Pub Date : 2025-12-17DOI: 10.1016/j.jhepr.2025.101713
Dong Yun Kim , Hyun-Soo Zhang , Jae Seung Lee , Hye Won Lee , Mi Na Kim , Beom Kyung Kim , Seung Up Kim , Do Young Kim , Sang Hoon Ahn , Hyun Woong Lee , Heon Yung Gee , Jung Il Lee , Jun Yong Park
<div><h3>Background & Aims</h3><div>Genetic information is not yet used for the clinical diagnosis of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we investigated whether incorporating genetic information regarding <em>PNPLA3</em> and <em>TM6SF2</em> into existing non-invasive fibrosis scoring systems could improve their predictive accuracy, particularly in patients with type 2 diabetes mellitus (T2DM), a high-risk population for MASLD-related complications.</div></div><div><h3>Methods</h3><div>Data were collected from a cohort of 637 patients with biopsy-proven MASLD. All participants underwent liver stiffness measurement (LSM), serum marker analysis, and genotyping for <em>PNPLA3</em> (rs738409), <em>TM6SF2</em> (rs58542926), and other relevant single nucleotide polymorphisms. We evaluated the benefit of adding genetic information to existing non-invasive tests (NITs) – including the Agile 3+, Fibrosis-4 (FIB-4) index, and NAFLD fibrosis score (NFS).</div></div><div><h3>Results</h3><div>Decision curve analysis in the validation cohort (n = 238) demonstrated that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information marginally enhanced net clinical benefit across all three models over a range of threshold probabilities (10-50%). At a 30% threshold probability, the net benefit of genotype-enhanced models increased from 22.0 to 22.8 per 100 patients for Agile 3+, from 17.0 to 18.4 for NFS, and from 13.0 to 16.9 for FIB-4. In the T2DM subgroup (n = 121), genotype incorporation led to small but statistically significant improvements in discrimination for NFS (AUROC increase: 0.053, <em>p</em> = 0.001) and FIB-4 (AUROC increase: 0.058, <em>p</em> = 0.010), while Agile 3+ showed a favorable trend (AUROC increase: 0.016, <em>p</em> = 0.058).</div></div><div><h3>Conclusions</h3><div>Incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis scoring systems for MASLD provides limited but measurable improvements, with statistically significant AUROC gains for NFS and FIB-4, particularly among patients with T2DM. Further validation is required before routine clinical implementation can be recommended.</div></div><div><h3>Impact and implications</h3><div>Our research demonstrates that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis tests provides modest but measurable improvements in clinical utility for patients with metabolic dysfunction-associated steatotic liver disease, particularly those with type 2 diabetes mellitus – a high-risk population prone to accelerated fibrosis progression and liver-related complications. These findings are relevant for clinicians managing these patients, as genotype-enhanced models (particularly NAFLD fibrosis score and Fibrosis-4 index) showed statistically significant improvements in diagnostic accuracy, enabling better identification of patients requiri
{"title":"Integration of PNPLA3 and TM6SF2 genotypes provides incremental improvement in advanced fibrosis prediction among MASLD patients with type 2 diabetes mellitus","authors":"Dong Yun Kim , Hyun-Soo Zhang , Jae Seung Lee , Hye Won Lee , Mi Na Kim , Beom Kyung Kim , Seung Up Kim , Do Young Kim , Sang Hoon Ahn , Hyun Woong Lee , Heon Yung Gee , Jung Il Lee , Jun Yong Park","doi":"10.1016/j.jhepr.2025.101713","DOIUrl":"10.1016/j.jhepr.2025.101713","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Genetic information is not yet used for the clinical diagnosis of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we investigated whether incorporating genetic information regarding <em>PNPLA3</em> and <em>TM6SF2</em> into existing non-invasive fibrosis scoring systems could improve their predictive accuracy, particularly in patients with type 2 diabetes mellitus (T2DM), a high-risk population for MASLD-related complications.</div></div><div><h3>Methods</h3><div>Data were collected from a cohort of 637 patients with biopsy-proven MASLD. All participants underwent liver stiffness measurement (LSM), serum marker analysis, and genotyping for <em>PNPLA3</em> (rs738409), <em>TM6SF2</em> (rs58542926), and other relevant single nucleotide polymorphisms. We evaluated the benefit of adding genetic information to existing non-invasive tests (NITs) – including the Agile 3+, Fibrosis-4 (FIB-4) index, and NAFLD fibrosis score (NFS).</div></div><div><h3>Results</h3><div>Decision curve analysis in the validation cohort (n = 238) demonstrated that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information marginally enhanced net clinical benefit across all three models over a range of threshold probabilities (10-50%). At a 30% threshold probability, the net benefit of genotype-enhanced models increased from 22.0 to 22.8 per 100 patients for Agile 3+, from 17.0 to 18.4 for NFS, and from 13.0 to 16.9 for FIB-4. In the T2DM subgroup (n = 121), genotype incorporation led to small but statistically significant improvements in discrimination for NFS (AUROC increase: 0.053, <em>p</em> = 0.001) and FIB-4 (AUROC increase: 0.058, <em>p</em> = 0.010), while Agile 3+ showed a favorable trend (AUROC increase: 0.016, <em>p</em> = 0.058).</div></div><div><h3>Conclusions</h3><div>Incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis scoring systems for MASLD provides limited but measurable improvements, with statistically significant AUROC gains for NFS and FIB-4, particularly among patients with T2DM. Further validation is required before routine clinical implementation can be recommended.</div></div><div><h3>Impact and implications</h3><div>Our research demonstrates that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis tests provides modest but measurable improvements in clinical utility for patients with metabolic dysfunction-associated steatotic liver disease, particularly those with type 2 diabetes mellitus – a high-risk population prone to accelerated fibrosis progression and liver-related complications. These findings are relevant for clinicians managing these patients, as genotype-enhanced models (particularly NAFLD fibrosis score and Fibrosis-4 index) showed statistically significant improvements in diagnostic accuracy, enabling better identification of patients requiri","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101713"},"PeriodicalIF":7.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034363","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 : 2025-12-06DOI: 10.1016/j.jhepr.2025.101706
Theresa Kirchner , Norman Junge , Nicole Henjes , Stephanie Loges , Muhammed Yuksel , Wojciech Janczyk , Claudine Lalanne , Kalliopi Zachou , Ye H. Oo , Jérôme Gournay , Simon Pape , Joost PH. Drenth , Amédée Renand , George N. Dalekos , Luigi Muratori , Piotr Socha , Cigdem Arikan , Yun Ma , Heiner Wedemeyer , Ulrich Baumann , Richard Taubert
<div><h3>Background & Aims</h3><div>The diagnosis of juvenile autoimmune hepatitis (AIH) is challenging given its heterogeneous presentation. Autoantibodies, typically detected by immunofluorescence testing (IFT), together with liver histology, represent key diagnostic features. Polyreactive immunoglobulin G (pIgG) has recently emerged as a complementary biomarker in AIH. This retrospective multicentre study aimed to compare ELISA-based autoantibody testing and IFT on HEp-2 cells with the gold standard of IFT on rodent tissue sections in children with autoimmune and non-autoimmune liver diseases.</div></div><div><h3>Methods</h3><div>Autoantibody detection was performed centrally at Hannover Medical School using three commercial antinuclear antibody (ANA) ELISAs, one commercial F-actin ELISA, one in-house pIgG ELISA, and IFT on HEp-2 cells, in comparison to the gold standard of IFT on rodent tissue sections. Samples from children with AIH (n = 69), autoimmune sclerosing cholangitis (AISC; n = 13) and other liver diseases (n = 120) were analysed from nine European centres.</div></div><div><h3>Results</h3><div>The AUCs for the detection of AIH/AISC were moderate to good for ANA detection by IFT (gold standard of rodent tissue AUC: 0.748; HEp-2 AUC: 0.756) and were comparable to ELISA-based detection (0.622-0.772). Anti-smooth muscle antibody (SMA) IFT on rodent tissue yielded an AUC of 0.694. Specificity was increased to 100% by including the SMA staining pattern of vessels, glomeruli and tubules. ELISA-based quantification of anti-F-actin (AUC = 0.868) and pIgG (AUC = 0.844) showed the highest AUCs. While the majority of F-actin–positive children were pIgG-positive (80.3%), pIgG was also detected in 52.4% of F-actin–negative children with AIH.</div></div><div><h3>Conclusion</h3><div>ELISA-based assays provide reliable ANA detection comparable to IFT. Anti-F-actin and pIgG ELISAs showed the highest accuracy for predicting juvenile AIH/AISC and may complement existing diagnostic criteria.</div></div><div><h3>Impact and implications</h3><div>Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) are rare paediatric liver diseases that can be difficult to distinguish from other hepatopathies. Autoantibody testing is central to diagnosis, yet paediatric performance across platforms has been poorly standardised and sparsely reported. In this multicentre comparison (202 sera from nine expert centres across eight European countries), indirect immunofluorescence (IFT) on rodent tissue showed suboptimal discrimination at the commonly advocated 1:20 cut-off, whereas accuracy for ANA and SMA improved markedly at 1:320. ANA detection by IFT on HEp-2 cells and by ELISA was comparable to rodent tissue IFT. ELISAs for F-actin and pIgG achieved the highest AUCs for identifying AIH/AISC and may complement current diagnostics. Substantial inter-platform discordance for ANA underscores the need for harmonisation. Collectively, these data support t
{"title":"Complementary use of autoantibody detection methods facilitates diagnosis of juvenile autoimmune hepatitis and autoimmune sclerosing cholangitis","authors":"Theresa Kirchner , Norman Junge , Nicole Henjes , Stephanie Loges , Muhammed Yuksel , Wojciech Janczyk , Claudine Lalanne , Kalliopi Zachou , Ye H. Oo , Jérôme Gournay , Simon Pape , Joost PH. Drenth , Amédée Renand , George N. Dalekos , Luigi Muratori , Piotr Socha , Cigdem Arikan , Yun Ma , Heiner Wedemeyer , Ulrich Baumann , Richard Taubert","doi":"10.1016/j.jhepr.2025.101706","DOIUrl":"10.1016/j.jhepr.2025.101706","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The diagnosis of juvenile autoimmune hepatitis (AIH) is challenging given its heterogeneous presentation. Autoantibodies, typically detected by immunofluorescence testing (IFT), together with liver histology, represent key diagnostic features. Polyreactive immunoglobulin G (pIgG) has recently emerged as a complementary biomarker in AIH. This retrospective multicentre study aimed to compare ELISA-based autoantibody testing and IFT on HEp-2 cells with the gold standard of IFT on rodent tissue sections in children with autoimmune and non-autoimmune liver diseases.</div></div><div><h3>Methods</h3><div>Autoantibody detection was performed centrally at Hannover Medical School using three commercial antinuclear antibody (ANA) ELISAs, one commercial F-actin ELISA, one in-house pIgG ELISA, and IFT on HEp-2 cells, in comparison to the gold standard of IFT on rodent tissue sections. Samples from children with AIH (n = 69), autoimmune sclerosing cholangitis (AISC; n = 13) and other liver diseases (n = 120) were analysed from nine European centres.</div></div><div><h3>Results</h3><div>The AUCs for the detection of AIH/AISC were moderate to good for ANA detection by IFT (gold standard of rodent tissue AUC: 0.748; HEp-2 AUC: 0.756) and were comparable to ELISA-based detection (0.622-0.772). Anti-smooth muscle antibody (SMA) IFT on rodent tissue yielded an AUC of 0.694. Specificity was increased to 100% by including the SMA staining pattern of vessels, glomeruli and tubules. ELISA-based quantification of anti-F-actin (AUC = 0.868) and pIgG (AUC = 0.844) showed the highest AUCs. While the majority of F-actin–positive children were pIgG-positive (80.3%), pIgG was also detected in 52.4% of F-actin–negative children with AIH.</div></div><div><h3>Conclusion</h3><div>ELISA-based assays provide reliable ANA detection comparable to IFT. Anti-F-actin and pIgG ELISAs showed the highest accuracy for predicting juvenile AIH/AISC and may complement existing diagnostic criteria.</div></div><div><h3>Impact and implications</h3><div>Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) are rare paediatric liver diseases that can be difficult to distinguish from other hepatopathies. Autoantibody testing is central to diagnosis, yet paediatric performance across platforms has been poorly standardised and sparsely reported. In this multicentre comparison (202 sera from nine expert centres across eight European countries), indirect immunofluorescence (IFT) on rodent tissue showed suboptimal discrimination at the commonly advocated 1:20 cut-off, whereas accuracy for ANA and SMA improved markedly at 1:320. ANA detection by IFT on HEp-2 cells and by ELISA was comparable to rodent tissue IFT. ELISAs for F-actin and pIgG achieved the highest AUCs for identifying AIH/AISC and may complement current diagnostics. Substantial inter-platform discordance for ANA underscores the need for harmonisation. Collectively, these data support t","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101706"},"PeriodicalIF":7.5,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034309","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 : 2025-12-05DOI: 10.1016/j.jhepr.2025.101628
Rakesh K. Arya , Emily Huang , Megan R. McMullen , Kyle L. Poulsen , Jianguo Wu , Jared Travers , Evi Paouri , Dimitrios Davalos , Laura E. Nagy
<div><h3>Background & Aims</h3><div>Endoplasmic reticulum (ER) stress is an important contributor to liver disease progression, including alcohol-associated liver disease. Although receptor-interacting protein kinase-3 (RIP3) and mixed lineage kinase domain-like pseudokinase (MLKL) are known for their roles in necroptosis, emerging evidence highlights their non-canonical functions in metabolic regulation and cellular-stress responses. However, their specific role in regulating hepatic ER stress remains unclear. This study investigates how RIP3 and MLKL regulate ER stress pathways during chronic ethanol exposure and pharmacological ER stress induction.</div></div><div><h3>Methods</h3><div><em>Rip3</em><sup><em>-/-</em></sup>, <em>Rip3</em><sup><em>K51A/K51A</em></sup>, and <em>Mlkl</em><sup><em>-/-</em></sup> mice alongside wild-type (WT) and pharmacological necroptosis inhibitors were used to study the role of RIP3 and MLKL in modulating ER stress. Chronic ethanol feeding and pharmacological agents were utilized to induce ER stress <em>in vivo</em> and in isolated primary hepatocytes. ER stress markers were assessed by qPCR and Western blot, ER expansion by confocal microscopy, and viability by MTS assay. (n = 8–11 for ethanol; n = 5–8 for tunicamycin; n = 3–12 for hepatocyte experiments).</div></div><div><h3>Results</h3><div>Chronic ethanol increased expression of ER stress markers in WT mice; this response was attenuated in <em>Rip3</em><sup><em>-/-</em></sup> mice (<em>p</em> <0.05). Tunicamycin exposure increased hepatic ER stress markers in WT mice; this response was diminished in <em>Rip3</em><sup><em>-/-</em></sup>, <em>Rip3</em><sup><em>K51A/K51A</em>,</sup> and <em>Mlkl</em><sup><em>-/-</em></sup> mice (<em>p</em> <0.05). In primary hepatocytes, genetic and pharmacological inhibition of RIP3 and MLKL also reduced thapsigargin-induced ER stress responses (<em>p</em> <0.05). Hepatocytes lacking <em>Rip3</em>, RIP3 kinase activity, or <em>Mlkl</em> showed enhanced viability (<em>p</em> <0.05) and greater ER expansion and sheet formation compared to WT hepatocytes (<em>p</em> <0.05), suggesting improved adaptive remodeling.</div></div><div><h3>Conclusions</h3><div>This study highlights a novel function of RIP3 and MLKL in regulating hepatic ER stress responses, expanding their known roles beyond programmed necrosis.</div></div><div><h3>Impact and implications</h3><div>This study provides new mechanistic insight into how RIP3 and MLKL regulate hepatic ER stress responses, extending their roles beyond necroptosis. By demonstrating that genetic or pharmacological inhibition of <em>Rip3</em>, RIP3 kinase activity and <em>Mlkl</em> attenuates ER stress signaling, reduces cell death, and promotes adaptive ER remodeling, our findings identify these proteins as key modulators of hepatocyte survival under stress. These results are important for researchers and clinicians focused on alcohol-associated liver disease and other ER stre
{"title":"RIP3 and MLKL regulate ER stress in alcohol-associated liver disease and pharmacological ER stress models: Insights beyond necroptosis","authors":"Rakesh K. Arya , Emily Huang , Megan R. McMullen , Kyle L. Poulsen , Jianguo Wu , Jared Travers , Evi Paouri , Dimitrios Davalos , Laura E. Nagy","doi":"10.1016/j.jhepr.2025.101628","DOIUrl":"10.1016/j.jhepr.2025.101628","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Endoplasmic reticulum (ER) stress is an important contributor to liver disease progression, including alcohol-associated liver disease. Although receptor-interacting protein kinase-3 (RIP3) and mixed lineage kinase domain-like pseudokinase (MLKL) are known for their roles in necroptosis, emerging evidence highlights their non-canonical functions in metabolic regulation and cellular-stress responses. However, their specific role in regulating hepatic ER stress remains unclear. This study investigates how RIP3 and MLKL regulate ER stress pathways during chronic ethanol exposure and pharmacological ER stress induction.</div></div><div><h3>Methods</h3><div><em>Rip3</em><sup><em>-/-</em></sup>, <em>Rip3</em><sup><em>K51A/K51A</em></sup>, and <em>Mlkl</em><sup><em>-/-</em></sup> mice alongside wild-type (WT) and pharmacological necroptosis inhibitors were used to study the role of RIP3 and MLKL in modulating ER stress. Chronic ethanol feeding and pharmacological agents were utilized to induce ER stress <em>in vivo</em> and in isolated primary hepatocytes. ER stress markers were assessed by qPCR and Western blot, ER expansion by confocal microscopy, and viability by MTS assay. (n = 8–11 for ethanol; n = 5–8 for tunicamycin; n = 3–12 for hepatocyte experiments).</div></div><div><h3>Results</h3><div>Chronic ethanol increased expression of ER stress markers in WT mice; this response was attenuated in <em>Rip3</em><sup><em>-/-</em></sup> mice (<em>p</em> <0.05). Tunicamycin exposure increased hepatic ER stress markers in WT mice; this response was diminished in <em>Rip3</em><sup><em>-/-</em></sup>, <em>Rip3</em><sup><em>K51A/K51A</em>,</sup> and <em>Mlkl</em><sup><em>-/-</em></sup> mice (<em>p</em> <0.05). In primary hepatocytes, genetic and pharmacological inhibition of RIP3 and MLKL also reduced thapsigargin-induced ER stress responses (<em>p</em> <0.05). Hepatocytes lacking <em>Rip3</em>, RIP3 kinase activity, or <em>Mlkl</em> showed enhanced viability (<em>p</em> <0.05) and greater ER expansion and sheet formation compared to WT hepatocytes (<em>p</em> <0.05), suggesting improved adaptive remodeling.</div></div><div><h3>Conclusions</h3><div>This study highlights a novel function of RIP3 and MLKL in regulating hepatic ER stress responses, expanding their known roles beyond programmed necrosis.</div></div><div><h3>Impact and implications</h3><div>This study provides new mechanistic insight into how RIP3 and MLKL regulate hepatic ER stress responses, extending their roles beyond necroptosis. By demonstrating that genetic or pharmacological inhibition of <em>Rip3</em>, RIP3 kinase activity and <em>Mlkl</em> attenuates ER stress signaling, reduces cell death, and promotes adaptive ER remodeling, our findings identify these proteins as key modulators of hepatocyte survival under stress. These results are important for researchers and clinicians focused on alcohol-associated liver disease and other ER stre","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101628"},"PeriodicalIF":7.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034364","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}
Steatotic liver disease (SLD), which encompasses alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and MASLD with increased alcohol intake (MetALD), is now the leading cause of liver transplantation (LT) worldwide. ALD and MASLD have become the first and second leading indications for LT (41% and 12% in Europe, respectively), with MetALD accounting for a rapidly increasing proportion of transplants (8-10%). Candidate evaluation must be multidisciplinary and account for the complex interplay between alcohol use, metabolic syndrome, cancer, cardiovascular disease, and obesity. Early LT for severe alcohol-related hepatitis is an established option in selected patients after the evaluation of alcohol use disorder (AUD) by addiction specialists. While the duration of abstinence remains a predictor of post-LT alcohol relapse in ALD recipients, an integrative assessment is required, and prolonged abstinence is no longer an absolute prerequisite. Cardiovascular risk stratification and assessment of frailty and metabolic comorbidities are essential. Obesity management includes lifestyle interventions, pharmacotherapy, and bariatric surgery in selected cases. SLD recipients generally demonstrate good 5-year survival (>75%), but long-term outcomes are influenced by cardiovascular events, malignancies, and alcohol relapse, with survival falling below 65% at 10 years. Early detection and management of alcohol relapse after LT are critical to optimising long-term outcomes. MASLD recurrence is common, but its impact on graft survival appears modest. Management focuses on controlling cardiometabolic risk factors, with emerging roles for GLP-1 receptor agonists and multidisciplinary care. Donor SLD is a growing concern. Normothermic and hypothermic oxygenated perfusion substantially expand donor utilisation – with up to ∼70% of marginal or previously discarded grafts now salvaged – and improve graft viability by reducing early allograft dysfunction by 60%. Further research is needed to refine risk stratification, develop effective pharmacotherapies, and optimise perfusion protocols for steatotic grafts.
{"title":"Steatotic liver disease and liver transplantation: Candidate selection and post-transplant management","authors":"Jordi Colmenero , Gonzalo Crespo , Line Carolle Ntandja Wandji , Yiliam Fundora , Alexandre Louvet","doi":"10.1016/j.jhepr.2025.101704","DOIUrl":"10.1016/j.jhepr.2025.101704","url":null,"abstract":"<div><div>Steatotic liver disease (SLD), which encompasses alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and MASLD with increased alcohol intake (MetALD), is now the leading cause of liver transplantation (LT) worldwide. ALD and MASLD have become the first and second leading indications for LT (41% and 12% in Europe, respectively), with MetALD accounting for a rapidly increasing proportion of transplants (8-10%). Candidate evaluation must be multidisciplinary and account for the complex interplay between alcohol use, metabolic syndrome, cancer, cardiovascular disease, and obesity. Early LT for severe alcohol-related hepatitis is an established option in selected patients after the evaluation of alcohol use disorder (AUD) by addiction specialists. While the duration of abstinence remains a predictor of post-LT alcohol relapse in ALD recipients, an integrative assessment is required, and prolonged abstinence is no longer an absolute prerequisite. Cardiovascular risk stratification and assessment of frailty and metabolic comorbidities are essential. Obesity management includes lifestyle interventions, pharmacotherapy, and bariatric surgery in selected cases. SLD recipients generally demonstrate good 5-year survival (>75%), but long-term outcomes are influenced by cardiovascular events, malignancies, and alcohol relapse, with survival falling below 65% at 10 years. Early detection and management of alcohol relapse after LT are critical to optimising long-term outcomes. MASLD recurrence is common, but its impact on graft survival appears modest. Management focuses on controlling cardiometabolic risk factors, with emerging roles for GLP-1 receptor agonists and multidisciplinary care. Donor SLD is a growing concern. Normothermic and hypothermic oxygenated perfusion substantially expand donor utilisation – with up to ∼70% of marginal or previously discarded grafts now salvaged – and improve graft viability by reducing early allograft dysfunction by 60%. Further research is needed to refine risk stratification, develop effective pharmacotherapies, and optimise perfusion protocols for steatotic grafts.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101704"},"PeriodicalIF":7.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034430","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}
<div><h3>Background & Aims</h3><div>Glycogen storage disease type III (GSDIII) is a rare metabolic disorder caused by mutations in the glycogen debranching enzyme (<em>AGL</em>), leading to hepatic glycogen accumulation, fibrosis and increased hepatocellular carcinoma (HCC) risk. This study investigates the metabolic mechanisms driving liver tumorigenesis in an <em>Agl</em><sup><em>-/-</em></sup> model of GSDIII.</div></div><div><h3>Methods</h3><div>Liver and tumor samples from 14-month-old <em>Agl</em><sup><em>-/-</em></sup> and <em>Agl</em><sup><em>+/+</em></sup> mice, and liver biopsies from patients with GSDIII (n = 4), were analyzed using histological, biochemical and molecular approaches.</div></div><div><h3>Results</h3><div><em>Agl</em><sup><em>-/-</em></sup> mice recapitulated key features of GSDIII, including a 3.5-fold hepatic glycogen overload (<em>p <</em>0.001), and chronic liver disease. More than 30% of the animals developed liver tumors, associated with a 2.5-fold increase in alpha-fetoprotein levels (<em>p <</em>0.005). Despite marked reductions in glucose (7.5-fold, <em>p <</em>0.0001), glucose-6 phosphate (266-fold, <em>p <</em>0.0001), lactate (8-fold, <em>p <</em>0.005), cholesterol (1.9-fold, <em>p <</em>0.001) and triglyceride levels (6.2-fold, <em>p <</em>0.001) in the liver, glycaemia was maintained at around 87.0 ± 9.6 mg/dl after 6 h of fasting, through activated extrahepatic, but not hepatic, gluconeogenesis. Intriguingly, most tumors exhibited lower glycogen content than surrounding tissue (3.3-fold decrease, <em>p <</em>0.0001), which was associated with increased lysosomal alpha-acid glucosidase activity (19.5 ± 5.5 in tumor <em>vs</em>. 9.9 ± 2.0 mmol/h/mg in <em>Agl</em><sup><em>-/-</em></sup> liver; <em>p <</em>0.0005) and the presence of glycophagosomes. PAS-negative staining in HCCs from patients with GSDIII supported these observations. Although YAP nuclear staining varied among tumors, the overall increase in YAP nuclear localization and CTGF expression suggests that inhibition of the Hippo/YAP pathway may contribute to tumorigenesis in GSDIII hepatocytes.</div></div><div><h3>Conclusions</h3><div>In GSDIII, liver metabolism is characterized by the accumulation of structurally abnormal glycogen and a significant reduction of key energy substrates. In this metabolic context, enhanced lysosomal glycogen degradation may support tumor growth, highlighting a mechanistic link between glycogen metabolism and the development of liver cancer.</div></div><div><h3>Impact and implications</h3><div>This study provides novel insights into the metabolic dysregulations driving liver tumorigenesis in glycogen storage disease type III (GSDIII). Our findings reveal a potential link between abnormal glycogen accumulation and liver cancer, highlighting the pivotal role of lysosomal glycogen degradation in supporting tumor growth. These results are particularly important for researchers and clinicians
{"title":"Enhanced lysosomal glycogen breakdown is associated with liver tumorigenesis in glycogen storage disease type III","authors":"Valle Montalvo-Romeral , Louisa Jauze , Gwendoline Perrot , Mouna Amaouche , Antoine Gardin , Araceli Aguilar González , Alicia Leblond , Carine Zitoun-Ardon , Félicie Evrard , Jérémie Cosette , Christophe Tatout , Fanny Bordier , Emilie Bertil-Froidevaux , Christophe Georger , Laetitia van Wittenberghe , Valérie Paradis , Simon Gay , Fanny Dujardin , François Maillot , Amandine Gautier-Stein , Fabienne Rajas","doi":"10.1016/j.jhepr.2025.101702","DOIUrl":"10.1016/j.jhepr.2025.101702","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Glycogen storage disease type III (GSDIII) is a rare metabolic disorder caused by mutations in the glycogen debranching enzyme (<em>AGL</em>), leading to hepatic glycogen accumulation, fibrosis and increased hepatocellular carcinoma (HCC) risk. This study investigates the metabolic mechanisms driving liver tumorigenesis in an <em>Agl</em><sup><em>-/-</em></sup> model of GSDIII.</div></div><div><h3>Methods</h3><div>Liver and tumor samples from 14-month-old <em>Agl</em><sup><em>-/-</em></sup> and <em>Agl</em><sup><em>+/+</em></sup> mice, and liver biopsies from patients with GSDIII (n = 4), were analyzed using histological, biochemical and molecular approaches.</div></div><div><h3>Results</h3><div><em>Agl</em><sup><em>-/-</em></sup> mice recapitulated key features of GSDIII, including a 3.5-fold hepatic glycogen overload (<em>p <</em>0.001), and chronic liver disease. More than 30% of the animals developed liver tumors, associated with a 2.5-fold increase in alpha-fetoprotein levels (<em>p <</em>0.005). Despite marked reductions in glucose (7.5-fold, <em>p <</em>0.0001), glucose-6 phosphate (266-fold, <em>p <</em>0.0001), lactate (8-fold, <em>p <</em>0.005), cholesterol (1.9-fold, <em>p <</em>0.001) and triglyceride levels (6.2-fold, <em>p <</em>0.001) in the liver, glycaemia was maintained at around 87.0 ± 9.6 mg/dl after 6 h of fasting, through activated extrahepatic, but not hepatic, gluconeogenesis. Intriguingly, most tumors exhibited lower glycogen content than surrounding tissue (3.3-fold decrease, <em>p <</em>0.0001), which was associated with increased lysosomal alpha-acid glucosidase activity (19.5 ± 5.5 in tumor <em>vs</em>. 9.9 ± 2.0 mmol/h/mg in <em>Agl</em><sup><em>-/-</em></sup> liver; <em>p <</em>0.0005) and the presence of glycophagosomes. PAS-negative staining in HCCs from patients with GSDIII supported these observations. Although YAP nuclear staining varied among tumors, the overall increase in YAP nuclear localization and CTGF expression suggests that inhibition of the Hippo/YAP pathway may contribute to tumorigenesis in GSDIII hepatocytes.</div></div><div><h3>Conclusions</h3><div>In GSDIII, liver metabolism is characterized by the accumulation of structurally abnormal glycogen and a significant reduction of key energy substrates. In this metabolic context, enhanced lysosomal glycogen degradation may support tumor growth, highlighting a mechanistic link between glycogen metabolism and the development of liver cancer.</div></div><div><h3>Impact and implications</h3><div>This study provides novel insights into the metabolic dysregulations driving liver tumorigenesis in glycogen storage disease type III (GSDIII). Our findings reveal a potential link between abnormal glycogen accumulation and liver cancer, highlighting the pivotal role of lysosomal glycogen degradation in supporting tumor growth. These results are particularly important for researchers and clinicians","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101702"},"PeriodicalIF":7.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076999","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 : 2025-12-01DOI: 10.1016/j.jhepr.2025.101600
Sarwa Darwish Murad , Maraika Black , Shira Zelber-Sagi , Ben C. Hainsworth , Debbie L. Shawcross
{"title":"From queues to questions: Reflections on EASL’s Love Your Liver campaign in Amsterdam","authors":"Sarwa Darwish Murad , Maraika Black , Shira Zelber-Sagi , Ben C. Hainsworth , Debbie L. Shawcross","doi":"10.1016/j.jhepr.2025.101600","DOIUrl":"10.1016/j.jhepr.2025.101600","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101600"},"PeriodicalIF":7.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733336","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 : 2025-12-01DOI: 10.1016/j.jhepr.2025.101568
Mattias Mandorfer , Georg Semmler
{"title":"Disease-modifying effect of efruxifermin in compensated cirrhosis due to MASH: To miss the forest for the tree(s)","authors":"Mattias Mandorfer , Georg Semmler","doi":"10.1016/j.jhepr.2025.101568","DOIUrl":"10.1016/j.jhepr.2025.101568","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 12","pages":"Article 101568"},"PeriodicalIF":7.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733337","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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