Pub Date : 2024-11-22DOI: 10.1097/hep.0000000000001172
Tom H. Karlsen, Kristin Kaasen Jørgensen, Annika Bergquist
It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations, leading to a situation of variable prescription rates depending on local reimbursement policies and physician preference. The difficulty in drug development in PSC is partly related to poor understanding of critical disease processes with failure to identify relevant mechanisms of action of putative drugs. The variable disease course, both intra-individually and between individuals, and lack of robust definitions of what success looks like for clinical trials in PSC have also contributed to the negative outcomes of trials performed. In this review article we will discuss these uncertainties and challenges, building on key previous and ongoing clinical trials. Despite the lack of consensus for an ideal phase II and phase III study design, several trials for diverse compounds are currently ongoing, indicating a shift from therapeutic nihilism towards hope for people with PSC. While waiting for robust efficacy data for drugs currently being tested, the current lack of effective interventions should not motivate prescription of compounds to people with PSC based on low-quality evidence.
{"title":"Medical treatment of primary sclerosing cholangitis: What have we learned and where are we going?","authors":"Tom H. Karlsen, Kristin Kaasen Jørgensen, Annika Bergquist","doi":"10.1097/hep.0000000000001172","DOIUrl":"https://doi.org/10.1097/hep.0000000000001172","url":null,"abstract":"It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations, leading to a situation of variable prescription rates depending on local reimbursement policies and physician preference. The difficulty in drug development in PSC is partly related to poor understanding of critical disease processes with failure to identify relevant mechanisms of action of putative drugs. The variable disease course, both intra-individually and between individuals, and lack of robust definitions of what success looks like for clinical trials in PSC have also contributed to the negative outcomes of trials performed. In this review article we will discuss these uncertainties and challenges, building on key previous and ongoing clinical trials. Despite the lack of consensus for an ideal phase II and phase III study design, several trials for diverse compounds are currently ongoing, indicating a shift from therapeutic nihilism towards hope for people with PSC. While waiting for robust efficacy data for drugs currently being tested, the current lack of effective interventions should not motivate prescription of compounds to people with PSC based on low-quality evidence.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"128 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690694","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}
Objective: Reliable novel non-invasive biomarkers for the diagnosis of advanced liver fibrosis are urgently needed in clinical practice. We aimed to investigate the accuracy of plasma Follistatin-like protein 1 (FSTL-1) in the diagnosis of advanced liver fibrosis in chronic liver diseases. Design: We collected cross-sectional clinical data for a Derivation Cohort (n=86) and a Validation Cohort (n=431), totaling 517 subjects with the liver biopsy. Advanced liver fibrosis was defined by the METAVIR pathological score (F≥3). Dual cut-off values for diagnosis were explored. Results: In the Derivation Cohort, plasma FSTL-1 levels were significantly elevated in patients with advanced liver fibrosis, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval [CI], 0.74-0.92). In the Validation Cohort, plasma FSTL-1 maintained good diagnostic performance, with an AUROC of 0.88 (95% CI, 0.83-0.92). Plasma FSTL-1 levels were significantly associated with individual histological features of METAVIR scoring system, including interface hepatitis, lobular necrosis, and hepatocellular ballooning (p<0.0001). A cut-off value≤0.43 ng/mL was the optimal rule-out threshold, with a sensitivity of 84.62% (95%CI 76.46%-90.30%) and a specificity of 79.51% (95%CI 74.81%-83.53%), while≥0.50 ng/mL was the best rule-in threshold, with a specificity of 86.41% (95%CI 81.06%-90.43%) and a sensitivity of 70.67% (95%CI 64.41%-76.23%). Conclusion: Plasma FSTL-1 has high diagnostic accuracy and could potentially reduce the need for liver biopsy in identifying patients with advanced liver fibrosis.
{"title":"Plasma FSTL-1 as a non-invasive diagnostic biomarker for patients with advanced liver fibrosis","authors":"Wenzhu Li, Yongquan Chi, Xuan Xiao, Junda Li, Minming Sun, Shanke Sun, Wei Xu, Long Zhang, Xiaoguo Li, Feng Cheng, Xiaolong Qi, Jianhua Rao","doi":"10.1097/hep.0000000000001167","DOIUrl":"https://doi.org/10.1097/hep.0000000000001167","url":null,"abstract":"Objective: Reliable novel non-invasive biomarkers for the diagnosis of advanced liver fibrosis are urgently needed in clinical practice. We aimed to investigate the accuracy of plasma Follistatin-like protein 1 (FSTL-1) in the diagnosis of advanced liver fibrosis in chronic liver diseases. Design: We collected cross-sectional clinical data for a Derivation Cohort (n=86) and a Validation Cohort (n=431), totaling 517 subjects with the liver biopsy. Advanced liver fibrosis was defined by the METAVIR pathological score (F≥3). Dual cut-off values for diagnosis were explored. Results: In the Derivation Cohort, plasma FSTL-1 levels were significantly elevated in patients with advanced liver fibrosis, with an area under the receiver operating characteristic curve (AUROC) of 0.83 (95% confidence interval [CI], 0.74-0.92). In the Validation Cohort, plasma FSTL-1 maintained good diagnostic performance, with an AUROC of 0.88 (95% CI, 0.83-0.92). Plasma FSTL-1 levels were significantly associated with individual histological features of METAVIR scoring system, including interface hepatitis, lobular necrosis, and hepatocellular ballooning (<jats:italic toggle=\"yes\">p</jats:italic><0.0001). A cut-off value≤0.43 ng/mL was the optimal rule-out threshold, with a sensitivity of 84.62% (95%CI 76.46%-90.30%) and a specificity of 79.51% (95%CI 74.81%-83.53%), while≥0.50 ng/mL was the best rule-in threshold, with a specificity of 86.41% (95%CI 81.06%-90.43%) and a sensitivity of 70.67% (95%CI 64.41%-76.23%). Conclusion: Plasma FSTL-1 has high diagnostic accuracy and could potentially reduce the need for liver biopsy in identifying patients with advanced liver fibrosis.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"8 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684436","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 : 2024-11-21DOI: 10.1097/hep.0000000000001163
Bernhard Scheiner, Beodeul Kang, Lorenz Balcar, Iuliana-Pompilia Radu, Florian P. Reiter, Gordan Adžić, Jiang Guo, Xu Gao, Xiao Yuan, Long Cheng, Joao Gorgulho, Michael Schultheiss, Frederik Peeters, Florian Hucke, Najib Ben Khaled, Ignazio Piseddu, Alexander Philipp, Friedrich Sinner, Antonio D’Alessio, Katharina Pomej, Anna Saborowski, Melanie Bathon, Birgit Schwacha-Eipper, Valentina Zarka, Katharina Lampichler, Naoshi Nishida, Pei-Chang Lee, Anja Krall, Anwaar Saeed, Vera Himmelsbach, Giulia Tesini, Yi-Hsiang Huang, Caterina Vivaldi, Gianluca Masi, Arndt Vogel, Kornelius Schulze, Michael Trauner, Angela Djanani, Rudolf Stauber, Masatoshi Kudo, Neehar D. Parikh, Jean-François Dufour, Juraj Prejac, Andreas Geier, Bertram Bengsch, Johann von Felden, Marino Venerito, Arndt Weinmann, Markus Peck-Radosavljevic, Fabian Finkelmeier, Jeroen Dekervel, Fanpu Ji, Hung-Wei Wang, Lorenza Rimassa, David J. Pinato, Mohamed Bouattour, Hong Jae Chon, Matthias Pinter
Background & Aims: The outcome of patients with hepatocellular carcinoma (HCC) who achieved complete response (CR) to immune-checkpoint-inhibitor (ICI)-based systemic therapies is unclear. Approach & Results: Retrospective study of patients with HCC who had CR according to mRECIST to ICI-based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated with ICI-based non-curative systemic therapies, 174 (4.4%) achieved CR according to mRECIST (CR-mRECIST) and 97 (2.5%) had CR according to RECISTv1.1 (CR-RECISTv1.1) as well. The mean age of the total cohort (male, 85%; BCLC-C, 70%) was 65.9±9.8 years. The majority (83%) received ICI-based combination therapies. Median follow-up was 32.2 (95%CI, 29.9-34.4) months. One- and 3-year overall survival (OS) rates were 98% and 86%. One- and 3-year recurrence-free survival (RFS) rates were excellent in patients with CR-mRECIST-only and CR-RECISTv1.1 (78% and 55%; 70% and 42%). Among patients who discontinued ICIs for reasons other than recurrence, those who received immunotherapy for ≥6 months after first mRECIST CR had a longer RFS than those who discontinued immunotherapy earlier (p=0.008). Of 9 patients who underwent curative surgical conversion therapy, 8 (89%) had pathological CR (CR-RECISTv1.1, n= 2/2; CR-mRECIST-only, n= 6/7). Conclusion: OS and RFS of patients with CR-mRECIST-only and CR-RECISTv1.1 were excellent, and 6 of 7 patients with CR-mRECIST-only who underwent surgical conversion therapy had pathological CR. Despite potential limitations, these findings support the use of mRECIST in the context of immunotherapy for clinical decision-making. When considering ICI discontinuation, treatment for at least 6 months beyond CR seems advisable.
{"title":"Outcome and management of patients with hepatocellular carcinoma who achieved complete response to immunotherapy-based systemic therapy","authors":"Bernhard Scheiner, Beodeul Kang, Lorenz Balcar, Iuliana-Pompilia Radu, Florian P. Reiter, Gordan Adžić, Jiang Guo, Xu Gao, Xiao Yuan, Long Cheng, Joao Gorgulho, Michael Schultheiss, Frederik Peeters, Florian Hucke, Najib Ben Khaled, Ignazio Piseddu, Alexander Philipp, Friedrich Sinner, Antonio D’Alessio, Katharina Pomej, Anna Saborowski, Melanie Bathon, Birgit Schwacha-Eipper, Valentina Zarka, Katharina Lampichler, Naoshi Nishida, Pei-Chang Lee, Anja Krall, Anwaar Saeed, Vera Himmelsbach, Giulia Tesini, Yi-Hsiang Huang, Caterina Vivaldi, Gianluca Masi, Arndt Vogel, Kornelius Schulze, Michael Trauner, Angela Djanani, Rudolf Stauber, Masatoshi Kudo, Neehar D. Parikh, Jean-François Dufour, Juraj Prejac, Andreas Geier, Bertram Bengsch, Johann von Felden, Marino Venerito, Arndt Weinmann, Markus Peck-Radosavljevic, Fabian Finkelmeier, Jeroen Dekervel, Fanpu Ji, Hung-Wei Wang, Lorenza Rimassa, David J. Pinato, Mohamed Bouattour, Hong Jae Chon, Matthias Pinter","doi":"10.1097/hep.0000000000001163","DOIUrl":"https://doi.org/10.1097/hep.0000000000001163","url":null,"abstract":"Background & Aims: The outcome of patients with hepatocellular carcinoma (HCC) who achieved complete response (CR) to immune-checkpoint-inhibitor (ICI)-based systemic therapies is unclear. Approach & Results: Retrospective study of patients with HCC who had CR according to mRECIST to ICI-based systemic therapies from 28 centers in Asia, Europe, and the United States. Of 3933 patients with HCC treated with ICI-based non-curative systemic therapies, 174 (4.4%) achieved CR according to mRECIST (CR-mRECIST) and 97 (2.5%) had CR according to RECISTv1.1 (CR-RECISTv1.1) as well. The mean age of the total cohort (male, 85%; BCLC-C, 70%) was 65.9±9.8 years. The majority (83%) received ICI-based combination therapies. Median follow-up was 32.2 (95%CI, 29.9-34.4) months. One- and 3-year overall survival (OS) rates were 98% and 86%. One- and 3-year recurrence-free survival (RFS) rates were excellent in patients with CR-mRECIST-only and CR-RECISTv1.1 (78% and 55%; 70% and 42%). Among patients who discontinued ICIs for reasons other than recurrence, those who received immunotherapy for ≥6 months after first mRECIST CR had a longer RFS than those who discontinued immunotherapy earlier (<jats:italic toggle=\"yes\">p</jats:italic>=0.008). Of 9 patients who underwent curative surgical conversion therapy, 8 (89%) had pathological CR (CR-RECISTv1.1, n= 2/2; CR-mRECIST-only, n= 6/7). Conclusion: OS and RFS of patients with CR-mRECIST-only and CR-RECISTv1.1 were excellent, and 6 of 7 patients with CR-mRECIST-only who underwent surgical conversion therapy had pathological CR. Despite potential limitations, these findings support the use of mRECIST in the context of immunotherapy for clinical decision-making. When considering ICI discontinuation, treatment for at least 6 months beyond CR seems advisable.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"63 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684453","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 : 2024-11-21DOI: 10.1097/hep.0000000000001171
Jiashu Han, Dan Shan
{"title":"Letter to the Editor: Refining the role of HAF in hepatocellular carcinoma","authors":"Jiashu Han, Dan Shan","doi":"10.1097/hep.0000000000001171","DOIUrl":"https://doi.org/10.1097/hep.0000000000001171","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"15 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684434","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 : 2024-11-21DOI: 10.1097/hep.0000000000001173
Scott A. Summers, Mei Yee Koh
{"title":"Reply: Refining the role of HAF in hepatocellular carcinoma","authors":"Scott A. Summers, Mei Yee Koh","doi":"10.1097/hep.0000000000001173","DOIUrl":"https://doi.org/10.1097/hep.0000000000001173","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"71 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684433","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 : 2024-11-20DOI: 10.1097/hep.0000000000001139
{"title":"Erratum: Expression and functional significance of Twist1 in hepatocellular carcinoma: Its role in vasculogenic mimicry","authors":"","doi":"10.1097/hep.0000000000001139","DOIUrl":"https://doi.org/10.1097/hep.0000000000001139","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"38 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678309","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 : 2024-11-15DOI: 10.1097/hep.0000000000001119
Michael R. Lucey
{"title":"Video introduction: Special issue on alcohol use disorder and liver disease","authors":"Michael R. Lucey","doi":"10.1097/hep.0000000000001119","DOIUrl":"https://doi.org/10.1097/hep.0000000000001119","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"46 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637187","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 : 2024-11-14DOI: 10.1097/hep.0000000000001147
Zhongqiu Pang, Hui Zhang, Shaoqin Zheng, Xueling Yang, Chang Liu, Qing Han, Yi Chen, Zexu Li, Xi Zhang, Liu Cao, Qiang Wang, Yanli Cao, Xun Sun, Pu Zhao, Xuexin Li, Qianqian Zheng, Ren Sheng
Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though being mild at early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine. Approach and Results: Herein, we identified Cyclin-dependent kinase like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific Cdkl3 ablation developed severe MASLD-related hepatic inflammation, fibrosis and diabetes. Mechanism-wise, CDKL3 directly phosphorylates FoxO1 on an unconventional site for the ubiquitination-dependent degradation of FoxO1, thereby remarkably alleviating glycogen and lipid accumulation and essentially preventing the onset of higher MASLD stages. Moreover, hepatic CDKL3 is a direct target gene of HNF4α. HNF4α is inhibited during MASLD, which led to diminished CDKL3 expression. The CDKL3-mediated crosstalk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression. Conclusions: We unearthed an alternative but critical regulatory path of FoxO1 by HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment.
{"title":"HNF4α-CDKL3 axis restricts MASLD progression by targeting FoxO1 via non-canonical phosphorylation","authors":"Zhongqiu Pang, Hui Zhang, Shaoqin Zheng, Xueling Yang, Chang Liu, Qing Han, Yi Chen, Zexu Li, Xi Zhang, Liu Cao, Qiang Wang, Yanli Cao, Xun Sun, Pu Zhao, Xuexin Li, Qianqian Zheng, Ren Sheng","doi":"10.1097/hep.0000000000001147","DOIUrl":"https://doi.org/10.1097/hep.0000000000001147","url":null,"abstract":"Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide disease with a broad spectrum of symptoms. Though being mild at early stages, further development of MASLD causes steatohepatitis, cirrhosis, liver cancers and accompanied diabetes. Discovery of the critical regulators in MASLD progression hold great values in both basic and translational medicine. Approach and Results: Herein, we identified Cyclin-dependent kinase like 3 (CDKL3) as a primary guardian against MASLD progression. Mice with liver-specific <jats:italic toggle=\"yes\">Cdkl3</jats:italic> ablation developed severe MASLD-related hepatic inflammation, fibrosis and diabetes. Mechanism-wise, CDKL3 directly phosphorylates FoxO1 on an unconventional site for the ubiquitination-dependent degradation of FoxO1, thereby remarkably alleviating glycogen and lipid accumulation and essentially preventing the onset of higher MASLD stages. Moreover, hepatic <jats:italic toggle=\"yes\">CDKL3</jats:italic> is a direct target gene of HNF4α. HNF4α is inhibited during MASLD, which led to diminished <jats:italic toggle=\"yes\">CDKL3</jats:italic> expression. The CDKL3-mediated crosstalk of HNF4α and FoxO1 hence forms a feedback loop in MASLD progression. Conclusions: We unearthed an alternative but critical regulatory path of FoxO1 by HNF4α-CDKL3 axis. CDKL3 serves as a guardian against MASLD and also may function as a prognosis indicator of FoxO1 inhibitor in MASLD treatment.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"20 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637215","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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