Pub Date : 2025-10-17DOI: 10.1016/j.jhepr.2025.101647
Frederik Schliephake , Isabella Lurje , Deniz Uluk , Janina Eden , Zoltan Czigany , Justus Pein , Peri Husen , Cornelius Engelmann , Christoph Michalski , Marlene Kohlhepp , Pavel Strnad , Philipp Dutkowski , Frank Tacke , Ulf Peter Neumann , David Meierhofer , Georg Lurje
<div><h3>Background & Aims</h3><div>In liver transplantation, bile acid (BA) toxicity contributes to injury of both hepatocytes and cholangiocytes. While hypothermic oxygenated machine perfusion (HOPE) reduces ischemia–reperfusion injury (IRI) and improves clinical outcomes, its impact on bile composition remains unclear because of the lack of bile samples available after LT.</div></div><div><h3>Methods</h3><div>Bile, blood, and liver tissue were collected within a multicentric randomized controlled trial (NCT03124641), from 26 patients receiving extended criteria donation (ECD) allografts from donors after brain death (DBD). Fourteen donor livers were static cold stored (SCS group), while 12 livers underwent end-ischemic HOPE. Grafts were randomly assigned. BA levels and metabolic parameters were analyzed across samples with mass spectrometry. Expression of bile transporters and enzymes was assessed in liver biopsies before and after transplantation.</div></div><div><h3>Results</h3><div>Serum and biliary levels of hydrophobic BAs were positively correlated with IRI severity, such as serum aspartate aminotransferase and alanine aminotransferase, and decreased across postoperative days (POD) for all allografts (bile: POD-1 <em>vs.</em> POD-2/-3, <em>p</em> <0.001; blood: admission <em>vs.</em> POD-1–3, <em>p</em> <0.001). Expression of the hepatocyte bile transporters ABCB4 and ABCG8 decreased post-reperfusion (<em>p</em> = 0.045; <em>p</em> <0.001). In the SCS group, intrahepatic BA levels increased post-reperfusion (8.71 to 10.77 pmol/mg, <em>p</em> = 0.023), while biliary BA levels decreased postoperatively (POD-1 <em>vs.</em> POD-3, <em>p</em> = 0.06). The HOPE group showed higher biliary BA and phosphatidylcholine (PC) levels on POD-3 compared with the SCS group (total BAs: 2.30 × 10<sup>9</sup> <em>vs.</em> 2.03 × 10<sup>9</sup> peak area, <em>p</em> = 0.047; PC: 6.49 × 10<sup>8</sup> <em>vs.</em> 4.48 × 10<sup>8</sup> peak area, <em>p</em> = 0.031), and a decline in biliary BA/PC ratio.</div></div><div><h3>Conclusions</h3><div>This is the first randomized study demonstrating effects of HOPE treatment on bile composition following ECD-DBD liver transplantation. Protection from BA toxicity may represent a novel mechanism underlying the effects of HOPE.</div></div><div><h3>Clinical trials registration</h3><div>This trial is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT03124641).</div></div><div><h3>Impact and implications</h3><div>Worldwide liver allograft scarcity has led to the implementation of hypothermic oxygenated machine perfusion (HOPE) to enhance the safety of liver transplantation (LT) using extended criteria donors. However, its protective mechanisms remain incompletely understood, largely because of limited human data. In this study, we provide evidence that HOPE improves biliary lipid secretion after LT, limits intrahepatic bile acid accumulation upon allograft reperfusion, re
背景和目的在肝移植中，胆汁酸（BA）毒性可导致肝细胞和胆管细胞损伤。虽然低温氧合机灌注（HOPE）可以减少缺血再灌注损伤（IRI）并改善临床结果，但由于缺乏肝胆样本，其对胆汁成分的影响尚不清楚。方法在一项多中心随机对照试验（NCT03124641）中收集了26例脑死亡（DBD）后接受延长标准捐赠（ECD）同种异体移植的患者的胆汁、血液和肝组织。14例供肝静冷保存（SCS组），12例肝缺血末HOPE。移植物随机分配。用质谱法分析样品中的BA水平和代谢参数。在移植前后肝活检中评估胆汁转运蛋白和酶的表达。结果血清和胆汁中疏水BAs水平与IRI严重程度呈正相关，如血清天冬氨酸转氨酶和丙氨酸转氨酶，并且在所有同种异体移植物术后（POD）天内下降（胆汁：POD-1 vs. POD-2/-3, p <0.001；血液：入院vs. POD-1 -3, p <0.001）。再灌注后肝细胞胆汁转运体ABCB4和ABCG8的表达降低（p = 0.045; p <0.001）。在SCS组，再灌注后肝内BA水平升高（8.71至10.77 pmol/mg, p = 0.023），而术后胆道BA水平下降（POD-1 vs. POD-3, p = 0.06）。与SCS组相比，HOPE组在POD-3上显示出更高的胆道BA和磷脂酰胆碱（PC）水平（总BAs: 2.30 × 109比2.03 × 109峰面积，p = 0.047; PC: 6.49 × 108比4.48 × 108峰面积，p = 0.031），胆道BA/PC比值下降。结论：这是首个证明HOPE治疗对ECD-DBD肝移植术后胆汁成分影响的随机研究。对BA毒性的保护可能是HOPE作用的一种新机制。临床试验注册本试验在ClinicalTrials.gov注册（NCT03124641）。影响和意义世界范围内同种异体肝脏移植的稀缺性导致了低温氧合机灌注（HOPE）的实施，以提高使用扩展标准供体的肝移植（LT）的安全性。然而，其保护机制仍然不完全清楚，主要是因为有限的人类数据。在本研究中，我们提供的证据表明，HOPE可以改善肝移植后的胆脂分泌，限制同种异体移植物再灌注时肝内胆汁酸的积累，降低胆汁酸与磷脂酰胆碱的比值，促进肝移植后血清胆汁酸水平的正常化。我们的研究结果表明，对胆汁酸毒性的保护可能构成HOPE作用的新机制。
{"title":"Effects of hypothermic oxygenated machine perfusion on bile composition after liver transplantation – Findings from a randomized controlled trial","authors":"Frederik Schliephake , Isabella Lurje , Deniz Uluk , Janina Eden , Zoltan Czigany , Justus Pein , Peri Husen , Cornelius Engelmann , Christoph Michalski , Marlene Kohlhepp , Pavel Strnad , Philipp Dutkowski , Frank Tacke , Ulf Peter Neumann , David Meierhofer , Georg Lurje","doi":"10.1016/j.jhepr.2025.101647","DOIUrl":"10.1016/j.jhepr.2025.101647","url":null,"abstract":"<div><h3>Background & Aims</h3><div>In liver transplantation, bile acid (BA) toxicity contributes to injury of both hepatocytes and cholangiocytes. While hypothermic oxygenated machine perfusion (HOPE) reduces ischemia–reperfusion injury (IRI) and improves clinical outcomes, its impact on bile composition remains unclear because of the lack of bile samples available after LT.</div></div><div><h3>Methods</h3><div>Bile, blood, and liver tissue were collected within a multicentric randomized controlled trial (NCT03124641), from 26 patients receiving extended criteria donation (ECD) allografts from donors after brain death (DBD). Fourteen donor livers were static cold stored (SCS group), while 12 livers underwent end-ischemic HOPE. Grafts were randomly assigned. BA levels and metabolic parameters were analyzed across samples with mass spectrometry. Expression of bile transporters and enzymes was assessed in liver biopsies before and after transplantation.</div></div><div><h3>Results</h3><div>Serum and biliary levels of hydrophobic BAs were positively correlated with IRI severity, such as serum aspartate aminotransferase and alanine aminotransferase, and decreased across postoperative days (POD) for all allografts (bile: POD-1 <em>vs.</em> POD-2/-3, <em>p</em> <0.001; blood: admission <em>vs.</em> POD-1–3, <em>p</em> <0.001). Expression of the hepatocyte bile transporters ABCB4 and ABCG8 decreased post-reperfusion (<em>p</em> = 0.045; <em>p</em> <0.001). In the SCS group, intrahepatic BA levels increased post-reperfusion (8.71 to 10.77 pmol/mg, <em>p</em> = 0.023), while biliary BA levels decreased postoperatively (POD-1 <em>vs.</em> POD-3, <em>p</em> = 0.06). The HOPE group showed higher biliary BA and phosphatidylcholine (PC) levels on POD-3 compared with the SCS group (total BAs: 2.30 × 10<sup>9</sup> <em>vs.</em> 2.03 × 10<sup>9</sup> peak area, <em>p</em> = 0.047; PC: 6.49 × 10<sup>8</sup> <em>vs.</em> 4.48 × 10<sup>8</sup> peak area, <em>p</em> = 0.031), and a decline in biliary BA/PC ratio.</div></div><div><h3>Conclusions</h3><div>This is the first randomized study demonstrating effects of HOPE treatment on bile composition following ECD-DBD liver transplantation. Protection from BA toxicity may represent a novel mechanism underlying the effects of HOPE.</div></div><div><h3>Clinical trials registration</h3><div>This trial is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT03124641).</div></div><div><h3>Impact and implications</h3><div>Worldwide liver allograft scarcity has led to the implementation of hypothermic oxygenated machine perfusion (HOPE) to enhance the safety of liver transplantation (LT) using extended criteria donors. However, its protective mechanisms remain incompletely understood, largely because of limited human data. In this study, we provide evidence that HOPE improves biliary lipid secretion after LT, limits intrahepatic bile acid accumulation upon allograft reperfusion, re","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101647"},"PeriodicalIF":7.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922399","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 : 2025-10-17DOI: 10.1016/j.jhepr.2025.101645
Xiao-Dong Zhou , Sherlot Juan Song , Chloe Yitian Guo , Qin-Fen Chen , Grace Lai-Hung Wong , Ting-Ran Ye , George Boon Bee Goh , Yong Mong Bee , Li-You Lian , Terry Cheuk-Fung Yip , Jimmy Che-To Lai , Si-Yi Lei , Wen-Yue Liu , Ren Chenghan Fan , Cheng-Lv Hong , Giovanni Targher , Christopher D. Byrne , Guillemette Marot , Violeta Raverdy , Francois Pattou , Ming-Hua Zheng
<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition that presents varying risks for liver-related and cardiovascular complications. Clustering methods have identified distinct MASLD subtypes, yet their applicability to Asian populations remains unclear. This study aims to validate a MASLD clustering model using clinical variables from three Asian cohorts: Wenzhou Real-World (WRW), Hong Kong Clinical Data Analysis and Reporting System (CDARS), and SingHealth Diabetes Registry.</div></div><div><h3>Methods</h3><div>Clustering analysis was conducted based on age, BMI, hemoglobin A<sub>1c</sub>, alanine aminotransferase, LDL-cholesterol, and triglycerides. Outcomes included major adverse cardiovascular events (MACE), liver-related events (LRE), and new-onset type 2 diabetes (T2DM). They were analyzed using Cox regression risk models and Kaplan–Meier analyses to assess risk and incident events across MASLD clusters.</div></div><div><h3>Results</h3><div>Across the three cohorts, distinct risk patterns emerged for MACE, LRE, and T2DM among various MASLD clusters. For MACE, the cardiometabolic cluster exhibited the highest risk in all cohorts: WRW (hazard ratio [HR] 1.315, <em>p</em> <0.001), Hong Kong CDARS (HR 1.559, <em>p</em> <0.001), and SingHealth Diabetes Registry (HR 1.262, <em>p</em> <0.001). For LRE, the liver-specific cluster showed the highest risk in the WRW (HR 1.578, <em>p</em> = 0.002) and SingHealth Diabetes Registry cohorts (HR 2.403, <em>p</em> <0.001). In contrast, in the Hong Kong CDARS cohort, both the cardiometabolic (HR 1.818, <em>p</em> <0.001) and liver-specific clusters (HR 1.557, <em>p</em> <0.001) exhibited similarly increased risks. For T2DM, the cardiometabolic cluster showed the highest risk in the WRW (HR 3.418, <em>p</em> <0.001) and Hong Kong CDARS cohorts (HR 2.761, <em>p</em> <0.001).</div></div><div><h3>Conclusions</h3><div>The proposed MASLD clustering model is applicable to Asian populations, facilitating personalized treatment and optimizing outcomes.</div></div><div><h3>Impact and implications</h3><div>This study provides scientific justification for applying a validated clustering model to metabolic dysfunction-associated steatotic liver disease (MASLD), demonstrating that patient subgroups identified by data-driven methods carry distinct risks for cardiovascular and liver-related outcomes. These findings are important for clinicians, researchers, and policymakers as they highlight that MASLD is not a uniform disease but rather comprises heterogeneous subgroups with differing prognoses. In practice, this work supports subgroup-based strategies to personalize treatment, improve risk stratification, and optimize the allocation of healthcare resources. The results also offer a foundation for future research into targeted therapeutic interventions while acknowledging the need for further validation in diverse pop
背景和目的代谢功能障碍相关脂肪变性肝病（MASLD）是一种异质性疾病，呈现出肝脏相关和心血管并发症的不同风险。聚类方法已经确定了不同的MASLD亚型，但它们对亚洲人群的适用性仍不清楚。本研究旨在利用三个亚洲队列的临床变量验证MASLD聚类模型：温州真实世界（WRW）、香港临床数据分析和报告系统（CDARS）和SingHealth糖尿病登记处。方法根据年龄、BMI、糖化血红蛋白、丙氨酸转氨酶、低密度脂蛋白胆固醇、甘油三酯进行聚类分析。结果包括主要不良心血管事件（MACE）、肝脏相关事件（LRE）和新发2型糖尿病（T2DM）。使用Cox回归风险模型和Kaplan-Meier分析来评估MASLD集群的风险和事件事件。结果在三个队列中，不同的MASLD集群中出现了不同的MACE、LRE和T2DM风险模式。对于MACE，心脏代谢组在所有队列中表现出最高的风险：WRW（风险比[HR] 1.315, p <0.001）， Hong Kong CDARS（风险比[HR] 1.559, p <0.001）和SingHealth Diabetes Registry（风险比[HR] 1.262, p <0.001）。对于LRE，肝脏特异性群集在WRW （HR 1.578, p = 0.002）和SingHealth Diabetes Registry队列（HR 2.403, p <0.001）中显示出最高的风险。相比之下，在香港CDARS队列中，心脏代谢（HR 1.818, p <0.001）和肝脏特异性聚集（HR 1.557, p <0.001）均表现出类似的风险增加。对于T2DM，心脏代谢组在WRW组（HR 3.418, p <0.001）和香港CDARS组（HR 2.761, p <0.001）的风险最高。结论MASLD聚类模型适用于亚洲人群，有利于个性化治疗和优化治疗效果。影响和意义本研究为将有效的聚类模型应用于代谢功能障碍相关脂肪变性肝病（MASLD）提供了科学依据，表明通过数据驱动方法确定的患者亚组具有心血管和肝脏相关结局的不同风险。这些发现对临床医生、研究人员和政策制定者很重要，因为它们强调了MASLD不是一种统一的疾病，而是由预后不同的异质亚群组成。在实践中，这项工作支持基于亚组的策略来个性化治疗，改善风险分层，优化医疗资源分配。该结果也为未来的针对性治疗干预研究提供了基础，同时承认需要在不同人群中进一步验证。
{"title":"Validation of a data-driven clustering model for MASLD: Evidence from three large-scale Asian cohorts","authors":"Xiao-Dong Zhou , Sherlot Juan Song , Chloe Yitian Guo , Qin-Fen Chen , Grace Lai-Hung Wong , Ting-Ran Ye , George Boon Bee Goh , Yong Mong Bee , Li-You Lian , Terry Cheuk-Fung Yip , Jimmy Che-To Lai , Si-Yi Lei , Wen-Yue Liu , Ren Chenghan Fan , Cheng-Lv Hong , Giovanni Targher , Christopher D. Byrne , Guillemette Marot , Violeta Raverdy , Francois Pattou , Ming-Hua Zheng","doi":"10.1016/j.jhepr.2025.101645","DOIUrl":"10.1016/j.jhepr.2025.101645","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition that presents varying risks for liver-related and cardiovascular complications. Clustering methods have identified distinct MASLD subtypes, yet their applicability to Asian populations remains unclear. This study aims to validate a MASLD clustering model using clinical variables from three Asian cohorts: Wenzhou Real-World (WRW), Hong Kong Clinical Data Analysis and Reporting System (CDARS), and SingHealth Diabetes Registry.</div></div><div><h3>Methods</h3><div>Clustering analysis was conducted based on age, BMI, hemoglobin A<sub>1c</sub>, alanine aminotransferase, LDL-cholesterol, and triglycerides. Outcomes included major adverse cardiovascular events (MACE), liver-related events (LRE), and new-onset type 2 diabetes (T2DM). They were analyzed using Cox regression risk models and Kaplan–Meier analyses to assess risk and incident events across MASLD clusters.</div></div><div><h3>Results</h3><div>Across the three cohorts, distinct risk patterns emerged for MACE, LRE, and T2DM among various MASLD clusters. For MACE, the cardiometabolic cluster exhibited the highest risk in all cohorts: WRW (hazard ratio [HR] 1.315, <em>p</em> <0.001), Hong Kong CDARS (HR 1.559, <em>p</em> <0.001), and SingHealth Diabetes Registry (HR 1.262, <em>p</em> <0.001). For LRE, the liver-specific cluster showed the highest risk in the WRW (HR 1.578, <em>p</em> = 0.002) and SingHealth Diabetes Registry cohorts (HR 2.403, <em>p</em> <0.001). In contrast, in the Hong Kong CDARS cohort, both the cardiometabolic (HR 1.818, <em>p</em> <0.001) and liver-specific clusters (HR 1.557, <em>p</em> <0.001) exhibited similarly increased risks. For T2DM, the cardiometabolic cluster showed the highest risk in the WRW (HR 3.418, <em>p</em> <0.001) and Hong Kong CDARS cohorts (HR 2.761, <em>p</em> <0.001).</div></div><div><h3>Conclusions</h3><div>The proposed MASLD clustering model is applicable to Asian populations, facilitating personalized treatment and optimizing outcomes.</div></div><div><h3>Impact and implications</h3><div>This study provides scientific justification for applying a validated clustering model to metabolic dysfunction-associated steatotic liver disease (MASLD), demonstrating that patient subgroups identified by data-driven methods carry distinct risks for cardiovascular and liver-related outcomes. These findings are important for clinicians, researchers, and policymakers as they highlight that MASLD is not a uniform disease but rather comprises heterogeneous subgroups with differing prognoses. In practice, this work supports subgroup-based strategies to personalize treatment, improve risk stratification, and optimize the allocation of healthcare resources. The results also offer a foundation for future research into targeted therapeutic interventions while acknowledging the need for further validation in diverse pop","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101645"},"PeriodicalIF":7.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682288","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 : 2025-10-17DOI: 10.1016/j.jhepr.2025.101646
Youxin Wang , Ruiqiu Chen , Shi Yan Lee , Eunice X.X. Tan , Mark Muthiah , Zhou Yu , Margaret L.P. Teng , Jazleen Leo , Cheng Han Ng , Ashok Choudhury , Daniel Q. Huang
Background & Aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) are rising causes of liver-related morbidity and mortality worldwide. The burden among women of childbearing age (15–49 years) is not well defined. We quantified global and regional trends from 2010 to 2021 and projected prevalence through 2035.
Methods
Prevalence, incident cases, and disability-adjusted life-years (DALYs) among women of childbearing age were estimated using the Global Burden of Disease 2021 framework. Temporal trends were evaluated using Joinpoint regression to estimate annual percent change. Inequality was assessed using the slope and concentration indices, and prevalence was projected using Bayesian age–period–cohort models.
Results
Between 2010 and 2021, global MASLD prevalence rose by 13.8%, reaching 15,759 per 100,000 population in 2021. The highest burden was observed in the Eastern Mediterranean region (24,530 per 100,000 population), with the most pronounced increases seen in high sociodemographic index countries (+20.0%) and the Western Pacific region (+21.9%). Conversely, ALD prevalence declined by 6.8% to 11.0 per 100,000 population, with notable declines in Europe (-15.5%) but modest increases in the Western Pacific (+10.5%) and Eastern Mediterranean (+3.7%). The burden of both MASLD and ALD rose steadily with age and peaked among women aged 45–49 years. Despite a higher prevalence, MASLD contributed modest DALY rates (20.4 per 100,000 population), whereas ALD, although less prevalent, imposed a greater burden (29.1 per 100,000 population). By 2035, MASLD prevalence is projected to reach 17,393 per 100,000 population (+10.4%), and ALD prevalence is projected to reach 11.5 per 100,000 population (+4.5%).
Conclusions
MASLD is rapidly increasing among women of childbearing age, with marked regional and socioeconomic disparities, whereas the burden of ALD appears to be in decline.
Impact and implications
Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) among women of childbearing age are often overlooked despite significant maternal and intergenerational health consequences. Our analysis shows a rising prevalence of MASLD and a modest decline in ALD, with marked regional and socioeconomic disparities, and projects continued MASLD growth through 2035. These findings are important for clinicians, researchers, and policymakers, given the associated maternal, neonatal, and intergenerational risks. Integrating metabolic and reproductive health services alongside equitable policy interventions may help mitigate these concerning trends.
{"title":"Rising burden of steatotic liver disease in women of childbearing age and projections to 2035","authors":"Youxin Wang , Ruiqiu Chen , Shi Yan Lee , Eunice X.X. Tan , Mark Muthiah , Zhou Yu , Margaret L.P. Teng , Jazleen Leo , Cheng Han Ng , Ashok Choudhury , Daniel Q. Huang","doi":"10.1016/j.jhepr.2025.101646","DOIUrl":"10.1016/j.jhepr.2025.101646","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) are rising causes of liver-related morbidity and mortality worldwide. The burden among women of childbearing age (15–49 years) is not well defined. We quantified global and regional trends from 2010 to 2021 and projected prevalence through 2035.</div></div><div><h3>Methods</h3><div>Prevalence, incident cases, and disability-adjusted life-years (DALYs) among women of childbearing age were estimated using the Global Burden of Disease 2021 framework. Temporal trends were evaluated using Joinpoint regression to estimate annual percent change. Inequality was assessed using the slope and concentration indices, and prevalence was projected using Bayesian age–period–cohort models.</div></div><div><h3>Results</h3><div>Between 2010 and 2021, global MASLD prevalence rose by 13.8%, reaching 15,759 per 100,000 population in 2021. The highest burden was observed in the Eastern Mediterranean region (24,530 per 100,000 population), with the most pronounced increases seen in high sociodemographic index countries (+20.0%) and the Western Pacific region (+21.9%). Conversely, ALD prevalence declined by 6.8% to 11.0 per 100,000 population, with notable declines in Europe (-15.5%) but modest increases in the Western Pacific (+10.5%) and Eastern Mediterranean (+3.7%). The burden of both MASLD and ALD rose steadily with age and peaked among women aged 45–49 years. Despite a higher prevalence, MASLD contributed modest DALY rates (20.4 per 100,000 population), whereas ALD, although less prevalent, imposed a greater burden (29.1 per 100,000 population). By 2035, MASLD prevalence is projected to reach 17,393 per 100,000 population (+10.4%), and ALD prevalence is projected to reach 11.5 per 100,000 population (+4.5%).</div></div><div><h3>Conclusions</h3><div>MASLD is rapidly increasing among women of childbearing age, with marked regional and socioeconomic disparities, whereas the burden of ALD appears to be in decline.</div></div><div><h3>Impact and implications</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) among women of childbearing age are often overlooked despite significant maternal and intergenerational health consequences. Our analysis shows a rising prevalence of MASLD and a modest decline in ALD, with marked regional and socioeconomic disparities, and projects continued MASLD growth through 2035. These findings are important for clinicians, researchers, and policymakers, given the associated maternal, neonatal, and intergenerational risks. Integrating metabolic and reproductive health services alongside equitable policy interventions may help mitigate these concerning trends.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101646"},"PeriodicalIF":7.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682289","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 : 2025-10-17DOI: 10.1016/j.jhepr.2025.101643
Lisa Sandmann , Mathias Jachs , Tammo L. Tergast , Lukas Hartl , Birgit Bremer , Martin A. Kabelitz , Michael Schwarz , Julius F.M. Egge , Lorenz Balcar , Benedikt Silvester Hofer , Christine S. Falk , Albert Friedrich Stättermayer , Markus Cornberg , Michael Trauner , Katja Deterding , Mattias Mandorfer , Heiner Wedemeyer , Thomas Reiberger , Benjamin Maasoumy
<div><h3>Background & Aims</h3><div>Portal hypertension (PH) drives decompensation in patients with advanced chronic liver disease. Effects of antiviral treatment with bulevirtide (BLV) and achievement of suggested treatment endpoints on PH in patients with chronic hepatitis D (CHD) are unknown.</div></div><div><h3>Methods</h3><div>BLV-treated CHD patients with PH were prospectively enrolled in this observational, multicenter study. Hepatic venous pressure gradient (HVPG) was measured before (BL) and after ≥12 months of BLV treatment (M12). HVPG response (≥10% decline) rates were compared between virological (VR), biochemical (BR), and combined (CR) responders <em>vs.</em> non-responders as defined in the BLV phase III studies. Associated changes in biomarkers of bacterial translocation, (dys)angiogenesis/endothelial dysfunction, and systemic inflammation (SI) were investigated.</div></div><div><h3>Results</h3><div>Of 34 patients receiving BL HVPG measurement, 20 patients with paired HVPG measurement and a BL clinically significant portal hypertension (CSPH) (≥10 mmHg HVPG) prevalence of 85% were included. At M12, HVPG significantly decreased in patients with CR (n = 12; 15.5 [IQR 10.5–21.8] to 12 [IQR 7.3–15.8] mmHg; <em>p</em> <0.001), VR (n = 14; 14.5 [IQR 10–21.3] to 12 [IQR 7.8–16.5] mmHg, <em>p</em> = 0.003), and BR (n = 16; 12.5 [IQR 10–20.5] to 10.5 [IQR 8–15] mmHg, <em>p</em> = 0.002); but not in non-responders. All patients with CSPH with CR (n = 10/10) and most of VR (83%, n = 10/12) and BR (85%, n = 11/13) achieved HVPG response, but no BLV non-responder. CSPH resolved in three of 17 (17.6%) patients. Markers of bacterial translocation (sCD163; <em>p</em> = 0.001), (dys)angiogenesis/endothelial dysfunction (Ang2; <em>p</em> = 0.001) and SI (IFNγ, IL-1RA, sCD25/IL-2Rα, CCL3/MIP-1alpha, HGF; all <em>p</em> <0.05) decreased in responders but not in non-responders.</div></div><div><h3>Conclusions</h3><div>Significant HVPG decreases accompanied by improvement of bacterial translocation, (dys)angiogenesis/endothelial dysfunction and SI are observed in patients with CHD achieving BLV response. These findings provide evidence for the validity and clinical relevance of the currently recommended on-treatment response criteria.</div></div><div><h3>Clinical trials registration</h3><div>This study is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT04863703).</div></div><div><h3>Impact and implications</h3><div>Portal hypertension is the main mechanism driving clinical deterioration in patients with compensated advanced chronic liver disease, for which patients with chronic hepatitis D (CHD) are at particularly high risk. This study demonstrates that in patients with CHD with portal hypertension, achieving response to antiviral treatment with bulevirtide decreases the hepatic venous pressure gradient (HVPG). Importantly, a clinical meaningful reduction in HVPG was observed only in treatment responder
背景：在晚期慢性肝病患者中，运动性高血压（PH）会导致代偿失调。布来韦肽（BLV）抗病毒治疗对慢性丁型肝炎（CHD）患者PH的影响和建议治疗终点的实现尚不清楚。方法采用blv治疗的冠心病合并PH患者前瞻性纳入这项观察性多中心研究。在BLV治疗前（BL）和治疗后≥12个月（M12）测量肝静脉压梯度（HVPG）。比较BLV III期研究中定义的病毒学（VR）、生化（BR）和联合（CR）应答者与无应答者之间的HVPG应答率（下降≥10%）。研究了细菌易位、血管生成/内皮功能障碍和全身性炎症（SI）等生物标志物的相关变化。结果34例接受BL HVPG测量的患者中，20例同时进行HVPG配对测量且BL临床显著门脉高压（CSPH） （HVPG≥10 mmHg）患病率为85%。在M12时，CR （n = 12; 15.5 [IQR 10.5 - 21.8]至12 [IQR 7.3-15.8] mmHg; p <0.001）、VR （n = 14; 14.5 [IQR 10-21.3]至12 [IQR 7.8-16.5] mmHg, p = 0.003）和BR （n = 16; 12.5 [IQR 10-20.5]至10.5 [IQR 8-15] mmHg, p = 0.002）患者的HVPG显著降低；但对无反应者则不然。所有伴有CR （n = 10/10）、大部分VR （83%, n = 10/12）和BR （85%, n = 11/13）的CSPH患者均达到HVPG应答，但无BLV无应答者。17例患者中3例（17.6%）CSPH消退。细菌易位（sCD163, p = 0.001）、血管生成/内皮功能障碍（Ang2, p = 0.001）和SI （IFNγ、IL-1RA、sCD25/IL-2Rα、CCL3/ mip -1 α、HGF，均p <；0.05）在应答者中下降，而在无应答者中没有下降。结论在达到BLV应答的冠心病患者中，HVPG显著降低，同时细菌易位、血管生成/内皮功能障碍和SI改善。这些发现为目前推荐的治疗反应标准的有效性和临床相关性提供了证据。临床试验注册本研究已在ClinicalTrials.gov注册（NCT04863703）。影响和意义运动高血压是代偿性晚期慢性肝病患者临床恶化的主要机制，其中慢性丁型肝炎（CHD）患者的风险特别高。本研究表明，在伴有门脉高压的冠心病患者中，布来韦肽抗病毒治疗获得应答可降低肝静脉压梯度（HVPG）。重要的是，HVPG的临床意义降低仅在临床试验中使用的终点定义的治疗应答者中观察到，特别是在所有达到联合应答的患者中。重要病理生理机制的生物标志物也得到了改进。对抗病毒治疗有反应的冠心病患者HVPG下降的临床意义的发现加强了建议的治疗反应标准的临床意义，支持BLV反应的疾病改善作用，可能转化为冠心病患者发病率和死亡率的降低。
{"title":"Treatment response to bulevirtide is linked to amelioration of portal hypertension in patients with chronic hepatitis D","authors":"Lisa Sandmann , Mathias Jachs , Tammo L. Tergast , Lukas Hartl , Birgit Bremer , Martin A. Kabelitz , Michael Schwarz , Julius F.M. Egge , Lorenz Balcar , Benedikt Silvester Hofer , Christine S. Falk , Albert Friedrich Stättermayer , Markus Cornberg , Michael Trauner , Katja Deterding , Mattias Mandorfer , Heiner Wedemeyer , Thomas Reiberger , Benjamin Maasoumy","doi":"10.1016/j.jhepr.2025.101643","DOIUrl":"10.1016/j.jhepr.2025.101643","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Portal hypertension (PH) drives decompensation in patients with advanced chronic liver disease. Effects of antiviral treatment with bulevirtide (BLV) and achievement of suggested treatment endpoints on PH in patients with chronic hepatitis D (CHD) are unknown.</div></div><div><h3>Methods</h3><div>BLV-treated CHD patients with PH were prospectively enrolled in this observational, multicenter study. Hepatic venous pressure gradient (HVPG) was measured before (BL) and after ≥12 months of BLV treatment (M12). HVPG response (≥10% decline) rates were compared between virological (VR), biochemical (BR), and combined (CR) responders <em>vs.</em> non-responders as defined in the BLV phase III studies. Associated changes in biomarkers of bacterial translocation, (dys)angiogenesis/endothelial dysfunction, and systemic inflammation (SI) were investigated.</div></div><div><h3>Results</h3><div>Of 34 patients receiving BL HVPG measurement, 20 patients with paired HVPG measurement and a BL clinically significant portal hypertension (CSPH) (≥10 mmHg HVPG) prevalence of 85% were included. At M12, HVPG significantly decreased in patients with CR (n = 12; 15.5 [IQR 10.5–21.8] to 12 [IQR 7.3–15.8] mmHg; <em>p</em> <0.001), VR (n = 14; 14.5 [IQR 10–21.3] to 12 [IQR 7.8–16.5] mmHg, <em>p</em> = 0.003), and BR (n = 16; 12.5 [IQR 10–20.5] to 10.5 [IQR 8–15] mmHg, <em>p</em> = 0.002); but not in non-responders. All patients with CSPH with CR (n = 10/10) and most of VR (83%, n = 10/12) and BR (85%, n = 11/13) achieved HVPG response, but no BLV non-responder. CSPH resolved in three of 17 (17.6%) patients. Markers of bacterial translocation (sCD163; <em>p</em> = 0.001), (dys)angiogenesis/endothelial dysfunction (Ang2; <em>p</em> = 0.001) and SI (IFNγ, IL-1RA, sCD25/IL-2Rα, CCL3/MIP-1alpha, HGF; all <em>p</em> <0.05) decreased in responders but not in non-responders.</div></div><div><h3>Conclusions</h3><div>Significant HVPG decreases accompanied by improvement of bacterial translocation, (dys)angiogenesis/endothelial dysfunction and SI are observed in patients with CHD achieving BLV response. These findings provide evidence for the validity and clinical relevance of the currently recommended on-treatment response criteria.</div></div><div><h3>Clinical trials registration</h3><div>This study is registered at <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> (NCT04863703).</div></div><div><h3>Impact and implications</h3><div>Portal hypertension is the main mechanism driving clinical deterioration in patients with compensated advanced chronic liver disease, for which patients with chronic hepatitis D (CHD) are at particularly high risk. This study demonstrates that in patients with CHD with portal hypertension, achieving response to antiviral treatment with bulevirtide decreases the hepatic venous pressure gradient (HVPG). Importantly, a clinical meaningful reduction in HVPG was observed only in treatment responder","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101643"},"PeriodicalIF":7.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682351","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 : 2025-10-16DOI: 10.1016/j.jhepr.2025.101640
Ian A. Rowe , Juan G. Abraldes
{"title":"MELD 3.i and the case for continuous updating in liver allocation","authors":"Ian A. Rowe , Juan G. Abraldes","doi":"10.1016/j.jhepr.2025.101640","DOIUrl":"10.1016/j.jhepr.2025.101640","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101640"},"PeriodicalIF":7.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617338","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 : 2025-10-16DOI: 10.1016/j.jhepr.2025.101638
Li-Ying Ou-Yang , Yi-Xiang Gan , Chao Zhang , Neng Jiang , Shi-Xun Lu , Zi-Liang Yang , Ming Shi , Yao-Jun Zhang , Zhong-Guo Zhou , Min-Shan Chen , Jing-Ping Yun , Li Xu
<div><h3>Background & Aims</h3><div>Pathological response closely correlates with the prognosis of hepatocellular carcinoma (HCC), but assessing major pathological response (MPR) in patients with larger HCCs is challenging. Given that loco-regional therapies are widely used for larger HCCs, we aimed to determine the optimal cut-off for MPR in patients who received loco-regional therapies preoperatively.</div></div><div><h3>Methods</h3><div>Specimens from consecutive patients with HCC who underwent preoperative loco-regional therapies were included. The most representative sections with residual tumour were sampled. The MPR threshold was derived from the optimal cut-off for residual viable tumour for predicting overall survival (OS) in patients receiving loco-regional therapies only (Cohort 1) and was validated in those receiving loco-regional plus systemic therapies (Cohort 2). Factors associated with pathological response were evaluated using logistic regression models. Subgroup analyses were performed to explore differences in these related factors across subgroups.</div></div><div><h3>Results</h3><div>A total of 6,530 samples from 303 patients were evaluated. With a median follow-up of 31.7 months, the 1- and 3-year overall survival (OS) rates were 92.5% and 73.8% for Cohort 1 (n = 191), and 89.2% and 73.9% for Cohort 2 (n = 112). In Cohort 1, 10% residual viable tumour was identified as the optimal cut-off for predicting better OS (hazard ratio [HR] 0.219; 95% CI 0.087-0.552; <em>p</em> <0.001). In Cohort 2, patients with pathological response ≥90% had superior OS (HR 0.242; 95% CI 0.125-0.467; <em>p</em> <0.001) and disease-free survival (HR 0.195; 95% CI 0.102-0.375; <em>p</em> <0.001). Additionally, complete/major pathological response was associated with better OS and disease-free survival in most subgroups.</div></div><div><h3>Conclusions</h3><div>We propose pathological response ≥90% as the threshold for defining MPR and as an appropriate surrogate endpoint for patients with HCC treated with loco-regional therapies when OS data are immature.</div></div><div><h3>Impact and implications</h3><div>The lack of a consistent definition of major pathological response (MPR) across different clinical trials has made it difficult to evaluate and compare the efficacy of treatments for hepatocellular carcinoma (HCC). In addition, assessing the pathological response in patients with large HCC tumours is challenging. Here, we analysed the most representative sections containing residual tumour cells from patients who received preoperative loco-regional therapies. We identified 10% residual viable tumour as the threshold to define MPR in such cases. The significant positive correlation between complete pathological response/MPR and overall survival suggests that pathological response ≥90% is an appropriate surrogate endpoint for large HCC when overall survival data are immature.</div></div><div><h3>Registration</h3><div>This study has been
背景和目的病理反应与肝细胞癌（HCC）的预后密切相关，但评估较大HCC患者的主要病理反应（MPR）具有挑战性。鉴于局部区域治疗被广泛用于较大的hcc，我们的目的是确定术前接受局部区域治疗的患者MPR的最佳截止值。方法连续接受术前局部局部治疗的HCC患者标本。选取最具代表性的残余肿瘤切片。MPR阈值来自残余活肿瘤的最佳截止值，用于预测仅接受局部区域治疗（队列1）的患者的总生存（OS），并在接受局部区域加全身治疗（队列2）的患者中得到验证。使用逻辑回归模型评估与病理反应相关的因素。进行亚组分析以探讨这些相关因素在亚组间的差异。结果共评估了303例患者的6530份样本。中位随访时间为31.7个月，队列1 （n = 191）的1年和3年总生存率（OS）分别为92.5%和73.8%，队列2 （n = 112）的OS分别为89.2%和73.9%。在队列1中，10%的残余活肿瘤被确定为预测更好的OS的最佳截止值（风险比[HR] 0.219; 95% CI 0.087-0.552; p <0.001）。在队列2中，病理反应≥90%的患者有更好的OS （HR 0.242; 95% CI 0.125-0.467; p <0.001）和无病生存（HR 0.195; 95% CI 0.102-0.375; p <0.001）。此外，在大多数亚组中，完全/主要病理反应与更好的OS和无病生存相关。我们建议病理反应≥90%作为定义MPR的阈值，并且在OS数据不成熟的情况下，作为局部区域治疗的HCC患者的合适替代终点。影响和意义在不同的临床试验中缺乏对主要病理反应（MPR）的一致定义，这使得评估和比较肝细胞癌（HCC）治疗的疗效变得困难。此外，评估大型HCC肿瘤患者的病理反应具有挑战性。在这里，我们分析了术前接受局部区域治疗的患者中含有残留肿瘤细胞的最具代表性的切片。我们确定10%的残余活肿瘤作为定义MPR在这种情况下的阈值。完全病理反应/MPR与总生存期之间的显著正相关表明，当总生存期数据不成熟时，病理反应≥90%是大肝癌合适的替代终点。本研究已在中国临床试验注册中心注册（唯一识别码：ChiCTR2300076241， https://www.chictr.org.cn/showprojEN.html?proj=208162）。
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Pub Date : 2025-10-16DOI: 10.1016/j.jhepr.2025.101637
Gloryanne Aidoo-Micah , Stephanie Kucykowicz , Nathalie Schmidt , Vishnu Naidu , Rushabh Shah , Sayani Khara , Tate Mckinnon-Snell , Yiya Zhong , Daniel Brown Romero , Jessica Davies , Laura Pallett , Leo Swadling , Mariana Diniz , Alexa Childs , Upkar Gill , Edward Green , Tim Meyer , Mala K. Maini
<div><h3>Background & Aims</h3><div>Antitumour immunity involves a complex balance of immune effectors and regulators, many of which are adapted or compartmentalised within the local microenvironment. How this influences responses to immunotherapy in hepatocellular carcinoma (HCC) is poorly understood because of limited access to the tumour immune landscape. We postulated that fine needle aspirates (FNA) could allow for minimally invasive, in-depth tumour immune profiling in patients with advanced HCC.</div></div><div><h3>Methods</h3><div>Patients with radiological evidence of advanced HCC were prospectively enrolled to provide matched blood, FNA (n = 29 baseline, 2 also on treatment) and biopsy (n = 20 baseline only) for <em>ex vivo</em> spectral flow cytometric characterisation of multiple immune populations.</div></div><div><h3>Results</h3><div>FNA yielded more viable leukocytes than biopsies (mean 800,000 <em>vs</em>. 250,000 cells) allowing reproducible characterisation of a broad range of viable immune effectors and regulators enriched within the tumour. Tissue-resident memory CD8<sup>+</sup>T cells (CD8<sup>+</sup>T<sub>RM</sub>), a subset critical to cancer control that are excluded from blood, could also be aspirated from HCC for phenotypic/functional assessment (mean 10% <em>vs.</em> 0.1%, <em>p <</em>0.0001). PD-1 and alternative checkpoints (TIM-3/LAG-3/2B4/CD39) were strikingly enriched on CD8<sup>+</sup>T<sub>RM</sub> and CD4<sup>+</sup>T<sub>RM</sub>, which were also more likely to co-express multiple checkpoints than their circulating counterparts (CD8<sup>+</sup>T<sub>RM</sub>: 21.6% <em>vs.</em> 7.4%, <em>p =</em> 0.0003, CD4<sup>+</sup>T<sub>RM</sub>: 16.4% <em>vs.</em> 5.6%, <em>p =</em> 0.011). Expression of checkpoints on circulating T cells was discordant with levels on the fraction compartmentalised within tumours. FNA revealed an intratumoral expansion of neutrophils with an immunosuppressive phenotype that were increased in non-responders to immunotherapy (mean 50.2% <em>vs.</em> 25.5% in responders, <em>p =</em> 0.015) and correlated inversely with CD8<sup>+</sup>T<sub>RM</sub> and CD4<sup>+</sup>T<sub>RM</sub> frequencies (r = 0.6, <em>p =</em> 0.001).</div></div><div><h3>Conclusion</h3><div>FNA are suitable for rapid, comprehensive sampling of HCC prior to and during immunotherapy, revealing features of the tissue-resident tumour immune niche that cannot be predicted from blood. These features have the capacity to predict clinical outcomes.</div></div><div><h3>Impact and implications</h3><div>This study addresses the need for simple and minimally invasive assessment of the tumour immune microenvironment in hepatocellular carcinoma, revealing key compartmentalised immunotherapy targets that are not predictable from blood. Findings are important for researchers, clinicians and patients to guide personalised immune checkpoint inhibitor selection and the development of novel approaches to block immunosuppressive ne
背景和目的抗肿瘤免疫涉及免疫效应器和调节因子的复杂平衡，其中许多在局部微环境中适应或划分。这如何影响肝细胞癌（HCC）免疫治疗的反应，由于对肿瘤免疫景观的了解有限，目前尚不清楚。我们假设细针抽吸（FNA）可以对晚期HCC患者进行微创、深入的肿瘤免疫分析。方法前瞻性纳入有放射学证据的晚期HCC患者，提供匹配的血液，FNA（基线n = 29, 2也在治疗中）和活检（基线n = 20），用于体外流式细胞术表征多个免疫群体。结果与活组织检查相比，fna产生了更多的活白细胞（平均80万个细胞对25万个细胞），允许对肿瘤内丰富的广泛的活免疫效应器和调节因子进行可重复的表征。组织驻留记忆CD8+T细胞（CD8+TRM）是一个对癌症控制至关重要的亚群，被排除在血液中，也可以从HCC中抽取用于表型/功能评估（平均10% vs. 0.1%, p <0.0001）。PD-1和替代检查点（TIM-3/LAG-3/2B4/CD39）在CD8+TRM和CD4+TRM上显著富集，它们也比它们的循环对应点更可能共同表达多个检查点（CD8+TRM: 21.6% vs. 7.4%, p = 0.0003, CD4+TRM: 16.4% vs. 5.6%, p = 0.011）。循环T细胞上检查点的表达与肿瘤内区隔部分的水平不一致。FNA显示肿瘤内具有免疫抑制表型的中性粒细胞的扩增，在免疫治疗无反应者中增加（平均50.2%对25.5%,p = 0.015），与CD8+TRM和CD4+TRM频率呈负相关（r = 0.6, p = 0.001）。结论fna适用于在免疫治疗前和治疗过程中对HCC进行快速、全面的采样，揭示了无法通过血液预测的组织驻留肿瘤免疫生态位的特征。这些特征具有预测临床结果的能力。影响和意义本研究解决了对肝细胞癌肿瘤免疫微环境进行简单和微创评估的需求，揭示了无法从血液中预测的关键区隔化免疫治疗靶点。研究结果对于研究人员、临床医生和患者指导个性化免疫检查点抑制剂的选择和开发阻断免疫抑制性中性粒细胞的新方法，以改善当前肝细胞癌治疗的有限反应具有重要意义。我们展示了基于细针吸痰的快速免疫分析的潜力，可以整合到包括临床试验在内的更大规模的研究中，指导患者对现有和未来免疫检查点抑制剂的个性化选择，提供对原发性和继发性耐药机制的见解，并为开发新的免疫治疗靶点提供信息。
{"title":"Fine needle aspirates characterise the hepatocellular carcinoma immune niche to predict immune checkpoint inhibitor outcomes","authors":"Gloryanne Aidoo-Micah , Stephanie Kucykowicz , Nathalie Schmidt , Vishnu Naidu , Rushabh Shah , Sayani Khara , Tate Mckinnon-Snell , Yiya Zhong , Daniel Brown Romero , Jessica Davies , Laura Pallett , Leo Swadling , Mariana Diniz , Alexa Childs , Upkar Gill , Edward Green , Tim Meyer , Mala K. Maini","doi":"10.1016/j.jhepr.2025.101637","DOIUrl":"10.1016/j.jhepr.2025.101637","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Antitumour immunity involves a complex balance of immune effectors and regulators, many of which are adapted or compartmentalised within the local microenvironment. How this influences responses to immunotherapy in hepatocellular carcinoma (HCC) is poorly understood because of limited access to the tumour immune landscape. We postulated that fine needle aspirates (FNA) could allow for minimally invasive, in-depth tumour immune profiling in patients with advanced HCC.</div></div><div><h3>Methods</h3><div>Patients with radiological evidence of advanced HCC were prospectively enrolled to provide matched blood, FNA (n = 29 baseline, 2 also on treatment) and biopsy (n = 20 baseline only) for <em>ex vivo</em> spectral flow cytometric characterisation of multiple immune populations.</div></div><div><h3>Results</h3><div>FNA yielded more viable leukocytes than biopsies (mean 800,000 <em>vs</em>. 250,000 cells) allowing reproducible characterisation of a broad range of viable immune effectors and regulators enriched within the tumour. Tissue-resident memory CD8<sup>+</sup>T cells (CD8<sup>+</sup>T<sub>RM</sub>), a subset critical to cancer control that are excluded from blood, could also be aspirated from HCC for phenotypic/functional assessment (mean 10% <em>vs.</em> 0.1%, <em>p <</em>0.0001). PD-1 and alternative checkpoints (TIM-3/LAG-3/2B4/CD39) were strikingly enriched on CD8<sup>+</sup>T<sub>RM</sub> and CD4<sup>+</sup>T<sub>RM</sub>, which were also more likely to co-express multiple checkpoints than their circulating counterparts (CD8<sup>+</sup>T<sub>RM</sub>: 21.6% <em>vs.</em> 7.4%, <em>p =</em> 0.0003, CD4<sup>+</sup>T<sub>RM</sub>: 16.4% <em>vs.</em> 5.6%, <em>p =</em> 0.011). Expression of checkpoints on circulating T cells was discordant with levels on the fraction compartmentalised within tumours. FNA revealed an intratumoral expansion of neutrophils with an immunosuppressive phenotype that were increased in non-responders to immunotherapy (mean 50.2% <em>vs.</em> 25.5% in responders, <em>p =</em> 0.015) and correlated inversely with CD8<sup>+</sup>T<sub>RM</sub> and CD4<sup>+</sup>T<sub>RM</sub> frequencies (r = 0.6, <em>p =</em> 0.001).</div></div><div><h3>Conclusion</h3><div>FNA are suitable for rapid, comprehensive sampling of HCC prior to and during immunotherapy, revealing features of the tissue-resident tumour immune niche that cannot be predicted from blood. These features have the capacity to predict clinical outcomes.</div></div><div><h3>Impact and implications</h3><div>This study addresses the need for simple and minimally invasive assessment of the tumour immune microenvironment in hepatocellular carcinoma, revealing key compartmentalised immunotherapy targets that are not predictable from blood. Findings are important for researchers, clinicians and patients to guide personalised immune checkpoint inhibitor selection and the development of novel approaches to block immunosuppressive ne","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101637"},"PeriodicalIF":7.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836590","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 : 2025-10-16DOI: 10.1016/j.jhepr.2025.101636
Christopher D. Malone , Tharun Alamuri , Sam Meiselman , Guilherme Ferreira , John Karageorgiou , J. Daniel Giardina , Naganathan B. Mani , Daniel A. Braga , Darren Cullinan , Maria Bernadette Doyle , William Chapman , Kevin Korenblat , Benjamin Tan , M. Allan Thomas
<div><h3>Background & Aims</h3><div>Radiation segmentectomy (RS) is an emerging curative-intent therapy for early-stage hepatocellular carcinoma (HCC) when resection or ablation is not feasible. In this study, we evaluated the safety, efficacy, and dosimetric correlates of ultra-selective RS, defined as glass <sup>90</sup>Y-radioembolization delivered to vessels at least one order beyond parent segmental arteries, targeting <1 Couinaud segment.</div></div><div><h3>Methods</h3><div>This retrospective study included 38 patients with 42 early-stage (BCLC 0–A) HCCs treated with ultra-selective RS from December 2022 to July 2024. All treatments used glass <sup>90</sup>Y-microspheres with perfused treatment volumes assessed by cone-beam CT. Post-treatment voxel-based dosimetry was conducted using <sup>90</sup>Y single-photon emission CT (SPECT)/CT. Tumor response and progression-free survival were assessed by modified RECIST. Explant pathology was used to evaluate treatment effect in transplant recipients, and albumin-bilirubin (ALBI) scores were tracked longitudinally.</div></div><div><h3>Results</h3><div>The median tumor size was 2.4 cm with a median perfused treatment volume of 66.3 cc (4.5% of total liver volume). The median administered activity was 1.36 GBq (median absorbed dose 837 Gy). Complete response (CR) was achieved in 87% (n = 33), with only one local progression. Median local progression-free survival was not reached. Among 16 tumors with explant data, 69% showed complete necrosis and 25% extensive necrosis (median 88%). Tumor D<sub>95</sub> >300 Gy predicted CR (97% CR <em>vs</em>. 0% CR with D<sub>95</sub> <300 Gy; <em>p</em> <0.001), with logistic regression yielding an AUC of 0.98. Models incorporating tumor alignment within high-activity <sup>90</sup>Y-SPECT regions improved predictive accuracy. Over 82% of patients retained or improved ALBI grade during follow-up, with only 2 of 15 patients with baseline ALBI 2b declining to grade 3.</div></div><div><h3>Conclusions</h3><div>Ultra-selective RS is a feasible and liver-sparing therapy for early-stage HCC. Voxel-based dosimetry confirms dose-response relationships and underscores the importance of tumor coverage.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates that ultra-selective radiation segmentectomy (uRS) with glass <sup>90</sup>Y microspheres can achieve high rates of complete imaging and pathologic response in early-stage HCC while treating very small liver volumes. These results replicate and extend prior radiation segmentectomy studies, underscoring that the ablative potential of <sup>90</sup>Y can be maintained with even greater liver parenchymal preservation. These findings are important for patients who are not candidates for surgery or ablation, especially given low rates of liver function decline after uRS. In practice, uRS may serve as a definitive therapy or as a bridge to liver transplantation, while voxel-based dosimetry pr
{"title":"Ultra-selective radiation segmentectomy for early-stage hepatocellular carcinoma","authors":"Christopher D. Malone , Tharun Alamuri , Sam Meiselman , Guilherme Ferreira , John Karageorgiou , J. Daniel Giardina , Naganathan B. Mani , Daniel A. Braga , Darren Cullinan , Maria Bernadette Doyle , William Chapman , Kevin Korenblat , Benjamin Tan , M. Allan Thomas","doi":"10.1016/j.jhepr.2025.101636","DOIUrl":"10.1016/j.jhepr.2025.101636","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Radiation segmentectomy (RS) is an emerging curative-intent therapy for early-stage hepatocellular carcinoma (HCC) when resection or ablation is not feasible. In this study, we evaluated the safety, efficacy, and dosimetric correlates of ultra-selective RS, defined as glass <sup>90</sup>Y-radioembolization delivered to vessels at least one order beyond parent segmental arteries, targeting <1 Couinaud segment.</div></div><div><h3>Methods</h3><div>This retrospective study included 38 patients with 42 early-stage (BCLC 0–A) HCCs treated with ultra-selective RS from December 2022 to July 2024. All treatments used glass <sup>90</sup>Y-microspheres with perfused treatment volumes assessed by cone-beam CT. Post-treatment voxel-based dosimetry was conducted using <sup>90</sup>Y single-photon emission CT (SPECT)/CT. Tumor response and progression-free survival were assessed by modified RECIST. Explant pathology was used to evaluate treatment effect in transplant recipients, and albumin-bilirubin (ALBI) scores were tracked longitudinally.</div></div><div><h3>Results</h3><div>The median tumor size was 2.4 cm with a median perfused treatment volume of 66.3 cc (4.5% of total liver volume). The median administered activity was 1.36 GBq (median absorbed dose 837 Gy). Complete response (CR) was achieved in 87% (n = 33), with only one local progression. Median local progression-free survival was not reached. Among 16 tumors with explant data, 69% showed complete necrosis and 25% extensive necrosis (median 88%). Tumor D<sub>95</sub> >300 Gy predicted CR (97% CR <em>vs</em>. 0% CR with D<sub>95</sub> <300 Gy; <em>p</em> <0.001), with logistic regression yielding an AUC of 0.98. Models incorporating tumor alignment within high-activity <sup>90</sup>Y-SPECT regions improved predictive accuracy. Over 82% of patients retained or improved ALBI grade during follow-up, with only 2 of 15 patients with baseline ALBI 2b declining to grade 3.</div></div><div><h3>Conclusions</h3><div>Ultra-selective RS is a feasible and liver-sparing therapy for early-stage HCC. Voxel-based dosimetry confirms dose-response relationships and underscores the importance of tumor coverage.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates that ultra-selective radiation segmentectomy (uRS) with glass <sup>90</sup>Y microspheres can achieve high rates of complete imaging and pathologic response in early-stage HCC while treating very small liver volumes. These results replicate and extend prior radiation segmentectomy studies, underscoring that the ablative potential of <sup>90</sup>Y can be maintained with even greater liver parenchymal preservation. These findings are important for patients who are not candidates for surgery or ablation, especially given low rates of liver function decline after uRS. In practice, uRS may serve as a definitive therapy or as a bridge to liver transplantation, while voxel-based dosimetry pr","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101636"},"PeriodicalIF":7.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682283","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 : 2025-10-16DOI: 10.1016/j.jhepr.2025.101639
Binu V. John , Dustin Bastaich , Elizabeth Paulus , Seth Spector , Bassam Dahman , Veterans Analysis of Liver Disease (VALID) group of investigators
<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) with increased alcohol consumption (MetALD) is an important, yet understudied cause of liver disease. This study aimed to examine hepatocellular carcinoma (HCC) rates in patients with MetALD and compare them with MASLD, alcohol-associated liver disease (ALD), and controls.</div></div><div><h3>Methods</h3><div>We conducted a retrospective cohort study of veterans with MetALD, MASLD, ALD, or no SLD. We used Poisson regression to estimate incidence rates within stratifications of patient characteristics, and a multivariable time-updated Fine and Gray model with death as a competing risk to examine HCC risks.</div></div><div><h3>Results</h3><div>We included 666,428 participants (392,286 MASLD, 104,065 MetALD, 40,230 ALD, and 129,847 controls) between 1 January 2011 and 31 December 2022, with a follow-up until 31 May 2023. All participants underwent abdominal imaging or transient elastography, confirming the presence (among SLD) or absence (among controls) of steatosis, along with identification of harmful alcohol use and ascertainment of cardiometabolic risk factors. In patients without cirrhosis, the adjusted HCC rates per 100,000 person-years were lowest for MASLD, higher for MetALD, and highest for ALD. The cumulative incidence of HCC at 5 years was highest with ALD, followed by MASLD and MetALD, with rates similar in the latter two groups. At 10 years, the cumulative incidence of HCC per 100,000 individuals was the highest with ALD (1,176.65), followed by MetALD (814.16), and MASLD (762.86).</div></div><div><h3>Conclusions</h3><div>The risk of HCC associated with MetALD is higher than MASLD, significantly lower than ALD, and likely driven by alcohol. Although HCC rates in non-cirrhotic patients with MetALD are not high enough to justify surveillance, this study identifies a relatively higher risk group compared to MASLD, which warrants counselling on alcohol cessation.</div></div><div><h3>Impact and implications</h3><div>Limited data exist on the risk of hepatocellular carcinoma (HCC) in patients with MetALD (metabolic dysfunction-associated steatotic liver disease [MASLD] with increased alcohol consumption) and how it compares with other steatotic liver diseases. In this retrospective study of 666,428 patients from the Veterans Analysis of Liver Disease cohort, we observed that the risk of HCC per 100,000 person-years in patients without cirrhosis with MetALD was 80.24 (95% CI 73.23–87.94), which was intermediate between MASLD (71.64, 95% CI 68.14–75.32) and ALD (104.83, 91.59–119.98). The cumulative incidence of HCC per 100,000 persons at 5 years was the highest with ALD (663.79, 581.77–754.83), followed by MASLD (450.71, 428.46–473.89), MetALD (449.89, 407.56-495.74), and controls (76.03, 61.47–93.46). The limitations of the study include its retrospective design and a study population enriched with male veterans with a higher prevalence of
背景和目的代谢功能障碍相关的脂肪变性肝病（MASLD）与酒精摄入增加（MetALD）是肝脏疾病的一个重要原因，但尚未得到充分研究。本研究旨在检测MetALD患者的肝细胞癌（HCC）发生率，并将其与MASLD、酒精相关肝病（ALD）和对照组进行比较。方法我们对患有MetALD、MASLD、ALD或无slld的退伍军人进行回顾性队列研究。我们使用泊松回归来估计患者特征分层内的发病率，并使用多变量时间更新的Fine和Gray模型，将死亡作为竞争风险来检查HCC风险。在2011年1月1日至2022年12月31日期间，我们纳入了666,428名参与者（392,286名MASLD， 104,065名MetALD， 40,230名ALD和129,847名对照），随访至2023年5月31日。所有参与者都进行了腹部成像或短暂弹性成像，以确认（SLD中）存在脂肪变性或（对照组中）不存在脂肪变性，同时确定有害酒精使用和确定心脏代谢危险因素。在没有肝硬化的患者中，每10万人年的HCC调整率MASLD最低，MetALD较高，ALD最高。ALD患者5年HCC累积发生率最高，其次是MASLD和MetALD，后两组发生率相似。10年时，每10万人中累积的HCC发病率最高的是ALD(1176.65)，其次是MetALD（814.16）和MASLD（762.86）。结论MetALD相关的HCC风险高于MASLD，显著低于ALD，且可能由酒精驱动。尽管非肝硬化MetALD患者的HCC发生率不足以证明监测的必要性，但与MASLD相比，该研究确定了一个相对较高的风险群体，值得进行戒酒咨询。影响和意义关于MetALD（代谢功能障碍相关脂肪性肝病[MASLD]伴饮酒增加）患者发生肝细胞癌（HCC）的风险以及与其他脂肪性肝病的比较的数据有限。在这项来自退伍军人肝病分析队列的666,428例患者的回顾性研究中，我们观察到无肝硬化合并MetALD的患者每10万人年发生HCC的风险为80.24 (95% CI 73.23-87.94)，介于MASLD （71.64, 95% CI 68.14-75.32）和ALD（104.83, 91.59-119.98）之间。5年每10万人HCC累积发病率最高的是ALD(663.79, 581.77-754.83)，其次是MASLD（450.71, 428.46-473.89）、MetALD（449.89, 407.56-495.74）和对照组（76.03,61.47-93.46）。该研究的局限性包括其回顾性设计和研究人群中富含代谢综合征患病率较高的男性退伍军人。
{"title":"Hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD)","authors":"Binu V. John , Dustin Bastaich , Elizabeth Paulus , Seth Spector , Bassam Dahman , Veterans Analysis of Liver Disease (VALID) group of investigators","doi":"10.1016/j.jhepr.2025.101639","DOIUrl":"10.1016/j.jhepr.2025.101639","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) with increased alcohol consumption (MetALD) is an important, yet understudied cause of liver disease. This study aimed to examine hepatocellular carcinoma (HCC) rates in patients with MetALD and compare them with MASLD, alcohol-associated liver disease (ALD), and controls.</div></div><div><h3>Methods</h3><div>We conducted a retrospective cohort study of veterans with MetALD, MASLD, ALD, or no SLD. We used Poisson regression to estimate incidence rates within stratifications of patient characteristics, and a multivariable time-updated Fine and Gray model with death as a competing risk to examine HCC risks.</div></div><div><h3>Results</h3><div>We included 666,428 participants (392,286 MASLD, 104,065 MetALD, 40,230 ALD, and 129,847 controls) between 1 January 2011 and 31 December 2022, with a follow-up until 31 May 2023. All participants underwent abdominal imaging or transient elastography, confirming the presence (among SLD) or absence (among controls) of steatosis, along with identification of harmful alcohol use and ascertainment of cardiometabolic risk factors. In patients without cirrhosis, the adjusted HCC rates per 100,000 person-years were lowest for MASLD, higher for MetALD, and highest for ALD. The cumulative incidence of HCC at 5 years was highest with ALD, followed by MASLD and MetALD, with rates similar in the latter two groups. At 10 years, the cumulative incidence of HCC per 100,000 individuals was the highest with ALD (1,176.65), followed by MetALD (814.16), and MASLD (762.86).</div></div><div><h3>Conclusions</h3><div>The risk of HCC associated with MetALD is higher than MASLD, significantly lower than ALD, and likely driven by alcohol. Although HCC rates in non-cirrhotic patients with MetALD are not high enough to justify surveillance, this study identifies a relatively higher risk group compared to MASLD, which warrants counselling on alcohol cessation.</div></div><div><h3>Impact and implications</h3><div>Limited data exist on the risk of hepatocellular carcinoma (HCC) in patients with MetALD (metabolic dysfunction-associated steatotic liver disease [MASLD] with increased alcohol consumption) and how it compares with other steatotic liver diseases. In this retrospective study of 666,428 patients from the Veterans Analysis of Liver Disease cohort, we observed that the risk of HCC per 100,000 person-years in patients without cirrhosis with MetALD was 80.24 (95% CI 73.23–87.94), which was intermediate between MASLD (71.64, 95% CI 68.14–75.32) and ALD (104.83, 91.59–119.98). The cumulative incidence of HCC per 100,000 persons at 5 years was the highest with ALD (663.79, 581.77–754.83), followed by MASLD (450.71, 428.46–473.89), MetALD (449.89, 407.56-495.74), and controls (76.03, 61.47–93.46). The limitations of the study include its retrospective design and a study population enriched with male veterans with a higher prevalence of","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101639"},"PeriodicalIF":7.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145682285","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 : 2025-10-11DOI: 10.1016/j.jhepr.2025.101630
Arndt Vogel , Anna Saborowski , Lorenza Rimassa , Anthony El-Khoueiry
In recent years, systemic treatment options for hepatocellular carcinoma have expanded significantly, with pivotal phase III trials reporting unprecedented improvements in survival and response outcomes. However, these advances have largely focused on first-line strategies, challenging existing treatment sequences and raising questions about the optimal therapeutic approach following disease progression. Several therapeutic options are available in second and later lines — including immunotherapies, tyrosine kinase inhibitors, and local therapies — but so far comprehensive head-to-head comparisons to establish the ideal treatment sequence are lacking. Consequently, most evidence guiding second-line therapy has been derived from post hoc analyses, real-world data, and select prospective studies, primarily based on phase II designs. In clinical practice, treatment decisions integrate this evolving evidence base with patient-specific factors such as prior treatment response, liver function, and performance status, often within the constraints of regulatory and accessibility considerations. Ongoing research is investigating novel approaches, including the continuation of immunotherapy following progression, the application of CAR T cells, and targeted treatments against specific markers like fibroblast growth factor 19 and glypican-3. This review summarises the current evidence for second-line and subsequent therapies, explores key considerations in treatment sequencing, and highlights emerging strategies that may further refine the therapeutic landscape for hepatocellular carcinoma.
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