JHEP Reports最新文献

{"title":"Alcohol-driven phenotypic transition in MASLD and risk of liver-related events.","authors":"Seohui Jang, Jihun Song, Eun Seok Kang, Sangwook Cheon, Taeho Kwak, Yihyun Kim, Seokjin Kong, Jinhyeok Choi, Minjeong Kang, Jaewon Khil, Hye Jun Kim, Jeongin Lee, Hwamin Lee, Seogsong Jeong","doi":"10.1016/j.jhepr.2026.101866","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101866","url":null,"abstract":"<p><strong>Background & aims: </strong>Changes in the amount of alcohol consumption among individuals with steatotic liver disease (SLD) result in shifts between the phenotypes of metabolic dysfunction-associated SLD (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD). Yet, real-world evidence on how these shifts affect the incidence of liver-related events (LREs) remains scarce. Therefore, we aimed to evaluate the impact of these dynamic subtype shifts on the risk of LREs.</p><p><strong>Methods: </strong>In the nationwide cohort, 2,795,409 Korean adults who completed two consecutive biennial health examinations (2009-2010 and 2011-2012) were classified as MASLD, MetALD, or ALD at both assessments. Subtype transitions were determined based on fatty liver index-defined hepatic steatosis, cardiometabolic risk factors, and alcohol consumption. Participants were retrospectively followed from 2013 to 2022 for the occurrence of LREs, ascertained through diagnostic codes. Adjusted subdistribution hazard ratios (aSHRs) were calculated using the Fine-Gray model, accounting for death as a competing event.</p><p><strong>Results: </strong>The shift in SLD subtype from baseline to follow-up was closely aligned with corresponding changes in LRE risk. Individuals who remained in MASLD at both time points exhibited the lowest risk of composite LREs during the 9-year follow-up. In contrast, shifts from MASLD or MetALD to ALD were associated with the greatest escalation in LRE risk (MASLD-to-ALD: aSHR, 1.92 [95% confidence interval (CI), 1.83-2.02]; MetALD-to-ALD: aSHR, 1.27 [95% CI, 1.19-1.35]). Conversely, transitions toward MASLD were linked to substantial reductions in risk (MetALD-to-MASLD: aSHR, 0.89 [95% CI, 0.85-0.94]; ALD-to-MASLD: aSHR, 0.78 [95% CI, 0.73-0.83]).</p><p><strong>Conclusions: </strong>Since dynamic changes in SLD subtypes strongly influence liver-related outcomes, regular reassessment of SLD classification is essential for timely and appropriate clinical management.</p><p><strong>Impact and implications: </strong>In this large, nationwide cohort of over 2.7 million Korean adults, we demonstrated marked heterogeneity in long-term liver outcomes according to dynamic steatotic liver disease subtype trajectories, providing strong scientific justification for monitoring disease evolution rather than relying on static classifications. These findings underscore the prognostic value of both alcohol intake reduction and metabolic risk management, highlighting the importance of integrated strategies for patients with hepatic steatosis. Clinicians and researchers should recognize the need for comprehensive care models that combine behavioral interventions such as alcohol screening, counseling, and referral to addiction services with pharmacological management of metabolic risk factors. Particularly, patients with MetALD and those with ALD represent highly vulnerable subgroups, underscoring the need for tailor","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101866"},"PeriodicalIF":7.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771950","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}

{"title":"Haemodynamic alterations associated with hepatic vascular malformations in hereditary haemorrhagic telangiectasia: a cohort study.","authors":"Pernille Darre Haahr, Mikael Kjær Poulsen, Jens Kjeldsen, Massar Omar, Simon Tholander, Annette Dam Fialla, Anette Drøhse Kjeldsen","doi":"10.1016/j.jhepr.2026.101867","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101867","url":null,"abstract":"<p><strong>Background & aims: </strong>Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder frequently associated with hepatic vascular malformations (HVMs). Up to 78% of patients develop HVMs, which may lead to haemodynamic alterations, increased cardiac preload, and progression to high-output heart failure (HOHF). This study aimed to determine the prevalence of HOHF and assess the relationship between HVM severity, stroke volume, and cardiac index in patients with HHT. A secondary aim was to explore the haemodynamic mechanisms underlying HOHF and evaluate the usefulness of transthoracic echocardiography (TTE).</p><p><strong>Methods: </strong>In this cohort study, all adult patients with HHT registered in the national Danish HHT database and residing in the regions of Zealand and Southern Denmark were invited to participate. Participants underwent clinical evaluation, hepatic Doppler ultrasound, and TTE. HVM severity was graded according to the Buscarini classification from 0 to 4.</p><p><strong>Results: </strong>Of 203 eligible patients, 152 (75%) participated. The mean age was 51 years (range 18-84), and 57.9% were female. HVMs were identified in 103 patients (67.8%), of whom 24 (15.8%) had grade 4 HVMs. HOHF was present in 10 patients (6.6%), nine of whom (90%) had grade 4 HVMs. Cardiac index measured by TTE correlated positively with HVM severity (ρ = 0.36, p < 0.001), with a mean increase of 0.81 L/min/m² between HVM grades 0-1 and grade 4 (95% CI 0.48-1.13).</p><p><strong>Conclusions: </strong>High output heart failure was present in 6.6% of patients and occurred predominantly in those with severe hepatic vascular malformations. Stroke volume and cardiac index increased in parallel with hepatic vascular malformation severity. Transthoracic echocardiography appears to be a useful non-invasive tool for identifying patients at risk of haemodynamic complications.</p><p><strong>Impact and implications: </strong>Increasing hepatic vascular malformation severity in hereditary haemorrhagic telangiectasia was associated with a higher cardiac index and clarified the haemodynamic basis of clinical high-output states. These findings may help clinicians identify patients at the greatest risk of this complication, even before symptom manifestation, supporting the use of transthoracic echocardiography alongside hepatic Doppler ultrasound for monitoring and early intervention.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101867"},"PeriodicalIF":7.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771887","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}

{"title":"Severe Hepatitis Flares After Antiviral Withdrawal in Chronic Hepatitis B With Lymphoma: Impact of Rituximab.","authors":"Yen-Chun Liu, Yu-Jia Shih, Chao-Wei Hsu, Wen-Juei Jeng, Rong-Nan Chien","doi":"10.1016/j.jhepr.2026.101863","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101863","url":null,"abstract":"<p><strong>Background & aims: </strong>Rituximab-containing chemotherapy predisposes chronic hepatitis B (CHB) patients to severe hepatitis B virus (HBV) reactivation, but the clinical outcomes after prophylactic nucleos(t)ide analogue (Nuc) withdrawal remain unclear. We aimed to evaluate the impact of rituximab on off-Nuc clinical course by comparing lymphoma-CHB patients treated with rituximab, without rituximab, and non-lymphoma HBeAg-negative CHB patients.</p><p><strong>Methods: </strong>We compared off-Nuc outcomes among rituximab-treated lymphoma-CHB (n=132), non-rituximab lymphoma (n=26), and HBeAg-negative CHB controls (n=939) using propensity score matching (PSM) and inverse probability treatment weighting (IPTW). Sensitivity analyses using the Fine and Gray competing risk model confirmed the robustness of predictors.</p><p><strong>Results: </strong>The 2-year severe flare incidence was significantly higher in rituximab-treated patients than in non-rituximab lymphoma (after IPTW, 22% vs. 8%, p<0.01) or HBeAg-negative CHB (after PSM, 32% vs. 7%, p<0.01). Notably, 88% of relapse events occurred within the first year after discontinuation. Rituximab-treated patients showed steeper HBV DNA rebound kinetics (57% vs. 25% with ΔHBV DNA ≥1 log₁₀ IU/month, p=0.23 vs. non-rituximab; 61% vs. 17%, p<0.01 vs. HBeAg-negative CHB). Use of lower genetic barrier Nucs, baseline HBV DNA ≥4 log₁₀ IU/mL, and end-of-treatment HBsAg ≥100 IU/mL predicted clinical relapse, while non-entecavir use and △HBV DNA ≥1 log₁₀ IU/month at relapse identified those at highest risk of severe flare.</p><p><strong>Conclusions: </strong>Rituximab-exposed lymphoma-CHB patients showed steeper off-therapy HBV DNA rebound and a higher risk of severe hepatitis flares after prophylactic Nuc withdrawal than those without rituximab and HBeAg-negative CHB patients. Close monitoring during the first year after Nuc cessation should be considered for rituximab-treated lymphoma-CHB, when most relapses occur.</p><p><strong>Impact and implications: </strong>Rituximab-treated patients had higher risk of severe flare with a steeper off-therapy HBV rebound kinetics than in non-rituximab lymphoma or HBeAg-negative CHB. Most clinical relapses occurred within the first year after discontinuation of prophylactic Nuc. Use of lower genetic barrier Nucs (LAM or LdT), a pretherapy HBV DNA ≥ 4 log₁₀ IU/mL, and an EOT HBsAg ≥ 100 IU/mL were significant predictors of CR in CHB patients with lymphoma. Close monitoring during the first year after Nuc cessation should be considered, particularly for rituximab-treated lymphoma-CHB.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101863"},"PeriodicalIF":7.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771859","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}

{"title":"Molecular evolution of mosaic chromosome 18 copy-number alterations from gametes to hepatoblastoma.","authors":"Elise Cendres, Marianna Cornet, Zoé Gautier, Aurore Pire, Noémie Urvoy, Guillaume Morcrette, Fatoumata Simaga, Anne Guimier, Christophe Chardot, Carmen Capito, Gudrun Schleiermacher, Julien Masliah-Planchon, Gaelle Pierron, Ilaria Taddei, Dominique Stoppa-Lyonnet, Jessica Zucman-Rossi, Serge Romana, Isabelle Aerts, Theo Z Hirsch","doi":"10.1016/j.jhepr.2026.101862","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101862","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Constitutive chromosomal abnormalities often underlie developmental defects, while somatic copy-number alterations are recurrent events in cancers. Although these processes are usually studied separately, they may occasionally converge, as illustrated by the increased incidence of hepatoblastoma in children with trisomy 18. Mosaic chromosomal abnormalities, present in only a fraction of cells, offer a unique biological context to explore how developmental defects and tumorigenesis can coexist within the same individual.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We employed an integrated genomic approach, combining fluorescent in situ hybridization (FISH), Whole Genome Sequencing (WGS), and single-nucleus RNA-sequencing (snRNAseq) to characterize molecular alterations in a female patient presenting with multiple developmental delays and hepatoblastoma diagnosed at age two.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We identified a mosaic supernumerary derivative chromosome 18, karyotypically described as 47,XX,+der(18), in 10% of liver and blood cells of the patient, and in 100% of the tumor cells. Integrated WGS and FISH analyses revealed that the der(18) resulted from complex chromosomal rearrangements involving eight breakpoints spanning 18p11.32 to 18q12.1. Haplotype phasing indicated a pre-zygotic origin, with mosaicism resulting from early embryonic rescue via loss of the der(18). SnRNAseq of liver and hepatoblastoma tissues enabled reconstruction of copy-number evolution across development and tumorigenesis and supported the prioritization of a restricted set of dosage-sensitive chromosome 18 candidate genes recurrently deregulated in hepatoblastoma. The patient has remained recurrence-free for 32 months following surgical resection and chemotherapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This case reconstructs the molecular evolution of chromosome 18 alterations from the zygote to tumor formation and highlights how mosaic chromosome abnormalities can intersect with developmental defects and pediatric liver cancer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;This case study illustrates how a single chromosomal abnormality can influence both human development and cancer formation. By combining genomics and single-cell analyses, we traced the history of a rare chromosome 18 rearrangement from its origin before fertilization to its role in hepatoblastoma, a childhood liver cancer. We found that this abnormal chromosome was present in only a small fraction of normal liver and blood cells, but in all tumor cells, indicating that the cancer arose from one of these mosaic cells. Integrating single-cell and transcriptomic data enabled the prioritization of a restricted set of chromosome 18 candidate genes. This work provides a detailed example of how complex chromosomal alterations can emerge early in life, be selectively lost during development, and still leave a small population of abnormal cells that may later give rise to can","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101862"},"PeriodicalIF":7.5,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771942","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}

{"title":"Persistent Loss of Intrahepatic IFN-γ in HBV Is Linked to Selective Impairment of Liver-Resident CXCR6+NK Cells Despite Long-Term NUC Therapy.","authors":"Boris J B Beudeker, Diren Arda Karaoglu, Shirin Nkongolo, Gertine W van Oord, Zwier M A Groothuismink, Karishma A Lila, Adam J Gehring, Thierry van den Bosch, Robert J de Knegt, Harmen J G van de Werken, Andre Boonstra","doi":"10.1016/j.jhepr.2026.101865","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101865","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and aims: &lt;/strong&gt;Chronic hepatitis B virus (HBV) infection remains incurable in most patients despite long-term nucleos(t)ide analogue (NUC) therapy. Interferon-γ (IFN-γ) is a cornerstone of antiviral immunity, but its in situ source and status in the human liver remain unknown. We aimed to define the primary source of IFN-γ in healthy liver and determine how this axis is altered in stably suppressed NUC-HBV.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Method: &lt;/strong&gt;Multiplex immunofluorescence for CD3, CD56, CXCR6, and IFN-γ was performed on liver biopsies from NUC-HBV patients (n=9) and healthy donors (n=7), with whole-slide scanning and AI-based segmentation for unbiased in-situ cell quantification. ScRNAseq was conducted on paired blood and liver fine-needle aspirates (FNA) from NUC-HBV (liver n=9, blood n=18) and integrated with control datasets (liver n=5, blood n=9). Differential gene expression was used for transcriptional readout, and cell-cell interaction analysis mapped altered signaling networks.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In healthy liver, CXCR6+NK cells were the dominant IFN-γ producers (24.2%; IQR 14.1-67.2%). In NUC-HBV, these cells were reduced (675 vs. 1,918; p=0.012) and rarely expressed IFN-γ (0.2%; IQR 0.0-1.4%), despite normal ALT and absence of fibrosis. To validate transcriptionally, we performed scRNAseq sequencing on FNA and paired blood. A single, liver-restricted CXCR6+NK cluster was identified, and showed selective downregulation of IFNG and chemokines (XCL1, CCL3, CCL4), while cytotoxic genes (GZMB, PRF1) were preserved. Interaction analysis revealed reduced pro-inflammatory signaling and enrichment of TGF-β-associated pathways. CXCR6+NK frequency correlated with serum HBsAg (p=0.037) but was unchanged after 24 weeks of NUC in a longitudinal dataset.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Long-term NUC therapy does not restore intrahepatic IFN-γ. Loss and transcriptional reprogramming of CXCR6+NK may contribute to a stable, altered immune state, representing a target for immune-based HBV cure strategies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Effective antiviral therapy for chronic HBV suppresses viral replication but does not provide cure, indicating persistent defects in intrahepatic antiviral immunity. By combining protein-level analysis of liver tissue from healthy living donors and NUC-treated HBV liver biopsies with single-cell RNA-seq of fine-needle aspiration-derived immune cells from clinically stable, long-term NUC-treated patients, we directly examined IFN-γ regulation in the human liver-an immune compartment that is largely inaccessible in this patient group. We demonstrate that IFN-γ is produced in situ predominantly by CXCR6+NK cells in healthy liver and is selectively reduced in the liver of NUC-treated patients, despite normal ALT levels, absence of fibrosis, and lack of inflammatory or exhaustion signatures, while no corresponding defect is observed in blood. These findings identify a liver-re","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101865"},"PeriodicalIF":7.5,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728907","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}

{"title":"Treatment of liver failure utilizing multi-cell lineage liver microtissue.","authors":"Mengqi Chen, Heming Wang, Yicheng Zhao, Huafeng Tao, Amar Deep Sharma, Qinggong Yuan, Michael Ott, Wenjuan Li, Liangxue Lai, Guangqi Song, Zhen Dai","doi":"10.1016/j.jhepr.2026.101864","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101864","url":null,"abstract":"<p><strong>Background and aims: </strong>The shortage of liver donors represents a critical challenge for the treatment of end-stage liver failure. Previous studies explored ectopic hepatocyte organoid or spheroid transplantation for support of instable liver function. We hypothesized that addition of non-parenchymal liver cells to hepatocyte organoids would improve overall survival in acute liver failure. Here, we aimed to engineer DNA origami-mediated multi-cell lineage liver microtissue (NAC-liver microtissue), and explored their therapeutic efficacy in a mouse model of acute liver failure.</p><p><strong>Methods: </strong>We employed self-assembling nucleic acid nanostructures (NAC) to construct two types of liver microtissues: one composed exclusively of hepatocytes (NAC-hepatocyte microtissue) and another incorporating both hepatocytes and non-parenchymal cells (NAC-liver microtissue). Next, we investigated their hepatic functional properties in vitro and explored therapeutic efficacy in vivo by intraperitoneal transplantation into mice with extended hepatectomy. To identify the mechanism, we performed histology analysis and RNA-seq of the remnant liver.</p><p><strong>Results: </strong>NAC-liver microtissue exhibited superior scalability and uniformity as well as stable and elevated hepatic functional activity compared to NAC-hepatocyte microtissue in vitro (n=4, p <0.001). In vivo delivery of NAC-liver microtissue induced remarkable improvement of survival in mice with extended hepatectomy compared to untreated group (70%, n=10, vs 8.3%, n=12, p <0.001), whereas NAC-hepatocyte microtissue showed moderate effectiveness (25%, n=8). Furthermore, we discovered that NAC-liver microtissue transplantation contributed to improved liver functions, lipid oxidation and sinusoidal vascular network formation of the remnant liver in mice with extended hepatectomy.</p><p><strong>Conclusions: </strong>Our findings provide therapeutic evidence of NAC-liver microtissue transplantation for the treatment of acute liver failure highlighting a novel avenue for extrahepatic cellular support in severe liver injury.</p><p><strong>Impact and implications: </strong>Transplantation of hepatocyte organoids or spheroids has long been explored as a potential therapy for liver diseases, however, they fail to mimic cellular intricacy of the liver, and led to inadequate cell functionality and limited therapeutic benefits. The utility of multi-cell lineage liver microtissue for liver failure treatment was not reported. Here, we show that NAC-liver microtissue comprised of hepatocytes and NPCs exhibited superior functional outcomes in vitro and in vivo compared to NAC-hepatocyte microtissue. These data support the indispensable role of NPCs for hepatic functionality and suggest a therapeutic potential for patients with severe liver diseases.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101864"},"PeriodicalIF":7.5,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729052","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}

{"title":"AI-guided automated identification of patients at high-risk for hepatocellular carcinoma in large US and Global datasets.","authors":"Eric Lahtinen, Kai Jia, Bowen Gu, Pasapol Saowakon, Steven Kundrot, Matvey B Palchuk, Jeff Warnick, Irving D Kaplan, Michael Curry, Ammar Sarwar, Martin Rinard, Limor Appelbaum","doi":"10.1016/j.jhepr.2026.101859","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101859","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background & aims: &lt;/strong&gt;Hepatocellular Carcinoma (HCC) screening targets patients with cirrhosis but lacks risk stratifi- cation and misses non-cirrhotic cases. We evaluated whether LIver cancer RIsk Computation (LIRIC) models built from routinely collected electronic health record (EHR) data can predict 3-year HCC risk in general and cirrhosis populations and generalize across diverse U.S. and international cohorts.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We conducted a multi-center study using longitudinal EHR data from 64 U.S. and 29 ex-U.S. (Latin America/Asia- Pacific) healthcare organizations. Adults &gt;40 without prior HCC were included; cases were identified using ICD codes 6-36 months pre-diagnosis. U.S. models were developed in general and cirrhosis cohorts (46,679 cases; 1,128,202 con- trols), internally-externally validated by site, race/ethnicity, and time, and evaluated in a simulated \"silent\" deployment. We benchmarked model-derived risk against population incidence using standardized incidence ratios (SIRs). External validation applied U.S. models to ex-U.S. cohorts; region-specific ex-U.S. models were also trained. Logistic regression and neural networks (LIRICLR, LIRICNN) were compared using area under the curve (AUC), calibration, and Geometric Mean of Overestimation (GMOE) risk ratios.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In the U.S. general population, LIRICNN achieved AUC 0.93 (95% CI: 0.9218-0.9289) using 46 features. Internal-external AUCs averaged 0.93 across sites and race/ethnicity strata, with good calibration (GMOE 0.89; 95% CI: 0.862-0.911). At a screening threshold corresponding to SIR≈31, sensitivity was 48% and specificity 97%. U.S.- trained models applied to ex-U.S. data yielded lower AUCs (0.84), but region-specific retraining restored performance (AUC 0.94).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;LIver cancer RIsk Computation (LIRIC) models accurately stratify Hepatocellular Carcinoma (HCC) risk using routine electronic health record (EHR) data in both general and cirrhosis populations and can be adapted for inter- national settings via local retraining. These results support LIRIC as a scalable foundation for risk-based HCC surveillance strategies and future prospective implementation studies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Impact and implications: &lt;/strong&gt;Current HCC screening targets patients with cirrhosis but lacks risk stratification and misses non-cirrhotic cases; we therefore evaluated whether LIRIC models built from routinely collected EHR data can predict 3-year HCC risk in general and cirrhosis populations and generalize across diverse U.S. and international cohorts. These findings are important for hepatologists, primary care clinicians, and health systems because they show that routine EHR data can support accurate and scalable HCC risk stratification across diverse populations. In practice, LIRIC could serve as a foundation for risk- based HCC surveillance strategies and future prospective implementation studies usi","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101859"},"PeriodicalIF":7.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722901","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}

{"title":"Scientific, regulatory, and practical considerations for bringing hepatocellular carcinoma biomarkers into clinical practice.","authors":"Blanca Botía Martínez-Artero, Eleonora Alimenti, James K Carter, David J Pinato, Augusto Villanueva","doi":"10.1016/j.jhepr.2026.101856","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101856","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide; early detection and accurate prediction of treatment response remain major clinical challenges. Current screening methods suffer from limited sensitivity and low adherence and emerging biomarkers show potential to address these challenges. For early HCC detection, biomarker panels such as GALAD and HES V2.0 have shown promising performance in phase III trials, however newer techniques studying methylation of cell-free DNA, fragmentomics and EV-derived RNA may improve sensitivity though they are in earlier validation phases. Biomarkers like programmed death ligand-1 (PD-L1) expression, tumor mutational burden and microsatellite stability status have limited roles in HCC and only AFP is used in clinical practice for prediction of treatment benefit in patients recieving ramucirumab. Bringing biomarkers to market involves different regulatory pathways. In the United States, developers must choose between laboratory-developed test pathway or as in vitro diagnostic approved by the FDA route, followed by securing reimbursement and demonstrating evidence of clinical benefit. In the European Union, the process involves EMA biomarker qualification procedures and conformity assessment under the In Vitro Diagnostic Regulation. Understanding these scientific, regulatory, and commercial considerations is essential for successfully translating HCC biomarker discoveries into clinical practice.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101856"},"PeriodicalIF":7.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722865","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}

{"title":"Targeting RuvBL1 disrupts mitochondrial metabolism and structure in hepatocellular carcinoma.","authors":"Tommaso Mello, Irene Simeone, Alice Guida, Dimitri Papini, Francesca Begnozzi, Alice Santi, Daniele Guasti, Patrizia Nardini, Simone Polvani, Matteo Lulli, Oxana Bereshchenko, Elisabetta Ceni, Armando Curto, Paolo Pinton, Massimo Bonora, Andrea Galli","doi":"10.1016/j.jhepr.2026.101858","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101858","url":null,"abstract":"<p><strong>Background & aims: </strong>The AAA+ ATPase RuvBL1 takes part in several biological processes, including chromatin remodelling and DNA repair, ribosome biogenesis, mTOR signalling, and oncogenic transformation. RUVBL1 overexpression correlates with poor survival in hepatocellular carcinoma patients. We previously found that RuvBL1 is a key regulator of liver glucose metabolism in mice. Here, we aimed at disentangling the metabolic function of RuvBL1 in HCC cells.</p><p><strong>Methods: </strong>Non-transformed AML-12, primary mouse hepatocytes, HCC cell lines, and RuvBL1^hep-/- mice were used (n=3). RuvBL1 was targeted by RNAi and by inhibition with CB-6644. Metabolomic profiling and mitochondrial functions were assessed by targeted GC/MS, Seahorse analysis, and ATP synthase activity. Mitochondrial morphology and membrane potential were investigated by fluorescence microscopy, High-Content Imaging, and TEM. Mitochondrial RuvBL1 was detected by WB, super-resolution microscopy, TEM, and PLA. Human HCC and normal liver samples from TCGA and GTEx databases were used for in silico analysis (T=369, N=160).</p><p><strong>Results: </strong>Targeting RuvBL1 impairs mitochondria-centred metabolic processes, including amino acid metabolism, TCA cycle, and OXPHOS. Inhibition of RuvBL1/2 activity induces loss of cristae integrity, mitochondrial hyperpolarization and fragmentation, a phenotype paralleled by the hepatocytes of RuvBL1^hep-/- mice. We detected RuvBL1 in proximity to mitochondrial ATP synthase, a previously unreported localization for this protein. Mechanistically, CB-6644 reduces ATP synthase-RuvBL1 interaction and impairs complex V activity even under a fuelled TCA cycle. In human HCC, higher RUVBL1 expression correlates with gene signatures associated with mitochondrial oxidative phosphorylation (FDR=5.64e^-03), ATP synthase complex (FDR=6.03e^-03), and poorer outcome (p=2e^-07).</p><p><strong>Conclusions: </strong>Targeting RuvBL1 impairs complex V activity, disrupting mitochondrial metabolic functions and structural integrity. The mitochondrial functions of RuvBL1 may inform novel therapeutic strategies in the fight against hepatocellular carcinoma.</p><p><strong>Impact and implications: </strong>Metabolic reprogramming is a key feature driving HCC onset, progression, and plasticity, contributing to treatment resistance and poor prognosis. RUVBL1 overexpression correlates with reduced survival of HCC patients and has emerged as a potential metabolic modulator. In this study, we found that targeting RuvBL1 impairs its interaction with mitochondrial ATP synthase, disrupting mitochondrial metabolism and cristae structure. In human HCC samples, RUVBL1 expression correlates with hallmark mitochondrial metabolic processes. These findings may inform the development of targeted therapeutic approaches aimed at impairing the metabolic rewiring and plasticity of HCC.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101858"},"PeriodicalIF":7.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723022","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}

{"title":"Fatigue, depression, and impaired health-related quality of life in patients with vascular liver diseases: a multicentric European study^☆.","authors":"Clémence Ramier, Virginia Hernandez-Gea, Laure Elkrief, Annalisa Berzigotti, Andrea De Gottardi, Antonina Antonenko, Audrey Payancé, Pierre-Emmanuel Rautou, Terhi Kangas, Hadewijch Vandenheede, Katrien Vanthomme, Gaël Brulé, Agnes Dumas, Aurélie Plessier","doi":"10.1016/j.jhepr.2026.101861","DOIUrl":"https://doi.org/10.1016/j.jhepr.2026.101861","url":null,"abstract":"<p><strong>Background & aims: </strong>Patient-reported outcomes (PROs) are scarce in vascular liver diseases (VLD), including portal vein thrombosis (PVT) and Budd-Chiari syndrome (BCS). This study aimed to assess health-related quality of life (HRQoL), fatigue, and depressive symptoms in patients with VLD and to identify associated factors.</p><p><strong>Methods: </strong>We performed a multicentre cross-sectional study in France, Spain, and Switzerland. Patients with PVT or BCS were asked to fill out validated questionnaires assessing HRQoL (EQ-5D-5L), fatigue (MFIS-5), and depressive symptoms (PHQ-8). Clinical and sociodemographic data were collected. Linear and logistic regression analyses were used to identify factors associated with the three PROs. Comparisons with the general population were conducted.</p><p><strong>Results: </strong>Among 1136 eligible patients, 488 respondents completed the three PROs. The mean±SD HRQoL score was 0.885±0.146, significantly lower than that of the French general population but comparable to the Spanish general population. Depressive symptoms were reported in 24.8% of patients (versus 9.8% and 3.7% in the French and Spanish general populations, respectively). After indirect standardisation for gender, age, and education, the prevalence of depressive symptoms was three times higher in French patients than in the French general population. Lower HRQoL and greater fatigue were significantly associated with female gender, financial difficulties, self-reported comorbidities, and a history of hepatic encephalopathy on multivariable analysis. Depressive symptoms were associated with female gender, financial difficulties, and antiphospholipid syndrome, while anticoagulation therapy was associated with better outcomes.</p><p><strong>Conclusions: </strong>The disease burden in patients with VLD is significant, with impaired HRQoL and high rates of fatigue and depressive symptoms. Hepatic encephalopathy, gender, and socioeconomic factors are key drivers, emphasising the need for comprehensive care approaches that integrate psychological and social support with clinical management.</p><p><strong>Impact and implications: </strong>This study provides new insight into the disease burden of VLDs by quantifying the prevalence of impaired HRQoL, fatigue, and depressive symptoms in patients with portal vein thrombosis and Budd-Chiari syndrome. Our findings show that female gender and socioeconomic factors, especially financial difficulties play a more important role than clinical severity in predicting PRO measures. These results show the association between anticoagulation therapy and lower levels of fatigue and depression, and the need to expand current care models beyond medical treatment to include psychological support and patient education programs to manage fatigue. Future longitudinal studies are needed to monitor the long-term evolution of these outcomes.</p>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":" ","pages":"101861"},"PeriodicalIF":7.5,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722862","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}