Elisabetta Tombolini, Alessandro Squizzato, Gian Marco Podda, Alessio Aghemo, Nicola Ferri, Simone Segato, Daniela Poli, Marco Paolo Donadini
The natural history of chronic hepatitis C virus (HCV) infection has changed after the introduction of direct-acting antiviral agents (DAAs). Screening programs have been ongoing to reach the World Health Organisation's goal of HCV elimination by 2030, and most infected people are eligible for treatment. Given the increased cardiovascular risk in people with HCV infection and the metabolic pathways of DAAs, it is not uncommon to face the issue of drug–drug interactions (DDIs) with antiplatelet or anticoagulant drugs. In the absence of clinical trials, we offer suggestions to deal with DDIs in case of treatment of patients with DAAs who are also receiving antiplatelet or anticoagulant drugs, based on the best available evidence from pharmacodynamics and pharmacokinetics studies in conjunction with clinical experience in the field of haemostasis and thrombosis.
{"title":"Drug–Drug Interactions Between DAAs and Anticoagulants or Antiplatelets: A Position Paper of the Italian Anticoagulation Clinics","authors":"Elisabetta Tombolini, Alessandro Squizzato, Gian Marco Podda, Alessio Aghemo, Nicola Ferri, Simone Segato, Daniela Poli, Marco Paolo Donadini","doi":"10.1111/liv.16177","DOIUrl":"10.1111/liv.16177","url":null,"abstract":"<p>The natural history of chronic hepatitis C virus (HCV) infection has changed after the introduction of direct-acting antiviral agents (DAAs). Screening programs have been ongoing to reach the World Health Organisation's goal of HCV elimination by 2030, and most infected people are eligible for treatment. Given the increased cardiovascular risk in people with HCV infection and the metabolic pathways of DAAs, it is not uncommon to face the issue of drug–drug interactions (DDIs) with antiplatelet or anticoagulant drugs. In the absence of clinical trials, we offer suggestions to deal with DDIs in case of treatment of patients with DAAs who are also receiving antiplatelet or anticoagulant drugs, based on the best available evidence from pharmacodynamics and pharmacokinetics studies in conjunction with clinical experience in the field of haemostasis and thrombosis.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906553","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}
Antonella Mannini, Mirella Pastore, Alessia Giachi, Margherita Correnti, Elena Spínola Lasso, Tiziano Lottini, Benedetta Piombanti, Ignazia Tusa, Elisabetta Rovida, Cédric Coulouarn, Jesper B. Andersen, Monika Lewinska, Claudia Campani, V. Lokesh Battula, Bin Yuan, Massimo Aureli, Emma V. Carsana, Caterina Peraldo Neia, Paola Ostano, Alessia Tani, Daniele Nosi, Anna Vanni, Laura Maggi, Luca Di Tommaso, Giuseppina Comito, Stefania Madiai, Annarosa Arcangeli, Fabio Marra, Chiara Raggi
Background & Aims
GD2, a member of the ganglioside (GS) family (sialic acid-containing glycosphingolipids), is a potential biomarker of cancer stem cells (CSC) in several tumours. However, the possible role of GD2 and its biosynthetic enzyme, GD3 synthase (GD3S), in intrahepatic cholangiocarcinoma (iCCA) has not been explored.
Methods
The stem-like subset of two iCCA cell lines was enriched by sphere culture (SPH) and compared to monolayer parental cells (MON). GS profiles were evaluated by chromatography, after feeding with radioactive sphingosine. Membrane GD2 expression was evaluated by FACS, and the expression of enzymes of GS biosynthesis was analysed by RT-qPCR. The modulation of stem features by GS was investigated in vitro and in vivo using GD3S-overexpressing cells and corroborated by global transcriptomic analysis.
Results
GS composition was markedly different comparing SPH and MON. Among complex GS, iCCA-SPH showed increased GD2 levels, in agreement with the high expression levels of GD3 and GM2/GD2 synthases. iCCA cells overexpressing GD3S had higher sphere-forming ability, invasive properties and drug resistance than parental cells. NOD/SCID mice implanted with CCLP1 cells overexpressing GD3S developed larger tumours than control cells. By global transcriptomic analysis, ontology investigation identified 74 processes shared by the iCCA-SPH and GD3S-transfected cells, with enrichment for development and morphogenesis processes, MAPK signalling and locomotion. In a cohort of patients with iCCA, GD3S expression was correlated with lymph node invasion, indicating a possible relevance of GD3S in the clinical setting.
Conclusions
The profile of GS derivatives regulates the stem-like properties of iCCA cells.
{"title":"Ganglioside GD2 Contributes to a Stem-Like Phenotype in Intrahepatic Cholangiocarcinoma","authors":"Antonella Mannini, Mirella Pastore, Alessia Giachi, Margherita Correnti, Elena Spínola Lasso, Tiziano Lottini, Benedetta Piombanti, Ignazia Tusa, Elisabetta Rovida, Cédric Coulouarn, Jesper B. Andersen, Monika Lewinska, Claudia Campani, V. Lokesh Battula, Bin Yuan, Massimo Aureli, Emma V. Carsana, Caterina Peraldo Neia, Paola Ostano, Alessia Tani, Daniele Nosi, Anna Vanni, Laura Maggi, Luca Di Tommaso, Giuseppina Comito, Stefania Madiai, Annarosa Arcangeli, Fabio Marra, Chiara Raggi","doi":"10.1111/liv.16208","DOIUrl":"10.1111/liv.16208","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background & Aims</h3>\u0000 \u0000 <p>GD2, a member of the ganglioside (GS) family (sialic acid-containing glycosphingolipids), is a potential biomarker of cancer stem cells (CSC) in several tumours. However, the possible role of GD2 and its biosynthetic enzyme, GD3 synthase (GD3S), in intrahepatic cholangiocarcinoma (iCCA) has not been explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The stem-like subset of two iCCA cell lines was enriched by sphere culture (SPH) and compared to monolayer parental cells (MON). GS profiles were evaluated by chromatography, after feeding with radioactive sphingosine. Membrane GD2 expression was evaluated by FACS, and the expression of enzymes of GS biosynthesis was analysed by RT-qPCR. The modulation of stem features by GS was investigated in vitro and in vivo using GD3S-overexpressing cells and corroborated by global transcriptomic analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GS composition was markedly different comparing SPH and MON. Among complex GS, iCCA-SPH showed increased GD2 levels, in agreement with the high expression levels of GD3 and GM2/GD2 synthases. iCCA cells overexpressing GD3S had higher sphere-forming ability, invasive properties and drug resistance than parental cells. NOD/SCID mice implanted with CCLP1 cells overexpressing GD3S developed larger tumours than control cells. By global transcriptomic analysis, ontology investigation identified 74 processes shared by the iCCA-SPH and GD3S-transfected cells, with enrichment for development and morphogenesis processes, MAPK signalling and locomotion. In a cohort of patients with iCCA, GD3S expression was correlated with lymph node invasion, indicating a possible relevance of GD3S in the clinical setting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The profile of GS derivatives regulates the stem-like properties of iCCA cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895645","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":"Reply to Yu and Chen","authors":"Simon J. Hume, Holmes, Alexander J. Thompson","doi":"10.1111/liv.16217","DOIUrl":"10.1111/liv.16217","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895662","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}
Alessandro Mantovani, Riccardo Morandin, Elena Sani, Veronica Fiorio, Emigela Shtembari, Stefano Bonapace, Salvatore Petta, Stergios A. Polyzos, Christopher D. Byrne, Giovanni Targher
Background
Studies have reported an association between metabolic dysfunction-associated steatotic liver disease (MASLD) and an increased risk of developing atrial fibrillation (AF). However, the magnitude of the risk and whether this risk varies with the severity of MASLD remains uncertain.
Methods
In this systematic review and meta-analysis, we searched three large electronic databases using predefined keywords to identify cohort studies (published up to 30 September 2024) in which MASLD was diagnosed by liver biopsy, imaging methods, International Classification of Diseases (ICD) codes, or blood-based scores. The primary outcome was the occurrence of AF based on ICD codes, medical records, or electrocardiograms. Meta-analysis was performed using random-effects modelling.
Results
We identified 16 retrospective cohort studies with aggregate data on ~19.5 million individuals followed for a median of 7.2 years. MASLD was significantly associated with an increased risk of developing incident AF (random-effects hazard ratio 1.20, 95% CI 1.10–1.32; I2 = 92%). This risk did not appear to further increase with the severity of liver fibrosis (n = 3 studies; random-effects hazard ratio 1.22, 95% CI 1.18–1.26; I2 = 10%). The risk of AF remained significant even after adjusting for age, sex, body mass index, hypertension, Type 2 diabetes or other cardiometabolic risk factors. Sensitivity analyses did not modify these findings. The funnel plot and Egger's test showed no significant publication bias.
Conclusions
This updated and comprehensive meta-analysis provides evidence that MASLD is significantly associated with an increased long-term risk of developing incident AF. Further research is required to better decipher the link between MASLD and increased AF incidence.
背景：研究报道了代谢功能障碍相关的脂肪变性肝病（MASLD）与发生心房颤动（AF）的风险增加之间的关联。然而，风险的大小以及这种风险是否随MASLD的严重程度而变化仍然不确定。方法：在这项系统评价和荟萃分析中，我们使用预定义的关键词检索了三个大型电子数据库，以确定通过肝活检、成像方法、国际疾病分类（ICD）代码或血液评分诊断MASLD的队列研究（发表于2024年9月30日之前）。主要结局是基于ICD编码、医疗记录或心电图的房颤发生情况。采用随机效应模型进行meta分析。结果：我们确定了16项回顾性队列研究，总数据约1950万人，随访时间中位数为7.2年。MASLD与发生AF事件的风险增加显著相关(随机效应风险比1.20,95% CI 1.10-1.32；i2 = 92%)。这种风险似乎没有随着肝纤维化的严重程度而进一步增加(n = 3项研究；随机效应风险比1.22,95% CI 1.18-1.26；i2 = 10%)。即使在调整了年龄、性别、体重指数、高血压、2型糖尿病或其他心脏代谢危险因素后，发生房颤的风险仍然显著。敏感性分析没有改变这些发现。漏斗图和Egger检验均未显示显著的发表偏倚。结论：这项最新的综合荟萃分析提供了证据，表明MASLD与发生事件性房颤的长期风险增加显著相关。需要进一步的研究来更好地解读MASLD与房颤发病率增加之间的联系。
{"title":"MASLD Is Associated With an Increased Long-Term Risk of Atrial Fibrillation: An Updated Systematic Review and Meta-Analysis","authors":"Alessandro Mantovani, Riccardo Morandin, Elena Sani, Veronica Fiorio, Emigela Shtembari, Stefano Bonapace, Salvatore Petta, Stergios A. Polyzos, Christopher D. Byrne, Giovanni Targher","doi":"10.1111/liv.16218","DOIUrl":"10.1111/liv.16218","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Studies have reported an association between metabolic dysfunction-associated steatotic liver disease (MASLD) and an increased risk of developing atrial fibrillation (AF). However, the magnitude of the risk and whether this risk varies with the severity of MASLD remains uncertain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this systematic review and meta-analysis, we searched three large electronic databases using predefined keywords to identify cohort studies (published up to 30 September 2024) in which MASLD was diagnosed by liver biopsy, imaging methods, International Classification of Diseases (ICD) codes, or blood-based scores. The primary outcome was the occurrence of AF based on ICD codes, medical records, or electrocardiograms. Meta-analysis was performed using random-effects modelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified 16 retrospective cohort studies with aggregate data on ~19.5 million individuals followed for a median of 7.2 years. MASLD was significantly associated with an increased risk of developing incident AF (random-effects hazard ratio 1.20, 95% CI 1.10–1.32; <i>I</i><sup><i>2</i></sup> = 92%). This risk did not appear to further increase with the severity of liver fibrosis (<i>n</i> = 3 studies; random-effects hazard ratio 1.22, 95% CI 1.18–1.26; <i>I</i><sup><i>2</i></sup> = 10%). The risk of AF remained significant even after adjusting for age, sex, body mass index, hypertension, Type 2 diabetes or other cardiometabolic risk factors. Sensitivity analyses did not modify these findings. The funnel plot and Egger's test showed no significant publication bias.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This updated and comprehensive meta-analysis provides evidence that MASLD is significantly associated with an increased long-term risk of developing incident AF. Further research is required to better decipher the link between MASLD and increased AF incidence.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886008","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}
Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection.
Aims
To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development.
Materials and Methods
We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy.
Results
We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention.
Conclusion
Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.
{"title":"HBV-Induced Carcinogenesis: Mechanisms, Correlation With Viral Suppression, and Implications for Treatment","authors":"Thomas Tu, Thomas J. McQuaid, Ira M. Jacobson","doi":"10.1111/liv.16202","DOIUrl":"10.1111/liv.16202","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886005","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}
Edoardo G. Giannini, Andrea Pasta, Francesco Calabrese, Sara Labanca, Simona Marenco, Giulia Pieri, Maria Corina Plaz Torres, Mario Strazzabosco
Background & Aims
Approximately 40% of patients with Primary Biliary Cholangitis (PBC) show incomplete response to ursodeoxycholic acid, thus needing second-line treatment to prevent disease progression. As no head-to-head comparison study is available, we used a network meta-analysis (NMA) to compare efficacy and safety of available second-line therapies.
Methods
We performed a systematic literature review including randomised, placebo-controlled trials of patients with PBC and incomplete response, or intolerance, to ursodeoxycholic acid, and compared relative risks (RRs) for primary (biochemical response at 52-week) and secondary outcomes [incidence of new-onset pruritus and serious adverse events (SAEs)].
Results
The NMA included three studies, each testing obeticholic acid (OCA), seladelpar or elafibranor versus placebo (active therapy/placebo: 379/191 patients). All treatments significantly increased the RR for biochemical response with an advantage of elafibranor versus seladelpar (RR: 4.37, 95% CI: 1.01–18.87). OCA 5–10 mg/10 mg was associated with a higher risk of new-onset pruritus compared to placebo (RR: 1.43; 95% CI: 1.09–1.88/RR: 1.79; 95% CI: 1.37–2.33), while seladelpar decreased this risk (RR: 0.30; 95% CI: 0.12–0.80). Compared to placebo, OCA 5–10 mg/10 mg was associated with an increased risk of SAE (RR: 3.82; 95% CI: 1.46–10.02/RR 2.67; 95% CI: 1.00–7.08).
Conclusions
Among second line therapies for patients with PBC, elafibranor is slightly more effective in obtaining biochemical response than seladelpar that, on the other hand, is the only drug associated with a lower incidence of pruritus. While of similar efficacy, OCA was associated with increased pruritus and SAEs. These findings may help personalise second-line treatment in patients with PBC.
{"title":"Second-Line Treatment for Patients With Primary Biliary Cholangitis: A Systematic Review With Network Meta-Analysis","authors":"Edoardo G. Giannini, Andrea Pasta, Francesco Calabrese, Sara Labanca, Simona Marenco, Giulia Pieri, Maria Corina Plaz Torres, Mario Strazzabosco","doi":"10.1111/liv.16222","DOIUrl":"10.1111/liv.16222","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background & Aims</h3>\u0000 \u0000 <p>Approximately 40% of patients with Primary Biliary Cholangitis (PBC) show incomplete response to ursodeoxycholic acid, thus needing second-line treatment to prevent disease progression. As no head-to-head comparison study is available, we used a network meta-analysis (NMA) to compare efficacy and safety of available second-line therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a systematic literature review including randomised, placebo-controlled trials of patients with PBC and incomplete response, or intolerance, to ursodeoxycholic acid, and compared relative risks (RRs) for primary (biochemical response at 52-week) and secondary outcomes [incidence of new-onset pruritus and serious adverse events (SAEs)].</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The NMA included three studies, each testing obeticholic acid (OCA), seladelpar or elafibranor versus placebo (active therapy/placebo: 379/191 patients). All treatments significantly increased the RR for biochemical response with an advantage of elafibranor versus seladelpar (RR: 4.37, 95% CI: 1.01–18.87). OCA 5–10 mg/10 mg was associated with a higher risk of new-onset pruritus compared to placebo (RR: 1.43; 95% CI: 1.09–1.88/RR: 1.79; 95% CI: 1.37–2.33), while seladelpar decreased this risk (RR: 0.30; 95% CI: 0.12–0.80). Compared to placebo, OCA 5–10 mg/10 mg was associated with an increased risk of SAE (RR: 3.82; 95% CI: 1.46–10.02/RR 2.67; 95% CI: 1.00–7.08).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Among second line therapies for patients with PBC, elafibranor is slightly more effective in obtaining biochemical response than seladelpar that, on the other hand, is the only drug associated with a lower incidence of pruritus. While of similar efficacy, OCA was associated with increased pruritus and SAEs. These findings may help personalise second-line treatment in patients with PBC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886012","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}
Iyiad Alabdul Razzak, Ahmed Fares, Jonathan G. Stine, Hirsh D. Trivedi
Background
The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), parallels the rise in sedentary lifestyles. MASLD is the most common form of steatotic liver disease (SLD), which represents the umbrella beneath which the vast majority of chronic liver diseases fall, including alcohol-related liver disease and their overlap. These conditions are the leading contributors to chronic liver disease, significantly impacting global morbidity and mortality. Despite the emergence of new pharmacotherapies, exercise represents the foundation of MASLD treatment.
Objective
This review aims to provide an updated perspective on the role of exercise in the management of SLD, highlight its molecular and clinical benefits, and explore its benefits and safety in the stage of cirrhosis.
Methods
Evidence from pre-clinical and clinical studies was reviewed to evaluate the impact of exercise on SLD (mainly MASLD), advanced chronic liver disease stages, and its relevance in the context of evolving therapies such as Resmetirom and incretin-based anti-obesity medications.
Conclusion
Exercise remains a cornerstone intervention in the management of MASLD, with suggested benefits even for patients who have progressed to cirrhosis. Personalized exercise regimens should be prioritized for all patients, including those receiving pharmacotherapy. Further research is needed to refine exercise protocols and investigate their impact on histologic and clinical outcomes, as well as their potential synergistic effects with emerging treatments.
{"title":"The Role of Exercise in Steatotic Liver Diseases: An Updated Perspective","authors":"Iyiad Alabdul Razzak, Ahmed Fares, Jonathan G. Stine, Hirsh D. Trivedi","doi":"10.1111/liv.16220","DOIUrl":"10.1111/liv.16220","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), parallels the rise in sedentary lifestyles. MASLD is the most common form of steatotic liver disease (SLD), which represents the umbrella beneath which the vast majority of chronic liver diseases fall, including alcohol-related liver disease and their overlap. These conditions are the leading contributors to chronic liver disease, significantly impacting global morbidity and mortality. Despite the emergence of new pharmacotherapies, exercise represents the foundation of MASLD treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This review aims to provide an updated perspective on the role of exercise in the management of SLD, highlight its molecular and clinical benefits, and explore its benefits and safety in the stage of cirrhosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Evidence from pre-clinical and clinical studies was reviewed to evaluate the impact of exercise on SLD (mainly MASLD), advanced chronic liver disease stages, and its relevance in the context of evolving therapies such as Resmetirom and incretin-based anti-obesity medications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Exercise remains a cornerstone intervention in the management of MASLD, with suggested benefits even for patients who have progressed to cirrhosis. Personalized exercise regimens should be prioritized for all patients, including those receiving pharmacotherapy. Further research is needed to refine exercise protocols and investigate their impact on histologic and clinical outcomes, as well as their potential synergistic effects with emerging treatments.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.16220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885974","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}
Racial/ethnic disparities have been previously reported in renal and hepatic disease care; however, acute kidney injury (AKI) in the setting of cirrhosis (hepatorenal syndrome [HRS]-AKI) despite its complexity requiring a multidisciplinary approach, remains understudied.
Methods
To identify unique associations of clinical and sociodemographic factors with mortality and length of stay (LOS) among patients hospitalised with HRS-AKI, hierarchical regression analysis was conducted, along with a mediation analysis to estimate how race-related differences in in-hospital mortality were influenced by payer type, area household income, and clinical severity.
Results
Black patients demonstrated a significantly higher odds of in-hospital mortality, compared to their white counterparts, adjusting for (1) sex and age, (2) sex, age, payer type, and area household income and (3) sex, age, and clinical severity [OR 1.16–1.20, 95% confidence intervals (CI) > 1]. Higher mortality rates among Black patients were partially mediated by clinical severity and area household income [proportion mediated (PM): 0.1890.190.192 and 0.160.170.18, respectively]. Black patients with HRS-AKI had longer LOS than White patients. Hispanic patients tended to have lower odds of in-hospital mortality [OR: 0.770.860.97] despite their lower income and more severe illness.
Conclusion
Our nationwide US study demonstrated that, partly due to higher clinical severity and lower household income, Black patients with HRS-AKI experience higher inpatient mortality, compared to White patients. On the other hand, Hispanics with HRS-AKI have a survival advantage. More awareness is warranted to address racial disparities in HRS-AKI outcomes.
{"title":"The Association of Race With Outcomes in Hospitalised Patients With Hepatorenal Syndrome: Nationwide Cohort Study","authors":"Shahana Prakash, Mark Vander Weg, Tomohiro Tanaka","doi":"10.1111/liv.16226","DOIUrl":"10.1111/liv.16226","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Racial/ethnic disparities have been previously reported in renal and hepatic disease care; however, acute kidney injury (AKI) in the setting of cirrhosis (hepatorenal syndrome [HRS]-AKI) despite its complexity requiring a multidisciplinary approach, remains understudied.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To identify unique associations of clinical and sociodemographic factors with mortality and length of stay (LOS) among patients hospitalised with HRS-AKI, hierarchical regression analysis was conducted, along with a mediation analysis to estimate how race-related differences in in-hospital mortality were influenced by payer type, area household income, and clinical severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Black patients demonstrated a significantly higher odds of in-hospital mortality, compared to their white counterparts, adjusting for (1) sex and age, (2) sex, age, payer type, and area household income and (3) sex, age, and clinical severity [OR 1.16–1.20, 95% confidence intervals (CI) > 1]. Higher mortality rates among Black patients were partially mediated by clinical severity and area household income [proportion mediated (PM): <sub>0.189</sub>0.19<sub>0.192</sub> and <sub>0.16</sub>0.17<sub>0.18</sub>, respectively]. Black patients with HRS-AKI had longer LOS than White patients. Hispanic patients tended to have lower odds of in-hospital mortality [OR: <sub>0.77</sub>0.86<sub>0.97</sub>] despite their lower income and more severe illness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our nationwide US study demonstrated that, partly due to higher clinical severity and lower household income, Black patients with HRS-AKI experience higher inpatient mortality, compared to White patients. On the other hand, Hispanics with HRS-AKI have a survival advantage. More awareness is warranted to address racial disparities in HRS-AKI outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11669052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886016","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}
Ana Virseda-Berdices, Rubén Martín-Escolano, Juan Berenguer, Juan González-García, Oscar Brochado-Kith, David Rojo, Cristina Díez, Víctor Hontañon, Leire Pérez-Latorre, Luis Ibañez-Samaniego, Elba Llop-Herrera, Antonio Olveira, Amanda Fernández-Rodríguez, Coral Barbas, Salvador Resino, María Ángeles Jiménez-Sousa, the ESCORIAL Study Group
Background and Aims
In response to direct-acting antivirals (DAAs) therapy, patients who experience a decrease in hepatic venous pressure gradient (HVPG) considerably reduce liver complications and have increased survival. This study aimed to assess the metabolomic changes associated with the changes in HVPG from the start of DAA therapy until 48 weeks after effective DAA therapy in patients with advanced HCV-related cirrhosis.
Methods
We carried out a multicenter longitudinal study in 31 patients with advanced hepatitis C virus (HCV)-related cirrhosis. We performed a non-targeted metabolomic analysis using gas chromatography–mass spectrometry and liquid chromatography-mass spectrometry, as well as analysis of inflammation-related biomarkers using Luminex technology. The statistical analysis was performed by Generalised Linear Mixed-effects Models (GLMM), correcting for multiple testing.
Results
We found that increases of 2,3-butanediol (AMR = 1.15; q-value = 0.023) and taurocholic acid (AMR = 1.06; q-value < 0.001) were significantly associated with increases in HVPG and inflammatory biomarker levels from before DAA therapy to one year after completion of successful HCV treatment.
Conclusions
These metabolites have a potential role as indicators of portal hypertension evolution.
{"title":"Metabolomic Changes Associated With the Change in HVPG After DAAs Therapy in HCV Cirrhotic Patients","authors":"Ana Virseda-Berdices, Rubén Martín-Escolano, Juan Berenguer, Juan González-García, Oscar Brochado-Kith, David Rojo, Cristina Díez, Víctor Hontañon, Leire Pérez-Latorre, Luis Ibañez-Samaniego, Elba Llop-Herrera, Antonio Olveira, Amanda Fernández-Rodríguez, Coral Barbas, Salvador Resino, María Ángeles Jiménez-Sousa, the ESCORIAL Study Group","doi":"10.1111/liv.16204","DOIUrl":"10.1111/liv.16204","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>In response to direct-acting antivirals (DAAs) therapy, patients who experience a decrease in hepatic venous pressure gradient (HVPG) considerably reduce liver complications and have increased survival. This study aimed to assess the metabolomic changes associated with the changes in HVPG from the start of DAA therapy until 48 weeks after effective DAA therapy in patients with advanced HCV-related cirrhosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We carried out a multicenter longitudinal study in 31 patients with advanced hepatitis C virus (HCV)-related cirrhosis. We performed a non-targeted metabolomic analysis using gas chromatography–mass spectrometry and liquid chromatography-mass spectrometry, as well as analysis of inflammation-related biomarkers using Luminex technology. The statistical analysis was performed by Generalised Linear Mixed-effects Models (GLMM), correcting for multiple testing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that increases of 2,3-butanediol (AMR = 1.15; <i>q</i>-value = 0.023) and taurocholic acid (AMR = 1.06; <i>q</i>-value < 0.001) were significantly associated with increases in HVPG and inflammatory biomarker levels from before DAA therapy to one year after completion of successful HCV treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These metabolites have a potential role as indicators of portal hypertension evolution.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872356","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}
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