE. Approach & Results: In a two-center prospective cohort study of 200 outpatients with cirrhosis and 50 controls, patients underwent baseline speech recording and validated HE diagnostic testing with psychometric HE score (PHES). Patients were followed for 6 months to identify episodes of OHE. 752 speech variables were extracted using an automated speech analysis platform, reflecting the acoustic, lexical, and semantic aspects of speech. Patients with cirrhosis were median 63 years old (IQR 54, 68), 49.5% (99) were female. Over 100 speech variables were significantly associated with PHES (p <0.05 with FDR adjustment). A three-variable speech model (two acoustic, one speech tempo variable) was similar to animal naming test in predicting MHE (AUC 0.76 vs. 0.69; p=0.11). Adding age and MELD-Na improved accuracy of the speech model (AUC: 0.82). A combined clinical-speech model (“HEAR-MHE model”) predicted time to OHE with a concordance of 0.74 (p=0.06). Conclusions: Automated speech analysis highly correlated with validated HE tests, associated with MHE, and may predict future OHE. Future research is needed to validate this tool and to understand how it can be implemented in clinical practice.
{"title":"HEAR-MHE study: Automated speech analysis identifies minimal hepatic encephalopathy and may predict future overt hepatic encephalopathy","authors":"Patricia P. Bloom, Caitlyn J. Fisher, Nicholas Tedesco, Neil Kamdar, Luis Garrido-Trevino, Jessica Robin, Sumeet K. Asrani, Anna S. Lok","doi":"10.1097/hep.0000000000001086","DOIUrl":"https://doi.org/10.1097/hep.0000000000001086","url":null,"abstract":"Background & Aims: Hepatic encephalopathy (HE) is a major cause of poor quality of life in patients with cirrhosis. A simple diagnostic test to identify minimal HE (MHE) and predict future overt HE (OHE) is lacking. We aimed to evaluate if analysis of speech patterns using a modern speech platform: 1) correlates with validated HE tests, 2) correlates with MHE, and 3) predicts future OHE. Approach & Results: In a two-center prospective cohort study of 200 outpatients with cirrhosis and 50 controls, patients underwent baseline speech recording and validated HE diagnostic testing with psychometric HE score (PHES). Patients were followed for 6 months to identify episodes of OHE. 752 speech variables were extracted using an automated speech analysis platform, reflecting the acoustic, lexical, and semantic aspects of speech. Patients with cirrhosis were median 63 years old (IQR 54, 68), 49.5% (99) were female. Over 100 speech variables were significantly associated with PHES (<jats:italic toggle=\"yes\">p</jats:italic> <0.05 with FDR adjustment). A three-variable speech model (two acoustic, one speech tempo variable) was similar to animal naming test in predicting MHE (AUC 0.76 vs. 0.69; <jats:italic toggle=\"yes\">p</jats:italic>=0.11). Adding age and MELD-Na improved accuracy of the speech model (AUC: 0.82). A combined clinical-speech model (“HEAR-MHE model”) predicted time to OHE with a concordance of 0.74 (<jats:italic toggle=\"yes\">p</jats:italic>=0.06). Conclusions: Automated speech analysis highly correlated with validated HE tests, associated with MHE, and may predict future OHE. Future research is needed to validate this tool and to understand how it can be implemented in clinical practice.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174616","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}
Pub Date : 2024-09-10DOI: 10.1097/hep.0000000000001091
Yael R Nobel,Justin R Boike,Nikhilesh R Mazumder,Bartley Thornburg,Rachel Hoffman,K Pallav Kolli,Michael Fallon,Jennifer C Lai,Giuseppi Morelli,Erin K Spengler,Adnan Said,Archita P Desai,Sonali Paul,Aparna Goel,Kelly Hu,Catherine Frenette,Dyanna Gregory,Cynthia Padilla,Yuan Zhang,Lisa B VanWagner,Elizabeth C Verna,
BACKGROUND AND AIMSWhile transjugular intrahepatic portosystemic shunt (TIPS) is traditionally considered a bridge to liver transplant (LT), some patients achieve long-term transplant-free survival (TFS) with TIPS alone. Prognosis and need for LT should not only be assessed at time of procedure, but also re-evaluated in patients with favorable early outcomes.APPROACH AND RESULTSAdult TIPS recipients in the multicenter Advancing Liver Therapeutic Approaches retrospective cohort study were included (N=1,127 patients; 2,040 person-years follow-up). Adjusted competing risk regressions were used to assess factors associated with long-term post-TIPS clinical outcomes at time of procedure and at 6 months post-TIPS. MELD-Na at TIPS was significantly associated with post-TIPS mortality (sHR of death 1.1 [p=0.42], 1.3 [p=0.04], and 1.7 [p<0.01] for MELD-Na 15-19, 20-24, and ≥25 relative to MELD-Na <15, respectively). MELD 3.0 was also associated with post-TIPS outcomes. Among the 694 (62%) patients who achieved early (6 mo) post-TIPS TFS, rates of long-term TFS were 88% at 1-year and 57% at 3-years post-TIPS. Additionally, a within-individual increase in MELD-Na score of >3 points from TIPS to 6 months post-TIPS was significantly associated with long-term mortality, regardless of initial MELD-Na score (sHR of death 1.8, p<0.01). For patients with long-term post-TIPS TFS, rates of complications of the TIPS or portal hypertension were low.CONCLUSIONSAmong patients with early post-TIPS TFS, prognosis and need for LT should be reassessed, informed by post-procedure changes in MELD-Na and clinical status. For selected patients, "destination TIPS" without LT may offer long-term survival with freedom from portal hypertensive complications.
{"title":"Predictors of long-term clinical outcomes after TIPS: An ALTA group study.","authors":"Yael R Nobel,Justin R Boike,Nikhilesh R Mazumder,Bartley Thornburg,Rachel Hoffman,K Pallav Kolli,Michael Fallon,Jennifer C Lai,Giuseppi Morelli,Erin K Spengler,Adnan Said,Archita P Desai,Sonali Paul,Aparna Goel,Kelly Hu,Catherine Frenette,Dyanna Gregory,Cynthia Padilla,Yuan Zhang,Lisa B VanWagner,Elizabeth C Verna,","doi":"10.1097/hep.0000000000001091","DOIUrl":"https://doi.org/10.1097/hep.0000000000001091","url":null,"abstract":"BACKGROUND AND AIMSWhile transjugular intrahepatic portosystemic shunt (TIPS) is traditionally considered a bridge to liver transplant (LT), some patients achieve long-term transplant-free survival (TFS) with TIPS alone. Prognosis and need for LT should not only be assessed at time of procedure, but also re-evaluated in patients with favorable early outcomes.APPROACH AND RESULTSAdult TIPS recipients in the multicenter Advancing Liver Therapeutic Approaches retrospective cohort study were included (N=1,127 patients; 2,040 person-years follow-up). Adjusted competing risk regressions were used to assess factors associated with long-term post-TIPS clinical outcomes at time of procedure and at 6 months post-TIPS. MELD-Na at TIPS was significantly associated with post-TIPS mortality (sHR of death 1.1 [p=0.42], 1.3 [p=0.04], and 1.7 [p<0.01] for MELD-Na 15-19, 20-24, and ≥25 relative to MELD-Na <15, respectively). MELD 3.0 was also associated with post-TIPS outcomes. Among the 694 (62%) patients who achieved early (6 mo) post-TIPS TFS, rates of long-term TFS were 88% at 1-year and 57% at 3-years post-TIPS. Additionally, a within-individual increase in MELD-Na score of >3 points from TIPS to 6 months post-TIPS was significantly associated with long-term mortality, regardless of initial MELD-Na score (sHR of death 1.8, p<0.01). For patients with long-term post-TIPS TFS, rates of complications of the TIPS or portal hypertension were low.CONCLUSIONSAmong patients with early post-TIPS TFS, prognosis and need for LT should be reassessed, informed by post-procedure changes in MELD-Na and clinical status. For selected patients, \"destination TIPS\" without LT may offer long-term survival with freedom from portal hypertensive complications.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170448","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}
Pub Date : 2024-09-10DOI: 10.1097/hep.0000000000001092
Binu V John,Dustin Bastaich,Mahmoud Manouchehri Amoli,Robert J Wong,Donna M Evon,Shari S Rogal,David B Ross,Timothy R Morgan,Seth A Spector,Gabriel Villada,Hann-Hsiang Chao,Bassam Dahman,
BACKGROUNDHepatitis Delta Virus (HDV) infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a United States-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with hepatitis B virus (HBV). infection.METHODSIn a national cohort of 4,817 HBV infected veterans tested for HDV (99.6% US-born, 3.3% HDV positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of hepatocellular carcinoma (HCC), decompensation, and liver-related mortality (LRM), as well as all-cause mortality of patients with HDV compared to HBV mono-infection.RESULTSHDV coinfection (vs. HBV monoinfection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p<0.001), and 10 years (19.14 vs. 10.18, p<0.001) respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by non-hepatic malignancies, (15.6 vs. 14.8%),cardiac (11.7 vs. 15.2%), and lung disease (5.2 vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (aHR 2.57, 95% CI 1.87-3.52, p<0.001), and all-cause mortality (aHR 1.52, 95% CI 1.20-1.93, p<0.001).CONCLUSIONIn a predominantly U.S born cohort of Veterans, HDV co-infection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.
背景三角洲肝炎病毒（HDV）感染是最严重的慢性肝炎。然而，在美国出生的人群中，由于 HDV 主要是水平传播，因此缺乏对其结果和死亡原因的研究。本研究的目的是对丁型肝炎患者进行一项全国性研究，以了解与乙型肝炎病毒（HBV）感染患者相比，丁型肝炎患者的自然病史和预后情况。方法在一个全国性队列中，4817 名感染了 HBV 的退伍军人接受了 HDV 检测（99.6% 在美国出生，3.我们使用多变量模型确定了与肝细胞癌 (HCC)、肝功能失代偿和肝脏相关死亡率 (LRM) 等综合结果相关的因素，以及与单感染 HBV 患者相比，HDV 患者的全因死亡率。结果HDV合并感染（与HBV单一感染相比）患者在5年（23.84 vs. 7.98，p<0.001）和10年（19.14 vs. 10.18，p<0.001）的肝脏相关综合结局发生率明显更高。最常见的死因是肝脏相关疾病（HDV 33.8% 对 HBV 24.7%），其次是非肝脏恶性肿瘤（15.6% 对 14.8%）、心脏病（11.7% 对 15.2%）和肺部疾病（5.2% 对 3.7%）。在多变量模型中，HDV 与综合肝脏结果风险增加（aHR 2.57，95% CI 1.87-3.52，p<0.001）和全因死亡率风险增加（aHR 1.52，95% CI 1.20-1.93，p<0.001）相关。我们的研究结果支持广泛开展早期识别 HDV 的检测。
{"title":"Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort.","authors":"Binu V John,Dustin Bastaich,Mahmoud Manouchehri Amoli,Robert J Wong,Donna M Evon,Shari S Rogal,David B Ross,Timothy R Morgan,Seth A Spector,Gabriel Villada,Hann-Hsiang Chao,Bassam Dahman,","doi":"10.1097/hep.0000000000001092","DOIUrl":"https://doi.org/10.1097/hep.0000000000001092","url":null,"abstract":"BACKGROUNDHepatitis Delta Virus (HDV) infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a United States-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with hepatitis B virus (HBV). infection.METHODSIn a national cohort of 4,817 HBV infected veterans tested for HDV (99.6% US-born, 3.3% HDV positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of hepatocellular carcinoma (HCC), decompensation, and liver-related mortality (LRM), as well as all-cause mortality of patients with HDV compared to HBV mono-infection.RESULTSHDV coinfection (vs. HBV monoinfection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p<0.001), and 10 years (19.14 vs. 10.18, p<0.001) respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by non-hepatic malignancies, (15.6 vs. 14.8%),cardiac (11.7 vs. 15.2%), and lung disease (5.2 vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (aHR 2.57, 95% CI 1.87-3.52, p<0.001), and all-cause mortality (aHR 1.52, 95% CI 1.20-1.93, p<0.001).CONCLUSIONIn a predominantly U.S born cohort of Veterans, HDV co-infection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170449","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}
Pub Date : 2024-09-10DOI: 10.1097/hep.0000000000001070
Karen Acuña-Pilarte, Ethan C. Reichert, Yangsook Song Green, Lily M-T. Halberg, Martin Golkowski, Kathleen M. Maguire, Patrice N. Mimche, Severin Donald Kamdem, Po-An Hu, Jillian Wright, Gregory S. Ducker, Warren P. Voth, Ryan M. O’Connell, Sydney A. McFarland, Erika Said Abu Egal, Amandine Chaix, Scott. A. Summers, Jordan W. Reelitz, J. Alan Maschek, James E. Cox, Kimberley J. Evason, Mei Yee Koh
Background: HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1 +/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. Results: We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS -/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-κB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver. Conclusions: HAF is novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.
{"title":"HAF prevents hepatocyte apoptosis and progression to MASH and hepatocellular carcinoma through transcriptional regulation of the NF-κB pathway","authors":"Karen Acuña-Pilarte, Ethan C. Reichert, Yangsook Song Green, Lily M-T. Halberg, Martin Golkowski, Kathleen M. Maguire, Patrice N. Mimche, Severin Donald Kamdem, Po-An Hu, Jillian Wright, Gregory S. Ducker, Warren P. Voth, Ryan M. O’Connell, Sydney A. McFarland, Erika Said Abu Egal, Amandine Chaix, Scott. A. Summers, Jordan W. Reelitz, J. Alan Maschek, James E. Cox, Kimberley J. Evason, Mei Yee Koh","doi":"10.1097/hep.0000000000001070","DOIUrl":"https://doi.org/10.1097/hep.0000000000001070","url":null,"abstract":"Background: HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (<jats:italic toggle=\"yes\">SART1</jats:italic> <jats:sup> +/-</jats:sup>) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. Results: We generated <jats:italic toggle=\"yes\">SART1</jats:italic>-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS<jats:sup>-/-</jats:sup>) or myeloid cells (LysM-Cre, macS<jats:sup>-/-</jats:sup>). <jats:italic toggle=\"yes\">HepS</jats:italic> <jats:sup> -/-</jats:sup> mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-κB pathway, which was recapitulated using HAF siRNA <jats:italic toggle=\"yes\">in vitro</jats:italic>. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating transcription of <jats:italic toggle=\"yes\">TRADD</jats:italic> and <jats:italic toggle=\"yes\">RIPK1</jats:italic>. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver. Conclusions: HAF is novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166284","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}
Pub Date : 2024-09-09DOI: 10.1097/hep.0000000000001093
Nidhi Jalan-Sakrikar, Maria Eugenia Guicciardi, Steven P. O’Hara, Adiba Azad, Nicholas F. LaRusso, Gregory J. Gores, Robert C. Huebert
Cholangiopathies comprise a spectrum of chronic intra- and extrahepatic biliary tract disorders culminating in progressive cholestatic liver injury, fibrosis and often cirrhosis and its sequela. Treatment for these diseases is limited and collectively they are one of the therapeutic “black boxes” in clinical hepatology. The etiopathogenesis of the cholangiopathies likely includes disease-specific mediators, but also common cellular and molecular events driving disease progression (e.g., cholestatic fibrogenesis, inflammation, and duct damage). The common pathways involve cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, which are central to the pathogenesis of these disorders. Current information suggests that cholangiocytes function as a signaling “hub” in biliary tract-associated injury. Herein, we review the pivotal role of cholangiocytes in cholestatic fibrogenesis, focusing on crosstalk between cholangiocytes and portal fibroblasts and hepatic stellate cells. The proclivity of these cells to undergo a senescence-associated secretory phenotype which is pro-inflammatory and –fibrogenic, and the intrinsic intracellular activation pathways resulting in secretion of cytokines and chemokines is reviewed. The crosstalk between cholangiocytes and cells of the innate (neutrophils and macrophages), and adaptive (T-cells and B-cells) immune systems is also examined in detail. The information will help consolidate information on this topic, guide further research and potential therapeutic strategies for these diseases.
胆道疾病包括一系列肝内和肝外慢性胆道疾病，最终导致进行性胆汁淤积性肝损伤、肝纤维化和肝硬化及其后遗症。对这些疾病的治疗非常有限，它们共同构成了临床肝病学的治疗 "黑箱"。胆道疾病的发病机制可能包括疾病特异性介质，但也包括驱动疾病进展的常见细胞和分子事件（如胆汁淤积性纤维化、炎症和导管损伤）。胆管细胞是肝内和肝外胆管的上皮细胞，是这些疾病发病机制的核心。目前的信息表明，胆管细胞在胆道相关损伤中起着信号 "枢纽 "的作用。在此，我们回顾了胆管细胞在胆汁淤积性纤维化中的关键作用，重点关注胆管细胞与门静脉成纤维细胞和肝星状细胞之间的相互影响。本文回顾了胆管细胞与门静脉成纤维细胞和肝星状细胞之间的相互关系，以及胆管细胞易发生与衰老相关的分泌表型，这种表型具有促炎和促纤维生成作用，并回顾了导致细胞因子和趋化因子分泌的细胞内激活途径。此外，还详细探讨了胆管细胞与先天性免疫系统细胞（中性粒细胞和巨噬细胞）和适应性免疫系统细胞（T 细胞和 B 细胞）之间的相互影响。这些信息将有助于整合有关这一主题的信息，指导进一步的研究和这些疾病的潜在治疗策略。
{"title":"Central role for cholangiocyte pathobiology in cholestatic liver diseases","authors":"Nidhi Jalan-Sakrikar, Maria Eugenia Guicciardi, Steven P. O’Hara, Adiba Azad, Nicholas F. LaRusso, Gregory J. Gores, Robert C. Huebert","doi":"10.1097/hep.0000000000001093","DOIUrl":"https://doi.org/10.1097/hep.0000000000001093","url":null,"abstract":"Cholangiopathies comprise a spectrum of chronic intra- and extrahepatic biliary tract disorders culminating in progressive cholestatic liver injury, fibrosis and often cirrhosis and its sequela. Treatment for these diseases is limited and collectively they are one of the therapeutic “black boxes” in clinical hepatology. The etiopathogenesis of the cholangiopathies likely includes disease-specific mediators, but also common cellular and molecular events driving disease progression (e.g., cholestatic fibrogenesis, inflammation, and duct damage). The common pathways involve cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, which are central to the pathogenesis of these disorders. Current information suggests that cholangiocytes function as a signaling “hub” in biliary tract-associated injury. Herein, we review the pivotal role of cholangiocytes in cholestatic fibrogenesis, focusing on crosstalk between cholangiocytes and portal fibroblasts and hepatic stellate cells. The proclivity of these cells to undergo a senescence-associated secretory phenotype which is pro-inflammatory and –fibrogenic, and the intrinsic intracellular activation pathways resulting in secretion of cytokines and chemokines is reviewed. The crosstalk between cholangiocytes and cells of the innate (neutrophils and macrophages), and adaptive (T-cells and B-cells) immune systems is also examined in detail. The information will help consolidate information on this topic, guide further research and potential therapeutic strategies for these diseases.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160632","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}
Pub Date : 2024-09-09DOI: 10.1097/hep.0000000000001085
Li Fan, Cheng Tian, Wentao Yang, Xiaoli Liu, Yogesh Dhungana, Wenjian Yang, Haiyan Tan, Evan S. Glazer, Jiyang Yu, Junmin Peng, Lichun Ma, Min Ni, Liqin Zhu
Background and Aims: Hexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis. Approach and Results: We found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models. Molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3β to stabilize β-catenin, leading to enhanced stemness of HCC cells. Conclusions: Overall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.
{"title":"HKDC1 promotes liver cancer stemness under hypoxia via stabilizing β-catenin","authors":"Li Fan, Cheng Tian, Wentao Yang, Xiaoli Liu, Yogesh Dhungana, Wenjian Yang, Haiyan Tan, Evan S. Glazer, Jiyang Yu, Junmin Peng, Lichun Ma, Min Ni, Liqin Zhu","doi":"10.1097/hep.0000000000001085","DOIUrl":"https://doi.org/10.1097/hep.0000000000001085","url":null,"abstract":"Background and Aims: Hexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis. Approach and Results: We found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models. Molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3β to stabilize β-catenin, leading to enhanced stemness of HCC cells. Conclusions: Overall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160554","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}
Pub Date : 2024-09-09DOI: 10.1097/hep.0000000000001082
Yi Wu, Linda Li, Wang Li, Ning Li, Xiaoyu Zhang, Lu Zheng, Shaoyu Zhong, Shouqin Lü, Xinyu Shu, Jin Zhou, Ding Ai, Ming Gao, Sijin Liu, Dongyuan Lü, Mian Long
Background & Aims: Partial hepatectomy (PHx)-induced liver regeneration causes the increase in relative blood flow rate within the liver, which dilates hepatic sinusoids and applies mechanical stretch on liver sinusoidal endothelial cells (LSECs). Heparin-binding EGF-like growth factor (HB-EGF) is a crucial growth factor during liver regeneration. We aimed to investigate whether this sinusoidal dilation-induced stretch promotes HB-EGF secretion in LSECs and what the related molecular mechanism is. Approach & Results: In vivo PHx, ex vivo liver perfusion and in vitro LSEC mechanical stretch were applied to detect HB-EGF expression in LSECs and hepatocyte proliferation. Knockdown or inhibition of mechanosensitive proteins were used to unravel the molecular mechanism in response to stretch. This stretch triggers amplitude- and duration-dependent HB-EGF up-regulation in LSECs, which is mediated by Yes-associated protein (YAP) nuclear translocation and binding to TEAD. This YAP translocation is achieved in two ways: On one hand, F-actin polymerization-mediated expansion of nuclear pores promotes YAP entry into nucleus passively. On the other hand, F-actin polymerization up-regulates the expression of BAG family molecular chaperone regulator 3 (BAG-3), which binds with YAP to enter nucleus cooperatively. In this process, β1-integrin serves as a target mechanosensory in stretch-induced signaling pathways. This HB-EGF secretion-promoted liver regeneration after 2/3 PHx is attenuated in endothelial cell-specific Yap1-deficient mice. Conclusions: Our findings indicate that mechanical stretch-induced HB-EGF up-regulation in LSECs via YAP translocation can promote the hepatocyte proliferation during liver regeneration through a mechanocrine manner, which deepens the understanding of the mechanical-biological coupling in liver regeneration.
{"title":"Stretch-induced hepatic endothelial mechanocrine promotes hepatocyte proliferation","authors":"Yi Wu, Linda Li, Wang Li, Ning Li, Xiaoyu Zhang, Lu Zheng, Shaoyu Zhong, Shouqin Lü, Xinyu Shu, Jin Zhou, Ding Ai, Ming Gao, Sijin Liu, Dongyuan Lü, Mian Long","doi":"10.1097/hep.0000000000001082","DOIUrl":"https://doi.org/10.1097/hep.0000000000001082","url":null,"abstract":"Background & Aims: Partial hepatectomy (PHx)-induced liver regeneration causes the increase in relative blood flow rate within the liver, which dilates hepatic sinusoids and applies mechanical stretch on liver sinusoidal endothelial cells (LSECs). Heparin-binding EGF-like growth factor (HB-EGF) is a crucial growth factor during liver regeneration. We aimed to investigate whether this sinusoidal dilation-induced stretch promotes HB-EGF secretion in LSECs and what the related molecular mechanism is. Approach & Results: <jats:italic toggle=\"yes\">In vivo</jats:italic> PHx, <jats:italic toggle=\"yes\">ex vivo</jats:italic> liver perfusion and <jats:italic toggle=\"yes\">in vitro</jats:italic> LSEC mechanical stretch were applied to detect HB-EGF expression in LSECs and hepatocyte proliferation. Knockdown or inhibition of mechanosensitive proteins were used to unravel the molecular mechanism in response to stretch. This stretch triggers amplitude- and duration-dependent HB-EGF up-regulation in LSECs, which is mediated by Yes-associated protein (YAP) nuclear translocation and binding to TEAD. This YAP translocation is achieved in two ways: On one hand, F-actin polymerization-mediated expansion of nuclear pores promotes YAP entry into nucleus passively. On the other hand, F-actin polymerization up-regulates the expression of BAG family molecular chaperone regulator 3 (BAG-3), which binds with YAP to enter nucleus cooperatively. In this process, β1-integrin serves as a target mechanosensory in stretch-induced signaling pathways. This HB-EGF secretion-promoted liver regeneration after 2/3 PHx is attenuated in endothelial cell-specific <jats:italic toggle=\"yes\">Yap1</jats:italic>-deficient mice. Conclusions: Our findings indicate that mechanical stretch-induced HB-EGF up-regulation in LSECs <jats:italic toggle=\"yes\">via</jats:italic> YAP translocation can promote the hepatocyte proliferation during liver regeneration through a mechanocrine manner, which deepens the understanding of the mechanical-biological coupling in liver regeneration.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160597","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}
Pub Date : 2024-09-09DOI: 10.1097/hep.0000000000001089
Cumali Efe, Ellina Lytvyak, Tuğçe Eşkazan, Rodrigo Liberal, Theodoros Androutsakos, Dilara Turan Gökçe, Benedetta Terziroli Beretta-Piccoli, Maciej Janik, Christine Bernsmeier, Pinelopi Arvaniti, Piotr Milkiewicz, Ersin Batıbay, Osman Yüksekyayla, Ilkay Ergenç, Çiğdem Arıkan, Albert Friedrich Stättermayer, Sezgin Barutçu, Mustafa Cengiz, Özlem Gül, Alexandra Heurgue, Michael A. Heneghan, Sumita Verma, Tuğrul Purnak, Murat Törüner, Meral Akdogan Kayhan, Ibrahim Hatemi, Kalliopi Zachou, Guilherme Macedo, Joost P. H. Drenth, Einar Björnsson, Aldo J. Montano-Loza, Staffan Wahlin, Fatima Higuera-de la Tijera
Background and Aims: A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific-recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH. Approach and Results: We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining six patients with active AIH (five on standard and one on both second and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of non-responders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in three patients of group 1. One patient had a severe allergic reaction and two developed anti-infliximab autoantibodies. Conclusion: Our study suggests that infliximab may be an effective and safe rescue therapy in AIH.
{"title":"Efficacy and safety of infliximab in patients with autoimmune hepatitis","authors":"Cumali Efe, Ellina Lytvyak, Tuğçe Eşkazan, Rodrigo Liberal, Theodoros Androutsakos, Dilara Turan Gökçe, Benedetta Terziroli Beretta-Piccoli, Maciej Janik, Christine Bernsmeier, Pinelopi Arvaniti, Piotr Milkiewicz, Ersin Batıbay, Osman Yüksekyayla, Ilkay Ergenç, Çiğdem Arıkan, Albert Friedrich Stättermayer, Sezgin Barutçu, Mustafa Cengiz, Özlem Gül, Alexandra Heurgue, Michael A. Heneghan, Sumita Verma, Tuğrul Purnak, Murat Törüner, Meral Akdogan Kayhan, Ibrahim Hatemi, Kalliopi Zachou, Guilherme Macedo, Joost P. H. Drenth, Einar Björnsson, Aldo J. Montano-Loza, Staffan Wahlin, Fatima Higuera-de la Tijera","doi":"10.1097/hep.0000000000001089","DOIUrl":"https://doi.org/10.1097/hep.0000000000001089","url":null,"abstract":"Background and Aims: A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific-recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH. Approach and Results: We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining six patients with active AIH (five on standard and one on both second and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of non-responders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in three patients of group 1. One patient had a severe allergic reaction and two developed anti-infliximab autoantibodies. Conclusion: Our study suggests that infliximab may be an effective and safe rescue therapy in AIH.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160593","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}
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