<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":"2026-03-01","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 : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.jhepr.2026.101731
Jan Henrik Klug , Blerina Aliraj , Lucia Alcober-Boquet , Dominic Denk , Lena Germann , Nadja M. Meindl-Beinker , Carolina De La Torre , Oliver Waidmann , Fabian Finkelmeier , Stefan Zeuzem , Bernhard Brüne , Thomas J. Vogl , Andreas Weigert , Albrecht Piiper
<div><h3>Background & Aims</h3><div>Immune checkpoint inhibitor (ICI) therapy has significantly improved the treatment of solid tumors such as hepatocellular carcinoma (HCC); however, most patients fail to respond. Here, we examined whether co-administration of the tumor-penetrating internalizing (i)RGD peptide, which selectively increases tumor vascular permeability in a neuropilin-1–dependent manner, enhances intratumoral delivery and therapeutic efficacy of αPD-L1 in mouse models of HCC.</div></div><div><h3>Methods</h3><div>αPD-L1, with or without iRGD, was administered intravenously to mice bearing endogenous HCCs (TGFα/c-myc and diethylnitrosamine [DEN]/carbon tetrachloride [CCl<sub>4</sub>] models). Tumor growth was monitored by MRI. Immune cell composition and activation were analyzed by flow cytometry. RNA sequencing was performed on whole tumors and isolated intratumoral CD45<sup>+</sup> immune cells.</div></div><div><h3>Results</h3><div>While αPD-L1 monotherapy had minimal impact on tumor progression, combination treatment with iRGD significantly improved therapeutic efficacy, resulting in markedly reduced tumor growth (mean difference −198.2%, <em>p</em> <0.0001 in TGFα/c-myc and −88.8%, <em>p</em> = 0.0159 in DEN/CCl<sub>4</sub>-induced HCC mice) and increased objective response rates from 0 to 33% (90% confidence interval 14.6–58.6) in TGFα/c-myc mice and to 80% (90% confidence interval 39.6–95.8) in DEN/CCl<sub>4</sub>-induced HCC mice. Flow cytometry revealed reduced PD-1<sup>high</sup> CD8<sup>+</sup> T cells and enhanced expression of activation markers (Ki67, CD44, IFN-γ) in the combination group. RNA sequencing of CD45<sup>+</sup> cells and whole-tumor transcriptomes indicated decreased immunosuppression and increased vascular permeability in mice receiving the combination therapy. Immunoblot analysis showed enhanced accumulation of αPD-L1 in tumors following iRGD co-administration.</div></div><div><h3>Conclusions</h3><div>iRGD co-administration significantly improves the therapeutic efficacy of αPD-L1 in HCC mouse models by increasing intratumoral αPD-L1 delivery and more effectively alleviating the immunosuppressive tumor microenvironment. This non-conjugated, systemic approach holds strong translational potential to enhance ICI responses in patients with HCC.</div></div><div><h3>Impact and implications</h3><div>Immune checkpoint inhibitors (ICIs) show limited efficacy in hepatocellular carcinoma (HCC), to which poor intratumoral drug delivery is likely to contribute. This study demonstrates that intravenous co-administration of the tumor-penetrating peptide iRGD with anti–PD-L1 significantly improves antibody distribution and therapeutic response without increasing toxicity in preclinical HCC models. These findings are highly relevant for clinicians and researchers aiming to enhance ICI effectiveness in solid tumors. Given the ongoing clinical evaluation of iRGD, this simple, non-conjugated strategy offers a feasible
{"title":"Co-administered internalizing RGD peptide boosts anti-PD-L1 therapy in hepatocellular carcinoma","authors":"Jan Henrik Klug , Blerina Aliraj , Lucia Alcober-Boquet , Dominic Denk , Lena Germann , Nadja M. Meindl-Beinker , Carolina De La Torre , Oliver Waidmann , Fabian Finkelmeier , Stefan Zeuzem , Bernhard Brüne , Thomas J. Vogl , Andreas Weigert , Albrecht Piiper","doi":"10.1016/j.jhepr.2026.101731","DOIUrl":"10.1016/j.jhepr.2026.101731","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Immune checkpoint inhibitor (ICI) therapy has significantly improved the treatment of solid tumors such as hepatocellular carcinoma (HCC); however, most patients fail to respond. Here, we examined whether co-administration of the tumor-penetrating internalizing (i)RGD peptide, which selectively increases tumor vascular permeability in a neuropilin-1–dependent manner, enhances intratumoral delivery and therapeutic efficacy of αPD-L1 in mouse models of HCC.</div></div><div><h3>Methods</h3><div>αPD-L1, with or without iRGD, was administered intravenously to mice bearing endogenous HCCs (TGFα/c-myc and diethylnitrosamine [DEN]/carbon tetrachloride [CCl<sub>4</sub>] models). Tumor growth was monitored by MRI. Immune cell composition and activation were analyzed by flow cytometry. RNA sequencing was performed on whole tumors and isolated intratumoral CD45<sup>+</sup> immune cells.</div></div><div><h3>Results</h3><div>While αPD-L1 monotherapy had minimal impact on tumor progression, combination treatment with iRGD significantly improved therapeutic efficacy, resulting in markedly reduced tumor growth (mean difference −198.2%, <em>p</em> <0.0001 in TGFα/c-myc and −88.8%, <em>p</em> = 0.0159 in DEN/CCl<sub>4</sub>-induced HCC mice) and increased objective response rates from 0 to 33% (90% confidence interval 14.6–58.6) in TGFα/c-myc mice and to 80% (90% confidence interval 39.6–95.8) in DEN/CCl<sub>4</sub>-induced HCC mice. Flow cytometry revealed reduced PD-1<sup>high</sup> CD8<sup>+</sup> T cells and enhanced expression of activation markers (Ki67, CD44, IFN-γ) in the combination group. RNA sequencing of CD45<sup>+</sup> cells and whole-tumor transcriptomes indicated decreased immunosuppression and increased vascular permeability in mice receiving the combination therapy. Immunoblot analysis showed enhanced accumulation of αPD-L1 in tumors following iRGD co-administration.</div></div><div><h3>Conclusions</h3><div>iRGD co-administration significantly improves the therapeutic efficacy of αPD-L1 in HCC mouse models by increasing intratumoral αPD-L1 delivery and more effectively alleviating the immunosuppressive tumor microenvironment. This non-conjugated, systemic approach holds strong translational potential to enhance ICI responses in patients with HCC.</div></div><div><h3>Impact and implications</h3><div>Immune checkpoint inhibitors (ICIs) show limited efficacy in hepatocellular carcinoma (HCC), to which poor intratumoral drug delivery is likely to contribute. This study demonstrates that intravenous co-administration of the tumor-penetrating peptide iRGD with anti–PD-L1 significantly improves antibody distribution and therapeutic response without increasing toxicity in preclinical HCC models. These findings are highly relevant for clinicians and researchers aiming to enhance ICI effectiveness in solid tumors. Given the ongoing clinical evaluation of iRGD, this simple, non-conjugated strategy offers a feasible ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101731"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213206","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 : 2026-03-01Epub Date: 2025-11-15DOI: 10.1016/j.jhepr.2025.101680
Mai Sedki , Zeyuan Yang , Ashwani K. Singal , Mário Guimarães Pessoa , Aleksander Krag , Jörn M. Schattenberg , Linda Henry , Saleh Alqahtani , Jeffrey V. Lazarus , Zobair M. Younossi , Robert J. Wong
Backgound & Aims
Steatotic liver disease (SLD), which includes metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic- and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD), is the leading cause of chronic liver disease in the US. However, the risk of disease progression varies by subtype. We aimed to evaluate long-term risks of cirrhosis and mortality across SLD subtypes in a longudinal cohort of US veterans.
Methods
Adults with MASLD, MetALD, and ALD were identified using the national Veterans Affairs health system database (2010-2023). Incidence of cirrhosis and all-cause mortality was stratified by SLD subtype and analyzed using competing risks and Cox proportional hazards models, adjusted for demographic and clinical covariates.
Results
Overall, 682,274 veterans had MASLD, 517,464 had MetALD, and 305,692 had ALD, with a median follow up of 7.2 years. The highest cirrhosis incidence was observed in ALD (0.66 per 100 person-years vs. 0.43 and 0.39 per 100 person-years in MASLD and MetALD, respectively, p <0.001). Mortality incidence was likewise highest in ALD (0.32 per 100 person-years), compared with MASLD (0.24 per 100 person-years) and MetALD (0.19 per 100 person-years) (p <0.001). Across subtypes, relative to non-Hispanic Whites, Hispanics had higher risk and African Americans lower risk of cirrhosis. The additive effect of concurrent obesity and diabetes was associated with 36% and 22% increased risk of cirrhosis in MASLD and MetALD, respectively, compared to patients without obesity or diabetes.
Conclusions
Among US veterans with SLD, the long-term risk of cirrhosis was highest in ALD, followed by MASLD and MetALD. Concurrent metabolic dysfunction and alcohol use exert a synergistic effect on cirrhosis risk, underscoring the need to aggressively address metabolic comorbidities and implement early screening and treatment for harmful alcohol use.
Impact and implications
Given the growing burden of steatotic liver disease (SLD) in the US, it is crucial to understand how different causes – namely alcohol use and metabolic dysfunction – contribute to the risk of developing cirrhosis. This large, national study demonstrates that patients with alcohol-related liver disease face the highest risk, with notable variation by race and ethnicity. These findings are especially important for clinicians and healthcare systems caring for diverse populations, as they highlight groups at elevated risk who may benefit from targeted prevention and early intervention strategies. Practically, these results support the need for integrated care approaches that address both harmful alcohol use and metabolic conditions like obesity and diabetes to reduce progression to advanced liver disease.
{"title":"Longitudinal risk of cirrhosis by steatotic liver disease subtype among 1.5 million individuals in the US","authors":"Mai Sedki , Zeyuan Yang , Ashwani K. Singal , Mário Guimarães Pessoa , Aleksander Krag , Jörn M. Schattenberg , Linda Henry , Saleh Alqahtani , Jeffrey V. Lazarus , Zobair M. Younossi , Robert J. Wong","doi":"10.1016/j.jhepr.2025.101680","DOIUrl":"10.1016/j.jhepr.2025.101680","url":null,"abstract":"<div><h3>Backgound & Aims</h3><div>Steatotic liver disease (SLD), which includes metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic- and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD), is the leading cause of chronic liver disease in the US. However, the risk of disease progression varies by subtype. We aimed to evaluate long-term risks of cirrhosis and mortality across SLD subtypes in a longudinal cohort of US veterans.</div></div><div><h3>Methods</h3><div>Adults with MASLD, MetALD, and ALD were identified using the national Veterans Affairs health system database (2010-2023). Incidence of cirrhosis and all-cause mortality was stratified by SLD subtype and analyzed using competing risks and Cox proportional hazards models, adjusted for demographic and clinical covariates.</div></div><div><h3>Results</h3><div>Overall, 682,274 veterans had MASLD, 517,464 had MetALD, and 305,692 had ALD, with a median follow up of 7.2 years. The highest cirrhosis incidence was observed in ALD (0.66 per 100 person-years <em>vs</em>. 0.43 and 0.39 per 100 person-years in MASLD and MetALD, respectively, <em>p</em> <0.001). Mortality incidence was likewise highest in ALD (0.32 per 100 person-years), compared with MASLD (0.24 per 100 person-years) and MetALD (0.19 per 100 person-years) (<em>p</em> <0.001). Across subtypes, relative to non-Hispanic Whites, Hispanics had higher risk and African Americans lower risk of cirrhosis. The additive effect of concurrent obesity and diabetes was associated with 36% and 22% increased risk of cirrhosis in MASLD and MetALD, respectively, compared to patients without obesity or diabetes.</div></div><div><h3>Conclusions</h3><div>Among US veterans with SLD, the long-term risk of cirrhosis was highest in ALD, followed by MASLD and MetALD. Concurrent metabolic dysfunction and alcohol use exert a synergistic effect on cirrhosis risk, underscoring the need to aggressively address metabolic comorbidities and implement early screening and treatment for harmful alcohol use.</div></div><div><h3>Impact and implications</h3><div>Given the growing burden of steatotic liver disease (SLD) in the US, it is crucial to understand how different causes – namely alcohol use and metabolic dysfunction – contribute to the risk of developing cirrhosis. This large, national study demonstrates that patients with alcohol-related liver disease face the highest risk, with notable variation by race and ethnicity. These findings are especially important for clinicians and healthcare systems caring for diverse populations, as they highlight groups at elevated risk who may benefit from targeted prevention and early intervention strategies. Practically, these results support the need for integrated care approaches that address both harmful alcohol use and metabolic conditions like obesity and diabetes to reduce progression to advanced liver disease.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101680"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213186","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 : 2026-03-01Epub Date: 2026-01-21DOI: 10.1016/j.jhepr.2026.101732
Janina Eden , Philip C. Müller , Christoph Kuemmerli , Marco Bongini , Francesca Albanesi , Carlo Sposito , Gabriela Berlakovich , Bettina M. Buchholz , Florin Botea , Stefania Camagni , Matteo Cescon , Umberto Cillo , Fabio Colli , Philippe Compagnon , Luciano G. De Carlis , Riccardo De Carlis , Fabrizio Di Benedetto , Jule Dingfelder , Dulce Diogo , Daniele Dondossola , Vincent E. de Meijer
<div><h3>Background & Aims</h3><div>Liver transplantation (LT) for hepatocellular carcinoma (HCC) is performed worldwide, with 5-year survival rates of approximately 70%. However, post-transplant HCC recurrence occurs in 15-20% of recipients. We aimed to evaluate, for the first time, long-term recurrence-free survival in a large international cohort of patients undergoing LT for HCC using grafts treated with hypothermic oxygenated machine perfusion (HOPE).</div></div><div><h3>Methods</h3><div>This observational <em>post hoc</em> analysis of the multicenter European HOPE-REAL study (NCT05520320) included adult recipients with HCC (N = 599) who received a liver from either a donation after brain death (DBD) or donation after circulatory death (DCD) donor, preserved using HOPE, dual-HOPE (DHOPE), or normothermic regional perfusion followed by HOPE (NRP-HOPE) between 2012 and 2022. Propensity score matching was used to compare outcomes between HCC and non-HCC recipients within the HOPE-REAL cohort, and between HOPE-treated HCC recipients and an external control cohort receiving non-perfused livers (n = 484).</div></div><div><h3>Results</h3><div>The overall HCC recurrence rate in the HOPE-REAL cohort was 6.9% (41/599), with no significant difference between DBD and DCD liver transplants (7.1% [25/350] <em>vs.</em> 6.4% [16/249]; <em>p =</em> 0.346). One-, 3-, and 5-year overall survival rates were 92%, 86%, and 81%, while recurrence-free survival rates were 90%, 83%, and 78%, respectively. Five-year overall survival was similar between 347 HOPE-treated HCC recipients (82%) and 347 matched non-HCC recipients (84%) (<em>p =</em> 0.625). In contrast, compared to an external cohort of 312 non-perfused HCC recipients, 5-year overall survival was significantly higher in 312 matched HOPE-treated HCC recipients (74% <em>vs.</em> 84%; <em>p =</em> 0.034).</div></div><div><h3>Conclusions</h3><div>HCC recurrence was rare after transplantation of livers treated with HOPE. Long-term survival in HOPE-treated HCC recipients was significantly better than in those receiving non-perfused livers, and comparable to outcomes in non-HCC recipients. These findings warrant validation in a randomized clinical trial.</div></div><div><h3>Impact and implications</h3><div>This <em>post hoc</em> analysis of the HOPE REAL study demonstrates, for the first time, low hepatocellular carcinoma (HCC) recurrence rates in a large cohort of hypothermic oxygenated machine perfusion-treated liver transplant recipients with HCC, and significantly better survival outcomes compared to matched recipients of non-perfused grafts. These findings may have important implications, particularly as tumor-related indications for liver transplantation continue to rise. Machine liver perfusion could emerge as a novel strategy to improve oncological outcomes in high-risk cancer conditions after transplantation, potentially via mitigation of inflammation and reduced tumor cell seeding.</div></div><div><h
{"title":"HCC recurrence in liver transplants treated with hypothermic oxygenated machine perfusion: An international matched cohort study","authors":"Janina Eden , Philip C. Müller , Christoph Kuemmerli , Marco Bongini , Francesca Albanesi , Carlo Sposito , Gabriela Berlakovich , Bettina M. Buchholz , Florin Botea , Stefania Camagni , Matteo Cescon , Umberto Cillo , Fabio Colli , Philippe Compagnon , Luciano G. De Carlis , Riccardo De Carlis , Fabrizio Di Benedetto , Jule Dingfelder , Dulce Diogo , Daniele Dondossola , Vincent E. de Meijer","doi":"10.1016/j.jhepr.2026.101732","DOIUrl":"10.1016/j.jhepr.2026.101732","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Liver transplantation (LT) for hepatocellular carcinoma (HCC) is performed worldwide, with 5-year survival rates of approximately 70%. However, post-transplant HCC recurrence occurs in 15-20% of recipients. We aimed to evaluate, for the first time, long-term recurrence-free survival in a large international cohort of patients undergoing LT for HCC using grafts treated with hypothermic oxygenated machine perfusion (HOPE).</div></div><div><h3>Methods</h3><div>This observational <em>post hoc</em> analysis of the multicenter European HOPE-REAL study (NCT05520320) included adult recipients with HCC (N = 599) who received a liver from either a donation after brain death (DBD) or donation after circulatory death (DCD) donor, preserved using HOPE, dual-HOPE (DHOPE), or normothermic regional perfusion followed by HOPE (NRP-HOPE) between 2012 and 2022. Propensity score matching was used to compare outcomes between HCC and non-HCC recipients within the HOPE-REAL cohort, and between HOPE-treated HCC recipients and an external control cohort receiving non-perfused livers (n = 484).</div></div><div><h3>Results</h3><div>The overall HCC recurrence rate in the HOPE-REAL cohort was 6.9% (41/599), with no significant difference between DBD and DCD liver transplants (7.1% [25/350] <em>vs.</em> 6.4% [16/249]; <em>p =</em> 0.346). One-, 3-, and 5-year overall survival rates were 92%, 86%, and 81%, while recurrence-free survival rates were 90%, 83%, and 78%, respectively. Five-year overall survival was similar between 347 HOPE-treated HCC recipients (82%) and 347 matched non-HCC recipients (84%) (<em>p =</em> 0.625). In contrast, compared to an external cohort of 312 non-perfused HCC recipients, 5-year overall survival was significantly higher in 312 matched HOPE-treated HCC recipients (74% <em>vs.</em> 84%; <em>p =</em> 0.034).</div></div><div><h3>Conclusions</h3><div>HCC recurrence was rare after transplantation of livers treated with HOPE. Long-term survival in HOPE-treated HCC recipients was significantly better than in those receiving non-perfused livers, and comparable to outcomes in non-HCC recipients. These findings warrant validation in a randomized clinical trial.</div></div><div><h3>Impact and implications</h3><div>This <em>post hoc</em> analysis of the HOPE REAL study demonstrates, for the first time, low hepatocellular carcinoma (HCC) recurrence rates in a large cohort of hypothermic oxygenated machine perfusion-treated liver transplant recipients with HCC, and significantly better survival outcomes compared to matched recipients of non-perfused grafts. These findings may have important implications, particularly as tumor-related indications for liver transplantation continue to rise. Machine liver perfusion could emerge as a novel strategy to improve oncological outcomes in high-risk cancer conditions after transplantation, potentially via mitigation of inflammation and reduced tumor cell seeding.</div></div><div><h","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101732"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283692","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 : 2026-03-01Epub Date: 2025-11-12DOI: 10.1016/j.jhepr.2025.101679
Yun Chen , Yinan Zheng , Longgang Zhao , Tao Gao , Yishu Qu , John Jeffrey Carr , James G. Terry , Hongyan Ning , Kyeezu Kim , Michelle T. Long , Xinyuan Zhang , John T. Wilkins , Aimin Chen , Kai Zhang , Norrina Bai Allen , Donald M. Lloyd-Jones , Lifang Hou , Xuehong Zhang
<div><h3>Background & Aims</h3><div>The importance of maintaining optimal lipid levels across young adulthood in preventing metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study aimed to evaluate associations of lipid profiles through young adulthood with midlife MASLD risk and assess the mediating effect of epigenomic biomarkers.</div></div><div><h3>Methods</h3><div>This study included 2,577 participants from the Coronary Artery Risk Development in Young Adults study using data from baseline (Year 0 [Y0], 1985-1986) to Y25 (2010-2011). Time-weighted average (TWA) lipid exposures during young adulthood (ages 18-39 years) were estimated using up to seven measurements (Y0–Y20). Non-contrast abdominal CT scans were performed to measure steatosis at Y25 (mean age, 50 years). Blood DNA methylation (DNAm) was measured at >840,000 methylation sites at Y20. A total of 492 MASLD cases were identified.</div></div><div><h3>Results</h3><div>Compared with optimal TWA lipid levels, multivariable-adjusted odds ratios of developing MASLD were 3.26 (95% CI 2.51-4.25) for abnormal triglycerides (≥100 <em>vs.</em> <75 mg/dl), 2.39 (95% CI 1.73-3.31) for high-density lipoprotein cholesterol (<40 [men]/50 [women] <em>vs.</em> ≥60 mg/dl), 1.77 (95% CI 1.37-2.30) for non-high-density lipoprotein cholesterol (≥150 <em>vs.</em> <130 mg/dl), 1.74 (95% CI 1.19-2.51) for apolipoprotein B (≥110 <em>vs.</em> <90 mg/dl), 1.43 (95% CI 1.08-1.90) for low-density lipoprotein cholesterol (≥130 <em>vs.</em> <100 mg/dl), and 1.39 (95% CI 1.07-1.81) for total cholesterol (≥200 <em>vs.</em> <180 mg/dl). These associations were consistent across sex, race, alcohol intake, and genetic susceptibility. DNAm markers located in <em>CPT1A, ABCG1</em>, and <em>DHCR24</em> genes mediated 2.9%-15.4% of observed associations.</div></div><div><h3>Conclusions</h3><div>Cumulative exposure to abnormal lipids through young adulthood contributes to MASLD development in midlife, with these associations partially mediated by lipid-associated DNAm.</div></div><div><h3>Impact and implications</h3><div>Dyslipidemia is a major modifiable risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). Evidence largely focuses on mid-to-late-life lipid levels, while the impact of cumulative lipid exposure through young adulthood on midlife MASLD risk remains unclear. Using seven repeated lipid measures in a longitudinal observational study, we found that cumulative abnormal lipid exposure during young adulthood (ages 18-39 years) strongly predicted MASLD risk over a 25-year follow-up, outperforming single-visit measures. DNA methylation markers in <em>CPT1A, ABCG1,</em> and <em>DHCR24</em> mediated 2.9%-15.4% of observed associations. Our findings underscore the value of assessing cumulative lipid exposure for midlife MASLD risk stratification and highlight epigenomic mediators as potential targets to strengthen MASLD prevention stra
背景和目的维持青年期最佳脂质水平对预防代谢功能障碍相关脂肪变性肝病（MASLD）的重要性尚不清楚。本研究旨在评估青年期脂质谱与中年MASLD风险的关系，并评估表观基因组生物标志物的中介作用。方法本研究纳入了2577名年轻成人冠状动脉风险发展研究的参与者，数据来自基线（1985-1986年）至25年（2010-2011年）。时间加权平均（TWA）脂质暴露在青年期（18-39岁）估计使用多达七个测量（Y0-Y20）。在25岁时（平均年龄50岁）进行非对比腹部CT扫描以测量脂肪变性。在20岁时测定血液DNA甲基化（DNAm）的84万个甲基化位点。共发现492例MASLD病例。结果与最佳TWA脂质水平相比，发生MASLD的多变量调整比值比：甘油三酯异常（≥100 vs. 75 mg/dl）为3.26 (95% CI 2.51-4.25)，高密度脂蛋白胆固醇异常（≥40[男性]/50[女性]vs.≥60 mg/dl）为2.39 (95% CI 1.73-3.31)，非高密度脂蛋白胆固醇异常（≥150 vs. 130 mg/dl）为1.77 (95% CI 1.37-2.30)，载脂蛋白B异常（≥110 vs. 90 mg/dl）为1.74 （95% CI 1.19-2.51）。低密度脂蛋白胆固醇（≥130 vs. 100 mg/dl）为1.43 (95% CI 1.08-1.90)，总胆固醇（≥200 vs. 180 mg/dl）为1.39 （95% CI 1.07-1.81）。这些关联在性别、种族、酒精摄入量和遗传易感性方面是一致的。位于CPT1A、ABCG1和DHCR24基因上的dna标记介导了2.9%-15.4%的观察到的关联。结论：在青年时期长期暴露于异常脂质会导致中年MASLD的发展，其中脂质相关的dna介导了部分关联。影响和意义血脂异常是代谢功能障碍相关脂肪变性肝病（MASLD）的主要可改变危险因素。证据主要集中在中晚年的脂质水平，而在青年时期累积的脂质暴露对中年MASLD风险的影响尚不清楚。在一项纵向观察研究中，我们发现，在25年的随访中，青年期（18-39岁）累积的异常脂质暴露强烈预测了MASLD的风险，优于单次随访。CPT1A、ABCG1和DHCR24中的DNA甲基化标记介导了2.9%-15.4%的观察到的关联。我们的研究结果强调了评估累积脂质暴露对中年MASLD风险分层的价值，并强调了表观基因组介质作为加强MASLD预防策略的潜在靶点。
{"title":"Cumulative lipid exposure in young adulthood and risk of midlife MASLD","authors":"Yun Chen , Yinan Zheng , Longgang Zhao , Tao Gao , Yishu Qu , John Jeffrey Carr , James G. Terry , Hongyan Ning , Kyeezu Kim , Michelle T. Long , Xinyuan Zhang , John T. Wilkins , Aimin Chen , Kai Zhang , Norrina Bai Allen , Donald M. Lloyd-Jones , Lifang Hou , Xuehong Zhang","doi":"10.1016/j.jhepr.2025.101679","DOIUrl":"10.1016/j.jhepr.2025.101679","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The importance of maintaining optimal lipid levels across young adulthood in preventing metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study aimed to evaluate associations of lipid profiles through young adulthood with midlife MASLD risk and assess the mediating effect of epigenomic biomarkers.</div></div><div><h3>Methods</h3><div>This study included 2,577 participants from the Coronary Artery Risk Development in Young Adults study using data from baseline (Year 0 [Y0], 1985-1986) to Y25 (2010-2011). Time-weighted average (TWA) lipid exposures during young adulthood (ages 18-39 years) were estimated using up to seven measurements (Y0–Y20). Non-contrast abdominal CT scans were performed to measure steatosis at Y25 (mean age, 50 years). Blood DNA methylation (DNAm) was measured at >840,000 methylation sites at Y20. A total of 492 MASLD cases were identified.</div></div><div><h3>Results</h3><div>Compared with optimal TWA lipid levels, multivariable-adjusted odds ratios of developing MASLD were 3.26 (95% CI 2.51-4.25) for abnormal triglycerides (≥100 <em>vs.</em> <75 mg/dl), 2.39 (95% CI 1.73-3.31) for high-density lipoprotein cholesterol (<40 [men]/50 [women] <em>vs.</em> ≥60 mg/dl), 1.77 (95% CI 1.37-2.30) for non-high-density lipoprotein cholesterol (≥150 <em>vs.</em> <130 mg/dl), 1.74 (95% CI 1.19-2.51) for apolipoprotein B (≥110 <em>vs.</em> <90 mg/dl), 1.43 (95% CI 1.08-1.90) for low-density lipoprotein cholesterol (≥130 <em>vs.</em> <100 mg/dl), and 1.39 (95% CI 1.07-1.81) for total cholesterol (≥200 <em>vs.</em> <180 mg/dl). These associations were consistent across sex, race, alcohol intake, and genetic susceptibility. DNAm markers located in <em>CPT1A, ABCG1</em>, and <em>DHCR24</em> genes mediated 2.9%-15.4% of observed associations.</div></div><div><h3>Conclusions</h3><div>Cumulative exposure to abnormal lipids through young adulthood contributes to MASLD development in midlife, with these associations partially mediated by lipid-associated DNAm.</div></div><div><h3>Impact and implications</h3><div>Dyslipidemia is a major modifiable risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). Evidence largely focuses on mid-to-late-life lipid levels, while the impact of cumulative lipid exposure through young adulthood on midlife MASLD risk remains unclear. Using seven repeated lipid measures in a longitudinal observational study, we found that cumulative abnormal lipid exposure during young adulthood (ages 18-39 years) strongly predicted MASLD risk over a 25-year follow-up, outperforming single-visit measures. DNA methylation markers in <em>CPT1A, ABCG1,</em> and <em>DHCR24</em> mediated 2.9%-15.4% of observed associations. Our findings underscore the value of assessing cumulative lipid exposure for midlife MASLD risk stratification and highlight epigenomic mediators as potential targets to strengthen MASLD prevention stra","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101679"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077001","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 : 2026-03-01Epub Date: 2025-12-23DOI: 10.1016/j.jhepr.2025.101720
Holly-May Lewis , Cheryl M. Isherwood , Ali R. Mani , Benita Middleton , Marsha Y. Morgan , Debra J. Skene , Sara Montagnese
Background & Aims
The aim of the present study was to evaluate the temporal dynamics of metabolites in patients with cirrhosis using hourly plasma samples collected over a full 24-hour cycle in 17 outpatients with cirrhosis of varying severity (9 males, 58 [39-77] years, 12 compensated/5 decompensated) and 9 matched healthy controls (8 males, 60 [38-84] years).
Methods
A total of 142 metabolites were quantified by targeted metabolomics, including 11 acylcarnitines, 19 amino acids, 9 biogenic amines, 88 glycerophospholipids, 14 sphingolipids, 1 monosaccharide and the circadian hormones melatonin and cortisol. Multivariate analyses were performed using PCA (principal component analysis) and OPLS-DA (orthogonal partial least squares-discriminant analysis). To assess 24-hour rhythmicity, a linear mixed-effect cosinor method was applied, providing peak times and amplitudes.
Results
PCA and OPLS-DA revealed clear differences between groups. The four metabolites which best distinguished the groups were the glycerophospholipids P32:0 and PC O-32:1, the amino acid tyrosine and the biogenic amine methionine sulfoxide (VIP scores 1.59-1.62), all of which were increased in decompensated patients. Significant 24-hour rhythms were detected in 46% of metabolites and both circadian hormones in healthy volunteers, compared with 16% of metabolites and both hormones in patients. A significant phase advance was observed for acylcarnitines, while amino acids, glycerophospholipids, and both circadian hormones exhibited phase delays in patients relative to healthy controls. Additionally, some rhythmic metabolites showed progressively increased amplitudes in patients, indicating larger oscillations over the 24 hours.
Conclusions
Major abnormalities in both absolute plasma metabolite concentrations and their daily rhythm were observed in a small but well characterised group of outpatients with cirrhosis of varying severity.
Impact and implications
This study demonstrates significant disruptions in the daily rhythms of plasma metabolites in patients with cirrhosis that parallel disease severity. Although the underlying mechanisms and direct clinical consequences of these rhythm disturbances require further investigation, their potential long-term effects are likely to be important, particularly in the context of metabolic and nutritional health in this patient population. These findings highlight the need to consider temporal dynamics in both the assessment and management of cirrhosis and may inform future strategies for chronotherapy, dietary interventions, and personalized care.
{"title":"Loss, amplification or mistiming of the daily rhythms of metabolic markers in patients with cirrhosis","authors":"Holly-May Lewis , Cheryl M. Isherwood , Ali R. Mani , Benita Middleton , Marsha Y. Morgan , Debra J. Skene , Sara Montagnese","doi":"10.1016/j.jhepr.2025.101720","DOIUrl":"10.1016/j.jhepr.2025.101720","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The aim of the present study was to evaluate the temporal dynamics of metabolites in patients with cirrhosis using hourly plasma samples collected over a full 24-hour cycle in 17 outpatients with cirrhosis of varying severity (9 males, 58 [39-77] years, 12 compensated/5 decompensated) and 9 matched healthy controls (8 males, 60 [38-84] years).</div></div><div><h3>Methods</h3><div>A total of 142 metabolites were quantified by targeted metabolomics, including 11 acylcarnitines, 19 amino acids, 9 biogenic amines, 88 glycerophospholipids, 14 sphingolipids, 1 monosaccharide and the circadian hormones melatonin and cortisol. Multivariate analyses were performed using PCA (principal component analysis) and OPLS-DA (orthogonal partial least squares-discriminant analysis). To assess 24-hour rhythmicity, a linear mixed-effect cosinor method was applied, providing peak times and amplitudes.</div></div><div><h3>Results</h3><div>PCA and OPLS-DA revealed clear differences between groups. The four metabolites which best distinguished the groups were the glycerophospholipids P32:0 and PC O-32:1, the amino acid tyrosine and the biogenic amine methionine sulfoxide (VIP scores 1.59-1.62), all of which were increased in decompensated patients. Significant 24-hour rhythms were detected in 46% of metabolites and both circadian hormones in healthy volunteers, compared with 16% of metabolites and both hormones in patients. A significant phase advance was observed for acylcarnitines, while amino acids, glycerophospholipids, and both circadian hormones exhibited phase delays in patients relative to healthy controls. Additionally, some rhythmic metabolites showed progressively increased amplitudes in patients, indicating larger oscillations over the 24 hours.</div></div><div><h3>Conclusions</h3><div>Major abnormalities in both absolute plasma metabolite concentrations and their daily rhythm were observed in a small but well characterised group of outpatients with cirrhosis of varying severity.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates significant disruptions in the daily rhythms of plasma metabolites in patients with cirrhosis that parallel disease severity. Although the underlying mechanisms and direct clinical consequences of these rhythm disturbances require further investigation, their potential long-term effects are likely to be important, particularly in the context of metabolic and nutritional health in this patient population. These findings highlight the need to consider temporal dynamics in both the assessment and management of cirrhosis and may inform future strategies for chronotherapy, dietary interventions, and personalized care.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101720"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226877","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 : 2026-03-01Epub Date: 2026-01-12DOI: 10.1016/j.jhepr.2026.101734
Susan Fischer , Martin Sebastian McCoy , Marta Fiocco , Annarein Kerbert , Eduardo Cervantes-Alvarez , Jan Hähner , Michael Praktiknjo , Maximilian Joseph Brol , Frank Erhard Uschner , Lena Wolters , Stefan Zeuzem , Josune Cabello , Kai-Henrik Peiffer , Jeetindra Balak , Sesmu Arbous , Jeroen Nieuwenhuizen , David van Westerloo , Anton Jan van Zonneveld , Jonel Trebicka , Minneke Coenraad
<div><h3>Background & Aims</h3><div>The prevalence and evolution of acute-on-chronic liver failure (ACLF), particularly extrarenal organ failures, in patients with cirrhosis and acute kidney injury (AKI) are not well characterized. This study investigated the development and progression of ACLF in patients with cirrhosis who develop AKI, aiming to improve understanding of disease course during the critical period following AKI onset.</div></div><div><h3>Methods</h3><div>We conducted a retrospective cohort study of hospitalized patients with cirrhosis and AKI at two tertiary centers between 2010 and 2023. Data on AKI etiology, treatment, ACLF development and progression, and survival were collected. Multivariable regression models were used to assess associations between baseline and AKI-related characteristics, ACLF outcomes, and mortality.</div></div><div><h3>Results</h3><div>A total of 672 patients (71% male) were included. AKI progression or non-response to therapy occurred in 47% of patients. ACLF was present at the time of AKI diagnosis in 406 patients (60%); among these, 106 (26%) experienced ACLF progression, predominantly involving renal, respiratory, and circulatory failure. Of the 266 patients without ACLF at AKI diagnosis (40%), 101 (38%) subsequently developed ACLF, most commonly with renal, respiratory, and liver failure. In multivariable analysis, patients with hepatorenal syndrome-AKI (HRS-AKI) or other/mixed AKI etiologies had a higher risk of ACLF development compared to those with pre-renal AKI (odds ratio [OR] 9.67, 95% CI 3.96–23.57; OR 4.98, 95% CI 1.78–12.95, respectively). HRS-AKI and AKI stage 2 were independently associated with ACLF progression after adjustment for MELD score and relevant clinical risk factors (OR 2.31, 95% CI 1.08–4.95; OR 2.35, 95% CI 1.03–5.36). The cumulative incidence of death was 47% at 90 days after AKI diagnosis (95% CI 44–51).</div></div><div><h3>Conclusions</h3><div>Patients with cirrhosis who develop AKI are at high risk of ACLF development and mortality. Respiratory failure is the most frequent extrarenal organ failure among patients who develop ACLF or experience ACLF progression.</div></div><div><h3>Impact and implications</h3><div>This study highlights the significant risk of acute-on-chronic liver failure development in patients with cirrhosis and acute kidney injury (AKI), particularly in those with hepatorenal syndrome-AKI or other/mixed types of AKI. Given the high short-term mortality observed, early recognition and risk stratification of AKI in cirrhosis are crucial. These findings are particularly relevant for hepatologists, nephrologists, and intensivists, as they underscore the need for improved therapeutic strategies targeting AKI non-responders. Future prospective studies should not only explore targeted interventions to improve outcomes in this high-risk population but also aim to elucidate the underlying pathophysiology driving AKI progression and acute-on-chronic liver fa
背景与目的：肝硬化和急性肾损伤（AKI）患者的急性慢性肝衰竭（ACLF），特别是肾外器官衰竭的患病率和演变尚不清楚。本研究探讨肝硬化AKI患者ACLF的发生和进展，旨在提高对AKI发病后关键时期病程的认识。方法：我们对2010年至2023年在两个三级中心住院的肝硬化和AKI患者进行了回顾性队列研究。收集AKI的病因、治疗、ACLF的发展和进展以及生存的数据。多变量回归模型用于评估基线和aki相关特征、ACLF结果和死亡率之间的关系。结果：共纳入672例患者，其中男性71%。47%的患者出现AKI进展或对治疗无反应。406例（60%）患者在AKI诊断时存在ACLF；其中，106例（26%）发生ACLF进展，主要包括肾脏、呼吸和循环衰竭。在266例AKI诊断时未出现ACLF的患者中（40%），101例（38%）随后发展为ACLF，最常见的是肾、呼吸和肝功能衰竭。在多变量分析中，肝肾综合征-AKI （hr -AKI）或其他/混合AKI病因的患者与肾前AKI患者相比，ACLF发展的风险更高（比值比[or] 9.67, 95% CI 3.96-23.57; or 4.98, 95% CI 1.78-12.95）。调整MELD评分和相关临床危险因素后，hr -AKI和AKI 2期与ACLF进展独立相关（OR 2.31, 95% CI 1.08-4.95; OR 2.35, 95% CI 1.03-5.36）。AKI诊断后90天的累计死亡率为47% （95% CI 44-51）。结论：肝硬化患者发生AKI的ACLF发展和死亡率较高。在发生ACLF或ACLF进展的患者中，呼吸衰竭是最常见的外器官衰竭。影响和启示：本研究强调了肝硬化和急性肾损伤（AKI）患者发生急性伴慢性肝衰竭的显著风险，特别是那些肝肾综合征-AKI或其他/混合类型AKI的患者。鉴于观察到的高短期死亡率，肝硬化AKI的早期识别和风险分层至关重要。这些发现对肝病学家、肾病学家和重症医师特别重要，因为它们强调了改进针对AKI无反应者的治疗策略的必要性。未来的前瞻性研究不仅应该探索有针对性的干预措施来改善这一高危人群的预后，还应该旨在阐明肝硬化和AKI患者AKI进展和急性慢性肝衰竭发展的潜在病理生理机制。
{"title":"Development and patterns of acute-on-chronic liver failure in patients with cirrhosis and acute kidney injury","authors":"Susan Fischer , Martin Sebastian McCoy , Marta Fiocco , Annarein Kerbert , Eduardo Cervantes-Alvarez , Jan Hähner , Michael Praktiknjo , Maximilian Joseph Brol , Frank Erhard Uschner , Lena Wolters , Stefan Zeuzem , Josune Cabello , Kai-Henrik Peiffer , Jeetindra Balak , Sesmu Arbous , Jeroen Nieuwenhuizen , David van Westerloo , Anton Jan van Zonneveld , Jonel Trebicka , Minneke Coenraad","doi":"10.1016/j.jhepr.2026.101734","DOIUrl":"10.1016/j.jhepr.2026.101734","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The prevalence and evolution of acute-on-chronic liver failure (ACLF), particularly extrarenal organ failures, in patients with cirrhosis and acute kidney injury (AKI) are not well characterized. This study investigated the development and progression of ACLF in patients with cirrhosis who develop AKI, aiming to improve understanding of disease course during the critical period following AKI onset.</div></div><div><h3>Methods</h3><div>We conducted a retrospective cohort study of hospitalized patients with cirrhosis and AKI at two tertiary centers between 2010 and 2023. Data on AKI etiology, treatment, ACLF development and progression, and survival were collected. Multivariable regression models were used to assess associations between baseline and AKI-related characteristics, ACLF outcomes, and mortality.</div></div><div><h3>Results</h3><div>A total of 672 patients (71% male) were included. AKI progression or non-response to therapy occurred in 47% of patients. ACLF was present at the time of AKI diagnosis in 406 patients (60%); among these, 106 (26%) experienced ACLF progression, predominantly involving renal, respiratory, and circulatory failure. Of the 266 patients without ACLF at AKI diagnosis (40%), 101 (38%) subsequently developed ACLF, most commonly with renal, respiratory, and liver failure. In multivariable analysis, patients with hepatorenal syndrome-AKI (HRS-AKI) or other/mixed AKI etiologies had a higher risk of ACLF development compared to those with pre-renal AKI (odds ratio [OR] 9.67, 95% CI 3.96–23.57; OR 4.98, 95% CI 1.78–12.95, respectively). HRS-AKI and AKI stage 2 were independently associated with ACLF progression after adjustment for MELD score and relevant clinical risk factors (OR 2.31, 95% CI 1.08–4.95; OR 2.35, 95% CI 1.03–5.36). The cumulative incidence of death was 47% at 90 days after AKI diagnosis (95% CI 44–51).</div></div><div><h3>Conclusions</h3><div>Patients with cirrhosis who develop AKI are at high risk of ACLF development and mortality. Respiratory failure is the most frequent extrarenal organ failure among patients who develop ACLF or experience ACLF progression.</div></div><div><h3>Impact and implications</h3><div>This study highlights the significant risk of acute-on-chronic liver failure development in patients with cirrhosis and acute kidney injury (AKI), particularly in those with hepatorenal syndrome-AKI or other/mixed types of AKI. Given the high short-term mortality observed, early recognition and risk stratification of AKI in cirrhosis are crucial. These findings are particularly relevant for hepatologists, nephrologists, and intensivists, as they underscore the need for improved therapeutic strategies targeting AKI non-responders. Future prospective studies should not only explore targeted interventions to improve outcomes in this high-risk population but also aim to elucidate the underlying pathophysiology driving AKI progression and acute-on-chronic liver fa","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 3","pages":"Article 101734"},"PeriodicalIF":7.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283681","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 : 2026-02-19DOI: 10.1016/j.jhepr.2026.101787
Ann M Farrell, Tonya Paris, Evelyn B Parr, Elena S George, Jessica Howell, Catherine Croagh, Tom Sutherland, Mark Page, Penny McKelvie, Alexander J Thompson, Marno Ryan
Background & aims: Weight loss is the cornerstone of treatment for metabolic dysfunction associated steatotic liver disease (MASLD). This pilot study compared the efficacy and safety of a very low energy ketogenic diet (VLED) versus a Mediterranean diet (MD) in improving hepatic steatosis and liver histology in individuals with overweight or obesity and MASLD.
Methods: We conducted a pilot randomised controlled trial in adults with histologically confirmed MASLD and BMI 27-35 kg/m2. Participants were assigned to either a 12-week VLED (3151 kJ/day) or MD program (8950 kJ/day) and monitored for 24 weeks. The VLED group received low-dose semaglutide (0.5 mg/weekly) from week 13 for weight maintenance. Primary outcome was change in hepatic steatosis by MRI liver-fat-fraction (MRI-LFF) at 12 weeks. Secondary outcomes included total body weight loss (TBWL) and change in liver histology over 24 weeks.
Results: The VLED group (n=14) achieved significantly greater reduction in MRI-LFF (-77% relative reduction (IQR 51, 88)) compared to the MD group (n=11, -14% (IQR 0, 30), p<0.01). The VLED also produced TBWL at week 12 (-13% (IQR -17, -9) vs -4% (-4.4, -0.2), p<0.01). At 24 weeks, the VLED/semaglutide group maintained a -14% TBWL (IQR -17,-10) from baseline vs -3% TBWL (IQR -4, 0) in the MD. Liver histology improved in both groups, with greater improvements in the VLED group (NAFLD activity score reduction VLED: -2 (IQR -3.5, -2) vs MD: -1 (IQR -1, -1), p<0.01).
Conclusions: The very low energy diet resulted in significantly greater reduction in hepatic steatosis and weight loss compared to Mediterranean diet. The very low energy diet is widely available, easily accessible and should be more commonly considered for MASLD patients with overweight/obesity. Clinical trial registration www.anzctr.org.au trial ID: ACTRN12623000756628 IMPACT AND IMPLICATIONS: This pilot randomised control trial provides the first direct comparison between a ketogenic Very Low Energy Diet (VLED) and a Mediterranean diet (MD) for MASLD treatment, demonstrating superior outcomes with the VLED including 77% vs 14% hepatic steatosis reduction and 13% vs 4% weight loss. The growing burden of people who are overweight and obese with early-stage MASLD means that effective dietary weight loss interventions with proven hepatic and metabolic benefits are urgently required. The VLED's accessibility, effectiveness and ease of implementation in clinical practice suggest it should be a more widely considered first-line therapy for MASLD patients with overweight or obesity.
{"title":"Very Low Energy Ketogenic Diet vs Mediterranean Diet for MASLD: Superior Steatosis Reduction in a Randomised Pilot Study.","authors":"Ann M Farrell, Tonya Paris, Evelyn B Parr, Elena S George, Jessica Howell, Catherine Croagh, Tom Sutherland, Mark Page, Penny McKelvie, Alexander J Thompson, Marno Ryan","doi":"10.1016/j.jhepr.2026.101787","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101787","url":null,"abstract":"<p><strong>Background & aims: </strong>Weight loss is the cornerstone of treatment for metabolic dysfunction associated steatotic liver disease (MASLD). This pilot study compared the efficacy and safety of a very low energy ketogenic diet (VLED) versus a Mediterranean diet (MD) in improving hepatic steatosis and liver histology in individuals with overweight or obesity and MASLD.</p><p><strong>Methods: </strong>We conducted a pilot randomised controlled trial in adults with histologically confirmed MASLD and BMI 27-35 kg/m<sup>2</sup>. Participants were assigned to either a 12-week VLED (3151 kJ/day) or MD program (8950 kJ/day) and monitored for 24 weeks. The VLED group received low-dose semaglutide (0.5 mg/weekly) from week 13 for weight maintenance. Primary outcome was change in hepatic steatosis by MRI liver-fat-fraction (MRI-LFF) at 12 weeks. Secondary outcomes included total body weight loss (TBWL) and change in liver histology over 24 weeks.</p><p><strong>Results: </strong>The VLED group (n=14) achieved significantly greater reduction in MRI-LFF (-77% relative reduction (IQR 51, 88)) compared to the MD group (n=11, -14% (IQR 0, 30), p<0.01). The VLED also produced TBWL at week 12 (-13% (IQR -17, -9) vs -4% (-4.4, -0.2), p<0.01). At 24 weeks, the VLED/semaglutide group maintained a -14% TBWL (IQR -17,-10) from baseline vs -3% TBWL (IQR -4, 0) in the MD. Liver histology improved in both groups, with greater improvements in the VLED group (NAFLD activity score reduction VLED: -2 (IQR -3.5, -2) vs MD: -1 (IQR -1, -1), p<0.01).</p><p><strong>Conclusions: </strong>The very low energy diet resulted in significantly greater reduction in hepatic steatosis and weight loss compared to Mediterranean diet. The very low energy diet is widely available, easily accessible and should be more commonly considered for MASLD patients with overweight/obesity. Clinical trial registration www.anzctr.org.au trial ID: ACTRN12623000756628 IMPACT AND IMPLICATIONS: This pilot randomised control trial provides the first direct comparison between a ketogenic Very Low Energy Diet (VLED) and a Mediterranean diet (MD) for MASLD treatment, demonstrating superior outcomes with the VLED including 77% vs 14% hepatic steatosis reduction and 13% vs 4% weight loss. The growing burden of people who are overweight and obese with early-stage MASLD means that effective dietary weight loss interventions with proven hepatic and metabolic benefits are urgently required. The VLED's accessibility, effectiveness and ease of implementation in clinical practice suggest it should be a more widely considered first-line therapy for MASLD patients with overweight or obesity.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101787"},"PeriodicalIF":7.5,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147457745","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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