JHEP Reports最新文献

{"title":"Hic-5 antisense oligonucleotide inhibits advanced hepatic fibrosis and steatosis in vivo","authors":"Masahito Noguchi ,&nbsp;Aya Miyauchi ,&nbsp;Yoshiaki Masaki ,&nbsp;Masashi Sakaki ,&nbsp;Xiao-Feng Lei ,&nbsp;Momoko Kobayashi-Tanabe ,&nbsp;Akira Miyazaki ,&nbsp;Takeshi Aoki ,&nbsp;Hitoshi Yoshida ,&nbsp;Kohji Seio ,&nbsp;Joo-ri Kim-Kaneyama","doi":"10.1016/j.jhepr.2024.101195","DOIUrl":"10.1016/j.jhepr.2024.101195","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Chronic liver diseases, including metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health burden. Progressive liver fibrosis can lead to severe outcomes; however, there is a lack of effective therapies targeting advanced fibrosis. Hydrogen peroxide-inducible clone-5 (Hic-5), an adaptor protein in focal adhesion, is critical for promoting liver fibrosis in hepatic stellate cells. This study investigated its clinical applicability by examining hepatic Hic-5 expression in human fibrotic tissues, exploring its association with MASH, and assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting Hic-5 in a MASH mouse model.</div></div><div><h3>Methods</h3><div>Hepatic Hic-5 expression in human fibrotic tissues underwent pathological image analysis and single-cell RNA sequencing. ASOs targeting Hic-5 were developed and tested using <em>in vitro</em> cell models. An <em>in vivo</em> MASH mouse model was used to evaluate the effects of anti-<em>Hic-5</em> ASOs on advanced fibrosis and steatosis.</div></div><div><h3>Results</h3><div>Hepatic Hic-5 expression increased with the progression of fibrosis, particularly in advanced stages. Single-cell RNA sequencing revealed Hic-5 expression primarily in hepatic stellate cells. In MASH-associated fibrosis, Hic-5 expression correlated with the expression of fibrotic genes. In the MASH mouse model, hepatic Hic-5 expression increased with disease progression. Anti-<em>Hic-5</em> ASOs effectively suppressed Hic-5 expression <em>in vitro</em> and attenuated advanced fibrosis and steatosis <em>in vivo</em>, indicating their therapeutic potential.</div></div><div><h3>Conclusions</h3><div>Hepatic Hic-5 expression is associated with advanced liver fibrosis and MASH. Anti-<em>Hic-5</em> ASOs are promising therapeutic interventions for MASH accompanied by advanced fibrosis. These findings provide valuable insights into potential clinical treatments for advanced liver fibrosis.</div></div><div><h3>Impact and implications:</h3><div>This study investigated the role of Hic-5 in liver fibrosis and steatohepatitis, highlighting its potential as a therapeutic target. We developed an antisense oligonucleotide (ASO) that was particularly transportable to the liver, and targeted Hic-5. Anti-<em>Hic-5</em> ASO exhibited therapeutic efficacy for liver fibrosis and steatosis <em>in vivo</em>, indicating its therapeutic potential for liver fibrosis and steatosis. ASOs have already achieved dramatic therapeutic effects as approved nucleic acid drugs. Thus, anti-<em>Hic-5</em> ASO is expected to lead the direct generation of seed compounds for the clinical development of drugs for liver fibrosis and steatosis.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101195"},"PeriodicalIF":9.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142427449","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}

{"title":"Understanding the complex macrophage landscape in MASLD","authors":"Federico F. De Ponti ,&nbsp;Zhuangzhuang Liu ,&nbsp;Charlotte L. Scott","doi":"10.1016/j.jhepr.2024.101196","DOIUrl":"10.1016/j.jhepr.2024.101196","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of disease states ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), which can eventually lead to the development of cirrhosis and hepatocellular carcinoma. Macrophages have long been implicated in driving the progression from steatosis to end-stage disease, yet we still know relatively little about the precise involvement of these cells in MASLD progression and/or regression. Rather, there are a considerable number of conflicting reports regarding the precise roles of these cells. This confusion stems from the fact that, until recently, macrophages in the liver were considered a homogenous population. However, thanks to recent technological advances including multi-parameter flow cytometry, single-cell RNA sequencing and spatial proteogenomics, we now know that this is not the case. Rather hepatic macrophages, even in the healthy liver, are heterogenous, existing in multiple subsets with distinct transcriptional profiles and hence likely functions. This heterogeneity is even more prominent in MASLD, where the macrophage pool consists of multiple different subsets of resident and recruited cells. To probe the unique functions of these cells and determine if targeting macrophages may be a viable therapeutic strategy in MASLD, we first need to unravel this complexity and decipher which populations and/or activation states are present and what functions each of these may play in driving MASLD progression. In this review, we summarise recent advances in the field, highlighting what is currently known about the hepatic macrophage landscape in MASLD and the questions that remain to be tackled.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101196"},"PeriodicalIF":9.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539610","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}

{"title":"Patient and physician expectations regarding disease and treatment of advanced HCC: The prospective PERCEPTION1 study","authors":"Jean-Charles Nault ,&nbsp;Nanthara Sritharan ,&nbsp;Gontran Verset ,&nbsp;Ivan Borbath ,&nbsp;Marie Lequoy ,&nbsp;Manon Allaire ,&nbsp;Hélène Regnault ,&nbsp;Isabelle Colle ,&nbsp;Hans Orlent ,&nbsp;Isabelle Sinapi ,&nbsp;Christophe Moreno ,&nbsp;Edouard Larrey ,&nbsp;Sabrina Sidali ,&nbsp;Clémence Hollande ,&nbsp;Giuliana Amaddeo ,&nbsp;Stanislas Pol ,&nbsp;Pierre Nahon ,&nbsp;Nathalie Ganne-Carrié ,&nbsp;Vincent Levy ,&nbsp;Coralie Bloch-Queyrat ,&nbsp;Mohammed Bouattour","doi":"10.1016/j.jhepr.2024.101192","DOIUrl":"10.1016/j.jhepr.2024.101192","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>We aimed to explore patient expectations regarding their treatments and prognosis in comparison to physicians' assessments in patients with advanced hepatocellular carcinoma (HCC) receiving systemic treatments.</div></div><div><h3>Methods</h3><div>We prospectively enrolled 205 patients in France and Belgium with Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC receiving systemic treatment (NCT04823754). Patients completed a 28-question survey and the hospital anxiety and depression scale (HADS), while physicians filled a 17-question survey after the initial consultation. Univariate and multivariate models were used to assess factors associated with concordant patient-physician responses, HADS, as well as predicted (by physicians) and observed overall survival.</div></div><div><h3>Results</h3><div>Patients had a median age of 68 years with 75% having BCLC C HCC; 86.3% received atezolizumab/bevacizumab. 60% of patients did not discuss life expectancy with the physician. 63% of the patients believed they had a life expectancy &gt;5 years. Among shared questions between patients and physicians, 36.4% concordance was observed; major differences centered on life expectancy with patients more optimistic than physicians. A lower patient-physician concordance was seen with shorter-consultations (<em>p =</em> 0.003), female physicians (<em>p =</em> 0.02), BCLC C (<em>p =</em> 0.03) and &gt;100 HCC patients/year per physician (<em>p =</em> 0.008). Compared to France, patients from Belgium were more likely to be satisfied with the consultation (<em>p</em> &lt;0.001) but were less optimistic about life expectancy. Using HADS, 52% of the patients had anxiety/depression that was correlated with alpha-fetoprotein level (<em>p =</em> 0.03). The predicted median overall survival by physicians was 18 months <em>vs</em>. 13 months for the observed overall survival (weak correlation, ρ = 0.31).</div></div><div><h3>Conclusion</h3><div>Expectations regarding systemic treatments for advanced HCC differ significantly between patients and physicians, showing notable variations across countries.</div></div><div><h3>Impact and implications:</h3><div>This multicentric prospective study, conducted in France and Belgium, focuses on patients with advanced hepatocellular carcinoma undergoing systemic treatments. The findings of our study underscore the disparities in expectations regarding systemic treatments for advanced hepatocellular carcinoma between patients and physicians, revealing also significant variations between France and Belgium. These results suggest the need for targeted interventions aimed at enhancing patients' comprehension of their disease and fostering better communication between patients and physicians.</div></div><div><h3>Clinical trial number</h3><div>NCT04823754.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101192"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142427462","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}

{"title":"Impact of SARS-CoV-2 vaccination in patients with vascular liver diseases: Observations from a VALDIG multicenter study","authors":"Valeria Perez-Campuzano ,&nbsp;Pierre-Emmanuel Rautou ,&nbsp;Thomas Marjot ,&nbsp;Michael Praktiknjo ,&nbsp;Edilmar Alvarado-Tapias ,&nbsp;Laura Turco ,&nbsp;Luis Ibáñez-Samaniego ,&nbsp;Carlos González-Alayón ,&nbsp;Ángela Puente ,&nbsp;Elba Llop ,&nbsp;Macarena Simón-Talero ,&nbsp;Carmen Álvarez-Navascués ,&nbsp;Thomas Reiberger ,&nbsp;Xavier Verhelst ,&nbsp;Luis Tellez ,&nbsp;Johanna Birte Bergmann ,&nbsp;Lara Orts ,&nbsp;Giuseppe Grassi ,&nbsp;Anna Baiges ,&nbsp;Payance Audrey ,&nbsp;Virginia Hernández-Gea","doi":"10.1016/j.jhepr.2024.101191","DOIUrl":"10.1016/j.jhepr.2024.101191","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Patients with vascular liver diseases (VLD) are at higher risk of both severe courses of COVID-19 disease and thromboembolic events. The impact of SARS-CoV-2 vaccination in patients with VLD has not been described and represents the aim of our study.</div></div><div><h3>Methods</h3><div>International, multicenter, prospective observational study in patients with VLD analyzing the incidence of COVID-19 infection after vaccination, severity of side effects, occurrence of thromboembolic events and hepatic decompensation. In a subgroup of patients, the humoral and cellular responses to vaccination were also analyzed.</div></div><div><h3>Results</h3><div>A total of 898 patients from 14 European centers – part of the VALDIG network – were included, 872 (97.1%) patients received two vaccine doses (fully vaccinated), and 674 (75.1%) three doses. Of the total cohort, 151/898 had a COVID-19 infection prior to vaccination, of whom 9/151 (5.9%) were re-infected. Of the 747/898 patients who were not previously infected, 11.2% (84/747) were diagnosed with a COVID-19 infection during the study period. Two infected patients required intensive care unit admission and infection was fatal in two fully vaccinated patients. Adverse effects were reported in around 40% of patients, with local side effects being the most frequent. During the study period, 31 (3.5%) patients had thromboembolic events and 21 (2.3%) hepatic decompensations. No cases of vaccine-induced thrombocytopenia were reported. Vaccine immunogenicity was assessed in 36 patients; seroconversion reached 100% and IFNy T-cell responses significantly increased post two mRNA-1273 vaccine doses.</div></div><div><h3>Conclusion</h3><div>Patients with VLD seem to have a preserved immune response to SARS-CoV-2 vaccination, which appears to be safe and effective in preventing severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, though the contribution of vaccination as a cofactor in VLD remains to be elucidated.</div></div><div><h3>Impact and implications:</h3><div>Patients with vascular liver disease (VLD) are at increased risk of both SARS-CoV-2 infection and severe COVID-19 disease. The potential risks associated with vaccination against this infection need thorough investigation. Our research enhances the understanding of the effects of COVID-19 vaccination in patients with VLD, highlighting its good tolerability. Moreover, patients with VLD appear to have a preserved immune response to SARS-CoV-2 vaccination, providing protection against severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, and no cases of vaccine-induced thrombocytopenia were reported.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101191"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657240","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}

{"title":"Differential prevalence and prognostic value of metabolic syndrome components among patients with MASLD","authors":"Jesse Pustjens ,&nbsp;Laurens A. van Kleef ,&nbsp;Harry L.A. Janssen ,&nbsp;Robert J. de Knegt ,&nbsp;Willem P. Brouwer","doi":"10.1016/j.jhepr.2024.101193","DOIUrl":"10.1016/j.jhepr.2024.101193","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming increasingly prevalent in the general population. This study aimed at describing the cardiometabolic burden of the MASLD population and to identify patients at the highest risk of all-cause mortality and liver fibrosis.</div></div><div><h3>Methods</h3><div>We analysed individuals with MASLD enrolled in the National Health and Nutrition Survey (NHANES) III study (N = 3,628) and in the NHANES 2017–2020 study (n = 2,618). MASLD was defined as hepatic steatosis (by ultrasonography or controlled attenuation parameter), together with cardiometabolic dysfunction. Primary endpoints were all-cause mortality and liver fibrosis (liver stiffness measurement ≥8 kPa). Regression models were adjusted for age, sex, race, marital status, education, and smoking, and results were stratified by age groups (20–40, 40–60, 60–80 years).</div></div><div><h3>Results</h3><div>Among the total MASLD population (median age = 48, [25th to 75th percentiles: 36–62] years, 44.8% males), 65% had three or more cardiometabolic disorders. The most frequent were obesity (89.1%), (pre-) diabetes (66.6%), and low-HDL (54.7%). During a median follow-up of 22.3 (25th to 75th percentiles: 16.9–24.2) years, 1,405 deaths occurred. Hypertension (adjusted hazard ratio [aHR] 1.42, 95% CI 1.26–1.61), (pre-)diabetes (aHR 1.28, 95% CI 1.09–1.49), and hypertriglyceridaemia (aHR 1.19, 95% CI 1.05–1.34) were the strongest predictors of all-cause mortality. Consistent results were obtained regarding the association between cardiometabolic disorders and fibrosis. Here, increased waist circumference (adjusted odds ratio [aOR] 3.45, 95% CI 1.44–8.25), (pre-)diabetes (aOR 1.90, 95% CI 1.44–2.25), and hypertension (aHR 1.84, 95% CI 1.40–2.43) showed the strongest associations.</div></div><div><h3>Conclusions</h3><div>MASLD patients vary greatly in their cardiometabolic burden and consequently, in their prognosis. Our results highlight MASLD as a disease spectrum rather than as a single disease entity, necessitating an individualised treatment approach.</div></div><div><h3>Impact and implications:</h3><div>The increasing cardiometabolic burden and incidence of MASLD, especially among younger adults, stresses the importance of the current study.² Understanding the disease burden of MASLD patients is key, but can be challenging for healthcare professionals. Results from the current study indicate that cardiometabolic risk management is particularly warranted in the younger adult population, with specific attention to hypertension and (pre-)diabetes.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101193"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142705061","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}

{"title":"Palmitoylcarnitine impairs immunity in decompensated cirrhosis","authors":"Ingrid Wei Zhang ,&nbsp;María Belén Sánchez-Rodríguez ,&nbsp;Cristina López-Vicario ,&nbsp;Mireia Casulleras ,&nbsp;Marta Duran-Güell ,&nbsp;Roger Flores-Costa ,&nbsp;Ferran Aguilar ,&nbsp;Michael Rothe ,&nbsp;Paula Segalés ,&nbsp;Carmen García-Ruiz ,&nbsp;José C. Fernández-Checa ,&nbsp;Jonel Trebicka ,&nbsp;Vicente Arroyo ,&nbsp;Joan Clària","doi":"10.1016/j.jhepr.2024.101187","DOIUrl":"10.1016/j.jhepr.2024.101187","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Plasma acylcarnitine levels were measured in 20 patients with AD cirrhosis and 10 healthy individuals. The effects of selected medium- and long-chain acylcarnitines on mitochondrial function were investigated in peripheral leucocytes from healthy donors by determining mitochondrial membrane potential (Δψm) and mitochondrial respiration using the JC-1 dye and Agilent Seahorse XF technology. Changes regarding mitochondrial ultrastructure and redox systems were assessed by transmission electron microscopy and gene and protein expression analysis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Plasma levels of several acylcarnitine species were significantly elevated in patients with AD cirrhosis compared with healthy individuals, alongside increased levels of inflammatory mediators (cytokines and chemokines). Notably, the long-chain acylcarnitine palmitoylcarnitine (C16:0-carnitine, 1.51-fold higher, &lt;em&gt;p =&lt;/em&gt; 0.0059) impaired Δψm and reduced the spare respiratory capacity of peripheral mononuclear leucocytes. Additionally, C16:0-carnitine induced mitochondrial oxidative stress, suppressed the expression of the antioxidant gene &lt;em&gt;HMOX1&lt;/em&gt;, and increased &lt;em&gt;CXCL8&lt;/em&gt; expression and IL-8 release. Etomoxir, which blocks acylcarnitine entry into the mitochondria, reversed the suppression of &lt;em&gt;HMOX1&lt;/em&gt;. Similarly, trimetazidine, a fatty acid beta-oxidation inhibitor, prevented C16:0-carnitine-induced &lt;em&gt;CXCL8&lt;/em&gt; expression. Importantly, oxidative stress and Δψm impairment caused by C16:0-carnitine were less severe in the presence of albumin, a standard therapy for AD cirrhosis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our findings suggest that long-chain acylcarnitines induce mitochondrial injury in immune cells, thereby contributing to the development of immune dysfunction associated with cirrhosis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Patients with acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF) display a systemic hyperinflammatory state and leukocyte mitochondrial dysfunction. We discovered that apart from being increased in the circulation of these patients, the long-chain palmitoylcarnitine is able to elicit cytokine secretion paired with mitochondrial dysfunction in leukocytes from healthy donors. In particular, we show that inhibiting the metabolism of palmitoylcarnitine could reverse these detrimental effects. Our findings unde","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101187"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142533173","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}

{"title":"Heterogeneity in adverse events related to atezolizumab-bevacizumab for hepatocellular carcinoma reported in real-world studies","authors":"Claudia Campani ,&nbsp;Dimitrios Pallas ,&nbsp;Sabrina Sidali ,&nbsp;Olga Giouleme ,&nbsp;Lorraine Blaise ,&nbsp;Véronique Grando ,&nbsp;Gisele Nkontchou ,&nbsp;Alix Demory ,&nbsp;Pierre Nahon ,&nbsp;Nathalie Ganne-Carrié ,&nbsp;Jean-Charles Nault","doi":"10.1016/j.jhepr.2024.101190","DOIUrl":"10.1016/j.jhepr.2024.101190","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Safety data for patients with hepatocellular carcinoma (HCC) treated with atezolizumab-bevacizumab in the real-world setting remain uncertain. Thus, the aim of this study was to evaluate the incidence of adverse events (AEs) in patients with HCC treated with atezolizumab-bevacizumab in the literature.</div></div><div><h3>Methods</h3><div>In this systematic review and meta-analysis, we searched PubMed for original studies reporting percentages of AEs in patients with HCC receiving atezolizumab-bevacizumab between 2020 to 2023, using the search terms “Atezolizumab/Bevacizumab”, “HCC” and “Adverse events”. We summarized the incidence of AEs and performed a meta-analysis in order to evaluate the incidence of AEs reported in the literature.</div></div><div><h3>Results</h3><div>A total of 30 studies (3,867 patients) were included. The analysis revealed heterogeneity in AE reporting, with arterial hypertension, proteinuria, and fatigue being the most frequently reported AEs whereas incidence of bleeding was reported in 66.7% of the studies and rare immune-related AEs were reported in 26.7% of the studies. The meta-analysis revealed pooled incidence rates of 79% for any grade AEs: 56% for grade 1/2 and 30% for grade ≥3. While the pooled rates of hypertension, anorexia, bleeding, pruritus, rash, and thyroid dysfunction were similar to those reported in the IMbrave150 trial, higher rates were observed in the literature for proteinuria, fatigue, ALT and AST elevations and gastrointestinal perforation. For grade ≥3 AEs, the percentages were consistent with the IMbrave150 trial, except for lower incidences of arterial hypertension and thrombosis in the literature. The exposure-adjusted incidence rates for proteinuria (55.7%), hypertension (45.3%) and fatigue (33.6%) were high. Heterogeneity was observed in the analysis of AEs across articles within the same cohorts of patients.</div></div><div><h3>Conclusion</h3><div>We observed a significant variability in AE reporting for atezolizumab-bevacizumab treatment in HCC in the literature, underscoring the need for standardized reporting practices.</div></div><div><h3>Impact and implications</h3><div>Considering the demonstrated safety of atezolizumab-bevacizumab in randomized-controlled trials, this meta-analysis offers valuable insights into reported occurrences of adverse events. Our study highlights significant heterogeneity among studies, underscoring the need to improve adverse event recording. Understanding the incidence and severity of treatment-related adverse events beyond clinical trials is essential for prompt intervention and may help in preventing treatment discontinuation and complications, potentially leading to better outcomes without significantly compromising quality of life due to adverse events.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101190"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142539623","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}

{"title":"Essential roles of B cell subsets in the progression of MASLD and HCC","authors":"Nataliia Petriv ,&nbsp;Huizhen Suo ,&nbsp;Inga Hochnadel ,&nbsp;Kai Timrott ,&nbsp;Nina Bondarenko ,&nbsp;Lavinia Neubert ,&nbsp;Elena Reinhard ,&nbsp;Nils Jedicke ,&nbsp;Patrick Kaufhold ,&nbsp;Carlos Alberto Guzmán ,&nbsp;Ralf Lichtinghagen ,&nbsp;Michael P. Manns ,&nbsp;Heike Bantel ,&nbsp;Tetyana Yevsa","doi":"10.1016/j.jhepr.2024.101189","DOIUrl":"10.1016/j.jhepr.2024.101189","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of HCC. Current treatment options for HCC are very limited. Recent evidence highlights B cells as key drivers in MASLD progression toward HCC. However, it remains unclear whether multiple B cell populations or a distinct B cell subset regulates inflammatory responses during liver disease progression. The scope of this study was to define protumorigenic B cell subsets in MASLD and HCC.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Multicolor flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed to investigate B cell populations locally (in liver tissue) and systemically (in the blood) in mice with MASLD (n = 6) and HCC (n = 5–6). The results obtained in mice were also verified in patients with MASLD (n = 19) and HCC (n = 16).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Our study revealed an increase of two regulatory B cell (Breg) subsets, CD19&lt;sup&gt;+&lt;/sup&gt;B220&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt;CD1d&lt;sup&gt;+&lt;/sup&gt; (&lt;em&gt;p&lt;/em&gt; &lt;0.0001) and CD19&lt;sup&gt;-&lt;/sup&gt;B220&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt;CD1d&lt;sup&gt;-&lt;/sup&gt; (&lt;em&gt;p&lt;/em&gt; &lt;0.0001), both of which highly overexpress IgM/IgD, PD-L1, and IL-10, in the livers of mice with MASLD and HCC. Furthermore, we showed that B-cell depletion therapy in combination with a &lt;em&gt;Listeria-&lt;/em&gt;based vaccine decreased CD19&lt;sup&gt;-&lt;/sup&gt;B220&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt;CD1d&lt;sup&gt;-&lt;/sup&gt; Bregs (&lt;em&gt;p&lt;/em&gt; = 0.0103), and improved survival of mice with HCC. We also found CD19&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt;IL-10&lt;sup&gt;+&lt;/sup&gt; (&lt;em&gt;p&lt;/em&gt; = 0.0167), CD19&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt;PD-L1&lt;sup&gt;+&lt;/sup&gt; (&lt;em&gt;p&lt;/em&gt; = 0.0333) and CD19&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt;IgM&lt;sup&gt;+&lt;/sup&gt;IgD&lt;sup&gt;+&lt;/sup&gt; (&lt;em&gt;p&lt;/em&gt; = 0.0317) B cells in human HCCs. In addition, strong overexpression of IgM/IgD, PD-L1, IL-10, were detected on non-switched memory B cells (&lt;em&gt;p&lt;/em&gt; = 0.0049) and plasmablasts (&lt;em&gt;p&lt;/em&gt; = 0.0020). The examination of blood samples obtained from patients with MASLD showed an increase of total B cells expressing IL-10 (&lt;em&gt;p&lt;/em&gt; &lt;0.0001) and IgM/IgD (&lt;em&gt;p&lt;/em&gt; = 0.3361), CD19&lt;sup&gt;+&lt;/sup&gt;CD20&lt;sup&gt;+&lt;/sup&gt;CD5&lt;sup&gt;+&lt;/sup&gt;CD1d&lt;sup&gt;+&lt;/sup&gt; Bregs (&lt;em&gt;p&lt;/em&gt; = 0.6424) and CD19&lt;sup&gt;+&lt;/sup&gt;CD20&lt;sup&gt;+&lt;/sup&gt;CD27&lt;sup&gt;+&lt;/sup&gt; non-switched memory B cells (&lt;em&gt;p&lt;/em&gt; = 0.0003).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our results provide novel insights into the protumorigenic roles of several B cell subsets, the specific targeting of which could abrogate the progression of liver disease.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Hepatocellular carcinoma (HCC) is the primary liver cancer with a constantly rising mortality rate. Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging important cause of HCC. Current treatment options for HCC are limited and there is a high risk of recurrence. The study aims to iden","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101189"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657238","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}

{"title":"Differential effects of low or high-fat dairy and fat derived from dairy products on MASLD","authors":"Oren Tirosh ,&nbsp;Michal Verman ,&nbsp;Dana Ivancovsky-Wajcman ,&nbsp;Laura Sol Grinshpan ,&nbsp;Naomi Fliss-Isakov ,&nbsp;Muriel Webb ,&nbsp;Oren Shibolet ,&nbsp;Revital Kariv ,&nbsp;Shira Zelber-Sagi","doi":"10.1016/j.jhepr.2024.101194","DOIUrl":"10.1016/j.jhepr.2024.101194","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly related to nutrition. However, only a few human and animal studies have tested the association between MASLD and dairy consumption and the effect of milk fat on liver damage. Therefore, we aimed at testing the association between consumption of dairy product and the incidence of MASLD and fibrosis markers in humans, and the effect of milk fat &lt;em&gt;vs.&lt;/em&gt; other fats on MASLD in animal studies.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A prospective 7-year follow-up cohort study was performed including baseline and follow-up fasting blood tests, liver evaluation and a face-to-face interview on health status and behaviour using structured questionnaires. MASLD was determined by ultrasonography or by controlled attenuation parameter (CAP), and liver fibrosis by FibroTest™ or FibroScan®. An animal study was performed in which 6-week-old C57BL/6j male mice were fed a high-fat diet (HFD) consisting of lard, soybean oil, and milk fat for 12 weeks. Metabolic impairment was assessed during the animal experiment, and serum advanced glycation end-products (AGEs) and liver damage were evaluated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;A total of 316 patients were included in the prospective cohort. In multivariable analysis, high consumption of low-medium fat low-sugar dairy products (g/day above the baseline sex-specific median) was associated with a lower risk for MASLD incidence (OR 0.42, 95% CI 0.18–0.95, &lt;em&gt;p =&lt;/em&gt; 0.037) or incidence/persistence at follow-up (OR 0.58, 0.34–0.97, &lt;em&gt;p =&lt;/em&gt; 0.039). Constantly high consumption of high-fat low-sugar dairy products was associated with greater odds for new onset/persistence of MASLD. Neither low-medium nor high-fat dairy consumption was related to fibrosis markers. In mice, all HFDs induced similar weight gain and steatosis and did not affect liver enzymes. Milk fat increases serum cholesterol and AGEs levels more than lard or soybean oil.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Low-medium fat low-sugar dairy products may be protective and should be preferred over high-fat dairy to prevent MASLD. HFDs from different fat sources with a wide spectrum of fatty acid saturation content are equally deleterious.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;MASLD is related to nutrition, but evidence of an association between high-fat and low-fat dairy products is lacking, therefore, we evaluated this association by performing experimental studies in mice and an observational human study. For MASLD prevention, a differential effect based on the type of dairy products should be considered: low-medium fat low-sugar dairy products were found to be protective, in contrast high-fat dairy and generally high-fat diets may be harmful. It would be advisable to prefer low-fat low-sugar dairy products and minimise intake of high-fat dairy products; however, additional evidence is needed to allow generalisa","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101194"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441926","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}

{"title":"Fecal deoxycholic acid associates with diet, intestinal microbes, and total bilirubin in primary sclerosing cholangitis","authors":"Connie Chan ,&nbsp;Mateus Lemos ,&nbsp;Peter Finnegan ,&nbsp;William Gagnon ,&nbsp;Richard Dean ,&nbsp;Maryam Yazdanafar ,&nbsp;Joseph Zepeda ,&nbsp;Marie-Claude Vohl ,&nbsp;Michael Trauner ,&nbsp;Joshua R. Korzenik ,&nbsp;Olivier Barbier ,&nbsp;Maria L. Marco ,&nbsp;Christopher L. Bowlus","doi":"10.1016/j.jhepr.2024.101188","DOIUrl":"10.1016/j.jhepr.2024.101188","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with a strong association with inflammatory bowel disease and variable disease progression. We aimed to gain insights into the role of fecal bile acids (BA) on disease progression by determining the relationships between fecal BA, diet, and gut microbes, with markers of disease progression, BA synthesis, and farnesoid X receptor (FXR) activity.</div></div><div><h3>Methods</h3><div>BA levels in serum and stool, dietary intake, and markers of BA synthesis, and FXR activity were measured in 26 patients with early stage, large duct PSC. Fecal microbiota were quantified by 16S rRNA gene sequencing.</div></div><div><h3>Results</h3><div>Compared with controls, fecal unconjugated deoxycholic acid (DCA) levels were lower in patients with PSC (<em>p</em>_adj = 0.04). Alcohol intake and the abundance of <em>Blautia</em> and <em>Lachnoclostridium</em> were associated with greater fecal DCA levels in patients with PSC after adjusting for inflammatory bowel disease and treatment with ursodeoxycholic acid. Fecal DCA levels were negatively associated with total bilirubin levels in patients with PSC (<em>p</em> = 0.006) suggesting a protective role. However, fecal DCA was associated with greater serum levels of 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, and was not associated with fibroblast growth factor 19, a marker of intestinal FXR activity.</div></div><div><h3>Conclusions</h3><div>Alcohol intake, <em>Blautia</em> and <em>Lachnoclostridium</em> abundance was associated with increased fecal DCA levels, which in turn seemed to have had a protective effect in patients with early-stage PSC. However, this effect was not mediated by BA synthesis or FXR activation.</div></div><div><h3>Impact and implications</h3><div>Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with a direct interaction between the gut and the liver. In this study of patients with early-stage PSC, levels of fecal deoxycholic acid correlated with serum total bilirubin, a marker of clinical outcomes. In addition, <em>Blautia</em> and <em>Lachnoclostridium</em> were associated with fecal deoxycholic acid suggesting an interaction between these gut bacteria, fecal bile acids, and disease progression. Future research to determine the underlying mechanisms of these associations may lead to novel targets to prevent PSC disease progression.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101188"},"PeriodicalIF":9.5,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657169","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}