JHEP Reports最新文献_第5页

Inflammation in liver fibrosis and atrial fibrillation: A prospective population-based proteomic study 肝纤维化和心房颤动中的炎症：一项基于人群的前瞻性蛋白质组学研究

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-18 DOI: 10.1016/j.jhepr.2024.101171

Joost Boeckmans , Maurice Michel , Alexander Gieswinkel , Oliver Tüscher , Stavros V. Konstantinides , Jochem König , Thomas Münzel , Karl J. Lackner , Jasmin Ghaemi Kerahrodi , Alexander K. Schuster , Philipp S. Wild , Peter R. Galle , Jörn M. Schattenberg

Background & Aims

Elevated liver stiffness has been associated with atrial fibrillation (AFib) in the general population. The mechanism underlying this association is unclear.

Methods

Participants were recruited from the general population and prospectively enrolled with follow-up for 5 years. The fibrosis-4 (FIB-4) index was used as a surrogate marker for liver fibrosis. Proteomics analysis was performed using the 92-target Olink inflammation panel. Validation was performed using the NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet index (APRI), and repeat confirmation proteomics.

Results

A sample of 11,509 participants with a mean age of 54.0 ± 11.1 years, 51.3% women, and a median FIB-4 index of 0.85 (0.65/1.12), was used. The FIB-4 index was predictive for prevalent (FIB-4 index adjusted odds ratio (aOR) per SD: 1.100 with 95% CI 1.011-1.196; p = 0.026), but not incident AFib (log[FIB-4 index]) adjusted hazard ratio: 1.125 with 95% CI 0.943-1.342, p = 0.19). Elastic net regularized regression identified CCL20, DNER, and CXCL10 for prevalent AFib, and AXIN1, CXCL10, and Flt3L for the log(FIB-4 index) (per SD) as most important in common regulated proteins. The relationship between the FIB-4 index, the identified proteins, and AFib was relevant and reproduced at the 5-year follow-up for CXCL10 after adjusting for confounders (log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p <0.0001; CXCL10 [per SD] - AFib aOR 1.455 with 95% CI 1.217-1.741, p <0.0001), reproduced using the NFS and APRI, and corresponding to increased serum levels.

Conclusions

CXCL10 is linked to liver fibrosis, as determined by the FIB-4 index, and to prevalent AFib.

Impact and implications:

How elevated liver stiffness relates to atrial fibrillation in the general population remains to be clarified. We hypothesized that systemic inflammation against a background of liver fibrosis produced from metabolic dysfunction-associated steatotic liver disease (MASLD), is involved in the pathophysiology of atrial fibrillation. Using large-scale targeted proteomics, we found that CXCL10 is related to both liver fibrosis, as defined by the fibrosis-4 index, and to atrial fibrillation. These results can aid evidence-based drug development for patients with atrial fibrillation and MASLD-related liver fibrosis.

背景& 目的在普通人群中，肝脏僵硬度升高与心房颤动（AFib）有关。方法从普通人群中招募参与者，进行为期5年的前瞻性随访。肝纤维化-4（FIB-4）指数被用作肝纤维化的替代标志物。蛋白质组学分析采用了92个靶点的Olink炎症面板。使用非酒精性脂肪肝纤维化评分（NFS）、天冬氨酸氨基转移酶与血小板指数（APRI）和重复确认蛋白质组学进行了验证。结果样本中有11509名参与者，平均年龄为54.0±11.1岁，女性占51.3%，FIB-4指数中位数为0.85（0.65/1.12）。FIB-4 指数可预测心房颤动的发病率（FIB-4 指数调整后每 SD 的比值比 (aOR)：1.100，95% CI 1.011-1.196；p = 0.026），但不能预测心房颤动的发病率（log[FIB-4 指数]）调整后的危险比：1.125，95% CI 0.943-1.342，p = 0.19）。弹性网正则化回归确定了CCL20、DNER和CXCL10对流行性心房颤动的影响，以及AXIN1、CXCL10和Flt3L对log(FIB-4指数)（每标清）的影响，它们是常见调节蛋白中最重要的。在对混杂因素进行调整后，FIB-4指数、已确定的蛋白质和心房颤动之间的关系是相关的，并且在5年随访中，CXCL10的关系再现（log[FIB-4 index] per SD - CXCL10 [per SD] adjusted β 0.160 with 95% CI 0.127-0.194, p <0.0001；CXCL10 [per SD] - AFib aOR 1.455 with 95% CI 1.217-1.结论CXCL10与肝纤维化（由FIB-4指数确定）以及心房颤动的流行有关。影响和意义：肝脏僵硬度升高与普通人群心房颤动的关系仍有待明确。我们假设，在代谢功能障碍相关性脂肪性肝病（MASLD）导致肝纤维化的背景下，全身性炎症参与了心房颤动的病理生理学过程。通过大规模靶向蛋白质组学研究，我们发现 CXCL10 既与肝纤维化（由纤维化-4 指数定义）有关，也与心房颤动有关。这些结果有助于为心房颤动和MASLD相关肝纤维化患者开发循证药物。

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引用次数: 0

Loss of biochemical response at any time worsens outcomes in UDCA-treated patients with primary biliary cholangitis 原发性胆汁性胆管炎患者在任何时候失去生化反应都会使病情恶化

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-08 DOI: 10.1016/j.jhepr.2024.101168

Surain B. Roberts , Woo Jin Choi , Lawrence Worobetz , Catherine Vincent , Jennifer A. Flemming , Angela Cheung , Karim Qumosani , Mark Swain , Dusanka Grbic , Hin Hin Ko , Kevork M. Peltekian , Lusine Abrahamyan , Monika Saini , Kattleya Tirona , Bishoi Aziz , Ellina Lytvyak , Pietro Invernizzi , Cyriel Y. Ponsioen , Tony Bruns , Nora Cazzagon , Bettina E. Hansen

Background & Aims

Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival.

Methods

We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry).

Results

A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results.

Conclusion

Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy.

Impact and implications:

Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

背景& 目的熊去氧胆酸（UDCA）治疗的生化反应与原发性胆汁性胆管炎（PBC）患者的良好预后有关。生化反应通常在疾病早期进行评估，目前尚不清楚有多大比例的患者失去了之前获得的生化反应，也不知道这是否会影响长期无肝移植（LT）生存率。方法我们从加拿大自身免疫性肝病网络中确定了所有接受过 UDCA 治疗的 PBC 患者，并在 1 年时进行了生化测量，评估了他们的肝脏生化随时间变化的情况。生化反应不充分的定义是在 UDCA 治疗 1 年及其后的所有时间点，血清碱性磷酸酶≥正常值上限的 1.67 倍或血清总胆红素异常。多态马尔可夫模型用于估算生化反应状态之间的转换率，以及从每个状态到LT或死亡的转换率。研究结果在外部队列（GLOBAL PBC 登记）中得到验证。诊断时的平均年龄为 53 岁，91% 为女性，33% 的患者在 1 年后对 UDCA 生化反应不足（n = 269）。与随后失去反应的患者相比，最初保持足够反应的患者发生LT或死亡的比例较低（相对比例为0.102，95% CI为0.047-0.223）。与未恢复充分应答的患者（0.016，95% CI 0.001-0.568）和再次失去应答的患者（0.010，95% CI 0.001-0.340）相比，恢复充分应答的患者的比率较低。第三次恢复充分应答的患者的应答率也低于未恢复应答的患者（0.151，95% CI 0.040-0.566）。对全球 PBC 登记（n = 2,237 人）的分析验证了这些结果。影响和意义：对熊去氧胆酸的早期生化反应与原发性胆汁性胆管炎（PBC）患者的良好预后有关。我们的研究表明，随着时间的推移，PBC 患者的生化反应状态会发生转变，而这些转变与肝移植或死亡风险的变化相对应。临床医生应该在整个随访过程中重新评估 PBC 患者的风险并优化治疗决策，无论早期生化治疗反应如何。

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引用次数: 0

Association of physical activity, including amount and maintenance, with the risk of HCC among patients with type 2 diabetes 体育锻炼（包括运动量和维持时间）与 2 型糖尿病患者罹患肝癌风险的关系

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-03 DOI: 10.1016/j.jhepr.2024.101166

Wonkyung Han , Kyungdo Han , Seong Gyu Hwang , Sang Hoon Ahn , Mi Na Kim

Background & Aims

We investigated the association of physical activity (PA) levels and changes with the risk of hepatocellular carcinoma (HCC) in patients with type 2 diabetes.

Methods

Patients with type 2 diabetes who had undergone health examinations in 2009 and 2011 were enrolled. In total, 1,439,152 patients were included in the analysis. The level of PA was classified as inactive (<500 metabolic equivalent task [MET]-min/week), moderately active (500-1,500 MET-min/week), and active (≥1,500 MET-min/week). Change in PA was categorized as persistently inactive PA, newly active PA, active PA quitter, and persistently active PA according to change of PA between 2009 and 2011.

Results

During a median of 5.2 years of follow-up, 22,686 patients developed HCC. Compared to the inactive group, the risk of HCC was significantly lower in the moderately active (adjusted hazard ratio [aHR] 0.96, 95% CI 0.93–0.99), and active (aHR 0.95, 95% CI 0.91–0.99) groups. The patients in the persistently active PA group had a significantly lower risk of HCC than those in the persistently inactive PA group (aHR 0.91, 95% CI 0.84–0.98).

Conclusions

Physical activity exhibited a dose-responsive preventive effect against HCC in patients with diabetes.

Impact and implications:

Our study investigated the impact of physical activity (PA) levels and changes on the risk of hepatocellular carcinoma (HCC) in patients with type 2 diabetes. PA was associated with a dose-responsive preventive effect against HCC. Patients in the persistently active PA group had a significantly lower risk of HCC than those in the persistently inactive PA group, while newly active patients and PA quitters had similar risks to the persistently inactive group. Our study highlighted the importance of maintaining regular PA as a preventive strategy against HCC.

背景& 目的我们研究了体力活动（PA）水平及其变化与 2 型糖尿病患者罹患肝细胞癌（HCC）风险的关联。共有 1,439,152 名患者被纳入分析。活动量水平分为不活跃（500 新陈代谢当量[MET]-min/周）、中等活跃（500-1,500 MET-min/周）和活跃（≥1,500 MET-min/周）。根据2009年至2011年期间PA的变化，将PA的变化分为持续不活跃PA、新近活跃PA、活跃PA戒断者和持续活跃PA。结果在中位5.2年的随访期间，22,686名患者患上了HCC。与不活跃组相比，中度活跃组（调整后危险比 [aHR] 0.96，95% CI 0.93-0.99）和活跃组（aHR 0.95，95% CI 0.91-0.99）患 HCC 的风险明显较低。结论：体育锻炼对糖尿病患者的肝细胞癌具有剂量反应性的预防作用。影响和意义：我们的研究调查了体育锻炼（PA）水平和变化对 2 型糖尿病患者肝细胞癌（HCC）风险的影响。体力活动对HCC具有剂量反应性的预防作用。持续积极参加体育锻炼组的患者患 HCC 的风险明显低于持续不参加体育锻炼组的患者，而新近参加体育锻炼的患者和放弃体育锻炼的患者患 HCC 的风险与持续不参加体育锻炼组的患者相似。我们的研究强调了保持规律的体育锻炼作为HCC预防策略的重要性。

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引用次数: 0

YAP mediates HIV-related liver fibrosis YAP 介导与艾滋病毒相关的肝纤维化

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-03 DOI: 10.1016/j.jhepr.2024.101163

Volney A. Spalding , Brian A. Fellenstein , James Ahodantin , Andre J. Jeyarajan , Yongtao Wang , Sanjoy K. Khan , Min Xu , Wenyu Lin , Nadia Alatrakchi , Lishan Su , Raymond T. Chung , Shadi Salloum

Background & Aims

HIV accelerates liver fibrosis attributable to multiple etiologies, including HCV, HBV, and steatotic liver disease. Evidence also suggests that HIV infection itself is associated with liver fibrogenesis. Recent studies have implicated Yes-associated protein 1 (YAP1) and the upstream lysophosphatidic acid (LPA)/PI3K/AKT pathway as critical regulators of hepatic fibrogenesis, and suggest a connection to HIV-related liver fibrosis. However, the relationship between YAP/PI3K/AKT pathway activation and HIV-related liver fibrosis remains uncertain.

Methods

qPCR, western blot, immunofluorescence, and ELISA (replicates n ≥3) were performed in an unbiased humanized mouse model (NRG-hu HSC mice, n = 6), the precision cut liver slice ex vivo model, and both traditional in vitro models as well as a 3D spheroid system.

Results

YAP target gene mRNA and protein levels (ANKRD, CTGF, CYR61) were upregulated across all models exposed to HIV. Humanized mice infected with HIV had significant increases in the percentage of YAP-positive nuclei (2.2-fold) and the percentage area of Sirius Red collagen staining (3.3-fold) compared to control mice. Serum concentrations of LPA were increased 5.8-fold in people living with HIV compared to healthy controls. Modulation of LPAR1, PI3K, and AKT by either inhibitors or small-interfering RNAs abrogated the fibrotic effects of HIV exposure and downregulated YAP target genes within cultured liver cells.

Conclusions

The LPAR/PI3K/AKT axis is vital for the activation of YAP and hepatic fibrogenesis due to HIV infection. This novel mechanistic insight suggests new pharmacologic targets for treatment of liver fibrosis in people living with HIV.

Impact and implications:

There are currently no FDA-approved treatments for cirrhosis, while liver disease is the second leading cause of mortality among people living with HIV after AIDS. Increased lysophosphatidic acid concentrations and AKT activation after HIV infection found in recent work suggest that the Hippo pathway may be a key regulator of HIV-related fibrogenesis. By linking lysophosphatidic acid signaling, YAP activation, and HIV-related fibrogenesis, this mechanism presents a target for future research into therapeutic interventions for not only HIV but also other liver diseases, e.g. metabolic dysfunction- or alcohol-associated liver disease.

背景& 目的HIV会加速多种病因引起的肝纤维化，包括HCV、HBV和脂肪肝。还有证据表明，HIV 感染本身也与肝纤维化有关。最近的研究表明，Yes 相关蛋白 1（YAP1）和上游溶血磷脂酸（LPA）/PI3K/AKT 通路是肝纤维化的关键调节因子，并与 HIV 相关的肝纤维化有关。然而，YAP/PI3K/AKT 通路激活与 HIV 相关肝纤维化之间的关系仍不确定。方法在无偏见的人源化小鼠模型（NRG-hu HSC 小鼠，n = 6）、精确切割肝切片体外模型、传统体外模型以及三维球状系统中进行了 qPCR、Western 印迹、免疫荧光和 ELISA（重复 n ≥3）。结果YAP靶基因mRNA和蛋白水平（ANKRD、CTGF、CYR61）在所有暴露于HIV的模型中均上调。与对照组小鼠相比，感染艾滋病毒的人源化小鼠的 YAP 阳性细胞核百分比（2.2 倍）和天狼星红胶原染色面积百分比（3.3 倍）显著增加。与健康对照组相比，HIV 感染者血清中的 LPA 浓度增加了 5.8 倍。通过抑制剂或小干扰 RNA 对 LPAR1、PI3K 和 AKT 进行调节，可减轻 HIV 暴露对肝纤维化的影响，并下调培养肝细胞中的 YAP 靶基因。这一新颖的机理见解为治疗艾滋病病毒感染者的肝纤维化提出了新的药物靶点。影响和意义：目前，美国食品及药物管理局还没有批准治疗肝硬化的药物，而肝病是艾滋病病毒感染者继艾滋病之后的第二大死亡原因。近期研究发现，HIV感染后溶血磷脂酸浓度升高和AKT活化表明，Hippo通路可能是HIV相关纤维化的关键调节因子。通过将溶血磷脂酸信号传导、YAP 激活和 HIV 相关纤维形成联系起来，这一机制为未来研究治疗干预措施提供了一个目标，不仅可以治疗 HIV，还可以治疗其他肝病，如代谢功能障碍或酒精相关肝病。

{"title":"YAP mediates HIV-related liver fibrosis","authors":"Volney A. Spalding , Brian A. Fellenstein , James Ahodantin , Andre J. Jeyarajan , Yongtao Wang , Sanjoy K. Khan , Min Xu , Wenyu Lin , Nadia Alatrakchi , Lishan Su , Raymond T. Chung , Shadi Salloum","doi":"10.1016/j.jhepr.2024.101163","DOIUrl":"10.1016/j.jhepr.2024.101163","url":null,"abstract":"<div><h3>Background & Aims</h3><div>HIV accelerates liver fibrosis attributable to multiple etiologies, including HCV, HBV, and steatotic liver disease. Evidence also suggests that HIV infection itself is associated with liver fibrogenesis. Recent studies have implicated Yes-associated protein 1 (YAP1) and the upstream lysophosphatidic acid (LPA)/PI3K/AKT pathway as critical regulators of hepatic fibrogenesis, and suggest a connection to HIV-related liver fibrosis. However, the relationship between YAP/PI3K/AKT pathway activation and HIV-related liver fibrosis remains uncertain.</div></div><div><h3>Methods</h3><div>qPCR, western blot, immunofluorescence, and ELISA (replicates n ≥3) were performed in an unbiased humanized mouse model (NRG-hu HSC mice, n = 6), the precision cut liver slice <em>ex vivo</em> model, and both traditional <em>in vitro</em> models as well as a 3D spheroid system.</div></div><div><h3>Results</h3><div>YAP target gene mRNA and protein levels (ANKRD, CTGF, CYR61) were upregulated across all models exposed to HIV. Humanized mice infected with HIV had significant increases in the percentage of YAP-positive nuclei (2.2-fold) and the percentage area of Sirius Red collagen staining (3.3-fold) compared to control mice. Serum concentrations of LPA were increased 5.8-fold in people living with HIV compared to healthy controls. Modulation of LPAR1, PI3K, and AKT by either inhibitors or small-interfering RNAs abrogated the fibrotic effects of HIV exposure and downregulated YAP target genes within cultured liver cells.</div></div><div><h3>Conclusions</h3><div>The LPAR/PI3K/AKT axis is vital for the activation of YAP and hepatic fibrogenesis due to HIV infection. This novel mechanistic insight suggests new pharmacologic targets for treatment of liver fibrosis in people living with HIV.</div></div><div><h3>Impact and implications:</h3><div>There are currently no FDA-approved treatments for cirrhosis, while liver disease is the second leading cause of mortality among people living with HIV after AIDS. Increased lysophosphatidic acid concentrations and AKT activation after HIV infection found in recent work suggest that the Hippo pathway may be a key regulator of HIV-related fibrogenesis. By linking lysophosphatidic acid signaling, YAP activation, and HIV-related fibrogenesis, this mechanism presents a target for future research into therapeutic interventions for not only HIV but also other liver diseases, <em>e.g</em>. metabolic dysfunction- or alcohol-associated liver disease.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 11","pages":"Article 101163"},"PeriodicalIF":9.5,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141698712","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

Liver fibrosis screening increases alcohol abstinence 肝纤维化筛查可提高戒酒率

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-02 DOI: 10.1016/j.jhepr.2024.101165

Emma Avitabile , Jordi Gratacós-Ginès , Martina Pérez-Guasch , Ana Belén Rubio , Queralt Herms , Marta Cervera , Ruth Nadal , Marta Carol , Núria Fabrellas , Pol Bruguera , Ana Llorente , Lluisa Ortega , Anna Lligoña , Laura Nuño , Neus Freixa , María Teresa Pons , Alba Díaz , Ramon Bataller , Pere Ginès , Hugo López-Pelayo , Elisa Pose

Background & Aims

Individuals with alcohol use disorder (AUD) are at risk of liver disease. There is scarce information on the effectiveness of screening for liver fibrosis on alcohol consumption. Thus, we evaluated the efficacy of a screening program for liver fibrosis on alcohol consumption in individuals with AUD.

Methods

We performed a prospective interventional study in the Hospital Clinic of Barcelona. The screening cohort included individuals with AUD from the addiction unit who underwent screening for liver fibrosis with transient elastography and counselling on lifestyle habits in the liver unit. The control cohort included individuals with similar characteristics who attended the same unit in a previous period but did not undergo screening. Effects on alcohol consumption were evaluated at 6 months, after clinical follow-up, with clinical assessment by addiction specialists and urine ethyl glucuronide monitoring.

Results

In the screening cohort, 149/334 (45%) individuals were abstinent at 6 months (68% confirmed with urine ethyl glucuronide). Alcohol abstinence was higher in the screening cohort than in the control cohort (40/137 [29%], p = 0.002). Factors associated with alcohol abstinence in the multivariate analysis of the two combined cohorts (n = 471) were: receiving AUD medications (odds ratio [OR] 1.72, 95% CI 1.11-2.67), absence of illicit drug use (OR 0.50, 95% CI 0.31-0.80) and participating in the screening program (OR 1.77, 95% CI 1.14-2.74). In the screening cohort, 40 (12%) individuals had increased liver stiffness (≥8 kPa), which was associated with obesity (p = 0.03), arterial hypertension (p = 0.03), gamma-glutamyltransferase (p <0.001) and platelet levels (p = 0.001).

Conclusions

This study shows that an integrated screening program for liver fibrosis associated with counselling on alcohol consumption in individuals with AUD allows for early diagnosis of alcohol-associated liver disease and is associated with alcohol abstinence.

Impact and implications:

Individuals with high alcohol consumption are at higher risk of liver disease compared to the general population. The potential beneficial effects of screening for liver disease in this population have scarcely been studied. We show that a screening program for liver fibrosis together with a lifestyle counselling intervention favoured alcohol abstinence among individuals with alcohol use disorder attending an addiction unit at 6 months, compared to a matched cohort who did not undergo screening. These findings suggest that screening programs for liver fibrosis have a therapeutic role in individuals with alcohol use disorder, supporting the implementation of these programs in addiction units.

背景& 目的酒精使用障碍（AUD）患者有罹患肝病的风险。有关肝纤维化筛查对饮酒量影响的信息很少。因此，我们评估了肝纤维化筛查项目对 AUD 患者饮酒量的影响。筛查队列包括成瘾科的 AUD 患者，他们在肝病科接受了瞬态弹性成像肝纤维化筛查和生活习惯咨询。对照组包括具有相似特征的患者，他们在前一阶段曾在同一科室就诊，但未接受筛查。结果在筛查队列中，149/334（45%）人在 6 个月后戒酒（68% 经尿液葡萄糖醛酸乙酯证实）。筛查人群中的戒酒率高于对照人群（40/137 [29%]，P = 0.002）。在对两个合并队列（n = 471）进行的多变量分析中，与戒酒相关的因素有：接受 AUD 药物治疗（几率比 [OR] 1.72，95% CI 1.11-2.67）、未使用非法药物（OR 0.50，95% CI 0.31-0.80）和参与筛查计划（OR 1.77，95% CI 1.14-2.74）。在筛查队列中，40 人（12%）的肝脏硬度增加（≥8 kPa），这与肥胖（p = 0.03）、动脉高血压（p = 0.03）、γ-谷氨酰转移酶（p <0.001）和血小板水平（p = 0.001）有关。影响和意义：与普通人群相比，高酒精消耗量人群罹患肝病的风险更高。对这一人群进行肝病筛查的潜在益处还鲜有研究。我们的研究表明，与未接受筛查的匹配人群相比，肝纤维化筛查项目和生活方式咨询干预措施有助于酗酒者在6个月后戒酒。这些研究结果表明，肝纤维化筛查项目对酒精使用障碍患者有治疗作用，支持在戒酒机构实施这些项目。

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引用次数: 0

Surrogate markers of bile duct disease progression in primary sclerosing cholangitis – A prospective study with repeated ERCP examinations 原发性硬化性胆管炎胆管疾病进展的替代标记物--一项通过重复 ERCP 检查进行的前瞻性研究

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-02 DOI: 10.1016/j.jhepr.2024.101161

Martti Färkkilä , Fredrik Åberg , Henrik Alfthan , Kalle Jokelainen , Lauri Puustinen , Hannu Kautiainen , Andrea Tenca

Background & Aims

Validated prognostic tools for estimating short-term bile duct disease progression in primary sclerosing cholangitis (PSC) are lacking. We evaluated the predictive value of serum and biliary biochemistry for the progression of bile duct disease in PSC using repeated endoscopic retrograde cholangiopancreatography (ERCP) examinations to identify surrogate markers for more personalized surveillance.

Methods

We conducted a prospective analysis including patients with PSC who underwent ERCP for confirmation of diagnosis, monitoring of disease progression, or dysplasia surveillance. ERCP findings were scored, and dilatation was performed if a dominant stricture was diagnosed or if a cytology brush could not be passed. Bile samples were aspirated for biliary IL8 and calprotectin. We analysed optimal cut-off values and AUCs for 20 laboratory markers and evaluated their association with the time to an ERCP score increase of ≥2 points or first dilatation, whichever came first. Of the 1,002 patients, 653 had ≥2 ERCP examinations and ≥3 years of follow-up. After excluding patients with PSC-overlap syndrome or initial dilatation, 398 patients were included.

Results

Of the patients included, 62% had mild or moderate and 38% had advanced bile duct disease. During follow-up, 41% of patients demonstrated progression of disease. Biliary calprotectin (AUC 0.76; 95% CI 0.69 to 0.82) and IL8 (AUC 0.76; 95% CI 0.69 to 0.84) were the only variables that demonstrated predictive value for disease progression and/or need for dilatation.

Conclusions

Biliary calprotectin and IL8 are promising surrogate markers for identifying patients with PSC at risk of progression and determining the timing for subsequent imaging. Conventional liver function tests may not be sensitive or specific enough to monitor PSC progression, particularly in the short term.

Impact and implications:

Validated prognostic tools for estimating short-term bile duct disease progression in primary sclerosing cholangitis are lacking. In this prospective study, based on sequential endoscopic retrograde cholangiopancreatography examinations, biliary calprotectin and IL8 levels turned out to be more sensitive for predicting bile duct progression than traditional liver function tests, such as alkaline phosphatase, in the short term. These findings could lead to more personalized patient surveillance and improve clinical practice by providing a more accurate method for monitoring disease progression and treatment responses. Additionally, these markers have potential as surrogate endpoints in clinical drug trials. The limitation is that measurement of biliary IL8 and calprotectin requires endoscopic retrograde cholangiopancreatography with bile sampling.

背景& 目的目前尚缺乏经过验证的预后工具来估计原发性硬化性胆管炎（PSC）胆管疾病的短期进展情况。我们利用重复内镜逆行胰胆管造影术（ERCP）检查评估了血清和胆汁生化对 PSC 胆管疾病进展的预测价值，以确定更个性化监测的替代标记物。对ERCP检查结果进行评分，如果确诊为显性狭窄或细胞学刷不能通过，则进行扩张术。抽取胆汁样本检测胆道 IL8 和钙粘蛋白。我们分析了 20 种实验室标记物的最佳临界值和 AUC，并评估了它们与 ERCP 评分增加≥2 分或首次扩张（以先发生者为准）的时间之间的关系。在 1002 名患者中，653 人接受了≥2 次 ERCP 检查，随访时间≥3 年。结果在纳入的患者中，62%患有轻度或中度胆管疾病，38%患有晚期胆管疾病。随访期间，41%的患者病情有所进展。胆汁钙蛋白（AUC 0.76；95% CI 0.69 至 0.82）和 IL8（AUC 0.76；95% CI 0.69 至 0.84）是唯一对疾病进展和/或扩张需求具有预测价值的变量。影响和意义：目前尚缺乏有效的预后工具来估计原发性硬化性胆管炎患者胆管疾病的短期进展。在这项前瞻性研究中，基于连续的内镜逆行胰胆管造影检查，胆汁钙蛋白和IL8水平在短期内预测胆管疾病进展方面比碱性磷酸酶等传统肝功能检测更敏感。这些发现可为监测疾病进展和治疗反应提供更准确的方法，从而实现更个性化的患者监测并改善临床实践。此外，这些标记物还有可能成为临床药物试验的替代终点。不足之处在于胆道 IL8 和钙粘蛋白的测量需要内镜逆行胰胆管造影术和胆汁取样。

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引用次数: 0

Copyright and information 版权和信息

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-01 DOI: 10.1016/S2589-5559(24)00161-7

引用次数: 0

Editorial Board page 编辑委员会页面

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-01 DOI: 10.1016/S2589-5559(24)00158-7

引用次数: 0

Tumor organoids for primary liver cancers: A systematic review of current applications in diagnostics, disease modeling, and drug screening 原发性肝癌的肿瘤组织实体：当前诊断、疾病建模和药物筛选应用的系统回顾

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-01 DOI: 10.1016/j.jhepr.2024.101164

Ayesha A. Qureshi , Chase J. Wehrle , Sofia Ferreira-Gonzalez , Chunbao Jiao , Hanna Hong , Neda Dadgar , Jorge Arpi-Palacios , Yee Phoon Phong , Jaekeun Kim , Keyue Sun , Koji Hashimoto , David CH. Kwon , Charles Miller , Nic Leipzig , Wen Wee Ma , Jos Melenhorst , Federico Aucejo , Andrea Schlegel

Background & Aims

Liver cancer-related deaths are projected to exceed one million annually by 2030. Existing therapies have significant limitations, including severe side effects and inconsistent efficacy. Innovative therapeutic approaches to address primary liver cancer (PLC) have led to the ongoing development of tumor-derived organoids. These are sophisticated three-dimensional structures capable of mimicking native tissue architecture and function in vitro, improving our ability to model in vivo homeostasis and disease.

Methods

This systematic review consolidates known literature on human and mouse liver organoids across all PLC subtypes, emphasizing diagnostic precision, disease modeling, and drug screening capabilities.

Results

Across all 39 included studies, organoids were most frequently patient-derived, closely followed by cancer cell line-derived. The literature concentrated on hepatocellular carcinoma and intrahepatic cholangiocarcinoma, while exploration of other subtypes was limited. These studies demonstrate a valuable role for PLC organoid cultures in biomarker discovery, disease modeling, and therapeutic exploration.

Conclusions

Encouraging advances such as organoid-on-a-chip and co-culturing systems hold promise for advancing treatment regimens for PLC. Standardizing in vitro protocols is crucial to integrate research breakthroughs into practical treatment strategies for PLC.

Impact and implications:

This study provides an overview of the current understanding of tumor-derived organoids in primary liver cancers, emphasizing their potential in diagnostics, disease modeling, and drug screening. The scientific foundation rests on the organoids' ability to replicate the tumor microenvironment and genetic landscape, opening new avenues for personalized therapies. These insights are crucial for both researchers and clinicians, as patient-derived organoids can help identify biomarkers and therapeutic targets. Physicians and policymakers can harness these advances to drive progress in precision medicine, while recognizing the challenges involved in standardizing organoid models for clinical implementation.

背景& 目的预计到 2030 年，每年因肝癌死亡的人数将超过一百万。现有疗法存在严重的局限性，包括严重的副作用和不一致的疗效。针对原发性肝癌（PLC）的创新治疗方法导致了肿瘤衍生有机体的不断发展。这是一种复杂的三维结构，能够在体外模拟原生组织的结构和功能，提高了我们模拟体内平衡和疾病的能力。方法本系统综述整合了所有原发性肝癌亚型中已知的人和小鼠肝脏组织器官的文献，强调诊断的精确性、疾病建模和药物筛选能力。文献主要集中于肝细胞癌和肝内胆管癌，而对其他亚型的探讨则很有限。这些研究表明，PLC类器官培养物在生物标记物发现、疾病建模和治疗探索方面具有重要作用。影响和意义：本研究概述了目前对原发性肝癌中肿瘤衍生类器官的认识，强调了它们在诊断、疾病建模和药物筛选方面的潜力。科学基础在于器官组织复制肿瘤微环境和遗传景观的能力，为个性化疗法开辟了新途径。这些见解对研究人员和临床医生都至关重要，因为源自患者的器官组织有助于确定生物标志物和治疗靶点。医生和政策制定者可以利用这些进步推动精准医学的发展，同时也要认识到在临床应用中标准化类器官模型所面临的挑战。

{"title":"Tumor organoids for primary liver cancers: A systematic review of current applications in diagnostics, disease modeling, and drug screening","authors":"Ayesha A. Qureshi , Chase J. Wehrle , Sofia Ferreira-Gonzalez , Chunbao Jiao , Hanna Hong , Neda Dadgar , Jorge Arpi-Palacios , Yee Phoon Phong , Jaekeun Kim , Keyue Sun , Koji Hashimoto , David CH. Kwon , Charles Miller , Nic Leipzig , Wen Wee Ma , Jos Melenhorst , Federico Aucejo , Andrea Schlegel","doi":"10.1016/j.jhepr.2024.101164","DOIUrl":"10.1016/j.jhepr.2024.101164","url":null,"abstract":"<div><h3>Background & Aims</h3><div>Liver cancer-related deaths are projected to exceed one million annually by 2030. Existing therapies have significant limitations, including severe side effects and inconsistent efficacy. Innovative therapeutic approaches to address primary liver cancer (PLC) have led to the ongoing development of tumor-derived organoids. These are sophisticated three-dimensional structures capable of mimicking native tissue architecture and function <em>in vitro</em>, improving our ability to model <em>in vivo</em> homeostasis and disease.</div></div><div><h3>Methods</h3><div>This systematic review consolidates known literature on human and mouse liver organoids across all PLC subtypes, emphasizing diagnostic precision, disease modeling, and drug screening capabilities.</div></div><div><h3>Results</h3><div>Across all 39 included studies, organoids were most frequently patient-derived, closely followed by cancer cell line-derived. The literature concentrated on hepatocellular carcinoma and intrahepatic cholangiocarcinoma, while exploration of other subtypes was limited. These studies demonstrate a valuable role for PLC organoid cultures in biomarker discovery, disease modeling, and therapeutic exploration.</div></div><div><h3>Conclusions</h3><div>Encouraging advances such as organoid-on-a-chip and co-culturing systems hold promise for advancing treatment regimens for PLC. Standardizing <em>in vitro</em> protocols is crucial to integrate research breakthroughs into practical treatment strategies for PLC.</div></div><div><h3>Impact and implications:</h3><div>This study provides an overview of the current understanding of tumor-derived organoids in primary liver cancers, emphasizing their potential in diagnostics, disease modeling, and drug screening. The scientific foundation rests on the organoids' ability to replicate the tumor microenvironment and genetic landscape, opening new avenues for personalized therapies. These insights are crucial for both researchers and clinicians, as patient-derived organoids can help identify biomarkers and therapeutic targets. Physicians and policymakers can harness these advances to drive progress in precision medicine, while recognizing the challenges involved in standardizing organoid models for clinical implementation.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"6 12","pages":"Article 101164"},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141696342","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

Durability and on-treatment predictors of recompensation in entecavir-treated patients with hepatitis B and decompensated cirrhosis 恩替卡韦治疗的乙型肝炎和失代偿期肝硬化患者康复的持久性和治疗中的预测因素

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports

Pub Date : 2024-07-01 DOI: 10.1016/j.jhepr.2024.101091

You Deng , Haiyan Kang , Huiling Xiang , Yuemin Nan , Jinhua Hu , Qinghua Meng , Hong Zhao , Qi Wang , Jilian Fang , Jie Xu , Xiaoming Wang , Calvin Q. Pan , Hong You , Xiaoyuan Xu , Wen Xie , Jidong Jia

Background & Aims

Hepatic recompensation may be achieved in patients with decompensated cirrhosis due to chronic hepatitis B (CHB) upon effective suppression of viral replication by nucleos(t)ide analogues (NAs). However, the optimal timing and predictors of recompensation and the subsequent clinical course of patients with CHB with vs. without recompensation are not well-defined.

Methods

This study was a retrospective extension of a multi-centre prospective cohort, focusing on patients with CHB and decompensated cirrhosis treated with entecavir. We followed patients beyond treatment week 120 until a second decompensation event or June 2023. We identified the optimal timing and predictors of recompensation by week 120, evaluated durability of recompensation in patients fulfilling recompensation criteria by week 120 and examined late recompensation in those who did not fulfil it by week 120.

Results

At treatment week 24, serum albumin ≥34 g/L predicted recompensation by week 120. The Brec-PAS model offered good predictive ability for recompensation by week 120. Of the 283 patients who finished 120 weeks of therapy, 175 were followed beyond week 120 (median follow-up: 240 weeks). Among the 106 patients achieving recompensation by week 120, 92 (86.8%) maintained recompensation for another 120 (72-168) weeks. Among the 69 patients without recompensation by week 120, 40.6% attained late recompensation during the subsequent 120 (72-168) weeks. Additionally, hepatocellular carcinoma incidence was lower in the recompensated group (5.0% vs. 16.13%, p = 0.002).

Conclusions

A serum albumin ≥34 g/L at treatment week 24 predicted recompensation by week 120. Recompensation achieved by week 120 of NA treatment is maintained in >80% of patients in the long term. Some patients may achieve recompensation only after >120 weeks of NA treatment. The incidence of hepatocellular carcinoma was reduced but not completely abolished after recompensation.

Impact and implications

Our research provides a meaningful contribution to understanding the long-term prognosis of recompensation in patients with chronic hepatitis B and decompensated cirrhosis, as well as to evaluating the predictive value of serum albumin levels, offering a comprehensive view of clinical outcomes after recompensation. The significance of early biomarkers in guiding therapeutic decisions is highlighted, shedding light on the continued benefits and possible risks after recompensation. This enhances the capability for more precise prognostic evaluations and informed therapeutic strategies. For healthcare providers, these insights afford a detailed perspective on patient monitoring and intervention planning, underscoring the need for ongoing assessment past the initial recompensation phase.

背景& 目的慢性乙型肝炎（CHB）引起的失代偿期肝硬化患者在使用核苷（t）ide 类似物（NAs）有效抑制病毒复制后可获得肝功能恢复。本研究是一项多中心前瞻性队列研究的回顾性延伸，重点关注接受恩替卡韦治疗的慢性乙型肝炎和失代偿性肝硬化患者。我们对治疗 120 周后的患者进行了随访，直至出现第二次失代偿事件或 2023 年 6 月。我们确定了第 120 周前失代偿的最佳时机和预测因素，评估了第 120 周前达到失代偿标准的患者失代偿的持久性，并对第 120 周前未达到失代偿标准的患者进行了晚期失代偿的研究。结果在治疗第 24 周时，血清白蛋白≥34 g/L 可预测第 120 周前的失代偿。Brec-PAS 模型能很好地预测 120 周前的恢复情况。在完成 120 周治疗的 283 名患者中，有 175 名患者的随访时间超过了 120 周（中位随访时间：240 周）。在 120 周前获得恢复的 106 名患者中，有 92 人（86.8%）在 120 周（72-168 周）后继续获得恢复。在第 120 周前未恢复的 69 名患者中，有 40.6% 的患者在随后的 120（72-168）周内实现了晚期恢复。结论治疗第 24 周时血清白蛋白≥34 克/升预示着第 120 周时病情恢复。80%的患者能在NA治疗第120周时长期保持恢复。有些患者可能要在NA治疗120周后才能获得恢复。影响和意义我们的研究为了解慢性乙型肝炎和失代偿期肝硬化患者恢复后的长期预后以及评估血清白蛋白水平的预测价值做出了有意义的贡献，为恢复后的临床预后提供了一个全面的视角。早期生物标志物在指导治疗决策方面的重要意义得到了强调，并揭示了恢复后的持续益处和可能存在的风险。这增强了更精确的预后评估和知情治疗策略的能力。对于医疗服务提供者来说，这些见解为患者监测和干预规划提供了详细的视角，强调了在最初的恢复阶段之后进行持续评估的必要性。

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引用次数: 0