Pub Date : 2025-12-17DOI: 10.1016/j.jhepr.2025.101713
Dong Yun Kim , Hyun-Soo Zhang , Jae Seung Lee , Hye Won Lee , Mi Na Kim , Beom Kyung Kim , Seung Up Kim , Do Young Kim , Sang Hoon Ahn , Hyun Woong Lee , Heon Yung Gee , Jung Il Lee , Jun Yong Park
<div><h3>Background & Aims</h3><div>Genetic information is not yet used for the clinical diagnosis of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we investigated whether incorporating genetic information regarding <em>PNPLA3</em> and <em>TM6SF2</em> into existing non-invasive fibrosis scoring systems could improve their predictive accuracy, particularly in patients with type 2 diabetes mellitus (T2DM), a high-risk population for MASLD-related complications.</div></div><div><h3>Methods</h3><div>Data were collected from a cohort of 637 patients with biopsy-proven MASLD. All participants underwent liver stiffness measurement (LSM), serum marker analysis, and genotyping for <em>PNPLA3</em> (rs738409), <em>TM6SF2</em> (rs58542926), and other relevant single nucleotide polymorphisms. We evaluated the benefit of adding genetic information to existing non-invasive tests (NITs) – including the Agile 3+, Fibrosis-4 (FIB-4) index, and NAFLD fibrosis score (NFS).</div></div><div><h3>Results</h3><div>Decision curve analysis in the validation cohort (n = 238) demonstrated that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information marginally enhanced net clinical benefit across all three models over a range of threshold probabilities (10-50%). At a 30% threshold probability, the net benefit of genotype-enhanced models increased from 22.0 to 22.8 per 100 patients for Agile 3+, from 17.0 to 18.4 for NFS, and from 13.0 to 16.9 for FIB-4. In the T2DM subgroup (n = 121), genotype incorporation led to small but statistically significant improvements in discrimination for NFS (AUROC increase: 0.053, <em>p</em> = 0.001) and FIB-4 (AUROC increase: 0.058, <em>p</em> = 0.010), while Agile 3+ showed a favorable trend (AUROC increase: 0.016, <em>p</em> = 0.058).</div></div><div><h3>Conclusions</h3><div>Incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis scoring systems for MASLD provides limited but measurable improvements, with statistically significant AUROC gains for NFS and FIB-4, particularly among patients with T2DM. Further validation is required before routine clinical implementation can be recommended.</div></div><div><h3>Impact and implications</h3><div>Our research demonstrates that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis tests provides modest but measurable improvements in clinical utility for patients with metabolic dysfunction-associated steatotic liver disease, particularly those with type 2 diabetes mellitus – a high-risk population prone to accelerated fibrosis progression and liver-related complications. These findings are relevant for clinicians managing these patients, as genotype-enhanced models (particularly NAFLD fibrosis score and Fibrosis-4 index) showed statistically significant improvements in diagnostic accuracy, enabling better identification of patients requiri
{"title":"Integration of PNPLA3 and TM6SF2 genotypes provides incremental improvement in advanced fibrosis prediction among MASLD patients with type 2 diabetes mellitus","authors":"Dong Yun Kim , Hyun-Soo Zhang , Jae Seung Lee , Hye Won Lee , Mi Na Kim , Beom Kyung Kim , Seung Up Kim , Do Young Kim , Sang Hoon Ahn , Hyun Woong Lee , Heon Yung Gee , Jung Il Lee , Jun Yong Park","doi":"10.1016/j.jhepr.2025.101713","DOIUrl":"10.1016/j.jhepr.2025.101713","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Genetic information is not yet used for the clinical diagnosis of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we investigated whether incorporating genetic information regarding <em>PNPLA3</em> and <em>TM6SF2</em> into existing non-invasive fibrosis scoring systems could improve their predictive accuracy, particularly in patients with type 2 diabetes mellitus (T2DM), a high-risk population for MASLD-related complications.</div></div><div><h3>Methods</h3><div>Data were collected from a cohort of 637 patients with biopsy-proven MASLD. All participants underwent liver stiffness measurement (LSM), serum marker analysis, and genotyping for <em>PNPLA3</em> (rs738409), <em>TM6SF2</em> (rs58542926), and other relevant single nucleotide polymorphisms. We evaluated the benefit of adding genetic information to existing non-invasive tests (NITs) – including the Agile 3+, Fibrosis-4 (FIB-4) index, and NAFLD fibrosis score (NFS).</div></div><div><h3>Results</h3><div>Decision curve analysis in the validation cohort (n = 238) demonstrated that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information marginally enhanced net clinical benefit across all three models over a range of threshold probabilities (10-50%). At a 30% threshold probability, the net benefit of genotype-enhanced models increased from 22.0 to 22.8 per 100 patients for Agile 3+, from 17.0 to 18.4 for NFS, and from 13.0 to 16.9 for FIB-4. In the T2DM subgroup (n = 121), genotype incorporation led to small but statistically significant improvements in discrimination for NFS (AUROC increase: 0.053, <em>p</em> = 0.001) and FIB-4 (AUROC increase: 0.058, <em>p</em> = 0.010), while Agile 3+ showed a favorable trend (AUROC increase: 0.016, <em>p</em> = 0.058).</div></div><div><h3>Conclusions</h3><div>Incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis scoring systems for MASLD provides limited but measurable improvements, with statistically significant AUROC gains for NFS and FIB-4, particularly among patients with T2DM. Further validation is required before routine clinical implementation can be recommended.</div></div><div><h3>Impact and implications</h3><div>Our research demonstrates that incorporating <em>PNPLA3</em> and <em>TM6SF2</em> genetic information into non-invasive fibrosis tests provides modest but measurable improvements in clinical utility for patients with metabolic dysfunction-associated steatotic liver disease, particularly those with type 2 diabetes mellitus – a high-risk population prone to accelerated fibrosis progression and liver-related complications. These findings are relevant for clinicians managing these patients, as genotype-enhanced models (particularly NAFLD fibrosis score and Fibrosis-4 index) showed statistically significant improvements in diagnostic accuracy, enabling better identification of patients requiri","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101713"},"PeriodicalIF":7.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-06DOI: 10.1016/j.jhepr.2025.101706
Theresa Kirchner , Norman Junge , Nicole Henjes , Stephanie Loges , Muhammed Yuksel , Wojciech Janczyk , Claudine Lalanne , Kalliopi Zachou , Ye H. Oo , Jérôme Gournay , Simon Pape , Joost PH. Drenth , Amédée Renand , George N. Dalekos , Luigi Muratori , Piotr Socha , Cigdem Arikan , Yun Ma , Heiner Wedemeyer , Ulrich Baumann , Richard Taubert
<div><h3>Background & Aims</h3><div>The diagnosis of juvenile autoimmune hepatitis (AIH) is challenging given its heterogeneous presentation. Autoantibodies, typically detected by immunofluorescence testing (IFT), together with liver histology, represent key diagnostic features. Polyreactive immunoglobulin G (pIgG) has recently emerged as a complementary biomarker in AIH. This retrospective multicentre study aimed to compare ELISA-based autoantibody testing and IFT on HEp-2 cells with the gold standard of IFT on rodent tissue sections in children with autoimmune and non-autoimmune liver diseases.</div></div><div><h3>Methods</h3><div>Autoantibody detection was performed centrally at Hannover Medical School using three commercial antinuclear antibody (ANA) ELISAs, one commercial F-actin ELISA, one in-house pIgG ELISA, and IFT on HEp-2 cells, in comparison to the gold standard of IFT on rodent tissue sections. Samples from children with AIH (n = 69), autoimmune sclerosing cholangitis (AISC; n = 13) and other liver diseases (n = 120) were analysed from nine European centres.</div></div><div><h3>Results</h3><div>The AUCs for the detection of AIH/AISC were moderate to good for ANA detection by IFT (gold standard of rodent tissue AUC: 0.748; HEp-2 AUC: 0.756) and were comparable to ELISA-based detection (0.622-0.772). Anti-smooth muscle antibody (SMA) IFT on rodent tissue yielded an AUC of 0.694. Specificity was increased to 100% by including the SMA staining pattern of vessels, glomeruli and tubules. ELISA-based quantification of anti-F-actin (AUC = 0.868) and pIgG (AUC = 0.844) showed the highest AUCs. While the majority of F-actin–positive children were pIgG-positive (80.3%), pIgG was also detected in 52.4% of F-actin–negative children with AIH.</div></div><div><h3>Conclusion</h3><div>ELISA-based assays provide reliable ANA detection comparable to IFT. Anti-F-actin and pIgG ELISAs showed the highest accuracy for predicting juvenile AIH/AISC and may complement existing diagnostic criteria.</div></div><div><h3>Impact and implications</h3><div>Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) are rare paediatric liver diseases that can be difficult to distinguish from other hepatopathies. Autoantibody testing is central to diagnosis, yet paediatric performance across platforms has been poorly standardised and sparsely reported. In this multicentre comparison (202 sera from nine expert centres across eight European countries), indirect immunofluorescence (IFT) on rodent tissue showed suboptimal discrimination at the commonly advocated 1:20 cut-off, whereas accuracy for ANA and SMA improved markedly at 1:320. ANA detection by IFT on HEp-2 cells and by ELISA was comparable to rodent tissue IFT. ELISAs for F-actin and pIgG achieved the highest AUCs for identifying AIH/AISC and may complement current diagnostics. Substantial inter-platform discordance for ANA underscores the need for harmonisation. Collectively, these data support t
{"title":"Complementary use of autoantibody detection methods facilitates diagnosis of juvenile autoimmune hepatitis and autoimmune sclerosing cholangitis","authors":"Theresa Kirchner , Norman Junge , Nicole Henjes , Stephanie Loges , Muhammed Yuksel , Wojciech Janczyk , Claudine Lalanne , Kalliopi Zachou , Ye H. Oo , Jérôme Gournay , Simon Pape , Joost PH. Drenth , Amédée Renand , George N. Dalekos , Luigi Muratori , Piotr Socha , Cigdem Arikan , Yun Ma , Heiner Wedemeyer , Ulrich Baumann , Richard Taubert","doi":"10.1016/j.jhepr.2025.101706","DOIUrl":"10.1016/j.jhepr.2025.101706","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The diagnosis of juvenile autoimmune hepatitis (AIH) is challenging given its heterogeneous presentation. Autoantibodies, typically detected by immunofluorescence testing (IFT), together with liver histology, represent key diagnostic features. Polyreactive immunoglobulin G (pIgG) has recently emerged as a complementary biomarker in AIH. This retrospective multicentre study aimed to compare ELISA-based autoantibody testing and IFT on HEp-2 cells with the gold standard of IFT on rodent tissue sections in children with autoimmune and non-autoimmune liver diseases.</div></div><div><h3>Methods</h3><div>Autoantibody detection was performed centrally at Hannover Medical School using three commercial antinuclear antibody (ANA) ELISAs, one commercial F-actin ELISA, one in-house pIgG ELISA, and IFT on HEp-2 cells, in comparison to the gold standard of IFT on rodent tissue sections. Samples from children with AIH (n = 69), autoimmune sclerosing cholangitis (AISC; n = 13) and other liver diseases (n = 120) were analysed from nine European centres.</div></div><div><h3>Results</h3><div>The AUCs for the detection of AIH/AISC were moderate to good for ANA detection by IFT (gold standard of rodent tissue AUC: 0.748; HEp-2 AUC: 0.756) and were comparable to ELISA-based detection (0.622-0.772). Anti-smooth muscle antibody (SMA) IFT on rodent tissue yielded an AUC of 0.694. Specificity was increased to 100% by including the SMA staining pattern of vessels, glomeruli and tubules. ELISA-based quantification of anti-F-actin (AUC = 0.868) and pIgG (AUC = 0.844) showed the highest AUCs. While the majority of F-actin–positive children were pIgG-positive (80.3%), pIgG was also detected in 52.4% of F-actin–negative children with AIH.</div></div><div><h3>Conclusion</h3><div>ELISA-based assays provide reliable ANA detection comparable to IFT. Anti-F-actin and pIgG ELISAs showed the highest accuracy for predicting juvenile AIH/AISC and may complement existing diagnostic criteria.</div></div><div><h3>Impact and implications</h3><div>Autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) are rare paediatric liver diseases that can be difficult to distinguish from other hepatopathies. Autoantibody testing is central to diagnosis, yet paediatric performance across platforms has been poorly standardised and sparsely reported. In this multicentre comparison (202 sera from nine expert centres across eight European countries), indirect immunofluorescence (IFT) on rodent tissue showed suboptimal discrimination at the commonly advocated 1:20 cut-off, whereas accuracy for ANA and SMA improved markedly at 1:320. ANA detection by IFT on HEp-2 cells and by ELISA was comparable to rodent tissue IFT. ELISAs for F-actin and pIgG achieved the highest AUCs for identifying AIH/AISC and may complement current diagnostics. Substantial inter-platform discordance for ANA underscores the need for harmonisation. Collectively, these data support t","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"8 2","pages":"Article 101706"},"PeriodicalIF":7.5,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034309","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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