W. Luo, L. Yi, Y. Zhang, J. Zhou, S. Li, F. A. Abouelnazar, Y. Wang, Y. Yan, “Targeting RNA Polymerase I Inhibits Ribosome Biogenesis to Block Liver Fibrosis Progression,” Liver International 46, no. 1 (2026): e70478, https://doi.org/10.1111/liv.70478.
In Figure 4J,L, the images for AgNO3 staining of the si-Ctr group and EU fluorescence staining of the si-Pol I group were inadvertently misplaced. Additionally, in Figure 6F, the Western blot image for Collagen 3A protein was similarly affected by a layout error. The revised figures can be found below.
{"title":"Correction to ‘Targeting RNA Polymerase I Inhibits Ribosome Biogenesis to Block Liver Fibrosis Progression’","authors":"","doi":"10.1111/liv.70519","DOIUrl":"10.1111/liv.70519","url":null,"abstract":"<p>W. Luo, L. Yi, Y. Zhang, J. Zhou, S. Li, F. A. Abouelnazar, Y. Wang, Y. Yan, “Targeting RNA Polymerase I Inhibits Ribosome Biogenesis to Block Liver Fibrosis Progression,” <i>Liver International</i> 46, no. 1 (2026): e70478, https://doi.org/10.1111/liv.70478.</p><p>In Figure 4J,L, the images for AgNO3 staining of the si-Ctr group and EU fluorescence staining of the si-Pol I group were inadvertently misplaced. Additionally, in Figure 6F, the Western blot image for Collagen 3A protein was similarly affected by a layout error. The revised figures can be found below.</p><p>We apologise for this error.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 2","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessia Di Costanzo, Ilaria Pirona, Silvia Buonaiuto, Stella Covino, Carlo Maiorca, Simone Bini, Daniele Tramontano, Ilenia Minicocci, Francesco Baratta, Vincenza Colonna, Allegra Via, Laura D'Erasmo, Marcello Arca
Background & Aims
Lifelong APOB gene inactivation lowers LDL-C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long-term cardiovascular protection and CLD risk in APOB variant carriers has never been evaluated.
Methods
Using UK Biobank data, we analysed 241 APOB loss-of-function (LoF) carriers and 410 721 non-carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the PNPLA3-rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages.
Results
APOB carriers had ~35% lower LDL-C and apoB levels, along with reduced total triglycerides and Lp(a) (all p < 0.001). Baseline ALT and AST were higher in carriers than in non-carriers (Padj = 3.6 × 10−7), particularly among those with obesity (p ≤ 0.003). The prevalence and incidence of CLD were consistently higher in carriers across all risk factor categories (p ≤ 0.01), with the strongest association in those with diabetes and obesity over 15 years of follow-up (Padj = 0.03). In contrast, APOB carriers as a whole had a 57% lower ASCVD risk (Padj= 0.009), with a similar atheroprotective trend across all risk factor categories. This corresponded to an absolute risk reduction of 2.30 ASCVD events/1000 person-years (p = 0.002) and an absolute increase of 3.48 CLD events/1000 person-years (p = 0.003).
Conclusions
Long-term exposure to low LDL-C levels due to APOB LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB-targeting therapies.
{"title":"Low Cholesterol due to APOB Variants: Exploring the Balance Between Liver and Cardiovascular Risk","authors":"Alessia Di Costanzo, Ilaria Pirona, Silvia Buonaiuto, Stella Covino, Carlo Maiorca, Simone Bini, Daniele Tramontano, Ilenia Minicocci, Francesco Baratta, Vincenza Colonna, Allegra Via, Laura D'Erasmo, Marcello Arca","doi":"10.1111/liv.70515","DOIUrl":"10.1111/liv.70515","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background & Aims</h3>\u0000 \u0000 <p>Lifelong <i>APOB</i> gene inactivation lowers LDL-C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long-term cardiovascular protection and CLD risk in <i>APOB</i> variant carriers has never been evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using UK Biobank data, we analysed 241 <i>APOB</i> loss-of-function (LoF) carriers and 410 721 non-carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the <i>PNPLA3</i>-rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>APOB</i> carriers had ~35% lower LDL-C and apoB levels, along with reduced total triglycerides and Lp(a) (all <i>p</i> < 0.001). Baseline ALT and AST were higher in carriers than in non-carriers (<i>P</i><sub>adj</sub> = 3.6 × 10<sup>−7</sup>), particularly among those with obesity (<i>p</i> ≤ 0.003). The prevalence and incidence of CLD were consistently higher in carriers across all risk factor categories (<i>p</i> ≤ 0.01), with the strongest association in those with diabetes and obesity over 15 years of follow-up (<i>P</i><sub>adj</sub> = 0.03). In contrast, <i>APOB</i> carriers as a whole had a 57% lower ASCVD risk (<i>P</i><sub>adj</sub> <i>=</i> 0.009), with a similar atheroprotective trend across all risk factor categories. This corresponded to an absolute risk reduction of 2.30 ASCVD events/1000 person-years (<i>p</i> = 0.002) and an absolute increase of 3.48 CLD events/1000 person-years (<i>p</i> = 0.003).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Long-term exposure to low LDL-C levels due to <i>APOB</i> LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB-targeting therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 2","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70515","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benedikt Silvester Hofer, Thomas Perkmann, Ksenia Brusilovskaya, Lorenz Balcar, Marlene Hintersteininger, Georg Kramer, Benedikt Simbrunner, Esther Caparros, Rubén Francés, Beate Eichelberger, Silvia Lee, Kerstin Zinober, Benjamin Bödendorfer, Borka Radovanovic-Petrova, Paul Thöne, Christian Sebesta, Mathias Jachs, Lukas Hartl, Philipp Schwabl, Mattias Mandorfer, Simon Panzer, Thomas Reiberger, Thomas Gremmel
Background &Aims
Growth differentiation factor-15 (GDF-15), a cell stress-induced cytokine, is implicated in liver disease pathophysiology. We investigated GDF-15 in cirrhosis, focusing on its association with disease-driving pathomechanisms, platelet function, hepatic decompensation, and mortality.
Methods
We included patients with cirrhosis undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital. Platelet surface P-selectin and glycoprotein IIb/IIIa (GPIIb/IIIa) expression after agonist stimulation were assessed by flow cytometry as platelet activation markers. GDF-15 serum levels were quantified by electrochemiluminescence immunoassay.
Results
Among 106 patients (median age 55.1 years; 70.8% male), median GDF-15 was 2880 (1850–4770) pg/mL. GDF-15 correlated with hepatic dysfunction (MELD Spearman's ρ: 0.50; albumin ρ: −0.57), HVPG (ρ: 0.47), systemic inflammation (C-reactive protein ρ: 0.45; interleukin 6 [IL-6] ρ: 0.55; procalcitonin ρ: 0.58), liver stiffness (ρ: 0.67) and enhanced liver fibrosis test (ρ: 0.64) (all p < 0.001). GDF-15 was higher in patients with detectable bacterial DNA in blood (3520 vs. 2250 pg/mL; p < 0.001) and correlated with lipopolysaccharide (ρ: 0.34; p = 0.010) and lipoteichoic acid (ρ: 0.37; p = 0.004). Platelet activation was not linked to GDF-15 after adjusting for liver disease severity, yet patients with undetectable GPIIb/IIIa activation after stimulation showed significantly higher GDF-15. Over a median follow-up of 51.5 (26.0–58.2) months, 38 patients decompensated and 21 died (61.9% liver-related). GDF-15 (aHR per 100 pg/mL: 1.015; 95% CI: 1.004–1.026; p = 0.007) predicted decompensation risk independently of HVPG, MELD, albumin and IL-6. Similarly, GDF-15 was associated with higher risk of all-cause (HR: 1.019; 95% CI: 1.009–1.029; p < 0.001) and liver-related mortality (HR: 1.019; 95% CI: 1.007–1.032; p = 0.002).
Conclusions
GDF-15 is a promising biomarker in cirrhosis that reflects disease-driving pathomechanisms and independently predicts decompensation and mortality.
Alessandro Mantovani, Enrico Scoccia, Riccardo Morandin, Maria Giovanna Lando, Veronica Fiorio, Antonio Taverna, Ilaria Milani, Mariana Chinucci, Maria Eugenia Parrotta, Luca Colangeli, Simonetta Palleschi, Paolo Sbraccia, Frida Leonetti, Luca Valenti, Danila Capoccia, Giovanni Targher, Valeria Guglielmi
Background
There is limited evidence on the prevalence of, and factors contributing to, metabolic dysfunction-associated steatotic liver disease (MASLD) among individuals with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus.
Methods
We consecutively enrolled 1304 adult individuals with T1DM (n = 237) or T2DM (n = 1067) who underwent vibration-controlled transient elastography (VCTE) with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) assessment. MASLD was defined as a CAP ≥ 248 dB/m in the presence of diabetes. Significant and advanced liver fibrosis were defined as LSM ≥ 8 kPa and ≥ 10 kPa, respectively.
Results
Compared to adult patients with T1DM, those with T2DM had higher prevalence rates of MASLD (65.7% vs. 38.4%, p < 0.001), significant liver fibrosis (18.6% vs. 5.1%, p < 0.001) and advanced fibrosis (9.8% vs. 3.8%, p = 0.003). Adiposity measures (higher BMI and larger waist circumference) and increased plasma triglyceride levels were the strongest predictors of MASLD in both patient groups. After a propensity score matching analysis for age, sex and BMI, patients with T2DM maintained a higher prevalence of MASLD (65.7% vs. 52.6%, p = 0.033) than those with T1DM, but they had similar rates of significant and advanced liver fibrosis.
Conclusions
Patients with T2DM have higher prevalence rates of MASLD, significant and advanced hepatic fibrosis, as detected by VCTE, compared to adult patients with T1DM. Biomarkers of insulin resistance (such as higher BMI, larger waist circumference and higher plasma triglycerides) are equally important in explaining the presence of MASLD in patients with T1DM and T2DM.
{"title":"MASLD in Adults With Type 1 Diabetes and Type 2 Diabetes Undergoing Vibration-Controlled Transient Elastography","authors":"Alessandro Mantovani, Enrico Scoccia, Riccardo Morandin, Maria Giovanna Lando, Veronica Fiorio, Antonio Taverna, Ilaria Milani, Mariana Chinucci, Maria Eugenia Parrotta, Luca Colangeli, Simonetta Palleschi, Paolo Sbraccia, Frida Leonetti, Luca Valenti, Danila Capoccia, Giovanni Targher, Valeria Guglielmi","doi":"10.1111/liv.70514","DOIUrl":"10.1111/liv.70514","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>There is limited evidence on the prevalence of, and factors contributing to, metabolic dysfunction-associated steatotic liver disease (MASLD) among individuals with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We consecutively enrolled 1304 adult individuals with T1DM (<i>n</i> = 237) or T2DM (<i>n</i> = 1067) who underwent vibration-controlled transient elastography (VCTE) with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) assessment. MASLD was defined as a CAP ≥ 248 dB/m in the presence of diabetes. Significant and advanced liver fibrosis were defined as LSM ≥ 8 kPa and ≥ 10 kPa, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to adult patients with T1DM, those with T2DM had higher prevalence rates of MASLD (65.7% vs. 38.4%, <i>p</i> < 0.001), significant liver fibrosis (18.6% vs. 5.1%, <i>p</i> < 0.001) and advanced fibrosis (9.8% vs. 3.8%, <i>p</i> = 0.003). Adiposity measures (higher BMI and larger waist circumference) and increased plasma triglyceride levels were the strongest predictors of MASLD in both patient groups. After a propensity score matching analysis for age, sex and BMI, patients with T2DM maintained a higher prevalence of MASLD (65.7% vs. 52.6%, <i>p</i> = 0.033) than those with T1DM, but they had similar rates of significant and advanced liver fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Patients with T2DM have higher prevalence rates of MASLD, significant and advanced hepatic fibrosis, as detected by VCTE, compared to adult patients with T1DM. Biomarkers of insulin resistance (such as higher BMI, larger waist circumference and higher plasma triglycerides) are equally important in explaining the presence of MASLD in patients with T1DM and T2DM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 2","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rachael Barrett, Annie Archer, Jennifer Cathcart, Kushala Abeysekera, John F. Dillon, Paul N. Brennan
Background & Aims
Metabolic associated steatotic liver disease (MASLD) is increasing in prevalence worldwide. Clinical practice is focused on identifying those with cirrhosis and monitoring for complications such as varices and hepatocellular carcinoma (HCC). Non-invasive tests of fibrosis differentiate between F3 and F4 fibrosis poorly. People with F3 fibrosis may progress and develop decompensated liver disease. The aim of this review is to examine the progression to decompensated liver disease in patients with F3 fibrosis compared to those with F4 fibrosis.
Methods
Searches were carried out in four databases; articles were screened by two independent reviewers against pre-specified inclusion and exclusion criteria.
Results
Twenty-nine studies were included in the review: 12 with paired liver biopsies, 2 progression to cirrhosis, 13 progression to decompensation, 2 portal hypertension in F3 fibrosis and 13 on HCC in F3 fibrosis. Rates of progression on paired biopsies were 16%–30% over varied follow-up. Varices were found in 16% of patients with F3 fibrosis and rates of non-cirrhotic HCC varied from 37%–75%. Pooled univariate HR for F3 progression and F4 progression to major adverse liver outcomes (MALO) were 8.15 (95% CI 3.42–19.43) and 38.16 (95% CI 11.58–125.76), respectively.
Conclusions
Progression to cirrhosis and decompensation events occurs in a significant proportion of patients with F3 fibrosis in MASLD. There is evidence of portal hypertension and HCC developing in F3 MASLD. Further work to identify risk groups, including those at risk of rapid progression to guide future clinical management is urgently required given the prognostic inflection of decompensated disease.
背景与目的：代谢性脂肪变性肝病（MASLD）在世界范围内的患病率正在上升。临床实践的重点是识别肝硬化和监测并发症，如静脉曲张和肝细胞癌（HCC）。非侵入性纤维化检查很难区分F3和F4纤维化。F3纤维化患者可能进展并发展为失代偿性肝病。本综述的目的是比较F3纤维化患者与F4纤维化患者向失代偿性肝病的进展。方法：在四个数据库中进行检索；文章由两名独立审稿人根据预先指定的纳入和排除标准进行筛选。结果：回顾纳入29项研究：12例配对肝活检，2例进展为肝硬化，13例进展为代偿失代偿，2例F3纤维化门脉高压，13例F3纤维化HCC。在不同的随访中，成对活检的进展率为16%-30%。16%的F3纤维化患者发现静脉曲张，非肝硬化HCC的发生率从37%-75%不等。F3进展和F4进展到主要不良肝脏结局（MALO）的合并单因素HR分别为8.15 （95% CI 3.42-19.43）和38.16 （95% CI 11.58-125.76）。结论：在MASLD的F3纤维化患者中，进展为肝硬化和失代偿事件发生的比例很大。F3 MASLD有门静脉高压和肝细胞癌发生的证据。鉴于失代偿性疾病的预后影响，迫切需要进一步开展工作，以确定风险群体，包括那些有快速进展风险的人群，以指导未来的临床管理。
{"title":"Progression to Decompensation of Severe Fibrosis Compared to Cirrhosis in MASLD: A Systematic Review and Meta-Analysis","authors":"Rachael Barrett, Annie Archer, Jennifer Cathcart, Kushala Abeysekera, John F. Dillon, Paul N. Brennan","doi":"10.1111/liv.70511","DOIUrl":"10.1111/liv.70511","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background & Aims</h3>\u0000 \u0000 <p>Metabolic associated steatotic liver disease (MASLD) is increasing in prevalence worldwide. Clinical practice is focused on identifying those with cirrhosis and monitoring for complications such as varices and hepatocellular carcinoma (HCC). Non-invasive tests of fibrosis differentiate between F3 and F4 fibrosis poorly. People with F3 fibrosis may progress and develop decompensated liver disease. The aim of this review is to examine the progression to decompensated liver disease in patients with F3 fibrosis compared to those with F4 fibrosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Searches were carried out in four databases; articles were screened by two independent reviewers against pre-specified inclusion and exclusion criteria.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty-nine studies were included in the review: 12 with paired liver biopsies, 2 progression to cirrhosis, 13 progression to decompensation, 2 portal hypertension in F3 fibrosis and 13 on HCC in F3 fibrosis. Rates of progression on paired biopsies were 16%–30% over varied follow-up. Varices were found in 16% of patients with F3 fibrosis and rates of non-cirrhotic HCC varied from 37%–75%. Pooled univariate HR for F3 progression and F4 progression to major adverse liver outcomes (MALO) were 8.15 (95% CI 3.42–19.43) and 38.16 (95% CI 11.58–125.76), respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Progression to cirrhosis and decompensation events occurs in a significant proportion of patients with F3 fibrosis in MASLD. There is evidence of portal hypertension and HCC developing in F3 MASLD. Further work to identify risk groups, including those at risk of rapid progression to guide future clinical management is urgently required given the prognostic inflection of decompensated disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 2","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12811796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Considerations on MRI-Based Stratification for Retreatment After TACE in HCC","authors":"Zhouyuan Wei","doi":"10.1111/liv.70518","DOIUrl":"10.1111/liv.70518","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 2","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Recent developments in hepatocellular carcinoma (HCC)-treatment have brought big changes for up-to-date approaches on how we manage patients throughout the different BCLC stages of disease. Since the initial introduction of the BCLC concept in 1999 [<span>1</span>], transarterial chemoembolization (TACE) has been the mainstay of therapy for intermediate stage HCC in all guidelines. But review of the evidence soon indicated that reduced liver function and large tumours were associated with poor outcome after TACE [<span>2</span>], while a large prospective observational study on the use of sorafenib in intermediate stage HCC had shown remarkable outcomes for drug treatment in these patients [<span>3</span>].</p><p>Let's revisit for a moment how TACE became the standard of care in intermediate HCC at a time when no other effective treatments but liver resection, local ablation, and transplantation were available for any stage of HCC: after a series of 5 failed multicenter trials on TACE versus no treatment, two single centre trials were able to show a survival benefit, which made the resulting meta-analysis significant in favour of TACE [<span>4</span>]. Looking into the two positive studies in greater detail, the median diameter of the HCC's treated with TACE in the European trial was 4.9 cm (with no tumour exceeding 5.8 cm in diameter) [<span>5</span>], while in the Asian trial only the subgroup with tumours up to 5 cm in diameter experienced a survival advantage with TACE, while patients with tumours exceeding 5 cm did not derive any benefit from TACE and liver failure was more prevalent in the TACE-group [<span>6</span>]. Excellent long-term survival was reported for patients undergoing TACE as well, but mostly in highly selected patients that would be considered good candidates for a curative treatment approach today [<span>7</span>].</p><p>A couple of years later, Kudo and coworkers were able to show in a retrospective proof-of-concept study with the tyrosine kinase inhibitor lenvatinib in intermediate stage HCC patients with tumours beyond the up-to-seven criteria that drug treatment in large tumours offers much superior survival outcomes compared to TACE through a combination of superior tumour response as well as less damage to liver function [<span>8</span>].</p><p>Now in the REPLACEMENT-trial reported in this issue of <i>Liver International</i>, Ueshima et al. are taking these findings one step further with a prospective, single-arm phase-2 trial using atezolizumab/bevacizumab instead of TACE for intermediate-stage HCC patients outside the up-to-seven criteria [<span>9</span>]. Even though this study is lacking a control group, the authors are able to show an impressive objective response rate (ORR) of 40.5%, a median progression-free survival of 9.1 months and a median OS of 33.8 months with the upper boundary of the confidence interval for OS still not reached for the immunooncologic combination therapy. Complete response is 12.2% a
{"title":"Do We Still Need a BCLC-Intermediate Stage for Hepatocellular Carcinoma-Management?","authors":"Markus Peck-Radosavljevic","doi":"10.1111/liv.70517","DOIUrl":"10.1111/liv.70517","url":null,"abstract":"<p>Recent developments in hepatocellular carcinoma (HCC)-treatment have brought big changes for up-to-date approaches on how we manage patients throughout the different BCLC stages of disease. Since the initial introduction of the BCLC concept in 1999 [<span>1</span>], transarterial chemoembolization (TACE) has been the mainstay of therapy for intermediate stage HCC in all guidelines. But review of the evidence soon indicated that reduced liver function and large tumours were associated with poor outcome after TACE [<span>2</span>], while a large prospective observational study on the use of sorafenib in intermediate stage HCC had shown remarkable outcomes for drug treatment in these patients [<span>3</span>].</p><p>Let's revisit for a moment how TACE became the standard of care in intermediate HCC at a time when no other effective treatments but liver resection, local ablation, and transplantation were available for any stage of HCC: after a series of 5 failed multicenter trials on TACE versus no treatment, two single centre trials were able to show a survival benefit, which made the resulting meta-analysis significant in favour of TACE [<span>4</span>]. Looking into the two positive studies in greater detail, the median diameter of the HCC's treated with TACE in the European trial was 4.9 cm (with no tumour exceeding 5.8 cm in diameter) [<span>5</span>], while in the Asian trial only the subgroup with tumours up to 5 cm in diameter experienced a survival advantage with TACE, while patients with tumours exceeding 5 cm did not derive any benefit from TACE and liver failure was more prevalent in the TACE-group [<span>6</span>]. Excellent long-term survival was reported for patients undergoing TACE as well, but mostly in highly selected patients that would be considered good candidates for a curative treatment approach today [<span>7</span>].</p><p>A couple of years later, Kudo and coworkers were able to show in a retrospective proof-of-concept study with the tyrosine kinase inhibitor lenvatinib in intermediate stage HCC patients with tumours beyond the up-to-seven criteria that drug treatment in large tumours offers much superior survival outcomes compared to TACE through a combination of superior tumour response as well as less damage to liver function [<span>8</span>].</p><p>Now in the REPLACEMENT-trial reported in this issue of <i>Liver International</i>, Ueshima et al. are taking these findings one step further with a prospective, single-arm phase-2 trial using atezolizumab/bevacizumab instead of TACE for intermediate-stage HCC patients outside the up-to-seven criteria [<span>9</span>]. Even though this study is lacking a control group, the authors are able to show an impressive objective response rate (ORR) of 40.5%, a median progression-free survival of 9.1 months and a median OS of 33.8 months with the upper boundary of the confidence interval for OS still not reached for the immunooncologic combination therapy. Complete response is 12.2% a","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"46 2","pages":""},"PeriodicalIF":5.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaofei Yin, Caroline Bickerton, Bryan MacDonald, Alessandro Arduini, Yunlong Shi, Mary Haas, Amy Deik, Mark Chaffin, Erika Kovacs-Bogdan, Julian Avila Pacheco, Maiwen Amegadjie, Bidur Bhandary, Shayan Sadre, Thomas Rathjen, Irinna Papangeli, Raymond T. Chung, Russell Goodman, Melina Claussnitzer, Clary Clish, Alexander Ehrmann, Alison Leed, Patrick T. Ellinor
Background & Aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) spans from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and can progress to cirrhosis or hepatocellular carcinoma. Despite its prevalence, effective therapies are lacking. Recent genome-wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (MTARC1) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss-of-function MTARC1 variant, suggesting mARC1 inhibition as a potential MASLD treatment.
Methods
To validate mARC1 loss-of-function as protective against MASLD, we generated Mtarc1 knockout (KO) mice and placed them on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Effects of Mtarc1 KO on obesity and type 2 diabetes were explored using a high-fat diet. Hepatocytes from Mtarc1 KO mice were isolated to explore the molecular mechanisms by which Mtarc1 KO impacts lipid metabolism.
Results
Mtarc1 KO mice exhibited no vital growth or development defects. With a high-fat diet-induced obesity model, obese Mtarc1 KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD-induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in Mtarc1 KO mice. Primary hepatocytes isolated from Mtarc1 KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion.
Conclusions
These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD/MASH.
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