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Proportion of pregnant women with HBV infection eligible for antiviral prophylaxis to prevent vertical transmission: A systematic review and meta-analysis 符合抗病毒预防条件以防止垂直传播的 HBV 感染孕妇比例：系统回顾和荟萃分析

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-03-26 DOI: 10.1016/j.jhepr.2024.101064

Hugues Delamare , Julian Euma Ishii-Rousseau , Adya Rao , Mélanie Cresta , Jeanne Perpétue Vincent , Olivier Ségéral , Shevanthi Nayagam , Yusuke Shimakawa

Background & Aims

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.

Methods

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.

Results

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%).

Conclusions

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.

Impact and implications

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

背景& 目的2020年，世界卫生组织（WHO）建议对高病毒血症（≥200,000 IU/ml）的乙型肝炎病毒（HBV）感染孕妇进行围产期抗病毒预防（PAP）。在无法获得 HBV DNA 的情况下，还建议将乙型肝炎 e 抗原（HBeAg）作为替代方法。为了给政策制定提供信息并指导预防母婴传播策略的实施，我们进行了一项系统回顾和荟萃分析，以估算全球和地区范围内符合 PAP 条件的 HBV 感染孕妇的比例。我们提取了高病毒血症（≥200,000 IU/ml）妇女的比例、HBeAg 阳性妇女的比例、根据 HBV DNA 和 HBeAg 进行交叉分层的妇女比例，以及这些孕产妇群体的儿童感染风险。结果在 6999 篇文章中，共纳入了 131 项研究，涉及 71712 名 HBV 感染孕妇。每个世界卫生组织地区的研究数量分别为 66 项（西太平洋）、21 项（欧洲）、17 项（非洲）、11 项（美洲）、9 项（东地中海）和 7 项（东南亚）。高病毒血症的总体汇总比例为 21.27%（95% CI 17.77-25.26%），地区差异显著：西太平洋（31.56%）、美洲（23.06%）、东南亚（15.62%）、非洲（12.45%）、欧洲（9.98%）和地中海东部（7.81%）。HBeAg 阳性率也显示出类似的地区差异。交叉分层后，高病毒血症和 HBeAg 阳性、高病毒血症和 HBeAg 阴性、低病毒血症和 HBeAg 阳性以及低病毒血症和 HBeAg 阴性的比例分别为 15.24% (95% CI 11.12-20.53%)、2.70% (95% CI 1.88-3.86%)、3.69% (95% CI 2.86-4.75%)和 75.59% (95% CI 69.15-81.05%)。接种无免疫球蛋白和 PAP 的出生剂量疫苗后，儿童感染的相应风险分别为 14.86% (95% CI 8.43-24.88%)、6.94% (95% CI 2.92-15.62%)、7.14% (95% CI 1.00-37.03%) 和 0.14% (95% CI 0.02-1.00%)。影响和意义2020 年，世界卫生组织建议乙肝表面抗原（HBsAg）检测呈阳性的孕妇接受 HBV DNA 检测或 HBeAg 检测，病毒血症高（≥200,000 IU/ml）或 HBeAg 呈阳性的孕妇接受 PAP 检测。为了有效实施新的 HBV 预防母婴传播干预措施，并将 HBV 筛查、风险分层和抗病毒预防纳入常规产前保健服务，估算符合 PAP 条件的 HBV 感染孕妇的比例至关重要。在这项系统回顾和荟萃分析中，我们发现约有五分之一的 HBV 感染孕妇根据 HBV DNA 检测符合 PAP 的条件，而根据 HBeAg 检测符合条件的孕妇比例与此相似。由于各地区符合条件的比例以及不同检测方法的可用性和成本存在很大差异，因此各国必须优化策略，将 HBV 筛查、风险分层和 PAP 纳入常规产前护理服务中。

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引用次数: 0

Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients 欧洲 DAA 患者队列中罕见的 HCV 亚型和再治疗结果

IF 9.5 1区医学 Q1 Medicine

JHEP Reports

Pub Date : 2024-03-25 DOI: 10.1016/j.jhepr.2024.101072

Julia Dietz , Christiana Graf , Christoph P. Berg , Kerstin Port , Katja Deterding , Peter Buggisch , Kai-Henrik Peiffer , Johannes Vermehren , Georg Dultz , Andreas Geier , Florian P. Reiter , Tony Bruns , Jörn M. Schattenberg , Elena Durmashkina , Thierry Gustot , Christophe Moreno , Janina Trauth , Thomas Discher , Janett Fischer , Thomas Berg , A. Zipf

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Impact and implications

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.

背景和目的有关所谓罕见HCV基因型（GT）在大型队列中的患病率和特征的数据十分有限。本研究调查了欧洲队列中罕见 GT 和耐药相关替代的频率以及再治疗的疗效。方法从欧洲耐药数据库中纳入了 129 例罕见 GT1-6 患者。结果1.5%（69/4,656）的无直接作用抗病毒药物（DAA）患者和4.4%（60/1,376）的DAA失败患者感染了罕见GT。虽然罕见GT几乎平均分布在DAA-免疫患者的GT1-6中，但我们在DAA-失败患者中主要检测到罕见GT4（47%，28/60 GT4；其中n=17，4r亚型）和GT3（25%，15/60 GT3，其中n=8，3b亚型）。在DAA失败的患者中，共有62%（37/60）的患者对第一代治疗方案无效，其中大多数感染了罕见的GT4（57%，21/37）。相比之下，在泛基因型DAA治疗失败的患者中（38%，23/60），感染罕见GT3的比例较高（57%，13/23）。虽然NS5A RAS在罕见的GT2、GT5a和GT6中并不常见，但我们在罕见的GT1、GT3和GT4中的28、30和31位观察到了合并的RAS，这可以被认为是固有的。完成再治疗随访的DAA失败患者实现了较高的SVR率（94%，45/48改良意向治疗分析；92%，45/49意向治疗）。结论在这个欧洲队列中，罕见的HCV GT并不常见。在这个欧洲队列中，罕见的HCV GT并不常见，DAA失败患者中特定罕见GT的累积表明DAA方案的抗病毒活性降低。在全球范围内，用于一线治疗的泛基因型治疗方案以及用于再治疗的多种靶向治疗方案的供应有限，这可能会导致HCV根除目标的实现被推迟。本研究发现，在欧洲的 HCV 感染者中，罕见的 HCV 基因型比例较低。在直接作用抗病毒（DAA）失败的患者中，罕见的 GT3 亚型在泛基因型 DAA 治疗后积累，罕见的 GT4 亚型在第一代 DAA 治疗失败后积累，并且在 NS5A 第 28、30 和 31 位检测到病毒耐药性。用于一线治疗的泛基因型 DAA 方案以及用于再治疗的多种靶向方案在全球的供应有限，这可能导致消除 HCV 的目标被推迟。

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引用次数: 0

Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide Peg-IFN对接受布来韦肽治疗的HDV感染者病毒动力学的影响

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-03-24 DOI: 10.1016/j.jhepr.2024.101070

Selma El Messaoudi , Ségolène Brichler , Claire Fougerou-Leurent , Emmanuel Gordien , Athenaïs Gerber , Amal Kortebi , Garance Lagadic , Miroslava Subic-Levrero , Sophie Metivier , Stanislas Pol , Anne Minello , Vlad Ratziu , Vincent Leroy , Philippe Mathurin , Laurent Alric , Fatoumata Coulibaly , Jean-Michel Pawlotsky , Fabien Zoulim , Victor de Lédinghen , Jérémie Guedj

Background & Aims

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.

Methods

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.

Results

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 (>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.

Conclusions

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.

Impact and implications

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.

背景& 目的布来韦肽是治疗慢性丁型肝炎的第一类入口抑制剂抗病毒疗法。布来韦肽治疗期间的病毒动力学以及布来韦肽与聚乙二醇化干扰素（Peg-IFN）联用的效果尚不清楚。结果据估计，布来韦肽阻断细胞感染的有效率为 90.3%，而 Peg-IFN 阻断病毒生成的有效率为 92.4%，但个体间差异较大。在布来韦肽基础上加用 Peg-IFN 可使病毒学下降更快，第 48 周的病毒学应答率（下降 2 log 或检测不到）为 86.9%（95% 预测区间 [PI] = [79.7-95.0]），而只用布来韦肽的应答率为 56.1%（95% 预测区间 [PI] = [46.4-66.7]）。该模型还用于预测病毒感染治愈的概率，布来韦肽的治愈率为 8.8%（95% PI = [3.5-13.2]），而布来韦肽 + Peg-IFN 的治愈率为 18.8%（95% PI = [11.6-29.0]）。数学模型显示，治疗 144 周后，布来韦肽的病毒治愈率可达 42.1%（95% PI = [33.3-52.6]），布来韦肽 + Peg-IFN 的病毒治愈率可达 66.7%（95% PI = [56.5-76.8]）。影响和意义布来韦肽因其良好的安全性和开始治疗后快速的病毒学应答，已被欧洲监管机构批准用于慢性 HDV 感染，但最佳治疗时间和获得持续病毒学应答的机会仍然未知。这项研究的结果对临床医生和研究人员具有重大影响，因为它们提供了关于Peg-IFN和布来韦肽联合疗法对CHD患者的长期病毒学益处的重要知识。现在需要进行临床试验来证实这些预测。

{"title":"Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide","authors":"Selma El Messaoudi , Ségolène Brichler , Claire Fougerou-Leurent , Emmanuel Gordien , Athenaïs Gerber , Amal Kortebi , Garance Lagadic , Miroslava Subic-Levrero , Sophie Metivier , Stanislas Pol , Anne Minello , Vlad Ratziu , Vincent Leroy , Philippe Mathurin , Laurent Alric , Fatoumata Coulibaly , Jean-Michel Pawlotsky , Fabien Zoulim , Victor de Lédinghen , Jérémie Guedj","doi":"10.1016/j.jhepr.2024.101070","DOIUrl":"10.1016/j.jhepr.2024.101070","url":null,"abstract":"<div><h3>Background & 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 (>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}

引用次数: 0

Interleukin-7-based identification of liver lymphatic endothelial cells reveals their unique structural features 基于白细胞介素-7的肝脏淋巴内皮细胞鉴定揭示了其独特的结构特征

IF 8.3 1区医学 Q1 Medicine

JHEP Reports

Pub Date : 2024-03-18 DOI: 10.1016/j.jhepr.2024.101069

Yilin Yang , Jain Jeong , Tingting Su , Sanchuan Lai , Pengpeng Zhang , Rolando Garcia-Milian , Morven Graham , Xinran Liu , Matthew J. McConnell , Teruo Utsumi , Joao Pereira , Yasuko Iwakiri

Background & Aims

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 (<0.01% of entire liver cell population) in a normal liver.

Methods

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.

Results

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.

Conclusions

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.

Impact and implications

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.

背景& 目的淋巴系统在维持体液平衡和免疫调节方面发挥着至关重要的作用。研究肝脏淋巴管一直被认为具有挑战性，因为其他肝细胞也表达常见的淋巴内皮细胞（LyEC）标记物。此外，由于正常肝脏中淋巴内皮细胞的丰度极低（占整个肝细胞总数的 0.01%），因此分离足够数量的淋巴内皮细胞一直是个挑战。方法利用我们已发表的小鼠肝脏单细胞 RNA 测序（scRNA-seq）数据集（GSE147581）鉴定潜在的淋巴内皮细胞标记物。白细胞介素-7（IL7）启动子驱动的绿色荧光蛋白敲入杂合小鼠被用于验证肝脏中LyECs的IL7表达、肝脏LyEC分离方案的开发以及肝脏缺血/再灌注（I/R）损伤的产生。扫描电子显微镜用于分析LyECs的结构。结果通过scRNA-seq分析，我们发现IL7是肝脏LyECs的唯一标记物，与其他肝细胞类型没有重叠。基于肝脏LyECs中IL7的表达，我们建立了一种LyEC分离方法，并观察到LyECs独特的细胞表面结构，包括栅栏和细胞孔（直径从100到400 nm不等）。此外，我们还发现了在 I/R 肝损伤过程中发生改变的 LyEC 基因。影响和意义由于缺乏肝脏 LyEC 的特异性标记物，因此了解肝脏淋巴系统具有挑战性。这项研究发现了IL7作为LyECs的可靠标记物，从而开发出了一种有效的方法来分离LyECs、阐明其独特的细胞表面结构并鉴定在肝损伤过程中发生变化的LyEC基因。未来，开发用于检测人体肝脏标本中 IL7 的抗体将进一步推动我们对肝脏淋巴系统的了解。

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引用次数: 0

Maternal obesity increases the risk of hepatocellular carcinoma through the transmission of an altered gut microbiome 母亲肥胖会通过改变肠道微生物群的传播增加肝细胞癌的风险

IF 8.3 1区医学 Q1 Medicine

JHEP Reports

Pub Date : 2024-03-12 DOI: 10.1016/j.jhepr.2024.101056

Beat Moeckli , Vaihere Delaune , Benoît Gilbert , Andrea Peloso , Graziano Oldani , Sofia El Hajji , Florence Slits , Joana Rodrigues Ribeiro , Ruben Mercier , Adrien Gleyzolle , Laura Rubbia-Brandt , Quentin Gex , Stephanie Lacotte , Christian Toso

Background & Aims

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.

Methods

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.

Results

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% vs. 3.09%, p = 0.0023) and fibrosis (3.75% vs. 2.70%, p = 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 vs. 1.0, p = 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% vs. 37.5%, p = 0.0084) with a higher mean tumor volume (234 vs. 3 μm³, p = 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 vs. 2.92, p = 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.

Conclusions

Maternal obesity increases female offspring’s susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition.

Impact and implications

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.

背景& 目的越来越多的证据表明，母亲肥胖会对后代的健康产生负面影响。此外，肥胖还是肝细胞癌（HCC）的一个风险因素。我们的研究旨在调查母体肥胖对后代发生 HCC 风险的影响，并阐明其潜在的传播机制。所有后代在断奶后都接受 ND。我们研究了N-二乙基亚硝胺（DEN）诱导的HCC小鼠模型的肝脏组织学和肿瘤负荷。40周时，与ND喂养母亲的后代（ND后代）相比，HFD喂养母亲的雌性后代（HFD后代）更容易发生脂肪变性（9.43% vs. 3.09%，p = 0.0023）和纤维化（3.75% vs. 2.70%，p = 0.039），并表现出炎症浸润数量增加（4.8 vs. 1.0，p = 0.018）以及纤维化和炎症相关基因表达增加。在 DEN 诱导后，HFD 后代出现肝肿瘤的比例更高（79.8% 对 37.5%，p = 0.0084），肿瘤的平均体积更大（234 对 3 μm3，p = 0.0041）。HFD后代微生物群的多样性明显低于ND后代（香农指数为2.56 vs. 2.92，p = 0.0089），而通过共同饲养，这种多样性得到了改善。在主成分分析中，无论母体饮食如何，共同饲养动物的微生物群特征都集中在一起。结论母体肥胖会增加雌性后代对 HCC 的易感性。母亲肥胖会增加女性后代对 HCC 的易感性，而肠道微生物组改变的传播在这种易感性中起着重要作用。在这项研究中，我们调查了母体饮食对肠道微生物组组成的影响及其在后代肝癌发生中的作用。我们发现，高脂肪饮食母亲所生的小鼠遗传了较少多样性的肠道微生物组，出现慢性肝损伤并增加了患肝癌的风险。将来自正常饮食和高脂肪饮食母亲的后代共同饲养，可恢复肠道微生物群，并显著降低罹患肝癌的风险。实施微生物筛查和恢复微生物多样性有望帮助识别和治疗高危人群，防止危害后代。

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引用次数: 0

Recommendations on maximising the clinical value of tissue in the management of patients with intrahepatic cholangiocarcinoma 在治疗肝内胆管癌患者过程中最大化组织临床价值的建议

IF 8.3 1区医学 Q1 Medicine

JHEP Reports

Pub Date : 2024-03-12 DOI: 10.1016/j.jhepr.2024.101067

Timothy Kendall , Diletta Overi , Maria Guido , Chiara Braconi , Jesus Banales , Vincenzo Cardinale , Eugenio Gaudio , Bas Groot Koerkamp , Guido Carpino

Background & Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Impact and Implications

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.

背景& 目的肝内胆管癌患者现在可以采用针对特定分子改变的靶向疗法进行治疗。因此，提交给病理部门的组织样本除了诊断信息外，还必须提供分子信息，对于切除标本，还必须提供分期信息。因此，病理学家在评估这些标本时的角色也发生了变化，以适应这种个性化的方法。方法我们通过对现有指南进行系统性回顾以产生候选声明，然后通过国际德尔菲流程为病理学家制定了建议和指南。来自六大洲 28 个国家的 59 名病理学家对标本从病理部门接收到最终书面报告授权的所有路径要素的声明进行了评分。另外还对报告的 "最终用户"（包括外科医生、肿瘤学家和胃肠病学家）进行了调查，以评估书面报告中应包含哪些信息，从而对患者进行适当的管理。结果有 48 项声明达成了共识，被纳入指南中，其中有 10 项关于书面报告内容的声明也得到了最终用户参与者的共识。结论这些指导原则和建议提供了一个框架，使病理学家在报告肝内胆管癌患者时能最大限度地提高个性化患者管理所需标本的信息量。影响和意义肝内胆管癌的活检或切除病变组织除了诊断和分期信息外，还必须提供有关肿瘤内分子异常的信息，以确定是否适合个性化治疗。在此，我们通过德尔菲法征求病理学家和 "病理报告最终用户 "的意见，为报告此类病例的病理学家制定了国际共识指南。该指南强调在报告病例时需要保留组织以便进行分子检测，并强调报告需要在更广泛的临床和放射学背景下解释组织学特征。该指南将使病理学家能够以统一的方式报告肝内胆管癌病例，从而最大限度地发挥所获组织的价值，促进多学科患者的最佳管理。

{"title":"Recommendations on maximising the clinical value of tissue in the management of patients with intrahepatic cholangiocarcinoma","authors":"Timothy Kendall , Diletta Overi , Maria Guido , Chiara Braconi , Jesus Banales , Vincenzo Cardinale , Eugenio Gaudio , Bas Groot Koerkamp , Guido Carpino","doi":"10.1016/j.jhepr.2024.101067","DOIUrl":"10.1016/j.jhepr.2024.101067","url":null,"abstract":"<div><h3>Background & 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}

引用次数: 0

Enhanced liver fibrosis (ELF) score predicts hepatic decompensation and mortality 增强型肝纤维化（ELF）评分可预测肝功能失代偿和死亡率

IF 8.3 1区医学 Q1 Medicine

JHEP Reports

Pub Date : 2024-03-11 DOI: 10.1016/j.jhepr.2024.101062

Madeline Pearson , Jennifer Nobes , Iain Macpherson , Lucy Gold , Michael Miller , Ellie Dow , John F. Dillon

Background & Aims

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.

Methods

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).

Results

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% vs. 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).

Conclusions

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.

Impact and implications

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.

背景& 目的在社区肝病检测路径中，最常见的转诊原因是纤维化评估。我们研究了将增强肝纤维化（ELF）评分作为二线检验（在纤维化-4指数[FIB-4]和/或非酒精性脂肪肝纤维化评分不确定或偏高之后）的影响，以指导我们的多病因路径中的转诊和预后。结果共纳入 1327 名患者，中位随访 859 天，ELF 评分中位数为 10.2。在9.8分的临界值下，肝硬化的总体灵敏度为94%（代谢相关性脂肪性肝病为100%，酒精相关性肝病为89%）。作为二线检测，ELF评分的确定将转诊率降低了34%。ELF评分可预测肝脏结果；每变化一个单位，失代偿率（调整后危险比[aHR] 2.215，95% CI：1.934-2.537）和肝脏相关死亡率（aHR 2.024，95% CI：1.674-2.446）都会增加。就肝脏相关死亡风险而言，ELF优于FIB-4，尤其是在短期内（曲线下面积[AUC]94.3%对6个月时的82.8%）。在FIB-4无法确定的情况下，ELF在至少两年内的所有结果中都具有更高的AUC。ELF≥13与较高的失代偿率（90天内26%）和全因死亡率（1年内38%）相关。ELF评分≥13分的患者被认为是高风险患者，需要进行紧急临床评估。影响和意义疑似肝病的初级护理路径越来越普遍，往往导致肝纤维化评估的专科转诊增加。本研究通过对肝脏相关结果的临床随访，提供了进一步的证据支持ELF检测与其他简单的纤维化标志物相结合，通过两步法安全地减少转诊。此外，ELF评分可预测与肝脏相关的发病率和死亡率，ELF评分≥13分的患者风险特别高。这项研究可能有助于为早期检测肝病的诊断路径的实施提供信息，并强调了对ELF评分非常高的患者进行紧急复查的必要性。

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引用次数: 0

Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial 肝细胞癌的碳离子放射治疗可提供出色的局部控制：前瞻性 I 期 PROMETHEUS 试验

IF 8.3 1区医学 Q1 Medicine

JHEP Reports

Pub Date : 2024-03-11 DOI: 10.1016/j.jhepr.2024.101063

Philipp Hoegen-Saßmannshausen , Patrick Naumann , Paula Hoffmeister-Wittmann , Semi Ben Harrabi , Katharina Seidensaal , Fabian Weykamp , Thomas Mielke , Malte Ellerbrock , Daniel Habermehl , Christoph Springfeld , Michael T. Dill , Thomas Longerich , Peter Schirmacher , Arianeb Mehrabi , De-Hua Chang , Juliane Hörner-Rieber , Oliver Jäkel , Thomas Haberer , Stephanie E. Combs , Jürgen Debus , Jakob Liermann

Background & Aims

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.

Methods

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.

Results

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.

Conclusions

CIRT of HCC yields excellent local control without dose-limiting toxicity.

Impact and implications

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.

Clinical Trials Registration

The study is registered at ClinicalTrials.gov (NCT01167374

背景& 目的无法手术的肝细胞癌（HCC）可采用立体定向体放射治疗。然而，碳离子放射治疗（CIRT）在保护非肿瘤肝脏方面更为有效。高线性能量传递可提高疗效。日本和中国的低分次碳离子放疗研究取得了很好的效果。由于不同的放射生物学模型和 HCC 病因谱不同，这些结果是否适用于欧洲队列和中心仍存在疑问。这项前瞻性研究旨在评估安全性和有效性，并根据局部效应模型（LEM）I确定主动光栅扫描CIRT的最佳剂量。方法CIRT每隔一天进行一次，分四次进行，相对生物效应（RBE）加权的分次剂量为8.1-10.5 Gy（总剂量为32.4-42.0 Gy [RBE]）。剂量升级分为五个剂量水平，每个剂量水平至少有三名患者接受治疗。结果20名患者接受了CIRT治疗（中位年龄74.7岁，肝硬化患者16人，Child-Pugh评分[CP] A5 [n = 10]、A6 [n = 4]、B8 [n = 1]和B9 [n = 1]）。中位随访时间为 23 个月。除了 CIRT 12 个月后出现一次 III 级γ-谷氨酰转移酶升高（与场外肝功能进展同步）外，未出现剂量限制性毒性反应和超过 II 级的毒性反应。在 CIRT 后的 12 个月内，CP 没有升高。可以安全地使用最高剂量。随访期间未出现局部复发。客观反应率为 80%。中位总生存期为30.8个月（1/2/3年：75%/64%/22%）。无进展生存期中位数为20.9个月（1/2/3年：59%/43%/43%）。结论CIRT治疗HCC可获得良好的局部控制效果，且无剂量限制性毒性。影响和意义迄今为止，只有日本和中国的研究对碳离子放疗治疗肝细胞癌的安全性和有效性进行了前瞻性评估。使用局部效应模型制定放疗计划时的最佳剂量和分次尚不清楚。我们的研究结果不仅对欧美粒子治疗中心具有重要意义，而且对所有参与肝细胞癌治疗和护理的专家也具有重要意义，因为我们首次在亚洲以外地区展示了碳离子放疗治疗肝细胞癌的前瞻性数据。出色的局部控制效果应鼓励进一步使用碳离子放射疗法治疗肝细胞癌，并鼓励设计随机对照试验。临床试验注册该研究已在ClinicalTrials.gov（NCT01167374）上注册。

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引用次数: 0

Xanthine oxidase promotes hepatic lipid accumulation through high fat absorption by the small intestine 黄嘌呤氧化酶通过小肠对脂肪的大量吸收促进肝脏脂质积累

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-03-09 DOI: 10.1016/j.jhepr.2024.101060

Lin Liu , Yuntao Zhang , Xuanyang Wang , Hongxue Meng , Yan He , Xiaoqing Xu , Huan Xu , Chunbo Wei , Xuemin Yan , Xinmiao Tao , Keke Dang , Pingnan Ma , Xiaoyu Guo , Sen Yang , Jiemei Wang , Ying Li

Background & Aims

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.

Methods

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.

Results

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; p-trend <0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, p <0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific Xdh 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.

Conclusions

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.

Impact and implications

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 in vivo. These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.

背景& 目的目前还没有研究调查黄嘌呤氧化酶（XO）升高对脂质代谢紊乱的直接影响。在此，我们旨在通过一项前瞻性队列研究明确 XO 在脂质代谢中的作用，并阐明其潜在机制。方法在一项包含 3358 名参与者（20-75 岁）的人群队列中，通过 Cox 比例危险模型研究了血清 XO 活性与代谢相关性脂肪性肝病（MASLD）之间的关系。结果经过平均 5.8 年的随访，我们发现血清 XO 活性的升高与 MASLD 患病风险的增加有关（危险比 [HR]：2.08；95% CI：1.44-3.01；p-trend <0.001）。此外，血清 XO 活性与血清甘油三酯水平显著相关（r = 0.68，p <0.001）。我们证实，在 MASLD 患者的肝脏样本中，肝脏 XO 表达增加。通过使用组织特异性 Xdh 基因敲除小鼠，我们观察到在高脂饮食而非正常饮食条件下，脂质代谢迅速紊乱。我们发现，XO 的过度表达会促进小肠吸收多余的膳食脂肪。结论我们的研究在一项大型人群前瞻性队列研究中阐明了血清 XO 活性水平与 MASLD 发病之间的关系。此外，我们的小鼠模型表明，XO 过度表达会通过小肠过度吸收脂肪的机制促进脂质积累。影响和意义通过基于人群的前瞻性队列研究和各种动物模型，我们发现了黄嘌呤氧化酶调节脂质代谢的新机制。我们的研究结果表明，黄嘌呤氧化酶的过度表达会增加对过量膳食脂肪的吸收，并可能促进脂质在体内的转运，从而促进脂质的积累。这些结果可能对开发治疗与脂质代谢紊乱相关疾病的疗法具有重要意义。

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引用次数: 0

CTLA-4 haplotype predicts HBsAg and HBcrAg levels and HBeAg seroconversion age in children with chronic HBV infection CTLA-4 单倍型可预测慢性 HBV 感染儿童的 HBsAg 和 HBcrAg 水平以及 HBeAg 血清转换年龄

IF 8.3 1区医学 Q1 Medicine

JHEP Reports

Pub Date : 2024-03-08 DOI: 10.1016/j.jhepr.2024.101061

Jia-Feng Wu , Chi-San Tai , Kai-Chi Chang , Ting-Wei Chen , Huey-Ling Chen , Yen-Hsuan Ni , Hong-Yuan Hsu , Mei-Hwei Chang

Background & Aim

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) attenuates cytotoxic T lymphocyte (CTL) activation. This study was performed to examine the relationships between CTLA-4 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.

Methods

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 CTLA-4 gene single nucleotide polymorphisms rs4553808 (–A1661G)/rs5742909 (–C318T) in both cohorts, and the serum HBsAg and HBcrAg levels in the study cohort.

Results

CTLA-4 promoter haplotypes were associated with HBsAg and HBcrAg levels at 10 and 15 years of age in the study cohort. Patients with the CTLA-4 AA/CC haplotype showed earlier spontaneous HBeAg seroconversion (hazard ratio = 1.58; p = 0.02), and a more rapid annual decline in the serum HBsAg level than other patients (0.09 vs. 0.03 log₁₀ IU/ml/year, p = 0.02). The CTLA-4 AA/CC haplotype was also predictive of HBeAg seroconversion in the validation cohort (p = 0.01).

Conclusions

Chronic HBV-infected patients with a CTLA-4 AA/CC haplotype had lower serum HBsAg and HBcrAg levels in childhood and earlier spontaneous HBeAg seroconversion.

Impact and implications

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 CTLA-4 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.

背景& 目的细胞毒性T淋巴细胞相关蛋白4（CTLA-4）可减轻细胞毒性T淋巴细胞（CTL）的活化。本研究旨在探讨 CTLA-4 基因型/单倍型与乙型肝炎表面抗原（HBsAg）和乙型肝炎核心相关抗原（HBcrAg）水平之间的关系及其对慢性 HBV 感染临床过程的潜在影响。方法我们招募了 145 名基因 B 型或 C 型慢性 HBV 感染的未经治疗的患者，他们最初的乙肝 e 抗原（HBeAg）呈阳性，并从平均年龄 7.08 岁开始接受随访，研究队列中的患者总计达 4,787 人年。我们还招募了另外 69 名基因 B 型或 C 型慢性 HBV 感染的治疗无效成人作为验证队列。我们对两个队列中的 CTLA-4 基因单核苷酸多态性 rs4553808 (-A1661G)/rs5742909 (-C318T) 以及研究队列中的血清 HBsAg 和 HBcrAg 水平进行了评估。与其他患者相比，CTLA-4 AA/CC 单倍型患者表现出更早的自发 HBeAg 血清转换（危险比 = 1.58；p = 0.02），血清 HBsAg 水平的年下降速度更快（0.09 对 0.03 log10 IU/ml/年，p = 0.02）。结论具有 CTLA-4 AA/CC 单倍型的慢性 HBV 感染者在儿童期的血清 HBsAg 和 HBcrAg 水平较低，自发 HBeAg 血清转换较早。影响和意义此前尚未研究过细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 在慢性 HBV 感染儿童中的作用。在一个从儿童到成年的长期队列中，我们发现 CTLA-4 单倍型与儿童期的 HBV 生物标志物水平相关，并与慢性 HBV 感染的临床过程相关。CTLA-4 通路可能是未来开发 HBV 感染治疗药物的靶点。

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