Piotr Chodup, Sophia L Samodelov, Michele Visentin, Gerd A Kullak-Ublick
Targeted therapies and immunotherapies have shown great promise as best-in-class treatments for several cancers with respect to efficacy and safety. While liver test abnormalities are rather common in patients treated with kinase inhibitors or immunotherapy, events of severe hepatotoxicity in these patients are rare in comparison with those associated with chemotherapeutics. The underlying mechanisms and risk factors for severe hepatotoxicity with novel oncology therapies are not well understood, complicating the drug-induced liver injury (DILI) risk assessment in the preclinical and clinical phases of drug development. The epidemiological and clinical characteristics, as well as mechanisms of liver toxicity, are described here to the current state of knowledge. Tools to study and assess the risk of DILI during drug development are concisely summarised, focusing on caveats thereof for novel oncology treatments. Emerging tools to optimise safety assessments and gather additional mechanistic insights into DILI are introduced. Particularly in oncology, where standard liver signals during drug development are tolerated to a marginally higher degree than in other indications due to the life-saving, life-extending and quality-of-life improvements for patients with severe or advanced cancers versus previous standard-of-care therapeutics, safety assessments must be tailored to the drug and indication. Trends in patient safety-centred drug development programmes and regulatory approval processes must continually be revisited and streamlined via obtaining an overall greater understanding of DILI and the tools available to assess mechanisms of injury, frequency, severity and prognosis.
{"title":"Drug-Induced Liver Injury Associated With Emerging Cancer Therapies.","authors":"Piotr Chodup, Sophia L Samodelov, Michele Visentin, Gerd A Kullak-Ublick","doi":"10.1111/liv.70002","DOIUrl":"10.1111/liv.70002","url":null,"abstract":"<p><p>Targeted therapies and immunotherapies have shown great promise as best-in-class treatments for several cancers with respect to efficacy and safety. While liver test abnormalities are rather common in patients treated with kinase inhibitors or immunotherapy, events of severe hepatotoxicity in these patients are rare in comparison with those associated with chemotherapeutics. The underlying mechanisms and risk factors for severe hepatotoxicity with novel oncology therapies are not well understood, complicating the drug-induced liver injury (DILI) risk assessment in the preclinical and clinical phases of drug development. The epidemiological and clinical characteristics, as well as mechanisms of liver toxicity, are described here to the current state of knowledge. Tools to study and assess the risk of DILI during drug development are concisely summarised, focusing on caveats thereof for novel oncology treatments. Emerging tools to optimise safety assessments and gather additional mechanistic insights into DILI are introduced. Particularly in oncology, where standard liver signals during drug development are tolerated to a marginally higher degree than in other indications due to the life-saving, life-extending and quality-of-life improvements for patients with severe or advanced cancers versus previous standard-of-care therapeutics, safety assessments must be tailored to the drug and indication. Trends in patient safety-centred drug development programmes and regulatory approval processes must continually be revisited and streamlined via obtaining an overall greater understanding of DILI and the tools available to assess mechanisms of injury, frequency, severity and prognosis.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e70002"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033384","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}
Imante Lasyte, Linnea Widman, Annika Bergquist, Hannes Hagström
Background/aims: Epidemiological data on mortality in autoimmune liver diseases (AILDs) are scarce. We examined all-cause and cancer-related mortality in individuals with AILD from Sweden.
Methods: We identified 9654 individuals with AILD (3342 with autoimmune hepatitis (AIH), 3751 with primary biliary cholangitis (PBC), and 2561 with primary sclerosing cholangitis (PSC)) using national Swedish registries between 2001 and 2020. These were matched with 80 685 comparators from the general population at a ratio of 1:10 on age, sex, year of diagnosis and municipality. Rates of outcomes were estimated using Cox regression models, adjusted for matching factors and cardiovascular disease, diabetes, inflammatory bowel disease, chronic obstructive pulmonary disease, and education.
Results: Individuals with AILD had higher mortality than comparators (adjusted hazard ratio (aHR) = 2.3, 95% CI = 2.2-2.4) and higher rates of cancer-related death (aHR = 2.1, 95% CI = 1.9-2.3). The presence of liver cirrhosis in AILD was related to even higher mortality, with aHR 5.8 (95% CI = 5.1-6.6). Both males and females with AILD had increased mortality (males aHR = 2.6, 95% CI = 2.4-3.0, and females aHR = 2.2, 95% CI = 2.1-2.3). The mortality was higher in individuals aged 18-50 years (aHR = 4.6, 95% CI = 3.6-5.8), than in individuals above 50 years (aHR = 2.2, 95% CI = 2.1-2.3). Overall mortality rates and cancer-related death were particularly high in individuals with PSC compared to their matched comparators, with aHR = 4.1 (95% CI = 3.2-5.2) and aHR = 6.4 (95% CI = 4.0-10.3), respectively.
Conclusions: Patients with AILDs have increased rates of overall and cancer-related mortality compared to matched comparators, and relative risks are highest in cirrhosis, younger age and PSC.
背景/目的:关于自身免疫性肝病(AILDs)死亡率的流行病学数据很少。我们研究了瑞典AILD患者的全因死亡率和癌症相关死亡率。方法:我们在2001年至2020年期间通过瑞典国家登记处确定了9654例AILD患者(3342例自身免疫性肝炎(AIH), 3751例原发性胆道炎(PBC), 2561例原发性硬化性胆管炎(PSC))。按年龄、性别、诊断年份和所在城市按1:10的比例与普通人群中的80685名比较者进行匹配。使用Cox回归模型估计结局率,并根据心血管疾病、糖尿病、炎症性肠病、慢性阻塞性肺病和教育等匹配因素进行调整。结果:与比较组相比,AILD患者的死亡率更高(校正危险比(aHR) = 2.3, 95% CI = 2.2-2.4),癌症相关死亡率更高(aHR = 2.1, 95% CI = 1.9-2.3)。肝硬化的存在与更高的死亡率相关,aHR为5.8 (95% CI = 5.1-6.6)。患有AILD的男性和女性死亡率均增加(男性aHR = 2.6, 95% CI = 2.4-3.0,女性aHR = 2.2, 95% CI = 2.1-2.3)。18-50岁人群的死亡率(aHR = 4.6, 95% CI = 3.6-5.8)高于50岁以上人群(aHR = 2.2, 95% CI = 2.1-2.3)。与匹配的比较组相比,PSC患者的总死亡率和癌症相关死亡率特别高,aHR分别为4.1 (95% CI = 3.2-5.2)和6.4 (95% CI = 4.0-10.3)。结论:与匹配的比较者相比,aild患者的总体死亡率和癌症相关死亡率增加,肝硬化、年轻和PSC患者的相对风险最高。
{"title":"Mortality in Autoimmune Liver Disease in Sweden: A Population-Based Cohort Study of 9,654 Patients.","authors":"Imante Lasyte, Linnea Widman, Annika Bergquist, Hannes Hagström","doi":"10.1111/liv.70007","DOIUrl":"10.1111/liv.70007","url":null,"abstract":"<p><strong>Background/aims: </strong>Epidemiological data on mortality in autoimmune liver diseases (AILDs) are scarce. We examined all-cause and cancer-related mortality in individuals with AILD from Sweden.</p><p><strong>Methods: </strong>We identified 9654 individuals with AILD (3342 with autoimmune hepatitis (AIH), 3751 with primary biliary cholangitis (PBC), and 2561 with primary sclerosing cholangitis (PSC)) using national Swedish registries between 2001 and 2020. These were matched with 80 685 comparators from the general population at a ratio of 1:10 on age, sex, year of diagnosis and municipality. Rates of outcomes were estimated using Cox regression models, adjusted for matching factors and cardiovascular disease, diabetes, inflammatory bowel disease, chronic obstructive pulmonary disease, and education.</p><p><strong>Results: </strong>Individuals with AILD had higher mortality than comparators (adjusted hazard ratio (aHR) = 2.3, 95% CI = 2.2-2.4) and higher rates of cancer-related death (aHR = 2.1, 95% CI = 1.9-2.3). The presence of liver cirrhosis in AILD was related to even higher mortality, with aHR 5.8 (95% CI = 5.1-6.6). Both males and females with AILD had increased mortality (males aHR = 2.6, 95% CI = 2.4-3.0, and females aHR = 2.2, 95% CI = 2.1-2.3). The mortality was higher in individuals aged 18-50 years (aHR = 4.6, 95% CI = 3.6-5.8), than in individuals above 50 years (aHR = 2.2, 95% CI = 2.1-2.3). Overall mortality rates and cancer-related death were particularly high in individuals with PSC compared to their matched comparators, with aHR = 4.1 (95% CI = 3.2-5.2) and aHR = 6.4 (95% CI = 4.0-10.3), respectively.</p><p><strong>Conclusions: </strong>Patients with AILDs have increased rates of overall and cancer-related mortality compared to matched comparators, and relative risks are highest in cirrhosis, younger age and PSC.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e70007"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007987","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}
Lisa Sandmann, Valerie Ohlendorf, Alena Ehrenbauer, Birgit Bremer, Anke R M Kraft, Markus Cornberg, Katja Deterding, Heiner Wedemeyer, Benjamin Maasoumy
Background and aims: Chronic hepatitis D virus (HDV) infection can cause severe liver disease. With new treatment options available, it is important to identify patients at risk for liver-related complications. We aimed to investigate kinetics and predictive values of novel virological and immunological markers in the natural course of chronic HDV infection.
Methods: HBcrAg, HBV RNA and quantitative anti-HBc were analysed in samples from HDV-infected patients at three consecutive time points. Results were linked to clinical outcome by univariable and multivariable analyses. Primary endpoint was the composite endpoint of any liver-related event.
Results: Samples from 190 individual patients were analysed with a median clinical follow-up time of 2.69 (IQR 1.13-6.51) years. The majority of patients had cirrhosis (98/190, 52%), and the primary endpoint occurred in 33% (62/190). In univariable analysis, age, cirrhosis, lower quantitative anti-HBc, higher ratio of HBcrAg/anti-HBc and detectable HDV RNA were associated with the primary endpoint. In multivariable analysis, only the presence of liver cirrhosis (HR 7.74, p < 0.001) and age (1.06, p < 0.001) remained independently associated with the primary endpoint. Kinetics of virological parameters during follow-up were similar between the groups. Quantitative anti-HBc was significantly lower in patients with liver cirrhosis (687 (IQR 188-3388) IU/ml vs. 309 (IQR 82-924) IU/ml, p < 0.0004), and lower levels were independently associated with the development of the primary endpoint (HR 1.0, p = 0.014).
Conclusion: In chronic HDV infection, neither baseline values nor kinetics of HBV RNA, HBcrAg and anti-HBc were independently associated with clinical outcome, while stage of liver disease and age were predictors of liver-related events.
{"title":"Value and Kinetics of Virological Markers in the Natural Course of Chronic Hepatitis D Virus Infection.","authors":"Lisa Sandmann, Valerie Ohlendorf, Alena Ehrenbauer, Birgit Bremer, Anke R M Kraft, Markus Cornberg, Katja Deterding, Heiner Wedemeyer, Benjamin Maasoumy","doi":"10.1111/liv.70003","DOIUrl":"10.1111/liv.70003","url":null,"abstract":"<p><strong>Background and aims: </strong>Chronic hepatitis D virus (HDV) infection can cause severe liver disease. With new treatment options available, it is important to identify patients at risk for liver-related complications. We aimed to investigate kinetics and predictive values of novel virological and immunological markers in the natural course of chronic HDV infection.</p><p><strong>Methods: </strong>HBcrAg, HBV RNA and quantitative anti-HBc were analysed in samples from HDV-infected patients at three consecutive time points. Results were linked to clinical outcome by univariable and multivariable analyses. Primary endpoint was the composite endpoint of any liver-related event.</p><p><strong>Results: </strong>Samples from 190 individual patients were analysed with a median clinical follow-up time of 2.69 (IQR 1.13-6.51) years. The majority of patients had cirrhosis (98/190, 52%), and the primary endpoint occurred in 33% (62/190). In univariable analysis, age, cirrhosis, lower quantitative anti-HBc, higher ratio of HBcrAg/anti-HBc and detectable HDV RNA were associated with the primary endpoint. In multivariable analysis, only the presence of liver cirrhosis (HR 7.74, p < 0.001) and age (1.06, p < 0.001) remained independently associated with the primary endpoint. Kinetics of virological parameters during follow-up were similar between the groups. Quantitative anti-HBc was significantly lower in patients with liver cirrhosis (687 (IQR 188-3388) IU/ml vs. 309 (IQR 82-924) IU/ml, p < 0.0004), and lower levels were independently associated with the development of the primary endpoint (HR 1.0, p = 0.014).</p><p><strong>Conclusion: </strong>In chronic HDV infection, neither baseline values nor kinetics of HBV RNA, HBcrAg and anti-HBc were independently associated with clinical outcome, while stage of liver disease and age were predictors of liver-related events.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e70003"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024066","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}
Michael J Nash, Evgenia Dobrinskikh, Saif I Al-Juboori, Rachel C Janssen, Jolyn Fernandes, Amy Argabright, Angelo D'Alessandro, Melissa A Kirigiti, Paul Kievit, Kjersti M Aagaard, Carrie E McCurdy, Maureen Gannon, Kenneth L Jones, Tiangang Li, Jacob E Friedman, Stephanie R Wesolowski
Background and aims: Maternal obesity increases the risk of the paediatric form of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting up to 30% of youth, but the developmental origins remain poorly understood.
Methods: Using a Japanese macaque model, we investigated the impact of maternal Western-style diet (mWSD) or chow diet followed by postweaning WSD (pwWSD) or chow diet focusing on bile acid (BA) homeostasis and hepatic fibrosis in livers from third-trimester fetuses and 3-year-old juvenile offspring.
Results: Juveniles exposed to mWSD had increased hepatic collagen I/III content and stellate cell activation in portal regions. mWSD increased transcriptional signatures of FXR activation, while pwWSD impaired FXR pathway genes and increased liver BA content. Both mWSD and pwWSD increased serum BA concentrations. Notably, mWSD-exposed juvenile offspring had increased periportal CK19 expression and cholangiocyte gene expression supporting proliferation compared with maternal chow-exposed offspring. Fetuses exposed to mWSD had increased CK19 expression and hepatic BAs which correlated positively with periportal collagen deposition and negatively with markers of fetal oxygenation. In juvenile offspring, increased serum BAs correlated positively with hepatic oxidative stress and portal fibrosis without elevated liver enzymes.
Conclusions: mWSD is associated with hallmarks of paediatric MASLD including portal bile ductular reaction, portal fibrosis and dysregulated BA homeostasis. These conditions begin in utero and persist in juvenile offspring regardless of their postweaning diet. These findings implicate changes in BA metabolism that may drive developmental programming of MASLD in juvenile offspring beginning in utero.
{"title":"Maternal Western Diet Programmes Bile Acid Dysregulation and Hepatic Fibrosis in Fetal and Juvenile Macaques.","authors":"Michael J Nash, Evgenia Dobrinskikh, Saif I Al-Juboori, Rachel C Janssen, Jolyn Fernandes, Amy Argabright, Angelo D'Alessandro, Melissa A Kirigiti, Paul Kievit, Kjersti M Aagaard, Carrie E McCurdy, Maureen Gannon, Kenneth L Jones, Tiangang Li, Jacob E Friedman, Stephanie R Wesolowski","doi":"10.1111/liv.16236","DOIUrl":"10.1111/liv.16236","url":null,"abstract":"<p><strong>Background and aims: </strong>Maternal obesity increases the risk of the paediatric form of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting up to 30% of youth, but the developmental origins remain poorly understood.</p><p><strong>Methods: </strong>Using a Japanese macaque model, we investigated the impact of maternal Western-style diet (mWSD) or chow diet followed by postweaning WSD (pwWSD) or chow diet focusing on bile acid (BA) homeostasis and hepatic fibrosis in livers from third-trimester fetuses and 3-year-old juvenile offspring.</p><p><strong>Results: </strong>Juveniles exposed to mWSD had increased hepatic collagen I/III content and stellate cell activation in portal regions. mWSD increased transcriptional signatures of FXR activation, while pwWSD impaired FXR pathway genes and increased liver BA content. Both mWSD and pwWSD increased serum BA concentrations. Notably, mWSD-exposed juvenile offspring had increased periportal CK19 expression and cholangiocyte gene expression supporting proliferation compared with maternal chow-exposed offspring. Fetuses exposed to mWSD had increased CK19 expression and hepatic BAs which correlated positively with periportal collagen deposition and negatively with markers of fetal oxygenation. In juvenile offspring, increased serum BAs correlated positively with hepatic oxidative stress and portal fibrosis without elevated liver enzymes.</p><p><strong>Conclusions: </strong>mWSD is associated with hallmarks of paediatric MASLD including portal bile ductular reaction, portal fibrosis and dysregulated BA homeostasis. These conditions begin in utero and persist in juvenile offspring regardless of their postweaning diet. These findings implicate changes in BA metabolism that may drive developmental programming of MASLD in juvenile offspring beginning in utero.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e16236"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047216","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}
Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of hepatocellular carcinoma (HCC). In this study, we combine metabolomic and gene expression analysis to compare HCC tissues with non-tumoural tissues (NTT).
Methods: A non-targeted metabolomic strategy LC-MS was applied to 52 pairs of human MASLD-HCC and NTT separated into 2 groups according to fibrosis severity F0F1-F2 versus F3F4. The expression of genes related to de Novo lipogenesis (DNL) and fatty acid oxidation (FAO) has been analysed by quantitative RT-PCR and/or interrogation of RNA-seq datasets in 259 pairs of tissues (MASLD-HCC vs. VIRUS-HCC).
Results: Metabolomic analysis revealed that acylcarnitines were the main discriminating metabolites according to fibrosis severity when we compared MASLD-HCC-F0F1-F2 versus NTT and MASLD-HCC-F3F4 versus NTT. Based on these metabolomic data, the analysis of a panel of 15 selected genes related to DNL and FAO indicated that there is no difference between the 2 groups of MASLD-HCC. In contrast the same comparative gene analysis according to the aetiology of HCC: MASLD-HCC versus VIRUS-HCC showed that both aetiologies shared the same upregulation of genes involved in DNL. However, five genes involved in FAO (HADHA, CRAT, CPT1, CPT2 and PPARA) are upregulated exclusively in MASLD-HCC. This result indicates that FAO and DNL pathways are simultaneously activated in MASLD-HCC in contrast to VIRUS-HCC.
Conclusions: These results suggest that, the involvement of adaptive metabolic pathways is different depending on the aetiology of HCC. Moreover, the dogma that simultaneous activation of FAO and DNL is incompatible in cancer would not apply to MASLD-HCC.
背景和目的:代谢功能障碍相关的脂肪变性肝病(MASLD)是肝细胞癌(HCC)最常见的病因。在这项研究中,我们结合代谢组学和基因表达分析来比较HCC组织和非肿瘤组织(NTT)。方法:采用非靶向代谢组学策略LC-MS对52对人MASLD-HCC和NTT按纤维化严重程度分为F0F1-F2和F3F4两组。通过定量RT-PCR和/或对259对组织(MASLD-HCC vs. VIRUS-HCC)的RNA-seq数据集分析了与从头脂肪生成(DNL)和脂肪酸氧化(FAO)相关的基因表达。结果:代谢组学分析显示,当我们比较MASLD-HCC-F0F1-F2与NTT、MASLD-HCC-F3F4与NTT时,酰基肉碱是区分纤维化严重程度的主要代谢物。基于这些代谢组学数据,对15个与DNL和FAO相关的基因进行分析表明,两组MASLD-HCC之间没有差异。相反,根据HCC的病因进行相同的基因比较分析:MASLD-HCC与病毒-HCC显示,这两种病因都有相同的DNL相关基因上调。然而,参与FAO的5个基因(HADHA、CRAT、CPT1、CPT2和PPARA)在MASLD-HCC中只表达上调。这一结果表明,与病毒型hcc相比,MASLD-HCC中FAO和DNL通路同时被激活。结论:这些结果表明,适应性代谢途径的参与是不同的,取决于HCC的病因。此外,在癌症中同时激活FAO和DNL不相容的教条不适用于MASLD-HCC。
{"title":"Simultaneous Activation of Beta-Oxidation and De Novo Lipogenesis in MASLD-HCC: A New Paradigm.","authors":"Fatima Dahboul, Jihan Sun, Benjamin Buchard, Natali Abeywickrama-Samarakoon, Estelle Pujos-Guillot, Stéphanie Durand, Mélanie Petera, Delphine Centeno, Francesca Guerrieri, Massimiliano Cocca, Massimo Levrero, Adrien Rossary, Delphine Weil, Vincent Di Martino, Aicha Demidem, Armando Abergel","doi":"10.1111/liv.70006","DOIUrl":"10.1111/liv.70006","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of hepatocellular carcinoma (HCC). In this study, we combine metabolomic and gene expression analysis to compare HCC tissues with non-tumoural tissues (NTT).</p><p><strong>Methods: </strong>A non-targeted metabolomic strategy LC-MS was applied to 52 pairs of human MASLD-HCC and NTT separated into 2 groups according to fibrosis severity F0F1-F2 versus F3F4. The expression of genes related to de Novo lipogenesis (DNL) and fatty acid oxidation (FAO) has been analysed by quantitative RT-PCR and/or interrogation of RNA-seq datasets in 259 pairs of tissues (MASLD-HCC vs. VIRUS-HCC).</p><p><strong>Results: </strong>Metabolomic analysis revealed that acylcarnitines were the main discriminating metabolites according to fibrosis severity when we compared MASLD-HCC-F0F1-F2 versus NTT and MASLD-HCC-F3F4 versus NTT. Based on these metabolomic data, the analysis of a panel of 15 selected genes related to DNL and FAO indicated that there is no difference between the 2 groups of MASLD-HCC. In contrast the same comparative gene analysis according to the aetiology of HCC: MASLD-HCC versus VIRUS-HCC showed that both aetiologies shared the same upregulation of genes involved in DNL. However, five genes involved in FAO (HADHA, CRAT, CPT1, CPT2 and PPARA) are upregulated exclusively in MASLD-HCC. This result indicates that FAO and DNL pathways are simultaneously activated in MASLD-HCC in contrast to VIRUS-HCC.</p><p><strong>Conclusions: </strong>These results suggest that, the involvement of adaptive metabolic pathways is different depending on the aetiology of HCC. Moreover, the dogma that simultaneous activation of FAO and DNL is incompatible in cancer would not apply to MASLD-HCC.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e70006"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11752690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008019","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}
Pietro Lampertico, Pavel O Bogomolov, Vladimir Chulanov, Tatiana Stepanova, Viacheslav Morozov, Lena Allweiss, Maura Dandri, Jürgen Burhenne, Antje Blank, Sandra Ciesek, Carina Elsner, Ulf Dittmer, Qi An, Dmitry Manuilov, Ben L Da, John F Flaherty, Stephan Urban, Heiner Wedemeyer
Background and aim: Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFNα-2a), with 24-week follow-up.
Methods: Ninety patients were enrolled into six arms of 15 each (A-F); 60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFNα-2a 180 μg once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFNα-2a 180 μg QW; (C) BLV 5 mg QD + Peg-IFNα-2a 180 μg QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFNα-2a 180 μg QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72.
Results: At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log10 IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment.
Conclusions: BLV combined with Peg-IFNα-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment.
Trial registration: NCT02888106.
{"title":"Phase 2 Randomised Study of Bulevirtide as Monotherapy or Combined With Peg-IFNα-2a as Treatment for Chronic Hepatitis Delta.","authors":"Pietro Lampertico, Pavel O Bogomolov, Vladimir Chulanov, Tatiana Stepanova, Viacheslav Morozov, Lena Allweiss, Maura Dandri, Jürgen Burhenne, Antje Blank, Sandra Ciesek, Carina Elsner, Ulf Dittmer, Qi An, Dmitry Manuilov, Ben L Da, John F Flaherty, Stephan Urban, Heiner Wedemeyer","doi":"10.1111/liv.70008","DOIUrl":"10.1111/liv.70008","url":null,"abstract":"<p><strong>Background and aim: </strong>Bulevirtide (BLV) leads to beneficial virologic and biochemical responses when given alone to treat hepatitis delta virus (HDV) infection, which causes the most severe form of chronic viral hepatitis. We evaluated 48 weeks of BLV monotherapy, BLV + tenofovir disoproxil fumarate (TDF) and BLV + pegylated interferon alfa-2a (Peg-IFNα-2a), with 24-week follow-up.</p><p><strong>Methods: </strong>Ninety patients were enrolled into six arms of 15 each (A-F); 60 patients were included in the main randomisation (arms A-D), and 30 patients (arms E-F) were randomised to the extension phase: (A) Peg-IFNα-2a 180 μg once weekly (QW); (B) BLV 2 mg once daily (QD) + Peg-IFNα-2a 180 μg QW; (C) BLV 5 mg QD + Peg-IFNα-2a 180 μg QW; (D) BLV 2 mg QD; (E) BLV 10 mg QD + Peg-IFNα-2a 180 μg QW and (F) BLV 10 mg (5 mg twice daily) + TDF QD. The primary endpoint was undetectable HDV RNA at week (W)72.</p><p><strong>Results: </strong>At W72, 53%, 27%, 7%, 7% and 33% of patients achieved undetectable HDV RNA in arms B, C, D, E and F, respectively, versus 0% in arm A. More arm B versus A patients had a > 1 log<sub>10</sub> IU/mL decline in or loss of hepatitis B surface antigen (HBsAg) at W72 (p = 0.017), including four patients with loss of HBsAg. Bile acid elevations were dose-dependent and reversible following the completion of BLV treatment.</p><p><strong>Conclusions: </strong>BLV combined with Peg-IFNα-2a was well tolerated and resulted in high rates of HDV RNA undetectability off-treatment.</p><p><strong>Trial registration: </strong>NCT02888106.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e70008"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033485","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}
Yasaman Vali, Anne-Marieke van Dijk, Jenny Lee, Jerome Boursier, Vlad Ratziu, Carla Yunis, Jörn M Schattenberg, Luca Valenti, Manuel Romero Gomez, Detlef Schuppan, Salvatore Petta, Mike Allison, Mark L Hartman, Kimmo Porthan, Jean-Francois Dufour, Elisabetta Bugianesi, Amalia Gastadelli, Zoltan Derdak, Celine Fournier-Poizat, Elizabeth Shumbayawonda, Michael Kalutkiewicz, Hannele Yki-Jarvinen, Mattias Ekstedt, Andreas Geier, Aldo Trylesinski, Sven Francque, Clifford Brass, Michael Pavlides, Adriaan G Holleboom, Max Nieuwdorp, Quentin M Anstee, Patrick M Bossuyt
Background and aims: The performance of non-invasive liver tests (NITs) is known to vary across settings and subgroups. We systematically evaluated whether the performance of three NITs in detecting advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) varies with age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) status or liver enzymes.
Methods: Data from 586 adult LITMUS Metacohort participants with histologically characterised MASLD were included. The diagnostic performance of the Fibrosis-4 Index (FIB-4), enhanced liver fibrosis (ELF) and vibration-controlled transient elastography liver stiffness measurement (VCTE LSM) was evaluated. Performance was expressed as the area under the receiver operating characteristics curve (AUC). Thresholds for detecting advanced fibrosis (≥F3) were calculated for each NIT for fixed (high) sensitivity, specificity and predictive values.
Results: Differences in AUC between all subgroups were small and statistically not significant, indicating comparable performance in detecting ≥F3, irrespective of these clinical factors. However, different thresholds were needed to achieve the same level of accuracy with each test. For example, for a fixed sensitivity and specificity, the thresholds for all three NITs were higher in patients with T2DM. Effects for sex, age and liver enzymes were less pronounced.
Conclusions: Performance of the selected NITs in detecting advanced liver fibrosis does not vary substantially with clinical characteristics. However, different thresholds have to be selected to achieve the same sensitivity, specificity and predictive values in the respective subgroups. Large prospective studies are called for to study NIT accuracy considering multiple patient characteristics.
{"title":"Precision in Liver Diagnosis: Varied Accuracy Across Subgroups and the Need for Variable Thresholds in Diagnosis of MASLD.","authors":"Yasaman Vali, Anne-Marieke van Dijk, Jenny Lee, Jerome Boursier, Vlad Ratziu, Carla Yunis, Jörn M Schattenberg, Luca Valenti, Manuel Romero Gomez, Detlef Schuppan, Salvatore Petta, Mike Allison, Mark L Hartman, Kimmo Porthan, Jean-Francois Dufour, Elisabetta Bugianesi, Amalia Gastadelli, Zoltan Derdak, Celine Fournier-Poizat, Elizabeth Shumbayawonda, Michael Kalutkiewicz, Hannele Yki-Jarvinen, Mattias Ekstedt, Andreas Geier, Aldo Trylesinski, Sven Francque, Clifford Brass, Michael Pavlides, Adriaan G Holleboom, Max Nieuwdorp, Quentin M Anstee, Patrick M Bossuyt","doi":"10.1111/liv.16240","DOIUrl":"10.1111/liv.16240","url":null,"abstract":"<p><strong>Background and aims: </strong>The performance of non-invasive liver tests (NITs) is known to vary across settings and subgroups. We systematically evaluated whether the performance of three NITs in detecting advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) varies with age, sex, body mass index (BMI), type 2 diabetes mellitus (T2DM) status or liver enzymes.</p><p><strong>Methods: </strong>Data from 586 adult LITMUS Metacohort participants with histologically characterised MASLD were included. The diagnostic performance of the Fibrosis-4 Index (FIB-4), enhanced liver fibrosis (ELF) and vibration-controlled transient elastography liver stiffness measurement (VCTE LSM) was evaluated. Performance was expressed as the area under the receiver operating characteristics curve (AUC). Thresholds for detecting advanced fibrosis (≥F3) were calculated for each NIT for fixed (high) sensitivity, specificity and predictive values.</p><p><strong>Results: </strong>Differences in AUC between all subgroups were small and statistically not significant, indicating comparable performance in detecting ≥F3, irrespective of these clinical factors. However, different thresholds were needed to achieve the same level of accuracy with each test. For example, for a fixed sensitivity and specificity, the thresholds for all three NITs were higher in patients with T2DM. Effects for sex, age and liver enzymes were less pronounced.</p><p><strong>Conclusions: </strong>Performance of the selected NITs in detecting advanced liver fibrosis does not vary substantially with clinical characteristics. However, different thresholds have to be selected to achieve the same sensitivity, specificity and predictive values in the respective subgroups. Large prospective studies are called for to study NIT accuracy considering multiple patient characteristics.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e16240"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047230","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}
Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the treatment of cancer, though they come with the risk of immune-related adverse (irAEs) events such as hepatotoxicity or Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation of ICI and initiation of immunosuppression. Cytotoxic T Lymphocytes (CTLs) play a central role in ILICI; however, they are just part of the picture as immunotherapy broadly impacts all aspects of the immune microenvironment and can directly and indirectly activate innate and adaptive immune cells. Clinically, as our understanding of this entity grows, we encounter new challenges. The presentation of ILICI is heterogeneous with respect to latency, pattern of injury (hepatitis vs. cholangitis) and severity. This review focuses on our knowledge regarding risk factors, presentation and treatment of ILICI including ILICI refractory to steroids. An emerging topic, the possibility of rechallenge while accepting some risk, in patients who experience ILICI but require immunotherapy, is also discussed. This review provides an update on the current knowns and unknowns in ILICI and highlights several knowledge gaps where studies are needed.
{"title":"Immune-Mediated Liver Injury From Checkpoint Inhibitor: An Evolving Frontier With Emerging Challenges.","authors":"Lily Dara, Eleonora De Martin","doi":"10.1111/liv.16198","DOIUrl":"10.1111/liv.16198","url":null,"abstract":"<p><p>Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the treatment of cancer, though they come with the risk of immune-related adverse (irAEs) events such as hepatotoxicity or Immune-mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation of ICI and initiation of immunosuppression. Cytotoxic T Lymphocytes (CTLs) play a central role in ILICI; however, they are just part of the picture as immunotherapy broadly impacts all aspects of the immune microenvironment and can directly and indirectly activate innate and adaptive immune cells. Clinically, as our understanding of this entity grows, we encounter new challenges. The presentation of ILICI is heterogeneous with respect to latency, pattern of injury (hepatitis vs. cholangitis) and severity. This review focuses on our knowledge regarding risk factors, presentation and treatment of ILICI including ILICI refractory to steroids. An emerging topic, the possibility of rechallenge while accepting some risk, in patients who experience ILICI but require immunotherapy, is also discussed. This review provides an update on the current knowns and unknowns in ILICI and highlights several knowledge gaps where studies are needed.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 2","pages":"e16198"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047213","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}
Cyriac Abby Philips, Arif Hussain Theruvath, Rizwan Ahamed, Philip Augustine
{"title":"G-CSF for Severe Alcohol-Associated Hepatitis-'That Which Can Be Asserted Without Evidence, Can Be Dismissed Without Evidence'.","authors":"Cyriac Abby Philips, Arif Hussain Theruvath, Rizwan Ahamed, Philip Augustine","doi":"10.1111/liv.16183","DOIUrl":"https://doi.org/10.1111/liv.16183","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007811","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}
Idiosyncratic hepatotoxicity induced by prescribed drugs has been known since the early 20th century. Identifying risk factors, including genetic factors, that trigger this drug-induced liver injury (DILI) has been an important priority for many years, both to prevent drugs that cause liver injury being licensed and as a potential means of preventing at-risk patients being prescribed causative drugs. Improved methods for genomic analysis, particularly the development of genome-wide association studies, have facilitated the identification of genomic risk factors for DILI, but, to date, there are only two main examples, liver injury caused by amoxicillin-clavulanate (AC) and by flucloxacillin, where genetic risk factors causing the injury have been identified and replicated with understanding of the underlying mechanism. There has also been progress on identifying genetic risk factors for liver injury caused by other anti-infective agents, herbal remedies and nonsteroidal anti-inflammatory drugs. The majority of genetic risk factors identified to date are specific human leucocyte antigen (HLA) alleles and evidence that these alleles preferentially present self-peptides inappropriately to T cells in the liver has been obtained. Non-HLA genes also contribute to genetic susceptibility, both as co-factors in T-cell responses and, in the case of isoniazid-only, drug metabolism. Polygenic risk scores to predict DILI have been developed, both a simple score that predicts AC injury and complex scores that may be applied to DILI more generally and provide evidence that additional risk factors other than HLA genes exist.
{"title":"Genetic and Genomic Approaches to the Study of Drug-Induced Liver Injury.","authors":"Ann K Daly","doi":"10.1111/liv.16191","DOIUrl":"10.1111/liv.16191","url":null,"abstract":"<p><p>Idiosyncratic hepatotoxicity induced by prescribed drugs has been known since the early 20th century. Identifying risk factors, including genetic factors, that trigger this drug-induced liver injury (DILI) has been an important priority for many years, both to prevent drugs that cause liver injury being licensed and as a potential means of preventing at-risk patients being prescribed causative drugs. Improved methods for genomic analysis, particularly the development of genome-wide association studies, have facilitated the identification of genomic risk factors for DILI, but, to date, there are only two main examples, liver injury caused by amoxicillin-clavulanate (AC) and by flucloxacillin, where genetic risk factors causing the injury have been identified and replicated with understanding of the underlying mechanism. There has also been progress on identifying genetic risk factors for liver injury caused by other anti-infective agents, herbal remedies and nonsteroidal anti-inflammatory drugs. The majority of genetic risk factors identified to date are specific human leucocyte antigen (HLA) alleles and evidence that these alleles preferentially present self-peptides inappropriately to T cells in the liver has been obtained. Non-HLA genes also contribute to genetic susceptibility, both as co-factors in T-cell responses and, in the case of isoniazid-only, drug metabolism. Polygenic risk scores to predict DILI have been developed, both a simple score that predicts AC injury and complex scores that may be applied to DILI more generally and provide evidence that additional risk factors other than HLA genes exist.</p>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 1","pages":"e16191"},"PeriodicalIF":6.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864368","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}