Liver International最新文献

{"title":"Elevated Porcupine Disrupts Lipid Metabolism and Promotes Inflammatory Response in MASLD.","authors":"Yalin Zhang, Fengyu Ju, Li Yan, Xin Shen, Shiqing Guo, Muchen Yu, Yujia Cao, Wenhui Wang","doi":"10.1111/liv.16130","DOIUrl":"https://doi.org/10.1111/liv.16130","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a high incidence globally and is a major cause of cirrhosis and hepatocellular carcinoma, lacking of efficient interventions. Patients with MASLD exhibit exceeded serum levels of palmitic acid (PA). However, the association between PA and MASLD remains obscure.</p><p><strong>Methods: </strong>Gene expression omnibus dataset analysis, western blotting, mRNA-sequencing, RT-qPCR, a click chemistry-immunoprecipitation-immunofluorescence system, ELISA, lipid extraction and UHPLC-MS/MS analysis, CyTOF mass cytometry, gene knockdown via lentivirus-mediated shRNA, and high-fat methionine and choline-deficient diet-fed WT and db/db mice models were used to reveal the expression and functions of Porcupine in MASLD development both in vitro and in vivo.</p><p><strong>Results: </strong>Our findings show that PA, as a crucial substrate for protein palmitoylation, induced the expression of palmitoyltransferase Porcupine in a time-dependent manner. This induction was closely associated with dysregulated lipid metabolism and stimulated inflammatory response observed in vitro. Porcupine protein levels were significantly increased in liver tissues from both MASLD mice models, which was predominantly localised in lipid droplet-rich hepatocytes. Pharmacological inhibition of Porcupine by Wnt974 markedly ameliorated the aberrant lipid accumulation and inflammatory response in mouse livers. Furthermore, increased Porcupine positively correlated with CD36 at protein levels, and its inhibition or knockdown decreased CD36 protein levels via mechanisms irrelevant to transcriptional regulation, but primarily dependent on protein palmitoylation.</p><p><strong>Conclusions: </strong>The current study reveals that PA-induced Porcupine disrupts lipid metabolism and promotes inflammatory response during MASLD development, which can be ameliorated by the Porcupine inhibitor Wnt974. Therefore, Porcupine may be a potential pharmacological target for the treatment of MASLD.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469095","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}

{"title":"Impact of GLP-1RA on the Risk of Adverse Liver Outcomes Among Patients With Alcohol-Associated Liver Disease and Type 2 Diabetes.","authors":"Zayed Rashid, Selamawit Woldesenbet, Mujtaba Khalil, Sidharth Iyer, Muhammad Muntazir Mehdi Khan, Abdullah Altaf, Muhammad Musaab Munir, Giovanni Catalano, Khalid Mumtaz, Timothy M Pawlik","doi":"10.1111/liv.16132","DOIUrl":"https://doi.org/10.1111/liv.16132","url":null,"abstract":"<p><strong>Background and aims: </strong>We sought to characterise the impact of GLP-1RA on adverse liver outcomes (ALO) among patients with alcohol-associated liver disease (ALD) and Type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>Patients with T2DM newly diagnosed with ALD between 2013 and 2020 were identified using IBM MarketScan database and were categorised by GLP-1RA exposure. Overlap propensity score weighting (OPSW) followed by Poisson regression models was used to analyse adjusted risk of ALO, a composite endpoint defined by first occurrence of hepatic decompensation (HD), portal hypertension (PH), hepatocellular carcinoma (HCC) or liver transplantation (LT) relative to GLP-1RA.</p><p><strong>Results: </strong>Among 14 730 patients, most individuals were male (n = 9752, 66.2%) with median age of 57 (IQR 52-61) years; 2.2% (n = 317) of patients had GLP-1RA exposure. Overall, 32.0% (n = 4717) of patients experienced HD, 15.9% (n = 2345) had PH, 3.8% (n = 563) developed HCC, while 2.5% (n = 374) underwent transplantation. Non-GLP-1RA patients had higher incidence of HD (32.2% vs. 22.4%) and HCC (3.9% vs. 0.3%) versus patients taking GLP-1RA (both p < 0.001); in contrast, there was no difference in incidence of PH (14.5% vs. 16.0%) and LT (1.3% vs. 2.6%) (both p > 0.05). After OPSW, overall incidence of ALO was lower in GLP-1RA cohort (GLP-1RA: 12.0%, 95%CI 9.0-16.0 vs. non-GLP-1RA: 21.0%, 95%CI 20.0-22.0) with an absolute incidence risk reduction of 9.0% (95%CI 3.0%-15.0%) associated with GLP-1RA. GLP-1RA was most strongly associated with lower likelihood of HD with reduced adjusted incidence rate of 0.56 (95%CI 0.36-0.86) relative to non-GLP-1RA individuals.</p><p><strong>Conclusions: </strong>GLP-1RA may have a hepatoprotective impact among patients with ALD and T2DM.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469098","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}

{"title":"Accuracy of Non-Invasive Imaging Techniques for the Diagnosis of MASH in Patients With MASLD: A Systematic Review.","authors":"Jennifer Cathcart, Rachael Barrett, James S Bowness, Ashis Mukhopadhya, Ruairi Lynch, John F Dillon","doi":"10.1111/liv.16127","DOIUrl":"https://doi.org/10.1111/liv.16127","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health problem. The secondary stage in MASLD is steatohepatitis (MASH), the co-existence of steatosis and inflammation, a leading cause of progression to fibrosis and mortality. MASH resolution alone improves survival. Currently, MASH diagnosis is via liver biopsy. This study sought to evaluate the accuracy of imaging-based tests for MASH diagnosis, which offer a non-invasive method of diagnosis.</p><p><strong>Methods: </strong>Eight academic literature databases were searched and references of previous systematic reviews and included papers were checked for additional papers. Liver biopsy was used for reference standard.</p><p><strong>Results: </strong>We report on 69 imaging-based studies. There were 31 studies on MRI, 27 on ultrasound, five on CT, 13 on transient elastography, eight on controlled attenuation parameter (CAP) and two on scintigraphy. The pathological definition of MASH was inconsistent, making it difficult to compare studies. 55/69 studies (79.71%) were deemed high-risk of bias as they had no preset thresholds and no validation. The two largest groups of imaging papers were on MRI and ultrasound. AUROCs were up to 0.93 for MRE, 0.90 for MRI, 1.0 for magnetic resonance spectroscopy (MRS) and 0.94 for ultrasound-based studies.</p><p><strong>Conclusions: </strong>Our study found that the most promising imaging tools are MRI techniques or ultrasound-based scores and confirmed there is potential to utilise these for MASH diagnosis. However, many publications are single studies without independent prospective validation. Without this, there is no clear imaging tool or score currently available that is reliably tested to diagnose MASH.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469092","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}

{"title":"Spatial and Single-Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis.","authors":"Jin-Zhong Li, Liu Yang, Min-Xi Xiao, Ni Li, Xin Huang, Li-Hong Ye, Hai-Cong Zhang, Zhi-Quan Liu, Jun-Qing Li, Yun-Yan Liu, Xu-Jing Liang, Tao-Yuan Li, Jie-Ying Li, Yang Cao, Yun Pan, Xun-Ge Lin, Hai-Mei Dai, Er-Hei Dai, Min-Ran Li","doi":"10.1111/liv.16125","DOIUrl":"https://doi.org/10.1111/liv.16125","url":null,"abstract":"<p><strong>Objective: </strong>To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis.</p><p><strong>Methods: </strong>Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq.</p><p><strong>Results: </strong>Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis.</p><p><strong>Conclusion: </strong>This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469033","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}

{"title":"Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk.","authors":"Maria Castanho Martins, Emmanuel Dauda Dixon, Giulia Lupo, Thierry Claudel, Michael Trauner, Krista Rombouts","doi":"10.1111/liv.16117","DOIUrl":"https://doi.org/10.1111/liv.16117","url":null,"abstract":"<p><strong>Aims: </strong>Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified.</p><p><strong>Methods: </strong>We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis.</p><p><strong>Results: </strong>Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling.</p><p><strong>Conclusions: </strong>The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469105","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}

{"title":"Global Trends and Inequalities of Liver Complications Related to Metabolic Dysfunction-Associated Steatotic Liver Disease: An Analysis From 1990 to 2021.","authors":"Fang Lu, Jinli Liu, Bingyang She, Hailin Yang, Fanpu Ji, Lei Zhang","doi":"10.1111/liv.16120","DOIUrl":"https://doi.org/10.1111/liv.16120","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease is a significant driver of the increasing global burden of chronic liver disease. This study aimed to describe the temporal trends and inequalities of liver complications related to metabolic dysfunction-associated steatotic liver disease (LC-MASLD) by geographical region, age and sex during 1990-2021.</p><p><strong>Methods: </strong>Global Burden of Diseases Study 2021 data were analysed to assess LC-MASLD incidence, prevalence, mortality and disability-adjusted life years (DALYs). Temporal trends during 1990-2021 were measured by 'estimated annual percentage change' (EAPC). Inequalities of LC-MASLD burden across countries were evaluated by the slope index of inequality (SII) and the relative concentration index (RCI).</p><p><strong>Results: </strong>During 1990-2021, LC-MASLD rose annually by 0.73% in incidence and prevalence, 0.19% in mortality and 0.16% in DALYs. In 2021, the Middle East and North Africa had the highest incidence and prevalence and Andean and Central Latin America had the highest mortality and DALY rates. While LC-MASLD incidence was earliest in the 15-19 age group, both prevalence and DALY rates peaked at 75-79 years for both sexes. Inequalities in mortality and DALYs by countries' socioeconomic development index increased during 1990-2021, demonstrated by a decline in SII from -0.09 to -0.56 per 100 000 for mortality and from 1.41 to -7.74 per 100 000 for DALYs. RCI demonstrated similar findings.</p><p><strong>Conclusion: </strong>The LC-MASLD burden is increasing globally, especially in economically disadvantaged countries, with widening disease inequalities during 1990-2021. Effective prevention and subregional interventions are crucial, with a specific focus on resource optimisation for disadvantaged populations.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469096","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}

{"title":"Featured Cover","authors":"Maria Arconzo,&nbsp;Elena Piccinin,&nbsp;Emanuela Pasculli,&nbsp;Marica Cariello,&nbsp;Nicolas Loiseau,&nbsp;Justine Bertrand-Michel,&nbsp;Hervé Guillou,&nbsp;Maria L. Matrella,&nbsp;Gaetano Villani,&nbsp;Antonio Moschetta","doi":"10.1111/liv.16129","DOIUrl":"https://doi.org/10.1111/liv.16129","url":null,"abstract":"<p>The cover image is based on the Article <i>Hepatic-specific Pgc-1α ablation drives fibrosis in a MASH model</i> by Maria Arconzo et al., https://doi.org/10.1111/liv.16052.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404236","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":"Global Epidemiological Impact of PNPLA3 I148M on Liver Disease.","authors":"Julia Kozlitina, Silvia Sookoian","doi":"10.1111/liv.16123","DOIUrl":"10.1111/liv.16123","url":null,"abstract":"<p><p>The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased exponentially over the past three decades, in parallel with the global rise in obesity and type 2 diabetes. It is currently the most common cause of liver-related morbidity and mortality. Although obesity has been identified as a key factor in the increased prevalence of MASLD, individual differences in susceptibility are significantly influenced by genetic factors. PNPLA3 I148M (rs738409 C>G) is the variant with the greatest impact on the risk of developing progressive MASLD and likely other forms of steatotic liver disease. This variant is prevalent across the globe, with the risk allele (G) frequency exhibiting considerable variation. Here, we review the contribution of PNPLA3 I148M to global burden and regional differences in MASLD prevalence, focusing on recent evidence emerging from population-based sequencing studies and prevalence assessments. We calculated the population attributable fraction (PAF) as a means of quantifying the impact of the variant on MASLD. Furthermore, we employ quantitative trait locus (QTL) analysis to ascertain the associations between rs738409 and a range of phenotypic traits. This analysis suggests that these QTLs may underpin pleiotropic effects on extrahepatic traits. Finally, we outline potential avenues for further research and identify key areas for investigation in future studies.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381231","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}

{"title":"Pharmaco-Economic Assessment of Screening Strategies for High-Risk MASLD in Primary Care.","authors":"Zobair M Younossi, James M Paik, Linda Henry, Maria Stepanova, Fatema Nader","doi":"10.1111/liv.16119","DOIUrl":"10.1111/liv.16119","url":null,"abstract":"<p><strong>Background and aims: </strong>Several scientific associations recommend a sequential combination of non-invasive tests (NITs) to identify high-risk MASLD patients but their cost-effectiveness is unknown.</p><p><strong>Methods: </strong>A cost-utility model was developed to assess the incremental cost-effectiveness ratio (ICER) of recommended screening strategies for patients with clinically suspected MASLD, specifically those with type 2 diabetes (T2D) and obesity with multiple cardiometabolic risk factors which will be initiated in primary care. Six screening strategies were assessed, using either vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test as a second-line test following an initial Fibrosis-4 (FIB-4) assessment as the first line NIT. The model included treatment effects of resmetirom for metabolic dysfunction-associated steatohepatitis (MASH) patients with F2 or F3 fibrosis.</p><p><strong>Results: </strong>All screening strategies for high-risk MASLD in US incurred additional costs compared to no screening, ranging from $13 587 to $14 730 per patient with T2D and $14 274 to $15 661 per patient with obesity. However, screening reduced long-term costs, ranging from $22 150 to $22 279 per patient with T2D and $13 704 to $13 705 per patient with obesity, compared to $24 221 and $14 956 for no screening, respectively. ICERs ranged from $26 913 to $27 884 per QALY for T2D patients and $23 265 to $24  992 per QALY for patients with obesity. While ICERs were influenced by VCTE availability, they remained cost-effective when using ELF as the second-line test. Our findings remain robust across a range of key parameters.</p><p><strong>Conclusions: </strong>Screening for high-risk MASLD is cost-effective according to recent guidelines. Implementing these screening strategies in primary care should be considered.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381232","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}

{"title":"Clinical Utility of Genetic Variants in PNPLA3 and TM6SF2 to Predict Liver-Related Events in Metabolic Dysfunction-Associated Steatotic Liver Disease.","authors":"Yuya Seko, Kanji Yamaguchi, Toshihide Shima, Michihiro Iwaki, Hirokazu Takahashi, Miwa Kawanaka, Saiyu Tanaka, Yasuhide Mitsumoto, Masato Yoneda, Atsushi Nakajima, Takeshi Okanoue, Yoshito Itoh","doi":"10.1111/liv.16124","DOIUrl":"10.1111/liv.16124","url":null,"abstract":"<p><strong>Background and aims: </strong>Fibrosis-4 (FIB-4) index and genetic polymorphisms have been used in assessing the risk of liver-related events (LRE) in metabolic dysfunction-associated steatotic liver disease (MASLD). To establish a more efficient prediction strategy for LRE, we investigated a combined approach that uses the FIB-4 index and genetic polymorphisms.</p><p><strong>Methods: </strong>We enrolled 1304 Japanese patients with biopsy-proven MASLD in this longitudinal multicenter cohort study. PNPLA3, TM6SF2, GCKR and MBOAT7 genotypes were genotyped, and polygenic risk score high fat content (PRS-HFC) were calculated.</p><p><strong>Results: </strong>During the follow-up period of 8.1 year, 96 LRE occurred and 53 patients died. PNPLA3, TM6SF2 and GCKR genotypes were associated with LRE development. We divided patients into three groups based on the FIB-4 index and PNPLA3 and TM6SF2 genotype. The cumulative LRE development rate in each group was 2.1%/28.9%/53.5%, respectively, at 10 years. Multivariate analysis revealed hazard ratios (HRs) for LRE of 10.72 in the high-risk group and 4.80 in the intermediate-risk group. Overall survival in each group was 98.8%/85.2%/72.4%, respectively, at 10 years. HRs for prognosis were 8.74 in the high-risk group and 5.62 in the intermediate-risk group. Patients with FIB-4 index > 2.67 and high PRS-HFC had HR of 6.70 for LRE development and HR of 6.07 for prognosis compared to patients with FIB-4 ≤ 2.67.</p><p><strong>Conclusions: </strong>The approach of measuring the FIB-4 index first followed by assessment of genetic polymorphisms efficiently detected patients at high risk of developing LRE. Therefore, this two-step strategy could be used as a screening method in large populations of patients with MASLD.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381230","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}