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Comparative evaluation of multimarker algorithms for early-stage HCC detection in multicenter prospective studies
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.jhepr.2024.101263
Jinlin Hou , Thomas Berg , Arndt Vogel , Teerha Piratvisuth , Jörg Trojan , Enrico N. De Toni , Masatoshi Kudo , Katarina Malinowsky , Peter Findeisen , Johannes Kolja Hegel , Wenzel Schöning , Kairat Madin , Konstantin Kroeniger , Henry Lik-Yuen Chan , Ashish Sharma
<div><h3>Background & Aims</h3><div>We compared the clinical performance of the novel GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], des-gamma carboxyprothrombin [DCP]) and GALAD (gender [biological sex], age, AFP, <em>Lens culinaris</em> agglutinin-reactive AFP [AFP-L3], DCP) algorithms to deduce the clinical utility of AFP-L3 for detecting early-stage hepatocellular carcinoma (HCC) from chronic liver disease (CLD).</div></div><div><h3>Methods</h3><div>An algorithm development study (STOP-HCC-ARP) and clinical validation study (STOP-HCC-MCE) were conducted, recruiting adult participants with HCC (confirmed by radiology or pathology) or CLD in an international, multicenter, case-control design. Serum biomarkers were measured using Elecsys assays (GAAD and GALAD [Cobas]) or μTASWAKO assays (GALAD [μTASWAKO]) while blinded to case/control status.</div></div><div><h3>Results</h3><div>In STOP-HCC-ARP (algorithm development cohort), 1,006 patients {297 HCC (41.4% early-stage [Barcelona Clinic Liver Cancer {BCLC} 0/A) and 709 CLD} were included. Area under the curve (AUCs) for discriminating between early-stage HCC <em>vs.</em> CLD were 91.4%, 91.4%, and 90.8% for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO), respectively. The clinical validation cohort of STOP-HCC-MCE comprised 1,142 patients, (366 HCC cases [48% early-stage], 468 specificity samples and 302 CLD); AUCs for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO) for discriminating between early-stage HCC <em>vs.</em> CLD were 91.4%, 91.5%, and 91.0%, respectively; AUCs were 94.7–95.0% for all-stage HCC. The GAAD and GALAD algorithms demonstrated similar good performance regardless of disease etiology, presence of cirrhosis, geographical region, and within pan-tumor specificity panels (<em>p</em> <0.001).</div></div><div><h3>Conclusions</h3><div>GAAD (Cobas) demonstrated good clinical performance, similar to GALAD (Cobas and μTASWAKO) algorithms, in differentiating HCC and CLD controls, across all disease stages, etiologies, and regions; therefore, AFP-L3 may have a negligible role in GALAD for HCC surveillance.</div></div><div><h3>Impact and implications</h3><div>To improve the detection of early-stage hepatocellular carcinoma (HCC) from benign chronic liver disease (CLD), algorithms combining demographic characteristics and serum biomarkers, such as GAAD and GALAD, have been developed. GAAD combines gender (biological sex), age, alpha-fetoprotein (AFP), des-gamma carboxy-prothrombin (DCP); GALAD combines the same characteristics and biomarkers as GAAD with the addition of <em>Lens culinaris</em> agglutinin-reactive AFP (AFP-L3). Changing disease etiologies and treatment paradigms have raised questions regarding the utility of AFP-L3 in HCC surveillance. Our work demonstrates that the GAAD (Cobas) algorithm demonstrated good clinical performance and was as sensitive and specific as the GALAD (Cobas) and GALAD (μTASWAKO) algorithms in differentiating HCC and CLD cont
{"title":"Comparative evaluation of multimarker algorithms for early-stage HCC detection in multicenter prospective studies","authors":"Jinlin Hou ,&nbsp;Thomas Berg ,&nbsp;Arndt Vogel ,&nbsp;Teerha Piratvisuth ,&nbsp;Jörg Trojan ,&nbsp;Enrico N. De Toni ,&nbsp;Masatoshi Kudo ,&nbsp;Katarina Malinowsky ,&nbsp;Peter Findeisen ,&nbsp;Johannes Kolja Hegel ,&nbsp;Wenzel Schöning ,&nbsp;Kairat Madin ,&nbsp;Konstantin Kroeniger ,&nbsp;Henry Lik-Yuen Chan ,&nbsp;Ashish Sharma","doi":"10.1016/j.jhepr.2024.101263","DOIUrl":"10.1016/j.jhepr.2024.101263","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;We compared the clinical performance of the novel GAAD (gender [biological sex], age, alpha-fetoprotein [AFP], des-gamma carboxyprothrombin [DCP]) and GALAD (gender [biological sex], age, AFP, &lt;em&gt;Lens culinaris&lt;/em&gt; agglutinin-reactive AFP [AFP-L3], DCP) algorithms to deduce the clinical utility of AFP-L3 for detecting early-stage hepatocellular carcinoma (HCC) from chronic liver disease (CLD).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;An algorithm development study (STOP-HCC-ARP) and clinical validation study (STOP-HCC-MCE) were conducted, recruiting adult participants with HCC (confirmed by radiology or pathology) or CLD in an international, multicenter, case-control design. Serum biomarkers were measured using Elecsys assays (GAAD and GALAD [Cobas]) or μTASWAKO assays (GALAD [μTASWAKO]) while blinded to case/control status.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In STOP-HCC-ARP (algorithm development cohort), 1,006 patients {297 HCC (41.4% early-stage [Barcelona Clinic Liver Cancer {BCLC} 0/A) and 709 CLD} were included. Area under the curve (AUCs) for discriminating between early-stage HCC &lt;em&gt;vs.&lt;/em&gt; CLD were 91.4%, 91.4%, and 90.8% for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO), respectively. The clinical validation cohort of STOP-HCC-MCE comprised 1,142 patients, (366 HCC cases [48% early-stage], 468 specificity samples and 302 CLD); AUCs for GAAD (Cobas), GALAD (Cobas), and GALAD (μTASWAKO) for discriminating between early-stage HCC &lt;em&gt;vs.&lt;/em&gt; CLD were 91.4%, 91.5%, and 91.0%, respectively; AUCs were 94.7–95.0% for all-stage HCC. The GAAD and GALAD algorithms demonstrated similar good performance regardless of disease etiology, presence of cirrhosis, geographical region, and within pan-tumor specificity panels (&lt;em&gt;p&lt;/em&gt; &lt;0.001).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;GAAD (Cobas) demonstrated good clinical performance, similar to GALAD (Cobas and μTASWAKO) algorithms, in differentiating HCC and CLD controls, across all disease stages, etiologies, and regions; therefore, AFP-L3 may have a negligible role in GALAD for HCC surveillance.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;To improve the detection of early-stage hepatocellular carcinoma (HCC) from benign chronic liver disease (CLD), algorithms combining demographic characteristics and serum biomarkers, such as GAAD and GALAD, have been developed. GAAD combines gender (biological sex), age, alpha-fetoprotein (AFP), des-gamma carboxy-prothrombin (DCP); GALAD combines the same characteristics and biomarkers as GAAD with the addition of &lt;em&gt;Lens culinaris&lt;/em&gt; agglutinin-reactive AFP (AFP-L3). Changing disease etiologies and treatment paradigms have raised questions regarding the utility of AFP-L3 in HCC surveillance. Our work demonstrates that the GAAD (Cobas) algorithm demonstrated good clinical performance and was as sensitive and specific as the GALAD (Cobas) and GALAD (μTASWAKO) algorithms in differentiating HCC and CLD cont","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 2","pages":"Article 101263"},"PeriodicalIF":9.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11782856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080182","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
First-line chemotherapy with selective internal radiation therapy for intrahepatic cholangiocarcinoma: The French ACABi GERCOR PRONOBIL cohort
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.jhepr.2024.101279
Nicolas Adamus , Julien Edeline , Julie Henriques , Nadim Fares , Thierry Lecomte , Anthony Turpin , Dewi Vernerey , Mathilde Vincens , Brice Chanez , David Tougeron , Christophe Tournigand , Eric Assenat , Matthieu Delaye , Sylvain Manfredi , Olivier Bouché , Nicolas Williet , Angelique Vienot , Lorraine Blaise , Léo Mas , Cindy Neuzillet , Gaël S. Roth
<div><h3>Background & Aims</h3><div>Selective internal radiation therapy (SIRT) is a promising option for liver-only unresectable intrahepatic cholangiocarcinoma (iCCA). The Real-SIRTCCA study retrospectively assessed the benefit of adding SIRT to chemotherapy in this setting within the French nationwide observational cohort ACABi-GERCOR-PRONOBIL.</div></div><div><h3>Methods</h3><div>Inclusion criteria were advanced iCCA with limited or no extrahepatic disease, treated with first-line gemcitabine plus platinum chemotherapy +/- concurrent SIRT. All patients treated with chemotherapy and concurrent SIRT were included. To ensure groups’ similarity, a rigorous selection was applied to the chemo-only group, with exclusion of patients with liver involvement >50% and extrahepatic metastases. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), objective response rate (ORR) and tumor resection rate. Propensity score and inverse probability of treatment weighting (IPTW) propensity approaches were used to address confounding factors between groups.</div></div><div><h3>Results</h3><div>Between July 2007 and December 2023, 277 patients met the Real-SIRTCCA inclusion criteria, with 88 in the chemo-SIRT group and 189 in chemo-only group. Chemo-SIRT was associated with longer PFS (median = 10.8 <em>vs.</em> 5.5 months, hazard ratio [HR] 0.54, 95% CI 0.41-0.71, <em>p <</em>0.0001), a trend for longer OS (median = 22.5 <em>vs.</em> 15.1 months, HR 0.76, 95% CI 0.57-1.01), higher ORR (58.3% <em>vs.</em> 28.5%, odds ratio [OR] 3.51, 95% CI 2.03-6.09, <em>p <</em>0.0001), and resection rate (18.7% <em>vs</em>. 8.8%, <em>p</em> = 0.0279) compared to chemo-alone. After IPTW, the superiority of chemo-SIRT was confirmed with better PFS (HR 0.55, 95% CI 0.45-0.66, <em>p <</em>0,0001), OS (HR 0.70, 95% CI 0.58-0.85, <em>p</em> = 0.0004), ORR (OR 3.17, 95% CI 2.18-4.49, <em>p <</em>0.0001) and resection rate (OR 2.94, 95% CI 1.71-5.03, <em>p <</em>0.0001).</div></div><div><h3>Conclusions</h3><div>Adding SIRT to first-line chemotherapy significantly improved survival outcomes, ORR, and secondary tumor resection rates in locally advanced iCCA. Prospective randomized data are needed to confirm these results.</div></div><div><h3>Impact and implications:</h3><div>Herein, we report the results of the Real-SIRTCCA study, comparing the efficacy of the gemcitabine-platinum systemic first-line chemotherapy with or without selective internal radiation therapy (SIRT) in 277 patients with locally advanced intrahepatic cholangiocarcinoma within the cohort ACABi-PRONOBIL. An improvement of progression-free survival, overall survival, tumor response and secondary surgical resection rate was observed in favor of chemo-SIRT, before adjustment and after inverse probability of treatment weighting propensity score analyses. Even though prospective randomized data would be needed to confirm these findings, we believe that
{"title":"First-line chemotherapy with selective internal radiation therapy for intrahepatic cholangiocarcinoma: The French ACABi GERCOR PRONOBIL cohort","authors":"Nicolas Adamus ,&nbsp;Julien Edeline ,&nbsp;Julie Henriques ,&nbsp;Nadim Fares ,&nbsp;Thierry Lecomte ,&nbsp;Anthony Turpin ,&nbsp;Dewi Vernerey ,&nbsp;Mathilde Vincens ,&nbsp;Brice Chanez ,&nbsp;David Tougeron ,&nbsp;Christophe Tournigand ,&nbsp;Eric Assenat ,&nbsp;Matthieu Delaye ,&nbsp;Sylvain Manfredi ,&nbsp;Olivier Bouché ,&nbsp;Nicolas Williet ,&nbsp;Angelique Vienot ,&nbsp;Lorraine Blaise ,&nbsp;Léo Mas ,&nbsp;Cindy Neuzillet ,&nbsp;Gaël S. Roth","doi":"10.1016/j.jhepr.2024.101279","DOIUrl":"10.1016/j.jhepr.2024.101279","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Selective internal radiation therapy (SIRT) is a promising option for liver-only unresectable intrahepatic cholangiocarcinoma (iCCA). The Real-SIRTCCA study retrospectively assessed the benefit of adding SIRT to chemotherapy in this setting within the French nationwide observational cohort ACABi-GERCOR-PRONOBIL.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Inclusion criteria were advanced iCCA with limited or no extrahepatic disease, treated with first-line gemcitabine plus platinum chemotherapy +/- concurrent SIRT. All patients treated with chemotherapy and concurrent SIRT were included. To ensure groups’ similarity, a rigorous selection was applied to the chemo-only group, with exclusion of patients with liver involvement &gt;50% and extrahepatic metastases. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), objective response rate (ORR) and tumor resection rate. Propensity score and inverse probability of treatment weighting (IPTW) propensity approaches were used to address confounding factors between groups.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Between July 2007 and December 2023, 277 patients met the Real-SIRTCCA inclusion criteria, with 88 in the chemo-SIRT group and 189 in chemo-only group. Chemo-SIRT was associated with longer PFS (median = 10.8 &lt;em&gt;vs.&lt;/em&gt; 5.5 months, hazard ratio [HR] 0.54, 95% CI 0.41-0.71, &lt;em&gt;p &lt;&lt;/em&gt;0.0001), a trend for longer OS (median = 22.5 &lt;em&gt;vs.&lt;/em&gt; 15.1 months, HR 0.76, 95% CI 0.57-1.01), higher ORR (58.3% &lt;em&gt;vs.&lt;/em&gt; 28.5%, odds ratio [OR] 3.51, 95% CI 2.03-6.09, &lt;em&gt;p &lt;&lt;/em&gt;0.0001), and resection rate (18.7% &lt;em&gt;vs&lt;/em&gt;. 8.8%, &lt;em&gt;p&lt;/em&gt; = 0.0279) compared to chemo-alone. After IPTW, the superiority of chemo-SIRT was confirmed with better PFS (HR 0.55, 95% CI 0.45-0.66, &lt;em&gt;p &lt;&lt;/em&gt;0,0001), OS (HR 0.70, 95% CI 0.58-0.85, &lt;em&gt;p&lt;/em&gt; = 0.0004), ORR (OR 3.17, 95% CI 2.18-4.49, &lt;em&gt;p &lt;&lt;/em&gt;0.0001) and resection rate (OR 2.94, 95% CI 1.71-5.03, &lt;em&gt;p &lt;&lt;/em&gt;0.0001).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Adding SIRT to first-line chemotherapy significantly improved survival outcomes, ORR, and secondary tumor resection rates in locally advanced iCCA. Prospective randomized data are needed to confirm these results.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;Herein, we report the results of the Real-SIRTCCA study, comparing the efficacy of the gemcitabine-platinum systemic first-line chemotherapy with or without selective internal radiation therapy (SIRT) in 277 patients with locally advanced intrahepatic cholangiocarcinoma within the cohort ACABi-PRONOBIL. An improvement of progression-free survival, overall survival, tumor response and secondary surgical resection rate was observed in favor of chemo-SIRT, before adjustment and after inverse probability of treatment weighting propensity score analyses. Even though prospective randomized data would be needed to confirm these findings, we believe that ","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 2","pages":"Article 101279"},"PeriodicalIF":9.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080189","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
Understanding virologic heterogeneity in chronic hepatitis B treatment
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.jhepr.2024.101249
Renqi Luo , Xue Ran , Ruihan Sun
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引用次数: 0
Reply to: “Understanding virologic heterogeneity in chronic hepatitis B treatment”
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.jhepr.2024.101280
Philippa C. Matthews , Tingyan Wang , Eleanor Barnes , the Health Informatics Collaborative for Viral Hepatitis
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引用次数: 0
Risk of hepatocellular carcinoma in Asian patients with primary biliary cholangitis: A nationwide and hospital cohort study 亚洲原发性胆管炎患者发生肝细胞癌的风险:一项全国性和医院队列研究
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.jhepr.2024.101251
Jihye Lim , Ye-Jee Kim , Sehee Kim , Jonggi Choi

Background & Aims

Large-scale studies on the association between primary biliary cholangitis (PBC) and hepatocellular carcinoma (HCC) in Asians are scarce. This study aimed to evaluate the incidence of HCC and its risk factors in a nationwide cohort.

Methods

The data of 4,882 patients with PBC and 38,603 matched controls were extracted from the Korean National Health Insurance Service (2007–2020) and analyzed. The incidence of HCC and its risk factors in patients with PBC were assessed and compared with those in the matched controls. The results were validated in a multicenter hospital cohort of 862 patients with PBC, recruited from Asan Medical Center (n = 815) and Yeouido St. Mary’s Hospital (n = 47) in Korea.

Results

In total, 105 patients with PBC developed HCC over the median follow-up period of 5.42 years, yielding an incidence rate of 3.7/1,000 person-years (PYs), which was significantly higher than that in the controls (0.5/1,000 PYs; adjusted hazard ratio: 9.07; 95% CI: 6.71–12.27). PBC, older age, male sex, diabetes, and smoking were identified as significant risk factors for HCC. Twenty-three of the 862 patients with PBC developed HCC in the multicenter hospital cohort, yielding an incidence of 4.0/1,000 PYs (95% CI: 2.4–5.7). Older age (subdistribution hazard ratio [SHR]: 1.05, 95% CI: 1.00–1.10), male sex (SHR: 3.00, 95% CI: 1.11–8.13), current alcohol consumption (SHR: 3.70, 95% CI: 1.08–12.59), and cirrhosis (SHR: 5.17, 95% CI: 2.07–12.93) were identified as risk factors in the hospital cohort.

Conclusions

Patients with PBC were at a significantly higher risk of developing HCC. Older age and male sex were consistent risk factors in both cohorts.

Impact and implications:

Notable heterogeneity has been observed among different studies in terms of the incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cholangitis (PBC). Large-scale studies on the association between PBC and HCC in Asians are scarce. In our nationwide cohort study, patients with PBC exhibited a significantly heightened risk of developing HCC and mortality than the age- and sex-matched controls. Individuals with PBC had a 9.1-fold higher risk of developing HCC than their matched counterparts, with an incidence rate of 3.7/1,000 person-years. Older age, male sex, smoking, and diabetes were identified as prominent risk factors for HCC in patients with PBC in the nationwide cohort. Older age, male sex, and alcohol consumption were identified as the factors significantly contributing to the elevated risk of HCC in patients with PBC in validation multicenter hospital cohort.
背景与目的:关于亚洲原发性胆道胆管炎(PBC)与肝细胞癌(HCC)之间关系的大规模研究很少。本研究旨在评估全国队列中HCC的发生率及其危险因素。方法:从韩国国民健康保险公团(2007-2020)中提取4,882例PBC患者和38,603例匹配对照组的数据并进行分析。评估PBC患者的HCC发生率及其危险因素,并与匹配对照组进行比较。研究结果在韩国峨山医疗中心(n = 815)和汝矣岛圣玛丽医院(n = 47)招募的862名PBC患者的多中心医院队列中得到验证。结果:共有105例PBC患者在中位随访5.42年期间发生HCC,发病率为3.7/ 1000人年(PYs),显著高于对照组(0.5/ 1000人年;调整风险比:9.07;95% ci: 6.71-12.27)。PBC、年龄较大、男性、糖尿病和吸烟被认为是HCC的重要危险因素。在多中心医院队列研究中,862例PBC患者中有23例发展为HCC,发病率为4.0/1,000 PYs (95% CI: 2.4-5.7)。年龄较大(亚分布风险比[SHR]: 1.05, 95% CI: 1.00-1.10)、男性(SHR: 3.00, 95% CI: 1.11-8.13)、当前饮酒(SHR: 3.70, 95% CI: 1.08-12.59)和肝硬化(SHR: 5.17, 95% CI: 2.07-12.93)被确定为医院队列中的危险因素。结论:PBC患者发生HCC的风险显著增高。在这两个队列中,年龄较大和男性是一致的危险因素。影响和意义:不同的研究在原发性胆道胆管炎(PBC)患者的肝细胞癌(HCC)发生率方面观察到显著的异质性。关于亚洲人PBC与HCC之间关系的大规模研究很少。在我们的全国队列研究中,PBC患者发生HCC的风险和死亡率明显高于年龄和性别匹配的对照组。PBC患者发生HCC的风险是匹配人群的9.1倍,发生率为3.7/ 1000人年。在全国队列中,年龄较大、男性、吸烟和糖尿病被确定为PBC患者HCC的主要危险因素。在验证性多中心医院队列中,年龄、男性和饮酒被确定为PBC患者HCC风险升高的显著因素。
{"title":"Risk of hepatocellular carcinoma in Asian patients with primary biliary cholangitis: A nationwide and hospital cohort study","authors":"Jihye Lim ,&nbsp;Ye-Jee Kim ,&nbsp;Sehee Kim ,&nbsp;Jonggi Choi","doi":"10.1016/j.jhepr.2024.101251","DOIUrl":"10.1016/j.jhepr.2024.101251","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Large-scale studies on the association between primary biliary cholangitis (PBC) and hepatocellular carcinoma (HCC) in Asians are scarce. This study aimed to evaluate the incidence of HCC and its risk factors in a nationwide cohort.</div></div><div><h3>Methods</h3><div>The data of 4,882 patients with PBC and 38,603 matched controls were extracted from the Korean National Health Insurance Service (2007–2020) and analyzed. The incidence of HCC and its risk factors in patients with PBC were assessed and compared with those in the matched controls. The results were validated in a multicenter hospital cohort of 862 patients with PBC, recruited from Asan Medical Center (n = 815) and Yeouido St. Mary’s Hospital (n = 47) in Korea.</div></div><div><h3>Results</h3><div>In total, 105 patients with PBC developed HCC over the median follow-up period of 5.42 years, yielding an incidence rate of 3.7/1,000 person-years (PYs), which was significantly higher than that in the controls (0.5/1,000 PYs; adjusted hazard ratio: 9.07; 95% CI: 6.71–12.27). PBC, older age, male sex, diabetes, and smoking were identified as significant risk factors for HCC. Twenty-three of the 862 patients with PBC developed HCC in the multicenter hospital cohort, yielding an incidence of 4.0/1,000 PYs (95% CI: 2.4–5.7). Older age (subdistribution hazard ratio [SHR]: 1.05, 95% CI: 1.00–1.10), male sex (SHR: 3.00, 95% CI: 1.11–8.13), current alcohol consumption (SHR: 3.70, 95% CI: 1.08–12.59), and cirrhosis (SHR: 5.17, 95% CI: 2.07–12.93) were identified as risk factors in the hospital cohort.</div></div><div><h3>Conclusions</h3><div>Patients with PBC were at a significantly higher risk of developing HCC. Older age and male sex were consistent risk factors in both cohorts.</div></div><div><h3>Impact and implications:</h3><div>Notable heterogeneity has been observed among different studies in terms of the incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cholangitis (PBC). Large-scale studies on the association between PBC and HCC in Asians are scarce. In our nationwide cohort study, patients with PBC exhibited a significantly heightened risk of developing HCC and mortality than the age- and sex-matched controls. Individuals with PBC had a 9.1-fold higher risk of developing HCC than their matched counterparts, with an incidence rate of 3.7/1,000 person-years. Older age, male sex, smoking, and diabetes were identified as prominent risk factors for HCC in patients with PBC in the nationwide cohort. Older age, male sex, and alcohol consumption were identified as the factors significantly contributing to the elevated risk of HCC in patients with PBC in validation multicenter hospital cohort.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 2","pages":"Article 101251"},"PeriodicalIF":9.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005511","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
Sex differences in murine MASH induced by a fructose-palmitate-cholesterol-enriched diet
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.jhepr.2024.101222
Lakshmi Arivazhagan , Sofie Delbare , Robin A. Wilson , Michaele B. Manigrasso , Boyan Zhou , Henry H. Ruiz , Kaamashri Mangar , Ryoko Higa , Emily Brown , Huilin Li , Michael J. Garabedian , Ravichandran Ramasamy , Kathryn J. Moore , Edward A. Fisher , Neil D. Theise , Ann Marie Schmidt
<div><h3>Background & Aims</h3><div>Metabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high-fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed.</div></div><div><h3>Methods</h3><div>Female and male C57BL/6J mice were fed a fructose-palmitate-cholesterol (FPC)-NASH diet <em>vs.</em> standard chow for 16 weeks (n = 40 mice). At sacrifice, plasma and liver were retrieved, the latter for single-nucleus RNA sequencing. Publicly available data sets of human male and female MASH liver were probed.</div></div><div><h3>Results</h3><div>The FPC-NASH diet-induced metabolic dysfunction in both female and male mice, with females exhibiting more severe hepatic steatosis (<em>p =</em> 0.0262), inflammation (<em>p =</em> 0.0206), and fibrosis (<em>p <</em>0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the standard chow. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts.</div></div><div><h3>Conclusions</h3><div>Molecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female individuals in MAFLD/MASH studies and clinical trials.</div></div><div><h3>Impact and implications:</h3><div>Despite the importance of metabolic dysfunction-associated steatohepatitis (MASH) in impairment of human health, the potential for and mechanisms of sex-dependent responses have yet to be well-studied, particularly with respect to the possible influence of high-fructose corn syrup additives to the diet, which has been linked to metabolic and hepatic disturbances. In a mouse model of fructose supplementation to a NASH diet, female mice displayed significantly higher MASH scores (steatosis, inflammation and fibrosis) compared to male mice. Single-nucleus RNA sequencing of livers revealed intrinsic, diet-dependent molecular disparities within sex, which were exaggerated when comparing female <em>vs.</em> male mice fed the fructose-containing NASH diet; many of these findings were recapitulated in human female <em>vs.</em> male patients with MASH. These results highlight potential mechanistic explana
{"title":"Sex differences in murine MASH induced by a fructose-palmitate-cholesterol-enriched diet","authors":"Lakshmi Arivazhagan ,&nbsp;Sofie Delbare ,&nbsp;Robin A. Wilson ,&nbsp;Michaele B. Manigrasso ,&nbsp;Boyan Zhou ,&nbsp;Henry H. Ruiz ,&nbsp;Kaamashri Mangar ,&nbsp;Ryoko Higa ,&nbsp;Emily Brown ,&nbsp;Huilin Li ,&nbsp;Michael J. Garabedian ,&nbsp;Ravichandran Ramasamy ,&nbsp;Kathryn J. Moore ,&nbsp;Edward A. Fisher ,&nbsp;Neil D. Theise ,&nbsp;Ann Marie Schmidt","doi":"10.1016/j.jhepr.2024.101222","DOIUrl":"10.1016/j.jhepr.2024.101222","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Metabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high-fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Female and male C57BL/6J mice were fed a fructose-palmitate-cholesterol (FPC)-NASH diet &lt;em&gt;vs.&lt;/em&gt; standard chow for 16 weeks (n = 40 mice). At sacrifice, plasma and liver were retrieved, the latter for single-nucleus RNA sequencing. Publicly available data sets of human male and female MASH liver were probed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The FPC-NASH diet-induced metabolic dysfunction in both female and male mice, with females exhibiting more severe hepatic steatosis (&lt;em&gt;p =&lt;/em&gt; 0.0262), inflammation (&lt;em&gt;p =&lt;/em&gt; 0.0206), and fibrosis (&lt;em&gt;p &lt;&lt;/em&gt;0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the standard chow. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Molecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female individuals in MAFLD/MASH studies and clinical trials.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;Despite the importance of metabolic dysfunction-associated steatohepatitis (MASH) in impairment of human health, the potential for and mechanisms of sex-dependent responses have yet to be well-studied, particularly with respect to the possible influence of high-fructose corn syrup additives to the diet, which has been linked to metabolic and hepatic disturbances. In a mouse model of fructose supplementation to a NASH diet, female mice displayed significantly higher MASH scores (steatosis, inflammation and fibrosis) compared to male mice. Single-nucleus RNA sequencing of livers revealed intrinsic, diet-dependent molecular disparities within sex, which were exaggerated when comparing female &lt;em&gt;vs.&lt;/em&gt; male mice fed the fructose-containing NASH diet; many of these findings were recapitulated in human female &lt;em&gt;vs.&lt;/em&gt; male patients with MASH. These results highlight potential mechanistic explana","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 2","pages":"Article 101222"},"PeriodicalIF":9.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143170898","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
Alcohol-associated hepatitis trends before and following the onset of the COVID-19 pandemic across two distinct cohorts in the United States and Hong Kong 美国和香港两个不同队列中 COVID-19 大流行前后的酒精相关肝炎趋势。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101254
Zeyuan Yang , Vicki Wing-Ki Hui , Terry Cheuk-Fung Yip , Mandy Sze-Man Lai , Jimmy Che-To Lai , Vincent Wai-Sun Wong , Ramsey Cheung , Grace Lai-Hung Wong , Robert J. Wong

Background & Aims

Alcohol-associated liver disease (ALD) burden has been rising globally, fueled by increases in high-risk alcohol use following the coronavirus disease 2019 (COVID-19) pandemic. We evaluated trends in annual incidence of alcohol-associated hepatitis (AH) before and following the onset of the COVID-19 pandemic across two geographically distinct populations in the USA and Hong Kong.

Methods

Using US national Veterans Affairs (VA) data and Hong Kong territory-wide data, trends in annual incidence of AH were evaluated from 2000 to 2023. AH was identified using a combination of International Classification of Diseases (ICD)-9/10 diagnostic codes, laboratory data, and available alcohol use data.

Results

Among the VA data, annual incidence of AH rose steadily from 39.4 to 53.7 per 100,000 persons (2010–2020), then declined to 36.2 per 100,000 persons in 2023. Annual AH incidence was substantially lower in Hong Kong, but demonstrated similar trends, peaking at 0.28 per 100,000 persons during the first year of the pandemic. Among both cohorts, incidence of AH was significantly higher in men vs. women, but particularly for the VA cohort, the increase in AH incidence was more rapid in women. Among both cohorts, the highest incidence of AH in 2023 was among the 40–49-year age group (VA: 72.7 per 100,000 persons; Hong Kong: 1.89 per 100,000 persons).

Conclusions

We provide a comprehensive analysis of epidemiological trends in AH incidence across two distinct populations, highlighting the need for continued awareness of targeted interventions to curb unhealthy alcohol use and its complications.

Impact and implications:

Alcohol-associated hepatitis (AH) is a severe complication of high-risk alcohol use associated with significant morbidity and mortality. Increasing alcohol use fueled by the COVID-19 pandemic has led to parallel increases in alcohol-related comorbidities. The current study provides a comprehensive analysis of trends in the incidence of AH across two distinct world regions before and following the onset of the COVID-19 pandemic. Better identification of epidemiological trends in AH incidence as well as highlighting populations most affected can help target public health resources and health system interventions to address the dangers of high-risk alcohol use more effectively.
背景与目的:2019年冠状病毒病(COVID-19)大流行后,高风险酒精使用的增加加剧了全球酒精相关肝病(ALD)负担的上升。我们评估了美国和香港两个地理位置不同的人群在2019冠状病毒病大流行之前和之后酒精相关性肝炎(AH)年发病率的趋势。方法:利用美国国家退伍军人事务(VA)数据和香港地区数据,评估2000年至2023年AH年发病率的趋势。综合使用国际疾病分类(ICD) 9/10诊断代码、实验室数据和现有酒精使用数据,确定了AH。结果:在VA数据中,AH的年发病率从2010-2020年的39.4 / 10万人稳步上升到53.7 / 10万人,然后在2023年下降到36.2 / 10万人。香港的年度AH发病率较低,但趋势相似,在大流行的第一年达到每10万人0.28例的峰值。在这两个队列中,男性AH的发病率明显高于女性,但特别是在VA队列中,女性AH发病率的增加更快。在这两个队列中,2023年AH发病率最高的是40-49岁年龄组(VA: 72.7 / 10万人;香港:每10万人1.89人)。结论:我们对两种不同人群中AH发病率的流行病学趋势进行了全面分析,强调有必要继续意识到有针对性的干预措施,以遏制不健康的酒精使用及其并发症。影响和意义:酒精相关性肝炎(AH)是高风险酒精使用的严重并发症,具有显著的发病率和死亡率。COVID-19大流行导致酒精使用增加,导致酒精相关合并症也随之增加。目前的研究对COVID-19大流行发生之前和之后两个不同世界区域的AH发病率趋势进行了全面分析。更好地确定AH发病率的流行病学趋势,并突出受影响最严重的人群,有助于针对公共卫生资源和卫生系统干预措施,更有效地解决高风险酒精使用的危险。
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引用次数: 0
Induction of phospholipase A2 group 4C by HCV infection regulates lipid droplet formation HCV感染诱导磷脂酶A2组4C调控脂滴形成。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101225
Masahiko Ito , Jie Liu , Masayoshi Fukasawa , Koji Tsutsumi , Yumi Kanegae , Mitsutoshi Setou , Michinori Kohara , Tetsuro Suzuki
<div><h3>Background & Aims</h3><div>Hepatic steatosis, characterized by lipid accumulation in hepatocytes, is a key diagnostic feature in patients with chronic hepatitis C virus (HCV) infection. This study aimed to clarify the involvement of phospholipid metabolic pathways in the pathogenesis of HCV-induced steatosis.</div></div><div><h3>Methods</h3><div>The expression and distribution of lipid species in the livers of human liver chimeric mice were analyzed using imaging mass spectrometry. Triglyceride accumulation and lipid droplet formation were studied in phospholipase A2 group 4C (<em>PLA2G4C</em>) knockout or overexpressing cells.</div></div><div><h3>Results</h3><div>Imaging mass spectrometry of the infected mouse model revealed increased lysophosphatidylcholine levels and decreased phosphatidylcholine levels in HCV-positive regions of the liver. Among the transcripts associated with phosphatidylcholine biosynthesis, upregulation of <em>PLA2G4C</em> mRNA was most pronounced following HCV infection. Activation of the transcription factor NF-κB and upregulation of c-Myc were important for activation of <em>PLA2G4C</em> transcription by HCV infection and expression of the viral proteins Core-NS2. The amount and size of lipid droplets were reduced in <em>PLA2G4C</em>-knockout cells. Inhibition of NF-κB or c-Myc activity suppressed lipid droplet formation in HCV-infected cells. HCV infection promoted the stabilization of lipid droplets, but this stability was reduced in <em>PLA2G4C</em>-knockout cells. Overexpression of <em>PLA2G4C</em> decreased the levels of phosphatidylcholine species in the lipid droplet fraction and led to lower levels of key factors involved in lipolysis (breakdown of triglycerides into glycerol and free fatty acids), such as ATGL, PLIN1 and ABHD5 on the lipid droplets.</div></div><div><h3>Conclusions</h3><div>HCV infection markedly increases <em>PLA2G4C</em> expression. This may alter the phospholipid composition of the lipid droplet membrane, leading to stabilization and enlargement of the droplets.</div></div><div><h3>Impact and implications:</h3><div>The involvement of phospholipid metabolism pathways in the pathogenesis of hepatitis C virus (HCV)-related liver diseases remains unclear. We found that <em>PLA2G4C</em> expression is upregulated through NF-κB and c-Myc activation upon HCV infection, and this upregulation is associated with a decrease in phosphatidylcholine species. The increased expression of <em>PLA2G4C</em> resulted in changes in the phospholipid composition of lipid droplets, led to the dissociation of lipolysis-related factors from the lipid droplet surface and the accumulation of lipid content within the droplets. These findings suggest that the disruption of the phospholipid metabolism pathway caused by HCV infection may contribute to the development of HCV-associated fatty liver. It would be interesting to determine whether alcohol- and/or metabolic dysfunction-associated steatohepatitis are al
背景与目的:肝脂肪变性以肝细胞脂质积累为特征,是慢性丙型肝炎病毒(HCV)感染患者的关键诊断特征。本研究旨在阐明磷脂代谢途径在hcv诱导的脂肪变性发病机制中的作用。方法:采用成像质谱法分析人肝嵌合小鼠肝脏中脂类的表达和分布。研究了磷脂酶A2 4C组(PLA2G4C)敲除或过表达细胞中甘油三酯的积累和脂滴的形成。结果:感染小鼠模型的成像质谱显示hcv阳性肝脏区域溶血磷脂酰胆碱水平升高,磷脂酰胆碱水平降低。在与磷脂酰胆碱生物合成相关的转录本中,PLA2G4C mRNA的上调在HCV感染后最为明显。转录因子NF-κB的激活和c-Myc的上调对于HCV感染激活PLA2G4C转录和病毒蛋白Core-NS2的表达具有重要意义。pla2g4c敲除细胞中脂滴的数量和大小均减少。抑制NF-κB或c-Myc活性可抑制hcv感染细胞的脂滴形成。HCV感染促进了脂滴的稳定,但在pla2g4c敲除细胞中,这种稳定性降低。PLA2G4C的过表达降低了脂滴部分磷脂酰胆碱种类的水平,并导致脂滴上参与脂解(甘油三酯分解为甘油和游离脂肪酸)的关键因子,如ATGL、PLIN1和ABHD5的水平降低。结论:HCV感染可显著增加PLA2G4C的表达。这可能会改变脂滴膜的磷脂组成,导致脂滴的稳定和扩大。影响和意义:磷脂代谢途径在丙型肝炎病毒(HCV)相关肝病发病机制中的作用尚不清楚。我们发现,在HCV感染时,PLA2G4C的表达通过NF-κB和c-Myc的激活而上调,这种上调与磷脂酰胆碱种类的减少有关。PLA2G4C表达增加导致脂滴磷脂组成改变,导致脂滴表面脂解相关因子解离,脂滴内脂含量积累。这些发现提示,HCV感染引起的磷脂代谢途径的破坏可能有助于HCV相关性脂肪肝的发展。确定酒精和/或代谢功能障碍相关的脂肪性肝炎是否也与PLA2活性增加、磷脂组成改变和脂滴膜中ATGL及其辅助因子水平降低有关,这将是一项有趣的研究。
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引用次数: 0
Hepatic stellate cell single cell atlas reveals a highly similar activation process across liver disease aetiologies 肝星状细胞单细胞图谱揭示了肝脏疾病病因中高度相似的激活过程。
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101223
Vincent Merens , Elisabeth Knetemann , Elif Gürbüz , Vincent De Smet , Nouredin Messaoudi , Hendrik Reynaert , Stefaan Verhulst , Leo A. van Grunsven

Background & Aims

The progression of chronic liver disease (CLD) is characterized by excessive extracellular matrix deposition, disrupting hepatic architecture and function. Upon liver injury, hepatic stellate cells (HSCs) differentiate towards myofibroblasts and become inflammatory, proliferative and fibrogenic. To date, it is still unclear whether HSC activation is driven by similar mechanisms in different aetiologies.

Methods

HSCs from multiple publicly available single-cell RNA-sequencing datasets were annotated and merged into a single-cell HSC activation atlas. Spheroid co-cultures of primary mouse hepatocytes/HSCs (n = 5) and ELISAs on patient plasma samples (n = 80) were performed to validate the mechanistic insight obtained from the HSC atlas.

Results

We established an HSC activation atlas in which HSCs are clearly divided into three distinct transcriptomic profiles: quiescent HSCs, initiatory HSCs and myofibroblasts. These transcriptomic profiles are present in each of the investigated mouse liver injury models as well as in human CLDs, indicating that HSC activation is a conserved process. This activation process is driven by a core set of transcription factors independent of liver injury or species. Furthermore, we reveal novel ligands associated with activation of HSCs in multiple liver injury models and validate the profibrotic effect of parathyroid hormone. Finally, we identify COLEC10 as a conserved marker for quiescent HSCs and a biomarker of liver fibrosis in patients with different CLDs (p <0.0001).

Conclusions

We reveal unexpected similarities in the regulatory mechanisms of HSCs across diverse liver injury settings and species. The HSC activation atlas has the potential to provide novel insights into liver fibrosis and steer novel treatment options.

Impact and implications:

This study establishes a single-cell atlas of hepatic stellate cells across various liver injuries, highlighting a conserved activation process between different injuries and across species. The discovery of novel activating ligands and the biomarker COLEC10 in human plasma could be used to enhance diagnostic and therapeutic strategies. Additionally, the conserved activation process supports the use of any mouse model for mechanistic studies and testing of new anti-fibrotic compounds, streamlining preclinical research efforts.
背景与目的:慢性肝病(CLD)的进展以过度的细胞外基质沉积,破坏肝脏结构和功能为特征。肝损伤后,肝星状细胞(hsc)向肌成纤维细胞分化,并发生炎症、增殖和成纤维。迄今为止,尚不清楚HSC激活是否由不同病因的相似机制驱动。方法:对来自多个公开的单细胞rna测序数据集的HSC进行注释并合并到单细胞HSC激活图谱中。对原代小鼠肝细胞/HSC (n = 5)和患者血浆样本(n = 80)进行球形共培养,以验证从HSC图谱中获得的机制见解。结果:我们建立了一个HSC激活图谱,其中HSC明确分为三种不同的转录组谱:静止HSC、起始HSC和肌成纤维细胞。这些转录组谱存在于所研究的每种小鼠肝损伤模型以及人类CLDs中,表明HSC激活是一个保守的过程。这个激活过程是由一组核心转录因子驱动的,与肝损伤或物种无关。此外,我们在多种肝损伤模型中发现了与hsc激活相关的新配体,并验证了甲状旁腺激素的促纤维化作用。最后,我们确定COLEC10是静止hsc的保守标记物,也是不同CLDs患者肝纤维化的生物标志物(p 0.0001)。结论:我们揭示了hsc在不同肝损伤环境和物种中的调节机制的意想不到的相似性。HSC激活图谱有可能为肝纤维化提供新的见解,并引导新的治疗选择。影响和意义:本研究建立了不同肝损伤的肝星状细胞单细胞图谱,强调了不同损伤和不同物种之间的保守激活过程。在人血浆中发现新的激活配体和生物标志物COLEC10可用于增强诊断和治疗策略。此外,保守的激活过程支持使用任何小鼠模型进行机制研究和测试新的抗纤维化化合物,简化临床前研究工作。
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引用次数: 0
The first year of the new Editorial Team of JHEP Reports
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-01 DOI: 10.1016/j.jhepr.2024.101292
Xavier Forns , Josep M. Llovet
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引用次数: 0
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JHEP Reports
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