Pub Date : 2025-12-08DOI: 10.1097/hep.0000000000001638
Zhengtong Zhou,Hua Zhou
{"title":"Letter to the editor: Methodological considerations for ITH quantification and model integration.","authors":"Zhengtong Zhou,Hua Zhou","doi":"10.1097/hep.0000000000001638","DOIUrl":"https://doi.org/10.1097/hep.0000000000001638","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"6 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1097/hep.0000000000001640
John F Dillon,Damien Leith,Paul Brennan
{"title":"Addressing the utility of a novel score for \"At-Risk\" MASH in those with significant obesity.","authors":"John F Dillon,Damien Leith,Paul Brennan","doi":"10.1097/hep.0000000000001640","DOIUrl":"https://doi.org/10.1097/hep.0000000000001640","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"29 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1097/hep.0000000000001633
Yanyu Zhang,Yehao Zhang,Tingting Hu
{"title":"Letter to the Editor: Timing shapes adjuvant PD-1 efficacy after hepatectomy in HCC.","authors":"Yanyu Zhang,Yehao Zhang,Tingting Hu","doi":"10.1097/hep.0000000000001633","DOIUrl":"https://doi.org/10.1097/hep.0000000000001633","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"6 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-05DOI: 10.1097/hep.0000000000001634
Nasir Hussain,Rodrigo V Motta,Usha Gungabissoon,Linda Casillas,Sumanta Mukherjee,Andrea Ribeiro,Megan M Mclaughlin,Kaitlin Hagan,Khushpreet Bhandal,Penelope Rogers,Martine Walmsley,James Ferguson,Andreas E Kremer,Emma L Culver,Palak Trivedi
BACKGROUNDDrug development in primary sclerosing cholangitis (PSC) is challenging, giving orphan disease status and variable rates of disease progression. A potential route for new therapies is through attenuation of symptoms. However, the epidemiology of symptomatic presentations and how they inherently fluctuate over time is not known.APPROACH AND RESULTSWe conducted a prospective, multicentre study (trial registration: ISRCTN:15518794) to quantify the prevalence, intensity and variability of pruritus in PSC. Participants underwent face-to-face symptom assessment through the itch numerical rating scale (NRS) and 5D-itch tool. Clinical, radiological and biochemical factors associated with pruritus intensity were determined, alongside the impact on health-related quality-of-life (EQ-5D 5L and chronic liver disease questionnaires [CLDQ]) over 12-week intervals (up to 48+/-4 weeks). In all, 220 patients participated, of whom n=116 reported pruritus, with n=56 scoring NRS worst itch ≥4. Median 5D-itch was greater in people with cirrhosis (11.0 vs 8.0), transient elastography readings >8.0 kPa (9.5 vs 5.0) and a history of ascending cholangitis (11.0 vs 7.0) (p<0.01; all). 5D-itch correlated positively with serum bilirubin, ALP, ALT and AST; and negatively with CLDQ and EQ-5D 5L. In patients scoring NRS≥4, 61.5% reported persistent pruritus intensity over 48 weeks. Reciprocally, 46.2% experienced a spontaneous ≥2 point reduction in NRS without the addition of a new anti-pruritic agent.CONCLUSIONOne in 4 PSC patients experience moderate-severe pruritus, with greater symptom intensity in those with advanced disease. Our dataset is able to serve as a reference tool to aid future interventional study design, with regards anti-pruritus therapies in PSC.
原发性硬化性胆管炎（PSC）的药物开发具有挑战性，具有孤儿病状态和疾病进展率的差异性。一种潜在的新疗法是通过减轻症状。然而，症状表现的流行病学以及它们如何随时间固有波动尚不清楚。方法和结果我们进行了一项前瞻性、多中心研究（试验注册：ISRCTN:15518794），以量化PSC患者瘙痒的患病率、强度和变异性。通过瘙痒数值评定量表（NRS）和5d -瘙痒工具对参与者进行面对面的症状评估。研究确定了与瘙痒强度相关的临床、放射学和生化因素，以及对健康相关生活质量（EQ-5D - 5L和慢性肝病问卷[CLDQ]）的影响，时间间隔为12周（最长为48+/-4周）。共纳入220例患者，其中n=116例报告瘙痒，n=56例评分NRS最严重瘙痒≥4。肝硬化（11.0 vs 8.0）、瞬时弹性图读数>8.0 kPa （9.5 vs 5.0）和升性胆管炎史（11.0 vs 7.0）患者的中位5D-itch更大（p<0.01；全部）。5D-itch与血清胆红素、ALP、ALT、AST呈正相关；与CLDQ、eq - 5d5l呈负相关。在NRS评分≥4的患者中，61.5%报告持续瘙痒强度超过48周。相反，46.2%的患者在没有添加新的止痒剂的情况下，NRS自发降低≥2点。结论1 / 4的PSC患者出现中重度瘙痒，晚期患者症状强度更大。我们的数据集可以作为参考工具，帮助未来的介入性研究设计，关于PSC的抗瘙痒治疗。
{"title":"Pruritus is common in primary sclerosing cholangitis, persists over time, and its intensity is associated with disease severity.","authors":"Nasir Hussain,Rodrigo V Motta,Usha Gungabissoon,Linda Casillas,Sumanta Mukherjee,Andrea Ribeiro,Megan M Mclaughlin,Kaitlin Hagan,Khushpreet Bhandal,Penelope Rogers,Martine Walmsley,James Ferguson,Andreas E Kremer,Emma L Culver,Palak Trivedi","doi":"10.1097/hep.0000000000001634","DOIUrl":"https://doi.org/10.1097/hep.0000000000001634","url":null,"abstract":"BACKGROUNDDrug development in primary sclerosing cholangitis (PSC) is challenging, giving orphan disease status and variable rates of disease progression. A potential route for new therapies is through attenuation of symptoms. However, the epidemiology of symptomatic presentations and how they inherently fluctuate over time is not known.APPROACH AND RESULTSWe conducted a prospective, multicentre study (trial registration: ISRCTN:15518794) to quantify the prevalence, intensity and variability of pruritus in PSC. Participants underwent face-to-face symptom assessment through the itch numerical rating scale (NRS) and 5D-itch tool. Clinical, radiological and biochemical factors associated with pruritus intensity were determined, alongside the impact on health-related quality-of-life (EQ-5D 5L and chronic liver disease questionnaires [CLDQ]) over 12-week intervals (up to 48+/-4 weeks). In all, 220 patients participated, of whom n=116 reported pruritus, with n=56 scoring NRS worst itch ≥4. Median 5D-itch was greater in people with cirrhosis (11.0 vs 8.0), transient elastography readings >8.0 kPa (9.5 vs 5.0) and a history of ascending cholangitis (11.0 vs 7.0) (p<0.01; all). 5D-itch correlated positively with serum bilirubin, ALP, ALT and AST; and negatively with CLDQ and EQ-5D 5L. In patients scoring NRS≥4, 61.5% reported persistent pruritus intensity over 48 weeks. Reciprocally, 46.2% experienced a spontaneous ≥2 point reduction in NRS without the addition of a new anti-pruritic agent.CONCLUSIONOne in 4 PSC patients experience moderate-severe pruritus, with greater symptom intensity in those with advanced disease. Our dataset is able to serve as a reference tool to aid future interventional study design, with regards anti-pruritus therapies in PSC.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"372 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1097/hep.0000000000001637
Xue Wang,Yi Zhou,Shu Zhang,Christine Farrar,Xuemei Xie,Jiaheng Li,Sophia M Zhang,Zheng Zhang,Andrew Yonemura,Jonathan Toshio Haynes,Xuping Feng,Runze Shang,Zhong Xu,Yanhui Wu,Yu Qiao,Guofei Cui,Weiting Liao,Rong Li,Diego F Calvisi,Shuxing Zhang,Meng Xu,Xin Chen,Haichuan Wang
BACKGROUND AND AIMSApproximately 10% of human hepatocellular carcinomas (HCC) exhibit concurrent c-MET activation and β-catenin gain-of-function mutations, representing a clinically relevant HCC subtype. This study aimed to investigate the role of mTORC2/AKT signaling in this subtype and identify potential therapeutic targets.APPROACH AND RESULTSThe mTORC2/AKT cascade was activated in c-Met/β-cateninΔ90 HCC lesions. Genetic ablation of Rictor, the essential mTORC2 subunit, strongly suppressed c-Met/β-cateninΔ90-dependent hepatocarcinogenesis. Mechanistically, both the TSC2/mTORC1 axis and FOXO1 transcription factors functioned as critical downstream effectors of mTORC2/AKT in this model. We further identified RNF125 as a direct transcriptional target of FOXO1. RNF125 overexpression significantly inhibited tumorigenesis in the c-Met/β-cateninΔ90 model and suppressed liver cancer cell growth in vitro. Notably, using an in vivo doxycycline-inducible system, we found that inducing RNF125 expression in established c-Met/β-cateninΔ90 HCC suppressed tumor progression, suggesting that activation of RNF125 may have translational implications for HCC treatment.CONCLUSIONSOur study, for the first time, established the mTORC2/AKT/FOXO1/RNF125 axis as a critical driver and therapeutic vulnerability in c-MET-activated/β-catenin-mutated HCC. Our study filled a critical gap by defining the tumor-suppressive role of FOXO1 specifically in this HCC subtype. Furthermore, our results positioned RNF125 as a promising therapeutic target for this aggressive HCC subtype.
{"title":"Targeting mTORC2-Dependent AKT/FOXO1/RNF125 signaling exploits a therapeutic vulnerability in c-MET-activated and β-catenin-mutated hepatocellular carcinoma.","authors":"Xue Wang,Yi Zhou,Shu Zhang,Christine Farrar,Xuemei Xie,Jiaheng Li,Sophia M Zhang,Zheng Zhang,Andrew Yonemura,Jonathan Toshio Haynes,Xuping Feng,Runze Shang,Zhong Xu,Yanhui Wu,Yu Qiao,Guofei Cui,Weiting Liao,Rong Li,Diego F Calvisi,Shuxing Zhang,Meng Xu,Xin Chen,Haichuan Wang","doi":"10.1097/hep.0000000000001637","DOIUrl":"https://doi.org/10.1097/hep.0000000000001637","url":null,"abstract":"BACKGROUND AND AIMSApproximately 10% of human hepatocellular carcinomas (HCC) exhibit concurrent c-MET activation and β-catenin gain-of-function mutations, representing a clinically relevant HCC subtype. This study aimed to investigate the role of mTORC2/AKT signaling in this subtype and identify potential therapeutic targets.APPROACH AND RESULTSThe mTORC2/AKT cascade was activated in c-Met/β-cateninΔ90 HCC lesions. Genetic ablation of Rictor, the essential mTORC2 subunit, strongly suppressed c-Met/β-cateninΔ90-dependent hepatocarcinogenesis. Mechanistically, both the TSC2/mTORC1 axis and FOXO1 transcription factors functioned as critical downstream effectors of mTORC2/AKT in this model. We further identified RNF125 as a direct transcriptional target of FOXO1. RNF125 overexpression significantly inhibited tumorigenesis in the c-Met/β-cateninΔ90 model and suppressed liver cancer cell growth in vitro. Notably, using an in vivo doxycycline-inducible system, we found that inducing RNF125 expression in established c-Met/β-cateninΔ90 HCC suppressed tumor progression, suggesting that activation of RNF125 may have translational implications for HCC treatment.CONCLUSIONSOur study, for the first time, established the mTORC2/AKT/FOXO1/RNF125 axis as a critical driver and therapeutic vulnerability in c-MET-activated/β-catenin-mutated HCC. Our study filled a critical gap by defining the tumor-suppressive role of FOXO1 specifically in this HCC subtype. Furthermore, our results positioned RNF125 as a promising therapeutic target for this aggressive HCC subtype.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"127 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1097/hep.0000000000001636
Benjamin E Rosenthal,Marina Serper
{"title":"From sex to size: Rethinking fairness in Liver Transplantation.","authors":"Benjamin E Rosenthal,Marina Serper","doi":"10.1097/hep.0000000000001636","DOIUrl":"https://doi.org/10.1097/hep.0000000000001636","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"25 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2024-03-28DOI: 10.1097/HEP.0000000000000818
Christofer Cruz, Carla M Prado, Chelsia Gillis, Robert Martindale, Chantal Bémeur, Jennifer C Lai, Puneeta Tandon
Malnutrition, sarcopenia (low muscle mass), and physical frailty have gained increasing recognition in candidates for liver transplant (LT) as these conditions can impact postoperative functional capacity. Multidimensional prehabilitation programs have been proposed as a safe intervention in adults awaiting LT but the nutritional pillar of prehabilitation has been understudied. This review summarizes the nutritional recommendations for prehabilitation for individuals with cirrhosis awaiting LT. Three major aspects of nutritional prehabilitation are discussed: (1) Assess: Evaluate nutritional status and assess for malnutrition, sarcopenia, and frailty to guide the nutritional prehabilitation intervention intensity, increasing across universal, targeted, and specialist levels; (2) Intervene: Prescribe a nutritional prehabilitation intervention to meet established nutrition guidelines in cirrhosis with a targeted focus on improving nutritional status and muscle health; (3) Reassess: Follow-up based on the required intensity of nutritional care with as needed intervention adjustment. Topics covered in the review include nutritional care levels for prehabilitation, energy prescriptions across body mass index strata, detailed considerations around protein intake (amount, distribution, and quality), carbohydrate and fat intake, other nutritional considerations, and the potential role of dietary supplements and nutraceuticals. Future research is warranted to more accurately evaluate energy needs, evaluate emerging dietary supplementation strategies, and establish the role of nutraceuticals alongside food-based interventions. While the general principles of nutritional prehabilitation are ready for immediate application, future large-scale randomized controlled trials in this space will help to quantify the benefit that can be gained by transitioning the LT approach from passive "transplant waitlist time" to active "transplant preparation time."
{"title":"Nutritional aspects of prehabilitation in adults with cirrhosis awaiting liver transplant.","authors":"Christofer Cruz, Carla M Prado, Chelsia Gillis, Robert Martindale, Chantal Bémeur, Jennifer C Lai, Puneeta Tandon","doi":"10.1097/HEP.0000000000000818","DOIUrl":"10.1097/HEP.0000000000000818","url":null,"abstract":"<p><p>Malnutrition, sarcopenia (low muscle mass), and physical frailty have gained increasing recognition in candidates for liver transplant (LT) as these conditions can impact postoperative functional capacity. Multidimensional prehabilitation programs have been proposed as a safe intervention in adults awaiting LT but the nutritional pillar of prehabilitation has been understudied. This review summarizes the nutritional recommendations for prehabilitation for individuals with cirrhosis awaiting LT. Three major aspects of nutritional prehabilitation are discussed: (1) Assess: Evaluate nutritional status and assess for malnutrition, sarcopenia, and frailty to guide the nutritional prehabilitation intervention intensity, increasing across universal, targeted, and specialist levels; (2) Intervene: Prescribe a nutritional prehabilitation intervention to meet established nutrition guidelines in cirrhosis with a targeted focus on improving nutritional status and muscle health; (3) Reassess: Follow-up based on the required intensity of nutritional care with as needed intervention adjustment. Topics covered in the review include nutritional care levels for prehabilitation, energy prescriptions across body mass index strata, detailed considerations around protein intake (amount, distribution, and quality), carbohydrate and fat intake, other nutritional considerations, and the potential role of dietary supplements and nutraceuticals. Future research is warranted to more accurately evaluate energy needs, evaluate emerging dietary supplementation strategies, and establish the role of nutraceuticals alongside food-based interventions. While the general principles of nutritional prehabilitation are ready for immediate application, future large-scale randomized controlled trials in this space will help to quantify the benefit that can be gained by transitioning the LT approach from passive \"transplant waitlist time\" to active \"transplant preparation time.\"</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":" ","pages":"1582-1602"},"PeriodicalIF":15.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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