Pub Date : 2025-04-09DOI: 10.1097/HEP.0000000000001335
Younis Hazari, Lama Habbouche, Valeria A Garcia Lopez, Hery Urra, Javier Diaz, Giovanni Tamburini, Mateus Milani, Sylvere Durand, Fanny Aprahamian, Reese Baxter, Menghao Huang, X Charlie Dong, Luis Gonzalez-Rojas, Juan Francisco Silva, Ignacio Tapia-Dufey, Helena Vihinen, Vlad Ratziu, Fabienne Foufelle, Jan G Hengstler, Eija Jokitalo, Jessica L Maiers, Lars Plate, Guido Kroemer, Beatrice Bailly-Maitre, Claudio Hetz
Collagen is the main cargo of the secretory pathway, contributing to hepatic fibrogenesis due to extensive accumulation of extracellular matrix. An excess of collagen deposition is a characteristic feature of several chronic liver diseases. Collagen overproduction imposes pressure on the secretory pathway, altering endoplasmic reticulum (ER) proteostasis. Here we investigated the possible contribution of the unfolded protein response UPR, the main adaptive pathway that monitors and adjusts protein production capacity at the ER, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 in the liver using conditional knockout mice reduced liver damage and collagen deposition in models of fibrosis, steatosis, and acute hepatotoxicity. Proteomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1) as a major IRE1-regulated gene, a critical factor involved in collagen maturation. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER, reducing its secretion, and this phenotype is rescued by P4HB/PDIA1 overexpression. Analyses of human MASH samples revealed a positive correlation between IRE1 signaling and P4HB/PDIA1 expression as well as the severity of the disease. Altogether, our results establish a role of the IRE1/P4HB axis in the regulation of collagen production and support its implication in the pathogenesis of liver fibrosis.
{"title":"Targeting the ER stress sensor IRE1 protects the liver from fibrosis through the downregulation of the proteostasis factor P4HB/PDIA1.","authors":"Younis Hazari, Lama Habbouche, Valeria A Garcia Lopez, Hery Urra, Javier Diaz, Giovanni Tamburini, Mateus Milani, Sylvere Durand, Fanny Aprahamian, Reese Baxter, Menghao Huang, X Charlie Dong, Luis Gonzalez-Rojas, Juan Francisco Silva, Ignacio Tapia-Dufey, Helena Vihinen, Vlad Ratziu, Fabienne Foufelle, Jan G Hengstler, Eija Jokitalo, Jessica L Maiers, Lars Plate, Guido Kroemer, Beatrice Bailly-Maitre, Claudio Hetz","doi":"10.1097/HEP.0000000000001335","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001335","url":null,"abstract":"<p><p>Collagen is the main cargo of the secretory pathway, contributing to hepatic fibrogenesis due to extensive accumulation of extracellular matrix. An excess of collagen deposition is a characteristic feature of several chronic liver diseases. Collagen overproduction imposes pressure on the secretory pathway, altering endoplasmic reticulum (ER) proteostasis. Here we investigated the possible contribution of the unfolded protein response UPR, the main adaptive pathway that monitors and adjusts protein production capacity at the ER, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 in the liver using conditional knockout mice reduced liver damage and collagen deposition in models of fibrosis, steatosis, and acute hepatotoxicity. Proteomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1) as a major IRE1-regulated gene, a critical factor involved in collagen maturation. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER, reducing its secretion, and this phenotype is rescued by P4HB/PDIA1 overexpression. Analyses of human MASH samples revealed a positive correlation between IRE1 signaling and P4HB/PDIA1 expression as well as the severity of the disease. Altogether, our results establish a role of the IRE1/P4HB axis in the regulation of collagen production and support its implication in the pathogenesis of liver fibrosis.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810137","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 : 2025-04-08DOI: 10.1097/HEP.0000000000001348
Benjamin J Bruno, Joshua C Weavil, Jonathan Ogle, Nachiappan Chidambaram, Anthony DelConte, Mahesh V Patel, Elizabeth J Carey, Arun J Sanyal, Jennifer C Lai
{"title":"Reply: Considerations on the use of LPCN 1148 in cirrhotic patients with sarcopenia.","authors":"Benjamin J Bruno, Joshua C Weavil, Jonathan Ogle, Nachiappan Chidambaram, Anthony DelConte, Mahesh V Patel, Elizabeth J Carey, Arun J Sanyal, Jennifer C Lai","doi":"10.1097/HEP.0000000000001348","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001348","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810132","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 : 2025-04-08DOI: 10.1097/HEP.0000000000001347
Xinxing Tantai, Lu Li, Shejiao Dai
{"title":"Letter to the editor: Considerations on the use of LPCN 1148 in cirrhotic patients with sarcopenia.","authors":"Xinxing Tantai, Lu Li, Shejiao Dai","doi":"10.1097/HEP.0000000000001347","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001347","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810129","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 : 2025-04-08DOI: 10.1097/HEP.0000000000001349
Xinxing Tantai, Lu Li, Shejiao Dai
{"title":"Letter to the editor: Post-TIPS hemodynamic target adherence fails to improve outcomes in cirrhotic patients.","authors":"Xinxing Tantai, Lu Li, Shejiao Dai","doi":"10.1097/HEP.0000000000001349","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001349","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810130","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 : 2025-04-07DOI: 10.1097/hep.0000000000001344
Maria Mironova, Harish Gopalakrishna, Christopher Koh, David E. Kleiner, Theo Heller
The term porto-sinusoidal vascular disease (PSVD) was introduced in 2019 to describe a group of liver conditions that can lead to portal hypertension (PH) in the absence of cirrhosis or portal vein thrombosis, with or without specific findings on liver histology. The new nomenclature has facilitated the consolidation of knowledge on diseases previously referred to by various terms, including Banti’s disease, non-cirrhotic portal hypertension, non-cirrhotic portal fibrosis, and idiopathic portal hypertension, while excluding certain etiologies like sarcoidosis, congenital hepatic fibrosis, and Budd-Chiari syndrome. The prevalence and recognition of the disorder has been increasing. Advances in diagnostics and treatment have improved life expectancy for patients with associated conditions, such as immunodeficiencies and autoimmune diseases. Similar to cirrhosis, patients with PSVD may experience complications of PH, including variceal bleeding and ascites. However, less is known about its natural history, screening strategies, prognosis, and treatment options. This review discusses methods for assessing PSVD, including clinical and histological features, imaging techniques, and currently available treatments. It also addresses the challenges posed by the new nomenclature and the remaining questions in disease assessment.
{"title":"Portal sinusoidal vascular diseases: Assessment and therapy","authors":"Maria Mironova, Harish Gopalakrishna, Christopher Koh, David E. Kleiner, Theo Heller","doi":"10.1097/hep.0000000000001344","DOIUrl":"https://doi.org/10.1097/hep.0000000000001344","url":null,"abstract":"The term porto-sinusoidal vascular disease (PSVD) was introduced in 2019 to describe a group of liver conditions that can lead to portal hypertension (PH) in the absence of cirrhosis or portal vein thrombosis, with or without specific findings on liver histology. The new nomenclature has facilitated the consolidation of knowledge on diseases previously referred to by various terms, including Banti’s disease, non-cirrhotic portal hypertension, non-cirrhotic portal fibrosis, and idiopathic portal hypertension, while excluding certain etiologies like sarcoidosis, congenital hepatic fibrosis, and Budd-Chiari syndrome. The prevalence and recognition of the disorder has been increasing. Advances in diagnostics and treatment have improved life expectancy for patients with associated conditions, such as immunodeficiencies and autoimmune diseases. Similar to cirrhosis, patients with PSVD may experience complications of PH, including variceal bleeding and ascites. However, less is known about its natural history, screening strategies, prognosis, and treatment options. This review discusses methods for assessing PSVD, including clinical and histological features, imaging techniques, and currently available treatments. It also addresses the challenges posed by the new nomenclature and the remaining questions in disease assessment.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"60 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798359","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 : 2025-04-07DOI: 10.1097/hep.0000000000001338
David Goldberg, Catherine Blandon, Cindy Delgado, Binu John, Ezekiel Emanuel, David Kaplan, Peter Reese
Background & Aims: In the US, and much of the world, prioritization for a deceased donor liver transplant focuses on sickest-first based on allocating organs using the MELD score. There have been calls to instead allocate organs based on transplant survival benefit, but the impact of such a system on the broader waitlist population is unknown. Approach & Results: We performed a simulation study using the Liver Simulated Allocation Model (LSAM) to compare the current US system of liver allocation to one, using different time horizons, focused on: pre-transplant survival only, post-transplant survival only, and survival benefit (difference of post-transplant survival and pre-transplant survival). Changing liver allocation to a survival benefit-based system was simulated to lead to a small improvement in average patient-level post-transplant survival (mean survival over 5-year time horizon of 4.24 y vs. 4.19 y in current system). However, this small improvement was associated with a simulated decrease in transplants and an increase in waitlist mortality of 400 deaths per year. The resulting net benefit overall (pre-transplant deaths and post-transplant survival) was negligible under a survival benefit-based allocation approach. Conclusions: Our simulations predicted that survival benefit-based allocation would only increase post-transplant survival by an average of 18 days per recipient, at the expense of a simulated increase in waitlist mortality of 400 deaths per year. The current practice of liver transplantation, with sickest-first allocation operating in a system where transplant physicians ration organs to maximize outcomes, survival benefit overall is maintained and not compromised.
{"title":"Simulating the impact of survival benefit-based liver transplant organ allocation","authors":"David Goldberg, Catherine Blandon, Cindy Delgado, Binu John, Ezekiel Emanuel, David Kaplan, Peter Reese","doi":"10.1097/hep.0000000000001338","DOIUrl":"https://doi.org/10.1097/hep.0000000000001338","url":null,"abstract":"Background & Aims: In the US, and much of the world, prioritization for a deceased donor liver transplant focuses on sickest-first based on allocating organs using the MELD score. There have been calls to instead allocate organs based on transplant survival benefit, but the impact of such a system on the broader waitlist population is unknown. Approach & Results: We performed a simulation study using the Liver Simulated Allocation Model (LSAM) to compare the current US system of liver allocation to one, using different time horizons, focused on: pre-transplant survival only, post-transplant survival only, and survival benefit (difference of post-transplant survival and pre-transplant survival). Changing liver allocation to a survival benefit-based system was simulated to lead to a small improvement in average patient-level post-transplant survival (mean survival over 5-year time horizon of 4.24 y vs. 4.19 y in current system). However, this small improvement was associated with a simulated decrease in transplants and an increase in waitlist mortality of 400 deaths per year. The resulting net benefit overall (pre-transplant deaths and post-transplant survival) was negligible under a survival benefit-based allocation approach. Conclusions: Our simulations predicted that survival benefit-based allocation would only increase post-transplant survival by an average of 18 days per recipient, at the expense of a simulated increase in waitlist mortality of 400 deaths per year. The current practice of liver transplantation, with sickest-first allocation operating in a system where transplant physicians ration organs to maximize outcomes, survival benefit overall is maintained and not compromised.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"13 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797954","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}
End-stage liver disease (ESLD) represents a critical hepatic condition with high mortality, for which liver transplantation remains the only effective treatment. However, the scarcity of suitable donors results in numerous patients dying while awaiting transplantation. Novel strategies, including cell therapies and technologies mimicking liver organogenesis, offer promising alternatives for treating ESLD by potentially providing new sources of liver grafts. Recently, significant progress has been made in this field, including stem cell transplantation, hepatocyte transplantation, in vitro liver tissue generation, and liver replacement technologies. Several clinical studies have demonstrated that stem cell transplantation and hepatocyte transplantation can prolong patient survival and serve as a bridge to liver transplantation. Furthermore, in vitro liver tissue generation technologies, such as liver organoids and three-dimensional bioprinting, can generate hepatic tissues with sophisticated structures and functions, making them promising transplantation materials. Notably, liver replacement technologies hold considerable potential for producing biologically functional and transplantable liver grafts. In this review, we discuss the fundamental principles and recent advancements in cell therapies and liver organogenesis technologies while also addressing the challenges and future prospects in this rapidly evolving field.
{"title":"Cell therapies and liver organogenesis technologies: Promising strategies for end-stage liver disease.","authors":"Shaoyang Qin, Xiaochen Bo, Hongyuan Liu, Zhishuo Zhang, Zhicong Zhao, Qiang Xia","doi":"10.1097/HEP.0000000000001321","DOIUrl":"https://doi.org/10.1097/HEP.0000000000001321","url":null,"abstract":"<p><p>End-stage liver disease (ESLD) represents a critical hepatic condition with high mortality, for which liver transplantation remains the only effective treatment. However, the scarcity of suitable donors results in numerous patients dying while awaiting transplantation. Novel strategies, including cell therapies and technologies mimicking liver organogenesis, offer promising alternatives for treating ESLD by potentially providing new sources of liver grafts. Recently, significant progress has been made in this field, including stem cell transplantation, hepatocyte transplantation, in vitro liver tissue generation, and liver replacement technologies. Several clinical studies have demonstrated that stem cell transplantation and hepatocyte transplantation can prolong patient survival and serve as a bridge to liver transplantation. Furthermore, in vitro liver tissue generation technologies, such as liver organoids and three-dimensional bioprinting, can generate hepatic tissues with sophisticated structures and functions, making them promising transplantation materials. Notably, liver replacement technologies hold considerable potential for producing biologically functional and transplantable liver grafts. In this review, we discuss the fundamental principles and recent advancements in cell therapies and liver organogenesis technologies while also addressing the challenges and future prospects in this rapidly evolving field.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":""},"PeriodicalIF":12.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770815","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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