JHEP Reports最新文献

{"title":"Proportion of pregnant women with HBV infection eligible for antiviral prophylaxis to prevent vertical transmission: A systematic review and meta-analysis","authors":"Hugues Delamare ,&nbsp;Julian Euma Ishii-Rousseau ,&nbsp;Adya Rao ,&nbsp;Mélanie Cresta ,&nbsp;Jeanne Perpétue Vincent ,&nbsp;Olivier Ségéral ,&nbsp;Shevanthi Nayagam ,&nbsp;Yusuke Shimakawa","doi":"10.1016/j.jhepr.2024.101064","DOIUrl":"10.1016/j.jhepr.2024.101064","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>In 2020, the World Health Organization (WHO) recommended peripartum antiviral prophylaxis (PAP) for pregnant women infected with hepatitis B virus (HBV) with high viremia (≥200,000 IU/ml). Hepatitis B e antigen (HBeAg) was also recommended as an alternative when HBV DNA is unavailable. To inform policymaking and guide the implementation of prevention of mother-to-child transmission strategies, we conducted a systematic review and meta-analysis to estimate the proportion of HBV-infected pregnant women eligible for PAP at global and regional levels.</p></div><div><h3>Methods</h3><p>We searched PubMed, EMBASE, Scopus, and CENTRAL for studies involving HBV-infected pregnant women. We extracted proportions of women with high viremia (≥200,000 IU/ml), proportions of women with positive HBeAg, proportions of women cross-stratified based on HBV DNA and HBeAg, and the risk of child infection in these maternal groups. Proportions were pooled using random-effects meta-analysis.</p></div><div><h3>Results</h3><p>Of 6,999 articles, 131 studies involving 71,712 HBV-infected pregnant women were included. The number of studies per WHO region was 66 (Western Pacific), 21 (Europe), 17 (Africa), 11 (Americas), nine (Eastern Mediterranean), and seven (South-East Asia). The overall pooled proportion of high viremia was 21.27% (95% CI 17.77–25.26%), with significant regional variation: Western Pacific (31.56%), Americas (23.06%), Southeast Asia (15.62%), Africa (12.45%), Europe (9.98%), and Eastern Mediterranean (7.81%). HBeAg positivity showed similar regional variation. After cross-stratification, the proportions of high viremia and positive HBeAg, high viremia and negative HBeAg, low viremia and positive HBeAg, and low viremia and negative HBeAg were 15.24% (95% CI 11.12–20.53%), 2.70% (95% CI 1.88–3.86%), 3.69% (95% CI 2.86–4.75%), and 75.59% (95% CI 69.15–81.05%), respectively. The corresponding risks of child infection following birth dose vaccination without immune globulin and PAP were 14.86% (95% CI 8.43–24.88%), 6.94% (95% CI 2.92–15.62%), 7.14% (95% CI 1.00–37.03%), and 0.14% (95% CI 0.02–1.00%).</p></div><div><h3>Conclusions</h3><p>Approximately 20% of HBV-infected pregnant women are eligible for PAP. Given significant regional variations, each country should tailor strategies for HBsAg screening, risk stratification, and PAP in routine antenatal care.</p></div><div><h3>Impact and implications</h3><p>In 2020, the WHO recommended that pregnant women who test positive for the hepatitis B surface antigen (HBsAg) undergo HBV DNA testing or HBeAg and those with high viremia (≥200,000 IU/ml) or positive HBeAg receive PAP. To effectively implement new HBV PMTCT interventions and integrate HBV screening, risk stratification, and antiviral prophylaxis into routine antenatal care services, estimating the proportion of HBV-infected pregnant women eligible for PAP is critical. In this systematic review and meta-analysis, we found t","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S258955592400065X/pdfft?md5=2027dfd80a36564806dff90afbecec17&pid=1-s2.0-S258955592400065X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140405961","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":"Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients","authors":"Julia Dietz ,&nbsp;Christiana Graf ,&nbsp;Christoph P. Berg ,&nbsp;Kerstin Port ,&nbsp;Katja Deterding ,&nbsp;Peter Buggisch ,&nbsp;Kai-Henrik Peiffer ,&nbsp;Johannes Vermehren ,&nbsp;Georg Dultz ,&nbsp;Andreas Geier ,&nbsp;Florian P. Reiter ,&nbsp;Tony Bruns ,&nbsp;Jörn M. Schattenberg ,&nbsp;Elena Durmashkina ,&nbsp;Thierry Gustot ,&nbsp;Christophe Moreno ,&nbsp;Janina Trauth ,&nbsp;Thomas Discher ,&nbsp;Janett Fischer ,&nbsp;Thomas Berg ,&nbsp;A. Zipf","doi":"10.1016/j.jhepr.2024.101072","DOIUrl":"10.1016/j.jhepr.2024.101072","url":null,"abstract":"<div><h3>Background and Aims</h3><p>Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort.</p></div><div><h3>Methods</h3><p>A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively.</p></div><div><h3>Results</h3><p>Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure.</p></div><div><h3>Conclusions</h3><p>In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.</p></div><div><h3>Impact and implications</h3><p>Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000764/pdfft?md5=105ce0e90f1ced4cfbb58462ff65be77&pid=1-s2.0-S2589555924000764-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140407045","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":"Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide","authors":"Selma El Messaoudi ,&nbsp;Ségolène Brichler ,&nbsp;Claire Fougerou-Leurent ,&nbsp;Emmanuel Gordien ,&nbsp;Athenaïs Gerber ,&nbsp;Amal Kortebi ,&nbsp;Garance Lagadic ,&nbsp;Miroslava Subic-Levrero ,&nbsp;Sophie Metivier ,&nbsp;Stanislas Pol ,&nbsp;Anne Minello ,&nbsp;Vlad Ratziu ,&nbsp;Vincent Leroy ,&nbsp;Philippe Mathurin ,&nbsp;Laurent Alric ,&nbsp;Fatoumata Coulibaly ,&nbsp;Jean-Michel Pawlotsky ,&nbsp;Fabien Zoulim ,&nbsp;Victor de Lédinghen ,&nbsp;Jérémie Guedj","doi":"10.1016/j.jhepr.2024.101070","DOIUrl":"10.1016/j.jhepr.2024.101070","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Bulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with pegylated-interferon (Peg-IFN) are unknown.</p></div><div><h3>Methods</h3><p>We used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks.</p></div><div><h3>Results</h3><p>The efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (&gt;2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7–95.0]), compared with 56.1% (95% PI = [46.4–66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5–13.2]) with bulevirtide compared with 18.8% (95% PI = [11.6–29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks of treatment, the rates of viral cure could be 42.1% (95% PI = [33.3–52.6]) with bulevirtide and 66.7% (95% PI = [56.5–76.8]) with bulevirtide + Peg-IFN.</p></div><div><h3>Conclusions</h3><p>In this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment.</p></div><div><h3>Impact and implications</h3><p>Bulevirtide has been approved for chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of Peg-IFN and bulevirtide in patients with CHD. Clinical trials are now warranted to confirm those predictions.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000715/pdfft?md5=36d53876256b04b200881a740561ac7d&pid=1-s2.0-S2589555924000715-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140402983","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":"Interleukin-7-based identification of liver lymphatic endothelial cells reveals their unique structural features","authors":"Yilin Yang ,&nbsp;Jain Jeong ,&nbsp;Tingting Su ,&nbsp;Sanchuan Lai ,&nbsp;Pengpeng Zhang ,&nbsp;Rolando Garcia-Milian ,&nbsp;Morven Graham ,&nbsp;Xinran Liu ,&nbsp;Matthew J. McConnell ,&nbsp;Teruo Utsumi ,&nbsp;Joao Pereira ,&nbsp;Yasuko Iwakiri","doi":"10.1016/j.jhepr.2024.101069","DOIUrl":"10.1016/j.jhepr.2024.101069","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>The lymphatic system plays crucial roles in maintaining fluid balance and immune regulation. Studying the liver lymphatics has been considered challenging, as common lymphatic endothelial cell (LyEC) markers are expressed by other liver cells. Additionally, isolation of sufficient numbers of LyECs has been challenging because of their extremely low abundance (&lt;0.01% of entire liver cell population) in a normal liver.</p></div><div><h3>Methods</h3><p>Potential LyEC markers was identified using our published single-cell RNA sequencing (scRNA-seq) dataset (GSE147581) in mouse livers. Interleukin-7 (IL7) promoter-driven green fluorescent protein knock-in heterozygous mice were used for the validation of IL7 expression in LyECs in the liver, for the development of liver LyEC isolation protocol, and generating liver ischemia/reperfusion (I/R) injury. Scanning electron microscopy was used for the structural analysis of LyECs. Changes in LyEC phenotypes in livers of mice with I/R were determined by RNA-seq analysis.</p></div><div><h3>Results</h3><p>Through scRNA-seq analysis, we have identified IL7 as an exclusive marker for liver LyECs, with no overlap with other liver cell types. Based on IL7 expression in liver LyECs, we have established an LyEC isolation method and observed distinct cell surface structures of LyECs with fenestrae and cellular pores (ranging from 100 to 400 nm in diameter). Furthermore, we identified LyEC genes that undergo alterations during I/R liver injuries.</p></div><div><h3>Conclusions</h3><p>This study not only identified IL7 as an exclusively expressed gene in liver LyECs, but also enhanced our understanding of LyEC structures and demonstrated transcriptomic changes in injured livers.</p></div><div><h3>Impact and implications</h3><p>Understanding the lymphatic system in the liver is challenging because of the absence of specific markers for liver LyEC. This study has identified IL7 as a reliable marker for LyECs, enabling the development of an effective method for their isolation, elucidating their unique cell surface structure, and identifying LyEC genes that undergo changes during liver damage. The development of IL7 antibodies for detecting it in human liver specimens will further advance our understanding of the liver lymphatic system in the future.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000703/pdfft?md5=0f686cd4ec5922a8f0326a5d96c94fec&pid=1-s2.0-S2589555924000703-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140283189","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":"Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome","authors":"Beat Moeckli ,&nbsp;Vaihere Delaune ,&nbsp;Benoît Gilbert ,&nbsp;Andrea Peloso ,&nbsp;Graziano Oldani ,&nbsp;Sofia El Hajji ,&nbsp;Florence Slits ,&nbsp;Joana Rodrigues Ribeiro ,&nbsp;Ruben Mercier ,&nbsp;Adrien Gleyzolle ,&nbsp;Laura Rubbia-Brandt ,&nbsp;Quentin Gex ,&nbsp;Stephanie Lacotte ,&nbsp;Christian Toso","doi":"10.1016/j.jhepr.2024.101056","DOIUrl":"10.1016/j.jhepr.2024.101056","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms.</p></div><div><h3>Methods</h3><p>Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model.</p></div><div><h3>Results</h3><p>Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% <em>vs.</em> 3.09%, <em>p =</em> 0.0023) and fibrosis (3.75% <em>vs.</em> 2.70%, <em>p =</em> 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 <em>vs.</em> 1.0, <em>p =</em> 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% <em>vs.</em> 37.5%, <em>p =</em> 0.0084) with a higher mean tumor volume (234 <em>vs.</em> 3 μm³, <em>p =</em> 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 <em>vs</em>. 2.92, <em>p =</em> 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load.</p></div><div><h3>Conclusions</h3><p>Maternal obesity increases female offspring’s susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition.</p></div><div><h3>Impact and implications</h3><p>The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000570/pdfft?md5=1f733817c996ee063781daee830d22bc&pid=1-s2.0-S2589555924000570-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140281722","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":"Recommendations on maximising the clinical value of tissue in the management of patients with intrahepatic cholangiocarcinoma","authors":"Timothy Kendall ,&nbsp;Diletta Overi ,&nbsp;Maria Guido ,&nbsp;Chiara Braconi ,&nbsp;Jesus Banales ,&nbsp;Vincenzo Cardinale ,&nbsp;Eugenio Gaudio ,&nbsp;Bas Groot Koerkamp ,&nbsp;Guido Carpino","doi":"10.1016/j.jhepr.2024.101067","DOIUrl":"10.1016/j.jhepr.2024.101067","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Patients with intrahepatic cholangiocarcinoma can now be managed with targeted therapies directed against specific molecular alterations. Consequently, tissue samples submitted to the pathology department must produce molecular information in addition to a diagnosis or, for resection specimens, staging information. The pathologist’s role when evaluating these specimens has therefore changed to accommodate such personalised approaches.</p></div><div><h3>Methods</h3><p>We developed recommendations and guidance for pathologists by conducting a systematic review of existing guidance to generate candidate statements followed by an international Delphi process. Fifty-nine pathologists from 28 countries in six continents rated statements mapped to all elements of the specimen pathway from receipt in the pathology department to authorisation of the final written report. A separate survey of ‘end-users’ of the report including surgeons, oncologists, and gastroenterologists was undertaken to evaluate what information should be included in the written report to enable appropriate patient management.</p></div><div><h3>Results</h3><p>Forty-eight statements reached consensus for inclusion in the guidance including 10 statements about the content of the written report that also reached consensus by end-user participants. A reporting proforma to allow easy inclusion of the recommended data points was developed.</p></div><div><h3>Conclusions</h3><p>These guiding principles and recommendations provide a framework to allow pathologists reporting on patients with intrahepatic cholangiocarcinoma to maximise the informational yield of specimens required for personalised patient management.</p></div><div><h3>Impact and Implications</h3><p>Biopsy or resection lesional tissue from intrahepatic cholangiocarcinoma must yield information about the molecular abnormalities within the tumour that define suitability for personalised therapies in addition to a diagnosis and staging information. Here, we have developed international consensus guidance for pathologists that report such cases using a Delphi process that sought the views of both pathologists and ‘end-users of pathology reports. The guide highlights the need to report cases in a way that preserves tissue for molecular testing and emphasises that reporting requires interpretation of histological characteristics within the broader clinical and radiological context. The guide will allow pathologists to report cases of intrahepatic cholangiocarcinoma in a uniform manner that maximises the value of the tissue received to facilitate optimal multidisciplinary patient management.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000685/pdfft?md5=20136774865be803e293834bae1f695c&pid=1-s2.0-S2589555924000685-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140271056","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":"Enhanced liver fibrosis (ELF) score predicts hepatic decompensation and mortality","authors":"Madeline Pearson ,&nbsp;Jennifer Nobes ,&nbsp;Iain Macpherson ,&nbsp;Lucy Gold ,&nbsp;Michael Miller ,&nbsp;Ellie Dow ,&nbsp;John F. Dillon","doi":"10.1016/j.jhepr.2024.101062","DOIUrl":"10.1016/j.jhepr.2024.101062","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>In community pathways for detection of liver disease the most common reason for referral is fibrosis assessment. We investigated the impact of adding the Enhanced Liver Fibrosis (ELF) score as a second-line test (subsequent to an indeterminate or high Fibrosis-4 index [FIB-4] and/or non-alcoholic fatty liver disease fibrosis score) to guide referral and prognostication in our multi-aetiology pathway.</p></div><div><h3>Methods</h3><p>Patients with ELF results from the intelligent Liver Function Testing (iLFT) pathway were recruited. Case note review was undertaken to compare ELF with endpoints of cirrhosis, hepatic decompensation, and mortality (liver-related and all-cause death).</p></div><div><h3>Results</h3><p>In total, 1,327 individuals were included with a median follow-up of 859 days and median ELF score of 10.2. Overall sensitivity for cirrhosis at the 9.8 threshold was 94% (100% for metabolic-associated steatotic liver disease, 89% for alcohol-related liver disease). Determination of the ELF score as a second-line test reduced the referral rate by 34%. ELF scores predicted hepatic outcomes; each unit change was associated with increased decompensation (adjusted Hazard Ratio [aHR] 2.215, 95% CI: 1.934–2.537) and liver-related mortality (aHR 2.024, 95% CI: 1.674–2.446). ELF outperformed FIB-4 for risk of liver-related mortality, particularly in the short-term (area under the curve [AUC] 94.3% <em>vs.</em> 82.8% at six months). Where FIB-4 was indeterminate, ELF had higher AUC for all outcomes within at least 2 years. ELF ≥13 was associated with particularly high rates of decompensation (26% within 90 days) and all-cause mortality (38% at 1 year).</p></div><div><h3>Conclusions</h3><p>The addition of ELF reduced the number of individuals referred for fibrosis assessment following iLFT pathway testing and provided useful prognostic information. Individuals with ELF scores ≥13 were considered at high-risk of negative outcomes warranting urgent clinical assessment.</p></div><div><h3>Impact and implications</h3><p>Primary care pathways for suspected liver disease are increasingly common and often lead to increased specialist hepatology referrals for fibrosis assessment. This study, using clinical follow-up for liver-related outcomes, provides further evidence supporting ELF testing to safely reduce referrals in a two-step approach when combined with other simple fibrosis markers. Additionally, ELF scores predict liver-related morbidity and mortality, with ELF scores ≥13 indicating particularly high-risk patients. This study may help inform the implementation of diagnostic pathways for early detection of liver disease and highlights the need for urgent review of individuals with very high ELF scores.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000636/pdfft?md5=18277e3fc7ea9c07efaab4551d7d8704&pid=1-s2.0-S2589555924000636-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140280049","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":"Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial","authors":"Philipp Hoegen-Saßmannshausen ,&nbsp;Patrick Naumann ,&nbsp;Paula Hoffmeister-Wittmann ,&nbsp;Semi Ben Harrabi ,&nbsp;Katharina Seidensaal ,&nbsp;Fabian Weykamp ,&nbsp;Thomas Mielke ,&nbsp;Malte Ellerbrock ,&nbsp;Daniel Habermehl ,&nbsp;Christoph Springfeld ,&nbsp;Michael T. Dill ,&nbsp;Thomas Longerich ,&nbsp;Peter Schirmacher ,&nbsp;Arianeb Mehrabi ,&nbsp;De-Hua Chang ,&nbsp;Juliane Hörner-Rieber ,&nbsp;Oliver Jäkel ,&nbsp;Thomas Haberer ,&nbsp;Stephanie E. Combs ,&nbsp;Jürgen Debus ,&nbsp;Jakob Liermann","doi":"10.1016/j.jhepr.2024.101063","DOIUrl":"10.1016/j.jhepr.2024.101063","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I.</p></div><div><h3>Methods</h3><p>CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1–10.5 Gy (total doses 32.4–42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks.</p></div><div><h3>Results</h3><p>Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression.</p></div><div><h3>Conclusions</h3><p>CIRT of HCC yields excellent local control without dose-limiting toxicity.</p></div><div><h3>Impact and implications</h3><p>To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials.</p></div><div><h3>Clinical Trials Registration</h3><p>The study is registered at <span>ClinicalTrials.gov</span><svg><path></path></svg> (<span>NCT01167374</span>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000648/pdfft?md5=27680ac00f1b796875d6093a99a12f03&pid=1-s2.0-S2589555924000648-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140272031","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":"Xanthine oxidase promotes hepatic lipid accumulation through high fat absorption by the small intestine","authors":"Lin Liu ,&nbsp;Yuntao Zhang ,&nbsp;Xuanyang Wang ,&nbsp;Hongxue Meng ,&nbsp;Yan He ,&nbsp;Xiaoqing Xu ,&nbsp;Huan Xu ,&nbsp;Chunbo Wei ,&nbsp;Xuemin Yan ,&nbsp;Xinmiao Tao ,&nbsp;Keke Dang ,&nbsp;Pingnan Ma ,&nbsp;Xiaoyu Guo ,&nbsp;Sen Yang ,&nbsp;Jiemei Wang ,&nbsp;Ying Li","doi":"10.1016/j.jhepr.2024.101060","DOIUrl":"10.1016/j.jhepr.2024.101060","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms.</p></div><div><h3>Methods</h3><p>The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20–75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders.</p></div><div><h3>Results</h3><p>After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44–3.01; <em>p</em>-trend &lt;0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, <em>p &lt;</em>0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific <em>Xdh</em> knockin mice, we observed rapid lipid metabolism disorders under a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excess dietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet.</p></div><div><h3>Conclusions</h3><p>Our study clarified the association between serum XO activity levels and the development of MASLD in a large population-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promotes lipid accumulation through mechanisms involving excessive fat absorption by the small intestine.</p></div><div><h3>Impact and implications</h3><p>Using a prospective population-based cohort and various animal models, we have identified novel mechanisms by which xanthine oxidase regulates lipid metabolism. Our findings indicate that xanthine oxidase overexpression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipid transport <em>in vivo</em>. These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000612/pdfft?md5=28b29278385aeca9c460675df2e2ad70&pid=1-s2.0-S2589555924000612-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140271716","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":"CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection","authors":"Jia-Feng Wu ,&nbsp;Chi-San Tai ,&nbsp;Kai-Chi Chang ,&nbsp;Ting-Wei Chen ,&nbsp;Huey-Ling Chen ,&nbsp;Yen-Hsuan Ni ,&nbsp;Hong-Yuan Hsu ,&nbsp;Mei-Hwei Chang","doi":"10.1016/j.jhepr.2024.101061","DOIUrl":"https://doi.org/10.1016/j.jhepr.2024.101061","url":null,"abstract":"<div><h3>Background &amp; Aim</h3><p>Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between <em>CTLA-4</em> genotypes/haplotypes, hepatitis B surface antigen (HBsAg), and hepatitis B core-related antigen (HBcrAg) levels, and their potential impact on the clinical course of chronic HBV infection.</p></div><div><h3>Methods</h3><p>We recruited 145 treatment-naïve patients with genotype B or C chronic HBV infection who were initially hepatitis B e-antigen (HBeAg)-positive and had been followed from a mean age of 7.08 years for a total of 4,787 person-years in the study cohort. We also recruited another 69 treatment-naïve adults with genotype B or C chronic HBV infection as a validation cohort. We assessed the <em>CTLA-4</em> gene single nucleotide polymorphisms rs4553808 (–A1661G)/rs5742909 (–C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort.</p></div><div><h3>Results</h3><p><em>CTLA-4</em> promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the <em>CTLA-4</em> AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; <em>p</em> = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 <em>vs.</em> 0.03 log₁₀ IU/ml/year, <em>p</em> = 0.02). The <em>CTLA-4</em> AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (<em>p</em> = 0.01).</p></div><div><h3>Conclusions</h3><p>Chronic HBV-infected patients with a <em>CTLA-4</em> AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion.</p></div><div><h3>Impact and implications</h3><p>The role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in chronic HBV-infected children has not been studied previously. In a very long-term cohort followed from childhood to adulthood, we showed that <em>CTLA-4</em> haplotypes are associated with HBV biomarker levels in childhood and are correlated with the clinical course of chronic HBV infection. CTLA-4 pathway may serve as a future target for the development of therapeutic agents against HBV infection.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000624/pdfft?md5=e9342693fd6a0ee89670eb57871848b4&pid=1-s2.0-S2589555924000624-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140350238","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}