Pub Date : 2025-11-01DOI: 10.1016/j.jhepr.2025.101658
Grainne M. O’Kane , Aruz Mesci , Raymond W. Jang , Aisling Barry , Cynthia M. Bocaya , Giselle M. Boukhaled , Holly Acton , David Doddington , Rowena Rodrigo , Leo M.L. Chan , Babak Noamani , Harry Harvey , Andrew Elia , Rhoda Law , Rebecca Prince , Mark Doherty , Anna Dodd , David K. Wong , Lisa Wang , Ben X. Wang , Jennifer J. Knox
Background & Aims
There is strong rationale for integrated approaches combining immune checkpoint inhibitors with locoregional therapies in hepatocellular carcinoma (HCC).
Methods
The PEMRAD phase II trial investigated pembrolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced HCC following progression on sorafenib. Patients received pembrolizumab on Day 1, and SBRT commenced on Day 2. Up to 10 hepatic lesions (<20 cm) were treated with SBRT. Pembrolizumab was continued every 21 days until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST v1.1, with a hypothesized improvement to 40% for the combination. Tissue and liquid biopsies were collected for correlative analyses, including immunohistochemistry, longitudinal blood cytometry by time-of-flight, and serum cytokine assessment.
Results
Between March 2018 and March 2023, 18 of a planned 22 patients were enrolled; 11 (61%) had macrovascular invasion (MVI) and 15 (83%) had extrahepatic metastases. Viral hepatitis was the underlying etiology in 50%. The ORR was 41% (95% CI 18–67%). Median progression-free survival was 5.4 months (2.8–9.9) and median overall survival was 12.6 months (5.7–25.8). Of 34 liver lesions treated with SBRT, only three progressed, in two patients. Among the 11 patients with MVI, 5 (45%) achieved a response, including one complete response. Treatment-related adverse events of grade ≥3 occurred in four patients (22%). One treatment-related death due to myocarditis was observed. Peripheral immunophenotyping showed that higher abundance of CD8+CD103+ T cells correlated with improved survival, whereas higher natural killer cell abundance was associated with inferior outcomes.
Conclusion
The combination of SBRT and pembrolizumab demonstrated a high response rate as second-line therapy for advanced HCC and warrants further evaluation, particularly in patients with MVI.
Impact and implications
This study demonstrates that combining stereotactic body radiotherapy with pembrolizumab is feasible and yields promising response rates in patients with advanced, previously treated hepatocellular carcinoma, including those with macrovascular invasion – a group typically associated with poor outcomes. These findings support further evaluation of this integrated approach and provide important guidance for the design of future clinical trials aimed at improving outcomes in advanced hepatocellular carcinoma.
背景和目的将免疫检查点抑制剂与局部治疗结合起来治疗肝细胞癌（HCC）有很强的理论基础。PEMRAD II期试验研究了派姆单抗联合立体定向放射治疗（SBRT）在索拉非尼进展的晚期HCC患者中的应用。患者在第1天接受派姆单抗治疗，第2天开始SBRT治疗。SBRT治疗了多达10个肝脏病变（< 20cm）。每21天继续使用派姆单抗，直到疾病进展、不可接受的毒性或停药。主要终点是RECIST v1.1的客观缓解率（ORR），假设联合用药可改善至40%。收集组织和液体活检进行相关分析，包括免疫组织化学、飞行时间纵向血液细胞术和血清细胞因子评估。结果在2018年3月至2023年3月期间，计划的22例患者中有18例入组；11例（61%）有大血管侵犯（MVI）， 15例（83%）有肝外转移。病毒性肝炎是50%的潜在病因。ORR为41% （95% CI 18-67%）。中位无进展生存期为5.4个月（2.8-9.9），中位总生存期为12.6个月（5.7-25.8）。在接受SBRT治疗的34例肝脏病变中，只有2例患者的3例进展。在11例MVI患者中，5例（45%）获得缓解，其中1例完全缓解。4例患者（22%）发生≥3级治疗相关不良事件。观察到一例治疗相关的心肌炎死亡。外周免疫表型分析显示，CD8+CD103+ T细胞丰度越高，生存率越高，而自然杀伤细胞丰度越高，预后越差。结论SBRT联合派姆单抗作为晚期HCC的二线治疗有很高的反应率，值得进一步评估，特别是在MVI患者中。影响和意义本研究表明，立体定向放射治疗联合派姆单抗在晚期、先前治疗过的肝细胞癌患者中是可行的，并产生了很好的缓解率，包括那些有大血管侵袭的患者，这一群体通常与不良预后相关。这些发现支持对这种综合方法的进一步评估，并为未来旨在改善晚期肝细胞癌预后的临床试验设计提供重要指导。
{"title":"Pembrolizumab and stereotactic body radiotherapy combined in advanced hepatocellular carcinoma post sorafenib – A phase II trial (PEMRAD)","authors":"Grainne M. O’Kane , Aruz Mesci , Raymond W. Jang , Aisling Barry , Cynthia M. Bocaya , Giselle M. Boukhaled , Holly Acton , David Doddington , Rowena Rodrigo , Leo M.L. Chan , Babak Noamani , Harry Harvey , Andrew Elia , Rhoda Law , Rebecca Prince , Mark Doherty , Anna Dodd , David K. Wong , Lisa Wang , Ben X. Wang , Jennifer J. Knox","doi":"10.1016/j.jhepr.2025.101658","DOIUrl":"10.1016/j.jhepr.2025.101658","url":null,"abstract":"<div><h3>Background & Aims</h3><div>There is strong rationale for integrated approaches combining immune checkpoint inhibitors with locoregional therapies in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>The PEMRAD phase II trial investigated pembrolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced HCC following progression on sorafenib. Patients received pembrolizumab on Day 1, and SBRT commenced on Day 2. Up to 10 hepatic lesions (<20 cm) were treated with SBRT. Pembrolizumab was continued every 21 days until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST v1.1, with a hypothesized improvement to 40% for the combination. Tissue and liquid biopsies were collected for correlative analyses, including immunohistochemistry, longitudinal blood cytometry by time-of-flight, and serum cytokine assessment.</div></div><div><h3>Results</h3><div>Between March 2018 and March 2023, 18 of a planned 22 patients were enrolled; 11 (61%) had macrovascular invasion (MVI) and 15 (83%) had extrahepatic metastases. Viral hepatitis was the underlying etiology in 50%. The ORR was 41% (95% CI 18–67%). Median progression-free survival was 5.4 months (2.8–9.9) and median overall survival was 12.6 months (5.7–25.8). Of 34 liver lesions treated with SBRT, only three progressed, in two patients. Among the 11 patients with MVI, 5 (45%) achieved a response, including one complete response. Treatment-related adverse events of grade ≥3 occurred in four patients (22%). One treatment-related death due to myocarditis was observed. Peripheral immunophenotyping showed that higher abundance of CD8<sup>+</sup>CD103<sup>+</sup> T cells correlated with improved survival, whereas higher natural killer cell abundance was associated with inferior outcomes.</div></div><div><h3>Conclusion</h3><div>The combination of SBRT and pembrolizumab demonstrated a high response rate as second-line therapy for advanced HCC and warrants further evaluation, particularly in patients with MVI.</div></div><div><h3>Impact and implications</h3><div>This study demonstrates that combining stereotactic body radiotherapy with pembrolizumab is feasible and yields promising response rates in patients with advanced, previously treated hepatocellular carcinoma, including those with macrovascular invasion – a group typically associated with poor outcomes. These findings support further evaluation of this integrated approach and provide important guidance for the design of future clinical trials aimed at improving outcomes in advanced hepatocellular carcinoma.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101658"},"PeriodicalIF":7.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145978056","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 : 2025-10-31DOI: 10.1016/j.jhepr.2025.101659
Maïté Verstraeten , Mattice De Clercq , Hanne De Craemer , Xavier Verhelst , Sander Lefere , Lindsey Devisscher , Anja Geerts , Hans Van Vlierberghe , Michael B. Fallon , Sarah Raevens
Background & Aims
Hepatopulmonary syndrome (HPS) is a severe pulmonary vascular complication of liver disease. Liver transplantation (LT) is the only definitive treatment, yet a contemporary synthesis of LT outcomes in HPS, alongside persisting uncertainties, is lacking.
Methods
We conducted a systematic review and meta-analysis of 22 studies to evaluate HPS prevalence, post-LT survival, and HPS resolution.
Results
Pooled HPS prevalence was 17.2% (11.6–24.7%, n = 1,171 studied patients) among patients with cirrhosis evaluated for LT, 26.1% (18.5–35.5%, n = 629) in patients with portal hypertension evaluated for LT and 21.6% (11.2–37.4%, n = 737) in LT recipients. Under current model for end-stage liver disease (MELD) exception policies, waitlist mortality was 13.1% (0.6–78.5%, n = 1,240 studied patients). Post-LT survival in patients with HPS was comparable to that in patients without HPS and aligned with international benchmarks. Pooled 1-year post-LT survival rates were 85.5% in prospective studies from the pre- and post-MELD era (n = 240 studied patients), 93.9% in the post-MELD era (n = 99), and 83.8% in registry-based studies (n = 800). Pooled estimates for 5-year post-LT survival rates were 85% (n = 144 studied patients), 92.9% (n = 99), and 76% (n = 739), respectively. Lower pre-LT PaO2 correlated with poorer post-LT survival, especially in very severe HPS. HPS resolved after LT in 90.1% (71.7-97.0%, n = 80 studied patients) of patients at 6 months, with complete resolution within 1 year in all patients assessed. Key gaps remain regarding the influence of underlying liver disease on HPS progression, the optimal timing of LT, and factors affecting post-LT recovery.
Conclusions
LT offers substantial survival and clinical benefits for patients with HPS, with high rates of HPS resolution within a year. Patients with very severe HPS warrant closer monitoring, and further research is needed to address unresolved questions regarding disease trajectory and post-transplant outcomes.
Impact and implications
This systematic review and meta-analysis shows that liver transplantation (LT) is an effective treatment for hepatopulmonary syndrome (HPS), resulting in high rates of syndrome resolution and post-transplant survival comparable to patients without HPS. These findings support the continued use of MELD exception policies and underscore the importance of timely referral for LT. While outcomes are generally favorable, patients with very severe HPS may experience worse post-transplant outcomes, highlighting the need for more tailored clinical management. A key unmet need remains in understanding the role of underlying liver disease severity in the natural history of HPS, as well as the optimal timing for LT and factors influencing post-transplant recovery.
{"title":"Liver transplantation for hepatopulmonary syndrome: A systematic review and meta-analysis","authors":"Maïté Verstraeten , Mattice De Clercq , Hanne De Craemer , Xavier Verhelst , Sander Lefere , Lindsey Devisscher , Anja Geerts , Hans Van Vlierberghe , Michael B. Fallon , Sarah Raevens","doi":"10.1016/j.jhepr.2025.101659","DOIUrl":"10.1016/j.jhepr.2025.101659","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Hepatopulmonary syndrome (HPS) is a severe pulmonary vascular complication of liver disease. Liver transplantation (LT) is the only definitive treatment, yet a contemporary synthesis of LT outcomes in HPS, alongside persisting uncertainties, is lacking.</div></div><div><h3>Methods</h3><div>We conducted a systematic review and meta-analysis of 22 studies to evaluate HPS prevalence, post-LT survival, and HPS resolution.</div></div><div><h3>Results</h3><div>Pooled HPS prevalence was 17.2% (11.6–24.7%, n = 1,171 studied patients) among patients with cirrhosis evaluated for LT, 26.1% (18.5–35.5%, n = 629) in patients with portal hypertension evaluated for LT and 21.6% (11.2–37.4%, n = 737) in LT recipients. Under current model for end-stage liver disease (MELD) exception policies, waitlist mortality was 13.1% (0.6–78.5%, n = 1,240 studied patients). Post-LT survival in patients with HPS was comparable to that in patients without HPS and aligned with international benchmarks. Pooled 1-year post-LT survival rates were 85.5% in prospective studies from the pre- and post-MELD era (n = 240 studied patients), 93.9% in the post-MELD era (n = 99), and 83.8% in registry-based studies (n = 800). Pooled estimates for 5-year post-LT survival rates were 85% (n = 144 studied patients), 92.9% (n = 99), and 76% (n = 739), respectively. Lower pre-LT PaO<sub>2</sub> correlated with poorer post-LT survival, especially in very severe HPS. HPS resolved after LT in 90.1% (71.7-97.0%, n = 80 studied patients) of patients at 6 months, with complete resolution within 1 year in all patients assessed. Key gaps remain regarding the influence of underlying liver disease on HPS progression, the optimal timing of LT, and factors affecting post-LT recovery.</div></div><div><h3>Conclusions</h3><div>LT offers substantial survival and clinical benefits for patients with HPS, with high rates of HPS resolution within a year. Patients with very severe HPS warrant closer monitoring, and further research is needed to address unresolved questions regarding disease trajectory and post-transplant outcomes.</div></div><div><h3>Impact and implications</h3><div>This systematic review and meta-analysis shows that liver transplantation (LT) is an effective treatment for hepatopulmonary syndrome (HPS), resulting in high rates of syndrome resolution and post-transplant survival comparable to patients without HPS. These findings support the continued use of MELD exception policies and underscore the importance of timely referral for LT. While outcomes are generally favorable, patients with very severe HPS may experience worse post-transplant outcomes, highlighting the need for more tailored clinical management. A key unmet need remains in understanding the role of underlying liver disease severity in the natural history of HPS, as well as the optimal timing for LT and factors influencing post-transplant recovery.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101659"},"PeriodicalIF":7.5,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836509","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 : 2025-10-30DOI: 10.1016/j.jhepr.2025.101649
Sophie Gensluckner , Helle Lindholm Schnefeld , Jan Embacher , Camilla Dalby Hansen , Lorenz Balcar , Katrine Tholstrup Bech , Paul Thöne , Nikolaj Torp , Bernhard Wernly , Laura Maarit Pikkupeura , Stephan Zandanell , Christian Datz , Michael Strasser , Mads Israelsen , Mattias Mandorfer , Torben Hansen , Aleksander Krag , Elmar Aigner , Maja Thiele , Georg Semmler
Background & Aims
Genetic predisposition (especially variants in PNPLA3 and TM6SF2), metabolic dysfunction, and alcohol consumption are established risk factors for steatotic liver disease (SLD) and progression of fibrosis. However, the clinical relevance of their interaction and its implications for patient management remain unclear.
Methods
We cross-sectionally analyzed data from two cohorts: patients referred to tertiary liver care (N = 1,554) and individuals at risk for SLD (N = 1,728). Multivariable regression models with and without interaction terms were used to assess the independent and interactive effects of genetic risk variants, metabolic dysfunction (HOMA-IR, BMI), and alcohol intake on liver fibrosis severity as assessed by liver stiffness measurement (LSM).
Results
Mean age was 52 and 56 years in the Tertiary-care cohort and the At-risk cohort, respectively. Most participants were male, 23% and 53% suffered from obesity, and 39% and 58% were categorized as insulin resistant, respectively. Median LSM was 5.5 kPa and 4.7 kPa, with 21% and 9.6% having LSM ≥8 kPa, respectively. In total, 48% and 44% carried at least one PNPLA3 G-allele (C/G or G/G), and 18% and 15% the TM6SF2 T-allele (C/T or T/T), respectively. In multivariable regression without interaction terms, LSM was associated with HOMA-IR, alcohol consumption, BMI (At-risk cohort), PNPLA3 and TM6SF2. However, when allowing for interactions, the independent effects of genetic risk variants disappeared. Instead, PNPLA3 potentiated the association of HOMA-IR (p <0.001/p = 0.016) and severe alcohol consumption (p <0.001/p = 0.093) with LSM. TM6SF2 amplified the effect of BMI (p = 0.006) and severe alcohol consumption (p <0.001) on LSM in the Tertiary-care-cohort.
Conclusions
Our findings indicate that PNPLA3 and TM6SF2 variants do not act as independent determinants of liver fibrosis once gene–environment interactions are considered. Instead, they amplify the harmful effects of metabolic dysfunction and alcohol consumption in individuals evaluated for SLD, creating a synergistic risk profile.
Impact and implications
Our findings indicate that fibrosis progression in steatotic liver disease is mediated by an interaction of environmental risk factors (obesity, insulin resistance, alcohol consumption) and genetic risk variants, such as PNPLA3 and TM6SF2, but not by genetic variants alone. This highlights the importance of acknowledging these gene–environment interactions for patient counselling and risk stratification.
{"title":"PNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis","authors":"Sophie Gensluckner , Helle Lindholm Schnefeld , Jan Embacher , Camilla Dalby Hansen , Lorenz Balcar , Katrine Tholstrup Bech , Paul Thöne , Nikolaj Torp , Bernhard Wernly , Laura Maarit Pikkupeura , Stephan Zandanell , Christian Datz , Michael Strasser , Mads Israelsen , Mattias Mandorfer , Torben Hansen , Aleksander Krag , Elmar Aigner , Maja Thiele , Georg Semmler","doi":"10.1016/j.jhepr.2025.101649","DOIUrl":"10.1016/j.jhepr.2025.101649","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Genetic predisposition (especially variants in <em>PNPLA3</em> and <em>TM6SF2</em>), metabolic dysfunction, and alcohol consumption are established risk factors for steatotic liver disease (SLD) and progression of fibrosis. However, the clinical relevance of their interaction and its implications for patient management remain unclear.</div></div><div><h3>Methods</h3><div>We cross-sectionally analyzed data from two cohorts: patients referred to tertiary liver care (N = 1,554) and individuals at risk for SLD (N = 1,728). Multivariable regression models with and without interaction terms were used to assess the independent and interactive effects of genetic risk variants, metabolic dysfunction (HOMA-IR, BMI), and alcohol intake on liver fibrosis severity as assessed by liver stiffness measurement (LSM).</div></div><div><h3>Results</h3><div>Mean age was 52 and 56 years in the Tertiary-care cohort and the At-risk cohort, respectively. Most participants were male, 23% and 53% suffered from obesity, and 39% and 58% were categorized as insulin resistant, respectively. Median LSM was 5.5 kPa and 4.7 kPa, with 21% and 9.6% having LSM ≥8 kPa, respectively. In total, 48% and 44% carried at least one <em>PNPLA3</em> G-allele (C/G or G/G), and 18% and 15% the <em>TM6SF2</em> T-allele (C/T or T/T), respectively. In multivariable regression without interaction terms, LSM was associated with HOMA-IR, alcohol consumption, BMI (At-risk cohort), <em>PNPLA3</em> and <em>TM6SF2</em>. However, when allowing for interactions, the independent effects of genetic risk variants disappeared. Instead, <em>PNPLA3</em> potentiated the association of HOMA-IR (<em>p</em> <0.001/<em>p</em> = 0.016) and severe alcohol consumption (<em>p</em> <0.001/<em>p</em> = 0.093) with LSM. <em>TM6SF2</em> amplified the effect of BMI (<em>p</em> = 0.006) and severe alcohol consumption (<em>p</em> <0.001) on LSM in the Tertiary-care-cohort.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that <em>PNPLA3</em> and <em>TM6SF2</em> variants do not act as independent determinants of liver fibrosis once gene–environment interactions are considered. Instead, they amplify the harmful effects of metabolic dysfunction and alcohol consumption in individuals evaluated for SLD, creating a synergistic risk profile.</div></div><div><h3>Impact and implications</h3><div>Our findings indicate that fibrosis progression in steatotic liver disease is mediated by an interaction of environmental risk factors (obesity, insulin resistance, alcohol consumption) and genetic risk variants, such as <em>PNPLA3</em> and <em>TM6SF2</em>, but not by genetic variants alone. This highlights the importance of acknowledging these gene–environment interactions for patient counselling and risk stratification.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101649"},"PeriodicalIF":7.5,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733850","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 : 2025-10-30DOI: 10.1016/j.jhepr.2025.101660
Tim van Zutphen , Dicky Struik , Weilin Liu , Sihao Liu , Benan Pelin Sermikli , Justina C. Wolters , Henkjan J. Verkade , Annette R. Atkins , Michael Downes , Ronald M. Evans , Johan W. Jonker
<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family.</div></div><div><h3>Methods</h3><div>The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling.</div></div><div><h3>Results</h3><div>We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, <em>p <</em>0.01, n = 8) via acute stimulation of very-low-density lipoprotein (VLDL, 3.9-fold, <em>p <</em>0.01, n = 8) secretion in an ER stress-dependent manner. This anti-steatotic effect was independent of adipose FGF receptor 1, which is required for the glucose-lowering effect of FGF1. Mechanistically, activation of the unfolded protein response (UPR), resulting in stabilization of apolipoprotein B (ApoB, 1.8-fold, <em>p <</em>0.01, n = 8), the main structural protein component of atherogenic lipoprotein particles, was identified as the key mechanism by which FGF1 drives VLDL secretion. Post-translational control of ApoB by FGF1 was potentiated by pre-existing ER stress. FGF1 stimulated major regulators of protein synthesis, and during ER stress, all three branches of the UPR were activated. In ER stress-primed lean mice, FGF1 adopted novel TG secretion activity (2.2-fold, <em>p <</em>0.05, n = 6). Conversely, alleviation of ER stress in obese mice suppressed FGF1-stimulated VLDL-TG production (49%, n = 11, <em>p <</em>0.05).</div></div><div><h3>Conclusion</h3><div>These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD.</div></div><div><h3>Impact and implications</h3><div>Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerati
背景和目的代谢功能障碍相关脂肪变性肝病（MASLD）是一种严重的慢性肝病，治疗选择有限。成纤维细胞生长因子（FGF）类似物显示出治疗MASLD的良好效果，但其潜在机制仍不完全清楚。在这里，我们研究了FGF1 （FGF家族的原型成员）抗脂肪变性特性的机制。方法研究FGF1在人、鼠肝细胞和肥胖小鼠急性或慢性内质网应激模型中的作用。代谢分析和蛋白质组学用于评估肝脏生理、内质网应激和信号传导。研究结果表明，FGF1通过急性刺激极低密度脂蛋白（VLDL， 3.9倍，p <0.01, n = 8）分泌，以内质网络应激依赖的方式降低肥胖小鼠肝脏甘油三酯（TG）水平（51%,p <0.01, n = 8）。这种抗脂肪变性作用不依赖于脂肪FGF受体1，而脂肪FGF受体1是FGF1降血糖作用所必需的。机制上，未折叠蛋白反应（UPR）的激活，导致载脂蛋白B （ApoB， 1.8倍，p <0.01, n = 8）的稳定，这是致动脉粥样硬化脂蛋白颗粒的主要结构蛋白成分，被认为是FGF1驱动VLDL分泌的关键机制。先前存在的内质网应激增强了FGF1对ApoB的翻译后控制。FGF1刺激了蛋白质合成的主要调节因子，在内质网应激期间，UPR的所有三个分支都被激活。在内质网应激引发的瘦小鼠中，FGF1具有新的TG分泌活性（2.2倍，p <0.05, n = 6）。相反，减轻肥胖小鼠内质网应激可抑制fgf1刺激的VLDL-TG生成（49%,n = 11, p <0.05）。结论内质网应激依赖性VLDL分泌调节是FGF1抗脂肪变性活性的一种机制。因此，靶向FGF-UPR通路可能具有治疗MASLD的治疗潜力。影响和意义成纤维细胞生长因子在治疗代谢功能障碍相关的脂肪变性肝病的临床前模型和临床试验中都显示出治疗潜力，脂肪变性肝病是一种非常普遍的疾病，治疗方案有限。确定其抗脂肪变性作用的机制可能会加速临床发展。我们发现甘油三酯分泌是FGF1抗脂肪变性作用的主要驱动因素，同时还参与了适应性未折叠蛋白反应，这为该途径的治疗潜力提供了更深入的了解。这些结果还强调了可能对肝脏生理学和循环脂蛋白谱的影响，与有效性和安全性考虑相关。
{"title":"FGF1 ameliorates hepatic steatosis through acute activation of the unfolded protein response and VLDL production","authors":"Tim van Zutphen , Dicky Struik , Weilin Liu , Sihao Liu , Benan Pelin Sermikli , Justina C. Wolters , Henkjan J. Verkade , Annette R. Atkins , Michael Downes , Ronald M. Evans , Johan W. Jonker","doi":"10.1016/j.jhepr.2025.101660","DOIUrl":"10.1016/j.jhepr.2025.101660","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family.</div></div><div><h3>Methods</h3><div>The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling.</div></div><div><h3>Results</h3><div>We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, <em>p <</em>0.01, n = 8) via acute stimulation of very-low-density lipoprotein (VLDL, 3.9-fold, <em>p <</em>0.01, n = 8) secretion in an ER stress-dependent manner. This anti-steatotic effect was independent of adipose FGF receptor 1, which is required for the glucose-lowering effect of FGF1. Mechanistically, activation of the unfolded protein response (UPR), resulting in stabilization of apolipoprotein B (ApoB, 1.8-fold, <em>p <</em>0.01, n = 8), the main structural protein component of atherogenic lipoprotein particles, was identified as the key mechanism by which FGF1 drives VLDL secretion. Post-translational control of ApoB by FGF1 was potentiated by pre-existing ER stress. FGF1 stimulated major regulators of protein synthesis, and during ER stress, all three branches of the UPR were activated. In ER stress-primed lean mice, FGF1 adopted novel TG secretion activity (2.2-fold, <em>p <</em>0.05, n = 6). Conversely, alleviation of ER stress in obese mice suppressed FGF1-stimulated VLDL-TG production (49%, n = 11, <em>p <</em>0.05).</div></div><div><h3>Conclusion</h3><div>These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD.</div></div><div><h3>Impact and implications</h3><div>Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerati","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101660"},"PeriodicalIF":7.5,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814290","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 : 2025-10-29DOI: 10.1016/j.jhepr.2025.101644
Angelo Di Giorgio
{"title":"Reply to: “Managing PFIC 7 with odevixibat: Alleviation of pruritus and biochemical response”","authors":"Angelo Di Giorgio","doi":"10.1016/j.jhepr.2025.101644","DOIUrl":"10.1016/j.jhepr.2025.101644","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101644"},"PeriodicalIF":7.5,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836507","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 : 2025-10-18DOI: 10.1016/j.jhepr.2025.101634
Jasmohan S. Bajaj , Andrew Fagan , Richard K. Sterling , Masoumeh Sikaroodi , Mary Leslie Gallagher , Hannah Lee , Scott C. Matherly , Amy Bartels , Travis Mousel , Brian C. Davis , Puneet Puri , Michael Fuchs , Leroy R. Thacker , Joseph P. McGinley , Alexander Khoruts , Patrick M. Gillevet
<div><h3>Background & Aims</h3><div>The THEMATIC trial demonstrated that fecal microbiota transplantation (FMT) reduces recurrence of hepatic encephalopathy (HE) in patients already receiving lactulose and rifaximin. The aim of this analysis was to identify multi-omic predictors of HE recurrence among THEMATIC trial participants.</div></div><div><h3>Methods</h3><div>The THEMATIC trial enrolled patients with cirrhosis and HE who received oral or enema FMT <em>vs.</em> placebo (1–3 administrations) and were followed for 6 months. Outcomes included safety and HE recurrence. Serum, urine, and stool samples were collected at baseline and post-FMT for all participants. Stool metagenomics, serum and urine metabolomics, inflammatory cytokines, and clinical data were analyzed. Differences between patients with and without HE recurrence were assessed using pathway, random forest, and latent factor analyses.</div></div><div><h3>Results</h3><div>HE recurred in 10 of 60 patients (17%), with significantly higher recurrence in the placebo <em>vs</em>. the FMT groups (40% <em>vs.</em> 8%; <em>p</em> = 0.005). Due to the low recurrence rate in the FMT arms, all patients with recurrence were combined and compared with those without recurrence. Stool metagenomics showed that the abundance of short-chain fatty acid (SCFA) producers (<em>Faecalibacterium, Eubacterium, Bacteroides, Blautia</em> spp.) was lower, while that of GABA-producing taxa (<em>Lactobacillus, Bifidobacterium</em> spp.) was higher, in patients with recurrence. Urine and serum metabolomes separated HE recurrence groups on PLS-DA, with serum butyrate and isobutyrate being most significantly associated (<em>p</em> = 0.008). Pathway analyses revealed upregulation of GABA and neurotransmitter pathways in patients with HE recurrence. Random forest and latent factor analysis indicated that SCFA producers and secondary bile acids were protective, whereas IL-6, GABA producers, nicotine metabolites, and primary bile acids were associated with HE recurrence.</div></div><div><h3>Conclusions</h3><div>Secondary analysis of the THEMATIC randomized controlled trial indicates that HE recurrence in patients on lactulose and rifaximin is associated with distinct microbiome and metabolomic profiles, particularly involving SCFAs, GABA metabolism, bile acids, and IL-6.</div></div><div><h3>Impact and implications</h3><div>Fecal microbiota transplantation (FMT) reduced hepatic encephalopathy (HE) recurrence in patients receiving lactulose and rifaximin in the THEMATIC trial, but the multi-omic mechanisms underlying this effect were unclear. In this secondary analysis, we found that HE recurrence – regardless of FMT or placebo assignment – was associated with distinct multi-omic signatures, including reduced short-chain fatty acid-producing and increased pathobiont taxa, lower urinary and serum short-chain fatty acids, secondary bile acids, and acetaminophen derivatives, and higher GABA-related and nicotine metabolite
背景和目的THEMATIC试验表明，粪便微生物群移植（FMT）可减少已经接受乳果糖和利福昔明治疗的患者肝性脑病（HE）的复发。本分析的目的是确定THEMATIC试验参与者中HE复发的多组学预测因子。方法THEMATIC试验纳入肝硬化和HE患者，接受口服或灌肠FMT与安慰剂（1-3次给药），随访6个月。结果包括安全性和HE复发率。在基线和fmt后收集所有参与者的血清、尿液和粪便样本。分析粪便宏基因组学、血清和尿液代谢组学、炎症细胞因子和临床数据。使用途径、随机森林和潜在因素分析评估HE复发和未复发患者之间的差异。结果60例患者中有10例（17%）复发，安慰剂组的复发率明显高于FMT组（40% vs 8%; p = 0.005）。由于FMT组复发率低，所有复发患者合并并与未复发患者进行比较。粪便元基因组学显示，复发患者的短链脂肪酸（SCFA）产生菌（Faecalibacterium, Eubacterium, Bacteroides, Blautia spp.）丰度较低，而产生gaba的分类菌（Lactobacillus, Bifidobacterium spp.）丰度较高。尿液和血清代谢组在PLS-DA上区分HE复发组，其中血清丁酸和异丁酸最显著相关（p = 0.008）。通路分析显示，在HE复发患者中，GABA和神经递质通路上调。随机森林和潜在因素分析表明，SCFA产生物和次级胆汁酸具有保护作用，而IL-6、GABA产生物、尼古丁代谢物和初级胆汁酸与HE复发相关。THEMATIC随机对照试验的二次分析表明，乳果糖和利福昔明治疗的HE复发与不同的微生物组和代谢组谱有关，特别是涉及SCFAs、GABA代谢、胆汁酸和IL-6。影响和意义：在THEMATIC试验中，粪便微生物群移植（FMT）减少了接受乳果糖和利福昔明治疗的肝性脑病（HE）复发，但这种效果背后的多组学机制尚不清楚。在这项二级分析中，我们发现HE复发-无论FMT或安慰剂分配-与明显的多组学特征相关，包括短链脂肪酸产生减少和病原体分类群增加，尿和血清短链脂肪酸，次级胆汁酸和对乙酰氨基酚衍生物减少，gaba相关和尼古丁代谢物增加，以及IL-6水平升高。值得注意的是，供体菌群植入较多的患者HE复发率较低。这些发现表明，FMT后HE复发反映了一个多因素过程，涉及肠道宏基因组学、全身代谢组学、炎症和供体植入的改变。试验注册www.clinicaltrials.gov: NCT03796598。
{"title":"The multi-omic basis for hepatic encephalopathy recurrence: Analysis of the THEMATIC trial","authors":"Jasmohan S. Bajaj , Andrew Fagan , Richard K. Sterling , Masoumeh Sikaroodi , Mary Leslie Gallagher , Hannah Lee , Scott C. Matherly , Amy Bartels , Travis Mousel , Brian C. Davis , Puneet Puri , Michael Fuchs , Leroy R. Thacker , Joseph P. McGinley , Alexander Khoruts , Patrick M. Gillevet","doi":"10.1016/j.jhepr.2025.101634","DOIUrl":"10.1016/j.jhepr.2025.101634","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The THEMATIC trial demonstrated that fecal microbiota transplantation (FMT) reduces recurrence of hepatic encephalopathy (HE) in patients already receiving lactulose and rifaximin. The aim of this analysis was to identify multi-omic predictors of HE recurrence among THEMATIC trial participants.</div></div><div><h3>Methods</h3><div>The THEMATIC trial enrolled patients with cirrhosis and HE who received oral or enema FMT <em>vs.</em> placebo (1–3 administrations) and were followed for 6 months. Outcomes included safety and HE recurrence. Serum, urine, and stool samples were collected at baseline and post-FMT for all participants. Stool metagenomics, serum and urine metabolomics, inflammatory cytokines, and clinical data were analyzed. Differences between patients with and without HE recurrence were assessed using pathway, random forest, and latent factor analyses.</div></div><div><h3>Results</h3><div>HE recurred in 10 of 60 patients (17%), with significantly higher recurrence in the placebo <em>vs</em>. the FMT groups (40% <em>vs.</em> 8%; <em>p</em> = 0.005). Due to the low recurrence rate in the FMT arms, all patients with recurrence were combined and compared with those without recurrence. Stool metagenomics showed that the abundance of short-chain fatty acid (SCFA) producers (<em>Faecalibacterium, Eubacterium, Bacteroides, Blautia</em> spp.) was lower, while that of GABA-producing taxa (<em>Lactobacillus, Bifidobacterium</em> spp.) was higher, in patients with recurrence. Urine and serum metabolomes separated HE recurrence groups on PLS-DA, with serum butyrate and isobutyrate being most significantly associated (<em>p</em> = 0.008). Pathway analyses revealed upregulation of GABA and neurotransmitter pathways in patients with HE recurrence. Random forest and latent factor analysis indicated that SCFA producers and secondary bile acids were protective, whereas IL-6, GABA producers, nicotine metabolites, and primary bile acids were associated with HE recurrence.</div></div><div><h3>Conclusions</h3><div>Secondary analysis of the THEMATIC randomized controlled trial indicates that HE recurrence in patients on lactulose and rifaximin is associated with distinct microbiome and metabolomic profiles, particularly involving SCFAs, GABA metabolism, bile acids, and IL-6.</div></div><div><h3>Impact and implications</h3><div>Fecal microbiota transplantation (FMT) reduced hepatic encephalopathy (HE) recurrence in patients receiving lactulose and rifaximin in the THEMATIC trial, but the multi-omic mechanisms underlying this effect were unclear. In this secondary analysis, we found that HE recurrence – regardless of FMT or placebo assignment – was associated with distinct multi-omic signatures, including reduced short-chain fatty acid-producing and increased pathobiont taxa, lower urinary and serum short-chain fatty acids, secondary bile acids, and acetaminophen derivatives, and higher GABA-related and nicotine metabolite","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 1","pages":"Article 101634"},"PeriodicalIF":7.5,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786926","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.2025.101642
Georg Kramer , Benedikt Simbrunner , Mathias Jachs , Lorenz Balcar , Benedikt Silvester Hofer , Nina Dominik , Lukas Hartl , Michael Schwarz , Georg Semmler , Christian Sebesta , Paul Thöne , Sophia Geisselbrecht , Benjamin Maasoumy , Eduardo Alvarez , Martin Sebastian McCoy , Oleksandr Petrenko , Jiří Reiniš , Philipp Schwabl , Albert F. Stättermayer , Michael Trauner , Thomas Reiberger
<div><h3>Background & Aims</h3><div>Invasive measurement of hepatic venous pressure gradient (HVPG) is the gold standard for diagnosing clinically significant portal hypertension (CSPH, <em>i.e.</em> HVPG ≥10 mmHg), which indicates an increased risk of decompensation. We evaluated the blood-based Vienna 3P/5P models for non-invasive assessment of portal hypertension (PH) severity and their prognostic value. Their performance was compared to HVPG, liver stiffness measurement (LSM) and the ANTICIPATE±NASH model.</div></div><div><h3>Methods</h3><div>Patients with compensated advanced chronic liver disease (cACLD) who underwent HVPG measurement and LSM within the prospective VICIS (Vienna Cirrhosis Study) were included. We assessed the ability of each model to detect CSPH and severe PH (HVPG ≥16 mmHg), predict decompensation, and stratify risk. Outcome prediction was further validated in an external cohort.</div></div><div><h3>Results</h3><div>Among 266 patients with diverse etiologies of cACLD, median HVPG was 11 (8-16) mmHg with a CSPH and severe PH prevalence of 62.8% and 25.6%, respectively. The 3P/5P models correlated with HVPG (both <em>p <</em>0.001), achieving AUROCs of 0.704 (5P) for CSPH and 0.800 (5P) for severe PH prediction. During a median follow-up of 23.9 (15.3-32.6) months, 48 (18%) patients decompensated. HVPG and the 5P model showed similar time-dependent AUROCs (at 0.5 and 1 year: 0.753-0.822), superior to ANTICIPATE±NASH (AUROCs: 0.689-0.691) and LSM (AUROCs: 0.621-0.636). The 5P (adjusted subdistribution hazard ratio [aSHR]: 1.32, <em>p</em> <em><</em>0.001) and 3P (aSHR: 1.15, <em>p =</em> 0.010) models predicted decompensation independent from age, sex, LSM, etiological cure and non-selective beta blocker use. Proposed cut-offs for the 3P/5P models distinguished between patients at low and high risk of decompensation (Grays test <em>p <</em>0.001).</div></div><div><h3>Conclusion</h3><div>The blood-based 3P/5P models demonstrated significant prognostic value for predicting hepatic decompensation and identifying patients with cACLD at high risk. Importantly, the 5P model performed comparably to HVPG.</div></div><div><h3>Impact and implications</h3><div>This study addresses the clinical need for accessible, reliable, and cost-effective non-invasive tools to predict hepatic decompensation in patients with compensated advanced chronic liver disease, given the limited availability of hepatic venous pressure gradient and liver stiffness measurement. By demonstrating that the Vienna 3P/5P models – machine learning tools based solely on routine laboratory parameters – achieve comparable prognostic accuracy to hepatic venous pressure gradient and outperform other non-invasive tools, such as liver stiffness measurement or the ANTICIPATE±NASH model, these findings have significant implications for clinicians providing care for patients with compensated advanced chronic liver disease. The models' simplicity, repeatability and
{"title":"Blood-based Vienna 3P/5P risk models accurately predict first hepatic decompensation in compensated advanced chronic liver disease","authors":"Georg Kramer , Benedikt Simbrunner , Mathias Jachs , Lorenz Balcar , Benedikt Silvester Hofer , Nina Dominik , Lukas Hartl , Michael Schwarz , Georg Semmler , Christian Sebesta , Paul Thöne , Sophia Geisselbrecht , Benjamin Maasoumy , Eduardo Alvarez , Martin Sebastian McCoy , Oleksandr Petrenko , Jiří Reiniš , Philipp Schwabl , Albert F. Stättermayer , Michael Trauner , Thomas Reiberger","doi":"10.1016/j.jhepr.2025.101642","DOIUrl":"10.1016/j.jhepr.2025.101642","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Invasive measurement of hepatic venous pressure gradient (HVPG) is the gold standard for diagnosing clinically significant portal hypertension (CSPH, <em>i.e.</em> HVPG ≥10 mmHg), which indicates an increased risk of decompensation. We evaluated the blood-based Vienna 3P/5P models for non-invasive assessment of portal hypertension (PH) severity and their prognostic value. Their performance was compared to HVPG, liver stiffness measurement (LSM) and the ANTICIPATE±NASH model.</div></div><div><h3>Methods</h3><div>Patients with compensated advanced chronic liver disease (cACLD) who underwent HVPG measurement and LSM within the prospective VICIS (Vienna Cirrhosis Study) were included. We assessed the ability of each model to detect CSPH and severe PH (HVPG ≥16 mmHg), predict decompensation, and stratify risk. Outcome prediction was further validated in an external cohort.</div></div><div><h3>Results</h3><div>Among 266 patients with diverse etiologies of cACLD, median HVPG was 11 (8-16) mmHg with a CSPH and severe PH prevalence of 62.8% and 25.6%, respectively. The 3P/5P models correlated with HVPG (both <em>p <</em>0.001), achieving AUROCs of 0.704 (5P) for CSPH and 0.800 (5P) for severe PH prediction. During a median follow-up of 23.9 (15.3-32.6) months, 48 (18%) patients decompensated. HVPG and the 5P model showed similar time-dependent AUROCs (at 0.5 and 1 year: 0.753-0.822), superior to ANTICIPATE±NASH (AUROCs: 0.689-0.691) and LSM (AUROCs: 0.621-0.636). The 5P (adjusted subdistribution hazard ratio [aSHR]: 1.32, <em>p</em> <em><</em>0.001) and 3P (aSHR: 1.15, <em>p =</em> 0.010) models predicted decompensation independent from age, sex, LSM, etiological cure and non-selective beta blocker use. Proposed cut-offs for the 3P/5P models distinguished between patients at low and high risk of decompensation (Grays test <em>p <</em>0.001).</div></div><div><h3>Conclusion</h3><div>The blood-based 3P/5P models demonstrated significant prognostic value for predicting hepatic decompensation and identifying patients with cACLD at high risk. Importantly, the 5P model performed comparably to HVPG.</div></div><div><h3>Impact and implications</h3><div>This study addresses the clinical need for accessible, reliable, and cost-effective non-invasive tools to predict hepatic decompensation in patients with compensated advanced chronic liver disease, given the limited availability of hepatic venous pressure gradient and liver stiffness measurement. By demonstrating that the Vienna 3P/5P models – machine learning tools based solely on routine laboratory parameters – achieve comparable prognostic accuracy to hepatic venous pressure gradient and outperform other non-invasive tools, such as liver stiffness measurement or the ANTICIPATE±NASH model, these findings have significant implications for clinicians providing care for patients with compensated advanced chronic liver disease. The models' simplicity, repeatability and ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101642"},"PeriodicalIF":7.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922546","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.2025.101647
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}
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