Pub Date : 2024-10-01Epub Date: 2024-02-15DOI: 10.1097/HEP.0000000000000780
Shifang Tang, Jürgen Borlak
Background and aims: NAFLD is a major disease burden and a foremost cause of chronic liver disease. Presently, nearly 300 trials evaluate the therapeutic efficacy of > 20 drugs. Remarkably, the majority of drugs fail. To better comprehend drug failures, we investigated the reproducibility of fatty liver genomic data across 418 liver biopsies and evaluated the interpatient variability of 18 drug targets.
Approach and results: Apart from our own data, we retrieved NAFLD biopsy genomic data sets from public repositories and considered patient demographics. We divided the data into test and validation sets, assessed the reproducibility of differentially expressed genes and performed gene enrichment analysis. Patients were stratified by disease activity score, fibrosis grades and sex, and we investigated the regulation of 18 drug targets across 418 NAFLD biopsies of which 278 are NASH cases. We observed poor reproducibility of differentially expressed genes across 9 independent studies. On average, only 4% of differentially expressed genes are commonly regulated based on identical sex and 2% based on identical NAS disease score and fibrosis grade. Furthermore, we observed sex-specific gene regulations, and for females, we noticed induced expression of genes coding for inflammatory response, Ag presentation, and processing. Conversely, extracellular matrix receptor interactions are upregulated in males, and the data agree with clinical findings. Strikingly, and with the exception of stearoyl-CoA desaturase, most drug targets are not regulated in > 80% of patients.
Conclusions: Lack of data reproducibility, high interpatient variability, and the absence of disease-dependent drug target regulations are likely causes of NASH drug failures in clinical trials.
{"title":"Genomics of human NAFLD: Lack of data reproducibility and high interpatient variability in drug target expression as major causes of drug failures.","authors":"Shifang Tang, Jürgen Borlak","doi":"10.1097/HEP.0000000000000780","DOIUrl":"10.1097/HEP.0000000000000780","url":null,"abstract":"<p><strong>Background and aims: </strong>NAFLD is a major disease burden and a foremost cause of chronic liver disease. Presently, nearly 300 trials evaluate the therapeutic efficacy of > 20 drugs. Remarkably, the majority of drugs fail. To better comprehend drug failures, we investigated the reproducibility of fatty liver genomic data across 418 liver biopsies and evaluated the interpatient variability of 18 drug targets.</p><p><strong>Approach and results: </strong>Apart from our own data, we retrieved NAFLD biopsy genomic data sets from public repositories and considered patient demographics. We divided the data into test and validation sets, assessed the reproducibility of differentially expressed genes and performed gene enrichment analysis. Patients were stratified by disease activity score, fibrosis grades and sex, and we investigated the regulation of 18 drug targets across 418 NAFLD biopsies of which 278 are NASH cases. We observed poor reproducibility of differentially expressed genes across 9 independent studies. On average, only 4% of differentially expressed genes are commonly regulated based on identical sex and 2% based on identical NAS disease score and fibrosis grade. Furthermore, we observed sex-specific gene regulations, and for females, we noticed induced expression of genes coding for inflammatory response, Ag presentation, and processing. Conversely, extracellular matrix receptor interactions are upregulated in males, and the data agree with clinical findings. Strikingly, and with the exception of stearoyl-CoA desaturase, most drug targets are not regulated in > 80% of patients.</p><p><strong>Conclusions: </strong>Lack of data reproducibility, high interpatient variability, and the absence of disease-dependent drug target regulations are likely causes of NASH drug failures in clinical trials.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139733999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-02-20DOI: 10.1097/HEP.0000000000000793
Yu Jun Wong, Margaret Teng, Alyssa Sim, Htay Myat Thet, Xuhui Teoh, Marianne Anastasia De Roza, Guan Sen Kew, Jia Hong Koh, Pooi Ling Loi, Kai Lim, Garrett Kang, Jonathan Kuang, En Xian Sarah Low, Jing Liang Ho, Liu Yuan Gabriel Cher, Kenny Sze, Guan Wee Wong, Boon Yew Andrew Kwek, Wei Lyn Yang, Juan G Abraldes, Jason Chang
Background and aims: Acute variceal bleeding (AVB) is a major complication in patients with cirrhosis. Using a nationwide AVB audit, we performed a nested cohort study to determine whether full adherence to the AVB quality indicator (QI) improves clinical outcomes in patients with cirrhosis and AVB.
Approach and results: We assessed real-world adherence to AVB QI among patients with cirrhosis admitted for AVB in all public hospitals in Singapore between January 2015 and December 2020. Full adherence was considered when all 5 QIs were fulfilled: prophylactic antibiotics, vasoactive agents, timely endoscopy, endoscopic hemostasis during index endoscopy, and nonselective beta-blockers after AVB. We compare 6-week mortality between the full adherence and suboptimal adherence groups using a propensity-matched cohort.A total of 989 patients with AVB were included. Full adherence to all AVB QI was suboptimal (56.5%). Analysis of the propensity-matched cohort with comparable baseline characteristics showed that full adherence was associated with a lower risk of early infection (20.0% vs. 26.9%), early rebleeding (5.2% vs. 10.2%), and mortality at 6 weeks (8.2% vs. 19.7%) and 1 year (21.3% vs. 35.4%) ( p <0.05 for all). While full adherence was associated with a lower 6-week mortality regardless of the MELD score, nonadherence was associated with a higher 6-week mortality despite a lower predicted risk of 6-week mortality. Despite high adherence to the recommended process measures, patients with CTP-C remain at a higher risk of rebleeding, 6-week and 1-year mortality.
Conclusions: Full adherence to the AVB QI should be the target for quality improvement in patients with cirrhosis.
{"title":"Full adherence to cirrhosis quality indicators is associated with lower mortality in acute variceal bleeding: Nationwide audit.","authors":"Yu Jun Wong, Margaret Teng, Alyssa Sim, Htay Myat Thet, Xuhui Teoh, Marianne Anastasia De Roza, Guan Sen Kew, Jia Hong Koh, Pooi Ling Loi, Kai Lim, Garrett Kang, Jonathan Kuang, En Xian Sarah Low, Jing Liang Ho, Liu Yuan Gabriel Cher, Kenny Sze, Guan Wee Wong, Boon Yew Andrew Kwek, Wei Lyn Yang, Juan G Abraldes, Jason Chang","doi":"10.1097/HEP.0000000000000793","DOIUrl":"10.1097/HEP.0000000000000793","url":null,"abstract":"<p><strong>Background and aims: </strong>Acute variceal bleeding (AVB) is a major complication in patients with cirrhosis. Using a nationwide AVB audit, we performed a nested cohort study to determine whether full adherence to the AVB quality indicator (QI) improves clinical outcomes in patients with cirrhosis and AVB.</p><p><strong>Approach and results: </strong>We assessed real-world adherence to AVB QI among patients with cirrhosis admitted for AVB in all public hospitals in Singapore between January 2015 and December 2020. Full adherence was considered when all 5 QIs were fulfilled: prophylactic antibiotics, vasoactive agents, timely endoscopy, endoscopic hemostasis during index endoscopy, and nonselective beta-blockers after AVB. We compare 6-week mortality between the full adherence and suboptimal adherence groups using a propensity-matched cohort.A total of 989 patients with AVB were included. Full adherence to all AVB QI was suboptimal (56.5%). Analysis of the propensity-matched cohort with comparable baseline characteristics showed that full adherence was associated with a lower risk of early infection (20.0% vs. 26.9%), early rebleeding (5.2% vs. 10.2%), and mortality at 6 weeks (8.2% vs. 19.7%) and 1 year (21.3% vs. 35.4%) ( p <0.05 for all). While full adherence was associated with a lower 6-week mortality regardless of the MELD score, nonadherence was associated with a higher 6-week mortality despite a lower predicted risk of 6-week mortality. Despite high adherence to the recommended process measures, patients with CTP-C remain at a higher risk of rebleeding, 6-week and 1-year mortality.</p><p><strong>Conclusions: </strong>Full adherence to the AVB QI should be the target for quality improvement in patients with cirrhosis.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139935161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-03-11DOI: 10.1097/HEP.0000000000000839
Alfredo Marchetti, Serena Pelusi, Alessio Marella, Francesco Malvestiti, Antony Ricchiuti, Luisa Ronzoni, Marta Lionetti, Vittoria Moretti, Elisabetta Bugianesi, Luca Miele, Umberto Vespasiani-Gentilucci, Paola Dongiovanni, Alessandro Federico, Giorgio Soardo, Roberta D'Ambrosio, Misti V McCain, Helen L Reeves, Vincenzo La Mura, Daniele Prati, Niccolò Bolli, Luca Valenti
Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of HCC. Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD.
Approach and results: We considered individuals with MASLD-HCC (n=208) and controls with (n =414) and without (n =259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with variant allele frequency ≥2%. CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 , and ASXL1 , and correlated with age ( p <0.0001) and advanced liver fibrosis (p=0.001). Higher aspartate aminotransferase levels predicted non- DNMT3A -CHIP, in particular with variant allele frequency ≥10% (OR: 1.14, 1.03 -1.28 and OR: 1.30, 1.12 -1.49, respectively, p <0.05). After adjustment for sex, diabetes, and a polygenic risk, a score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30 -3.15, p =0.02), and with HCC even after further adjustment for cirrhosis (OR: 1.81, 1.11 -2.00, 1.30 -3.15, p =0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non- DNTM3A -CHIP, and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR: 2.45, 1.35 -4.53; OR: 4.8, 1.60 -17.0, p =0.02).
Conclusions: We observed an independent association between CHIP, particularly related to non- DNTM3A and TET2 genetic lesions and MASLD-HCC.
{"title":"Impact of clonal hematopoiesis of indeterminate potential on hepatocellular carcinoma in individuals with steatotic liver disease.","authors":"Alfredo Marchetti, Serena Pelusi, Alessio Marella, Francesco Malvestiti, Antony Ricchiuti, Luisa Ronzoni, Marta Lionetti, Vittoria Moretti, Elisabetta Bugianesi, Luca Miele, Umberto Vespasiani-Gentilucci, Paola Dongiovanni, Alessandro Federico, Giorgio Soardo, Roberta D'Ambrosio, Misti V McCain, Helen L Reeves, Vincenzo La Mura, Daniele Prati, Niccolò Bolli, Luca Valenti","doi":"10.1097/HEP.0000000000000839","DOIUrl":"10.1097/HEP.0000000000000839","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of HCC. Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD.</p><p><strong>Approach and results: </strong>We considered individuals with MASLD-HCC (n=208) and controls with (n =414) and without (n =259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with variant allele frequency ≥2%. CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 , and ASXL1 , and correlated with age ( p <0.0001) and advanced liver fibrosis (p=0.001). Higher aspartate aminotransferase levels predicted non- DNMT3A -CHIP, in particular with variant allele frequency ≥10% (OR: 1.14, 1.03 -1.28 and OR: 1.30, 1.12 -1.49, respectively, p <0.05). After adjustment for sex, diabetes, and a polygenic risk, a score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30 -3.15, p =0.02), and with HCC even after further adjustment for cirrhosis (OR: 1.81, 1.11 -2.00, 1.30 -3.15, p =0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non- DNTM3A -CHIP, and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR: 2.45, 1.35 -4.53; OR: 4.8, 1.60 -17.0, p =0.02).</p><p><strong>Conclusions: </strong>We observed an independent association between CHIP, particularly related to non- DNTM3A and TET2 genetic lesions and MASLD-HCC.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140100603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-07-17DOI: 10.1097/HEP.0000000000001024
Zheng Li, Yi Zhang, Ying Li, Jie Lan, Yuzhu Hu, Qianqian Meng, Laraib Nadeem, Bingwen Zou
{"title":"Letter to the Editor: The causal analysis of missing confounding factors for the association between HDV and specific liver events.","authors":"Zheng Li, Yi Zhang, Ying Li, Jie Lan, Yuzhu Hu, Qianqian Meng, Laraib Nadeem, Bingwen Zou","doi":"10.1097/HEP.0000000000001024","DOIUrl":"10.1097/HEP.0000000000001024","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632153","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 : 2024-10-01Epub Date: 2024-07-17DOI: 10.1097/HEP.0000000000001025
Robert G Gish, Robert J Wong, Gian Luca Di Tanna, Ankita Kaushik, Chong Kim, Nathaniel J Smith, Patrick T F Kennedy
{"title":"Reply: The causal analysis of missing confounding factors for the association between HDV and specific liver events.","authors":"Robert G Gish, Robert J Wong, Gian Luca Di Tanna, Ankita Kaushik, Chong Kim, Nathaniel J Smith, Patrick T F Kennedy","doi":"10.1097/HEP.0000000000001025","DOIUrl":"10.1097/HEP.0000000000001025","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632155","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 : 2024-10-01Epub Date: 2024-07-17DOI: 10.1097/HEP.0000000000001012
Jing Zhao, Yue Bi
{"title":"Letter to the Editor: Accurate predictor for liver disease progression in patients with DC/TBD.","authors":"Jing Zhao, Yue Bi","doi":"10.1097/HEP.0000000000001012","DOIUrl":"10.1097/HEP.0000000000001012","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632149","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 : 2024-10-01Epub Date: 2023-04-28DOI: 10.1097/HEP.0000000000000426
Daniel D Penrice, Nidhi Jalan-Sakrikar, Diana Jurk, João F Passos, Douglas A Simonetto
{"title":"Telomere dysfunction in chronic liver disease: The link from aging.","authors":"Daniel D Penrice, Nidhi Jalan-Sakrikar, Diana Jurk, João F Passos, Douglas A Simonetto","doi":"10.1097/HEP.0000000000000426","DOIUrl":"10.1097/HEP.0000000000000426","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10848919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9791870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-03-06DOI: 10.1097/HEP.0000000000000829
Georg Semmler, Lukas Hartl, Yuly Paulin Mendoza, Benedikt Simbrunner, Mathias Jachs, Lorenz Balcar, Michael Schwarz, Benedikt Silvester Hofer, Laurenz Fritz, Anna Schedlbauer, Katharina Stopfer, Daniela Neumayer, Jurij Maurer, Robin Szymanski, Elias Laurin Meyer, Bernhard Scheiner, Peter Quehenberger, Michael Trauner, Elmar Aigner, Annalisa Berzigotti, Thomas Reiberger, Mattias Mandorfer
Background and aims: Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO).
Approach and results: Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated.
Conclusions: Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.
{"title":"Simple blood tests to diagnose compensated advanced chronic liver disease and stratify the risk of clinically significant portal hypertension.","authors":"Georg Semmler, Lukas Hartl, Yuly Paulin Mendoza, Benedikt Simbrunner, Mathias Jachs, Lorenz Balcar, Michael Schwarz, Benedikt Silvester Hofer, Laurenz Fritz, Anna Schedlbauer, Katharina Stopfer, Daniela Neumayer, Jurij Maurer, Robin Szymanski, Elias Laurin Meyer, Bernhard Scheiner, Peter Quehenberger, Michael Trauner, Elmar Aigner, Annalisa Berzigotti, Thomas Reiberger, Mattias Mandorfer","doi":"10.1097/HEP.0000000000000829","DOIUrl":"10.1097/HEP.0000000000000829","url":null,"abstract":"<p><strong>Background and aims: </strong>Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO).</p><p><strong>Approach and results: </strong>Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated.</p><p><strong>Conclusions: </strong>Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048357","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 : 2024-10-01Epub Date: 2024-04-01DOI: 10.1097/HEP.0000000000000865
Edgar N Tafaleng, Jie Li, Yan Wang, Tunda Hidvegi, Alex Soto-Gutierrez, Adam E Locke, Thomas J Nicholas, Yung-Chun Wang, Stephen Pak, Michael H Cho, Edwin K Silverman, Gary A Silverman, Sheng Chih Jin, Ira J Fox, David H Perlmutter
Background and aims: In the classical form of α1-antitrypsin deficiency, a misfolded variant α1-antitrypsin Z accumulates in the endoplasmic reticulum of liver cells and causes liver cell injury by gain-of-function proteotoxicity in a sub-group of affected homozygotes but relatively little is known about putative modifiers. Here, we carried out genomic sequencing in a uniquely affected family with an index case of liver failure and 2 homozygous siblings with minimal or no liver disease. Their sequences were compared to sequences in well-characterized cohorts of homozygotes with or without liver disease, and then candidate sequence variants were tested for changes in the kinetics of α1-antitrypsin variant Z degradation in iPS-derived hepatocyte-like cells derived from the affected siblings themselves.
Approach and results: Specific variants in autophagy genes MTMR12 and FAM134A could each accelerate the degradation of α1-antitrypsin variant Z in cells from the index patient, but both MTMR12 and FAM134A variants were needed to slow the degradation of α1-antitrypsin variant Z in cells from a protected sib, indicating that inheritance of both variants is needed to mediate the pathogenic effects of hepatic proteotoxicity at the cellular level. Analysis of homozygote cohorts showed that multiple patient-specific variants in proteostasis genes are likely to explain liver disease susceptibility at the population level.
Conclusions: These results validate the concept that genetic variation in autophagy function can determine susceptibility to liver disease in α1-antitrypsin deficiency and provide evidence that polygenic mechanisms and multiple patient-specific variants are likely needed for proteotoxic pathology.
{"title":"Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency.","authors":"Edgar N Tafaleng, Jie Li, Yan Wang, Tunda Hidvegi, Alex Soto-Gutierrez, Adam E Locke, Thomas J Nicholas, Yung-Chun Wang, Stephen Pak, Michael H Cho, Edwin K Silverman, Gary A Silverman, Sheng Chih Jin, Ira J Fox, David H Perlmutter","doi":"10.1097/HEP.0000000000000865","DOIUrl":"10.1097/HEP.0000000000000865","url":null,"abstract":"<p><strong>Background and aims: </strong>In the classical form of α1-antitrypsin deficiency, a misfolded variant α1-antitrypsin Z accumulates in the endoplasmic reticulum of liver cells and causes liver cell injury by gain-of-function proteotoxicity in a sub-group of affected homozygotes but relatively little is known about putative modifiers. Here, we carried out genomic sequencing in a uniquely affected family with an index case of liver failure and 2 homozygous siblings with minimal or no liver disease. Their sequences were compared to sequences in well-characterized cohorts of homozygotes with or without liver disease, and then candidate sequence variants were tested for changes in the kinetics of α1-antitrypsin variant Z degradation in iPS-derived hepatocyte-like cells derived from the affected siblings themselves.</p><p><strong>Approach and results: </strong>Specific variants in autophagy genes MTMR12 and FAM134A could each accelerate the degradation of α1-antitrypsin variant Z in cells from the index patient, but both MTMR12 and FAM134A variants were needed to slow the degradation of α1-antitrypsin variant Z in cells from a protected sib, indicating that inheritance of both variants is needed to mediate the pathogenic effects of hepatic proteotoxicity at the cellular level. Analysis of homozygote cohorts showed that multiple patient-specific variants in proteostasis genes are likely to explain liver disease susceptibility at the population level.</p><p><strong>Conclusions: </strong>These results validate the concept that genetic variation in autophagy function can determine susceptibility to liver disease in α1-antitrypsin deficiency and provide evidence that polygenic mechanisms and multiple patient-specific variants are likely needed for proteotoxic pathology.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11407773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}