Pub Date : 2026-01-29DOI: 10.1097/hep.0000000000001695
Jiwon Yang, Yeongseok Hwang, Jin-Sung Ju, Seungbong Han, Jihyun An, Ju Hyun Shim
Background & Aims: Type 2 diabetes mellitus (T2DM) is a recognized modifiable risk factor for hepatocellular carcinoma (HCC) and liver-related mortality. The effects of newer antidiabetic agents—including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors—on hepatic outcomes remain uncertain. We aimed to evaluate whether these therapies reduce the risk of HCC and non-HCC liver-related events (LREs) in patients with T2DM. Approach and Results: A systematic literature search was performed to identify studies reporting hepatic complications among patients with T2DM prescribed GLP-1 RAs, SGLT-2 inhibitors, or DPP-4 inhibitors. Comparisons were made against patients receiving various glucose-lowering therapies other than the drug of interest. Subgroup analyses were conducted in patients with chronic liver disease. Random-effects meta-analyses were used to estimate pooled hazard ratios (HRs). Of 2,228 records screened, 36 cohort studies comprising 5,363,858 patients were included. Compared with other glucose-lowering therapies, GLP-1 RAs were associated with significantly reduced risks of HCC (pooled HR 0.77, 95% CI [0.66–0.90]) and LREs (0.79 [0.65–0.95]). SGLT-2 inhibitors similarly conferred protection against HCC (0.76 [0.67–0.86]) and LREs (0.82 [0.73–0.92]). By contrast, DPP-4 inhibitors were not associated with hepatoprotection, showing neutral effects on HCC (1.12 [0.91–1.39]) and increased risk of LREs (1.24 [1.15–1.34]). In patients with chronic liver disease, GLP-1 RAs were uniquely associated with reduced hepatic decompensation (0.79 [0.71–0.88]). Conclusions: GLP-1 RAs and SGLT-2 inhibitors were associated with hepatoprotective effects compared with other glucose-lowering therapies in patients with T2DM, with GLP-1 RAs showing additional benefits in chronic liver disease. These findings provide evidence on the relationships between antidiabetic drug classes and liver-related outcomes in patients with T2DM and may inform clinical decision-making.
{"title":"Impact of newer antihyperglycemic agents on hepatic complications: A systematic review and meta-analysis of data from 5.3 million patients with type 2 diabetes mellitus","authors":"Jiwon Yang, Yeongseok Hwang, Jin-Sung Ju, Seungbong Han, Jihyun An, Ju Hyun Shim","doi":"10.1097/hep.0000000000001695","DOIUrl":"https://doi.org/10.1097/hep.0000000000001695","url":null,"abstract":"Background & Aims: Type 2 diabetes mellitus (T2DM) is a recognized modifiable risk factor for hepatocellular carcinoma (HCC) and liver-related mortality. The effects of newer antidiabetic agents—including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors—on hepatic outcomes remain uncertain. We aimed to evaluate whether these therapies reduce the risk of HCC and non-HCC liver-related events (LREs) in patients with T2DM. Approach and Results: A systematic literature search was performed to identify studies reporting hepatic complications among patients with T2DM prescribed GLP-1 RAs, SGLT-2 inhibitors, or DPP-4 inhibitors. Comparisons were made against patients receiving various glucose-lowering therapies other than the drug of interest. Subgroup analyses were conducted in patients with chronic liver disease. Random-effects meta-analyses were used to estimate pooled hazard ratios (HRs). Of 2,228 records screened, 36 cohort studies comprising 5,363,858 patients were included. Compared with other glucose-lowering therapies, GLP-1 RAs were associated with significantly reduced risks of HCC (pooled HR 0.77, 95% CI [0.66–0.90]) and LREs (0.79 [0.65–0.95]). SGLT-2 inhibitors similarly conferred protection against HCC (0.76 [0.67–0.86]) and LREs (0.82 [0.73–0.92]). By contrast, DPP-4 inhibitors were not associated with hepatoprotection, showing neutral effects on HCC (1.12 [0.91–1.39]) and increased risk of LREs (1.24 [1.15–1.34]). In patients with chronic liver disease, GLP-1 RAs were uniquely associated with reduced hepatic decompensation (0.79 [0.71–0.88]). Conclusions: GLP-1 RAs and SGLT-2 inhibitors were associated with hepatoprotective effects compared with other glucose-lowering therapies in patients with T2DM, with GLP-1 RAs showing additional benefits in chronic liver disease. These findings provide evidence on the relationships between antidiabetic drug classes and liver-related outcomes in patients with T2DM and may inform clinical decision-making.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"42 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071506","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 : 2026-01-26DOI: 10.1097/hep.0000000000001686
Anna Saborowski, Simon Peters, Jinbo Zhao, Silke Marhenke, Valery Volk, Josephine Sophie Reschke, Anastasiia Korosteleva, Dawei Yi, Tanja Reineke-Plaaß, Jeremy Augustin, Doan Duy Hai Tran, Miguel A. Ibarra-Arellano, Denis Schapiro, Steffen Lemke, Nicole Krönke, Ilario Giovanni Rapposelli, Oreste Segatto, Melanie Bathon, Christoph Gerdes, Julien Calderaro, Walter Kolch, Vadim Zhernovkov, Friedrich Feuerhake, Arndt Vogel
Background and Aims: Immune checkpoint inhibitors are now considered as part of standard of care in biliary tract cancer, based on a statistically significant but overall modest survival benefit in recent pivotal trials. Unlike in other gastrointestinal malignancies, PD-L1-based scores were not significantly associated with survival. Intrahepatic cholangiocarcinomas (iCCA) are morphologically heterogeneous tumors, with a subset of iCCA dominated by stroma rich areas. We aimed at understanding the potential impact of the inter- and intratumoral heterogeneity on PD-L1 expression in iCCA. Methods: Bulk transcriptome analysis and multiplex immunohistochemistry were performed on 141 clinically annotated resected iCCA. Results: Molecular signatures are critically driven by the relative stroma content with higher inflammatory gene expression scores in tumor microenvironment (TME)-rich compared to TME-poor tumors. In addition to this inter-tumoral heterogeneity we observed a striking intra-tumoral heterogeneity reflected by an enrichment of PD-L1 expressig cells in stroma-dominant areas. The effect of intra-tumoral heterogeneity on PD-L1 based scores was confirmed by analysing “virtual biopsies”, i.e. randomly selected adjacent tumor regions designed to mimic clinical biopsies, further highlighting the broad challenges associated with biomarker development using needle biopsies. By integrating clinical data, we provide evidence that the prognostic value of PD-L1-expressing tumor cells is overall modest and may depend not only on the magnitude of expression but also on their localization within the tumor. Conclusion: Our data indicate that stroma content may be a surrogate for inflamed iCCA. Moreover, the inter- and intratumoral heterogeneity of iCCA poses a significant challenge to interpreting the PD-L1 signal. To establish tissue-based biomarkers in iCCA, a more granular annotation of their expression in different intratumoral compartments will be critical.
{"title":"Stroma-driven inter- and intratumoral heterogeneity of PD-L1 expression in cholangiocarcinoma: Implications for biomarker development and prognostic evaluation","authors":"Anna Saborowski, Simon Peters, Jinbo Zhao, Silke Marhenke, Valery Volk, Josephine Sophie Reschke, Anastasiia Korosteleva, Dawei Yi, Tanja Reineke-Plaaß, Jeremy Augustin, Doan Duy Hai Tran, Miguel A. Ibarra-Arellano, Denis Schapiro, Steffen Lemke, Nicole Krönke, Ilario Giovanni Rapposelli, Oreste Segatto, Melanie Bathon, Christoph Gerdes, Julien Calderaro, Walter Kolch, Vadim Zhernovkov, Friedrich Feuerhake, Arndt Vogel","doi":"10.1097/hep.0000000000001686","DOIUrl":"https://doi.org/10.1097/hep.0000000000001686","url":null,"abstract":"Background and Aims: Immune checkpoint inhibitors are now considered as part of standard of care in biliary tract cancer, based on a statistically significant but overall modest survival benefit in recent pivotal trials. Unlike in other gastrointestinal malignancies, PD-L1-based scores were not significantly associated with survival. Intrahepatic cholangiocarcinomas (iCCA) are morphologically heterogeneous tumors, with a subset of iCCA dominated by stroma rich areas. We aimed at understanding the potential impact of the inter- and intratumoral heterogeneity on PD-L1 expression in iCCA. Methods: Bulk transcriptome analysis and multiplex immunohistochemistry were performed on 141 clinically annotated resected iCCA. Results: Molecular signatures are critically driven by the relative stroma content with higher inflammatory gene expression scores in tumor microenvironment (TME)-rich compared to TME-poor tumors. In addition to this inter-tumoral heterogeneity we observed a striking intra-tumoral heterogeneity reflected by an enrichment of PD-L1 expressig cells in stroma-dominant areas. The effect of intra-tumoral heterogeneity on PD-L1 based scores was confirmed by analysing “virtual biopsies”, i.e. randomly selected adjacent tumor regions designed to mimic clinical biopsies, further highlighting the broad challenges associated with biomarker development using needle biopsies. By integrating clinical data, we provide evidence that the prognostic value of PD-L1-expressing tumor cells is overall modest and may depend not only on the magnitude of expression but also on their localization within the tumor. Conclusion: Our data indicate that stroma content may be a surrogate for inflamed iCCA. Moreover, the inter- and intratumoral heterogeneity of iCCA poses a significant challenge to interpreting the PD-L1 signal. To establish tissue-based biomarkers in iCCA, a more granular annotation of their expression in different intratumoral compartments will be critical.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"1 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047925","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 : 2026-01-26DOI: 10.1097/hep.0000000000001694
Maria Stepanova, Zobair M. Younossi
{"title":"Reply: From weight to waist: Refining fibrosis prediction in the global MASLD cohort","authors":"Maria Stepanova, Zobair M. Younossi","doi":"10.1097/hep.0000000000001694","DOIUrl":"https://doi.org/10.1097/hep.0000000000001694","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"7 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047919","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}
Background & Aims: Fontan-associated liver disease (FALD) could lead to liver cirrhosis and hepatocellular carcinoma (HCC). The prognosis of FALD patients is worse when HCC develops. Therefore, better understanding of the mechanisms of FALD hepatocarcinogenesis is critical. We investigated the genomic and transcriptomic signatures of FALD HCC. Approach & Results: Ten patients with FALD HCCs, two patients with non-Fontan congenital heart surgery (CHS) HCC, and one patient with FALD focal nodular hyperplasia (FNH) were enrolled. Whole-genome sequencing and transcriptome sequencing were performed, and the results were compared with other etiology-related HCCs in common databases. FALD HCCs exhibited comparable tumor mutation burdens to those of HCCs in the databases, as well as mutation signatures related to DNA double-strand break repair deficiency. These features were shared by non-Fontan CHS HCCs and FALD FNH, suggesting that post-operative stress has an impact on genomic alterations. Of note, FALD and non-Fontan CHS HCCs showed a higher amount of copy number alterations and structural variants, including short deletions and translocations, which were rarely detected in FALD FNH. These structural variants were implicated in frequently altered genes of HCC, suggesting a possible trigger of hepatocarcinogenesis. Transcriptome analysis revealed that individual FALD and non-Fontan CHS HCCs were grouped into the reported HCC subclasses, namely progenitor phenotype, rather than an uncommon HCC subclass. Conclusions: Genomic mutational profiles of FALD and non-Fontan CHS HCCs are distinct from HCCs with other etiologies. Copy number alterations and transcriptional profiles in FALD HCCs classified these into a poor-prognosis group of HCCs.
{"title":"Genomic and transcriptomic profiling of hepatocellular carcinoma in patients with Fontan-associated liver disease","authors":"Taiji Yamazoe, Eiji Kakazu, Michitaka Matsuda, Masaaki Mino, Taizo Mori, Sachiyo Yoshio, Yuriko Tsutsui, Takashi Motomura, Shinji Itoh, Koichiro Haruki, Kenei Furukawa, Shinichiro Yamada, Takeshi Takamoto, Takehiro Noda, Hidetoshi Eguchi, Kiyoshi Hasegawa, Yuji Morine, Toru Ikegami, Tomoharu Yoshizumi, Tatsuya Kanto","doi":"10.1097/hep.0000000000001693","DOIUrl":"https://doi.org/10.1097/hep.0000000000001693","url":null,"abstract":"Background & Aims: Fontan-associated liver disease (FALD) could lead to liver cirrhosis and hepatocellular carcinoma (HCC). The prognosis of FALD patients is worse when HCC develops. Therefore, better understanding of the mechanisms of FALD hepatocarcinogenesis is critical. We investigated the genomic and transcriptomic signatures of FALD HCC. Approach & Results: Ten patients with FALD HCCs, two patients with non-Fontan congenital heart surgery (CHS) HCC, and one patient with FALD focal nodular hyperplasia (FNH) were enrolled. Whole-genome sequencing and transcriptome sequencing were performed, and the results were compared with other etiology-related HCCs in common databases. FALD HCCs exhibited comparable tumor mutation burdens to those of HCCs in the databases, as well as mutation signatures related to DNA double-strand break repair deficiency. These features were shared by non-Fontan CHS HCCs and FALD FNH, suggesting that post-operative stress has an impact on genomic alterations. Of note, FALD and non-Fontan CHS HCCs showed a higher amount of copy number alterations and structural variants, including short deletions and translocations, which were rarely detected in FALD FNH. These structural variants were implicated in frequently altered genes of HCC, suggesting a possible trigger of hepatocarcinogenesis. Transcriptome analysis revealed that individual FALD and non-Fontan CHS HCCs were grouped into the reported HCC subclasses, namely progenitor phenotype, rather than an uncommon HCC subclass. Conclusions: Genomic mutational profiles of FALD and non-Fontan CHS HCCs are distinct from HCCs with other etiologies. Copy number alterations and transcriptional profiles in FALD HCCs classified these into a poor-prognosis group of HCCs.","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"44 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047918","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 : 2026-01-26DOI: 10.1097/hep.0000000000001696
Luisa Giudice, Stefano Granieri, Stefania Galassi, Sante De Santis, Emmanuel Pio Pastore
{"title":"Letter to the editor: Deep learning and digital pathology for HCC prediction in steatotic liver disease","authors":"Luisa Giudice, Stefano Granieri, Stefania Galassi, Sante De Santis, Emmanuel Pio Pastore","doi":"10.1097/hep.0000000000001696","DOIUrl":"https://doi.org/10.1097/hep.0000000000001696","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"29 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047922","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 : 2026-01-26DOI: 10.1097/hep.0000000000001691
Hong Zeng, Xi Huang
{"title":"Letter to the Editor: From weight to waist: Refining fibrosis prediction in the global MASLD cohort","authors":"Hong Zeng, Xi Huang","doi":"10.1097/hep.0000000000001691","DOIUrl":"https://doi.org/10.1097/hep.0000000000001691","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"7 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047920","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 : 2026-01-21DOI: 10.1097/hep.0000000000001687
Luis Antonio Díaz, Winston Dunn, Ashwani K. Singal
{"title":"Alcohol use dominates determining liver related events in steatotic liver disease: Rethinking the role of metabolic dysfunction","authors":"Luis Antonio Díaz, Winston Dunn, Ashwani K. Singal","doi":"10.1097/hep.0000000000001687","DOIUrl":"https://doi.org/10.1097/hep.0000000000001687","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"185 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014347","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 : 2026-01-15DOI: 10.1097/hep.0000000000001625
Prowpanga Udompap
{"title":"Metabolic syndrome and cholangiocarcinoma: A signal too strong to ignore","authors":"Prowpanga Udompap","doi":"10.1097/hep.0000000000001625","DOIUrl":"https://doi.org/10.1097/hep.0000000000001625","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"18 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972282","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 : 2026-01-15DOI: 10.1097/hep.0000000000001626
Vinay Jahagirdar, Juan Pablo Arab
{"title":"From intuition to index: Combining frailty and comorbidities to stratify liver transplant risk","authors":"Vinay Jahagirdar, Juan Pablo Arab","doi":"10.1097/hep.0000000000001626","DOIUrl":"https://doi.org/10.1097/hep.0000000000001626","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"29 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972283","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 : 2026-01-15DOI: 10.1097/hep.0000000000001624
Hanna Erickson
{"title":"Fueling fibrosis: The PBX1–IL7R axis and its role in hepatic stellate cell activation","authors":"Hanna Erickson","doi":"10.1097/hep.0000000000001624","DOIUrl":"https://doi.org/10.1097/hep.0000000000001624","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":"41 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145972285","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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