This study aimed to identify and establish novel biomarkers for human drug-induced liver injury (DILI).
Methods
Patients with DILI (N = 52) or other liver diseases (N = 486) and healthy participants (N = 60) were recruited from the hospitals enrolled in this study. Metabolomics was conducted using serum samples from patients with DILI and healthy participants to screen for candidate DILI biomarkers. Subsequently, the serum concentrations of the candidate biomarkers were determined using a validated assay to characterize their properties and evaluate their ability to differentiate the patients with DILI from those who recovered from DILI and those with other liver diseases.
Results
Three metabolites, pyroglutamylglycine (pyroGluGly), phenylalanine (Phe), and phenylalanyltryptophan (PheTrp), were identified as candidate DILI biomarkers. The serum concentrations of pyroGluGly, Phe, and PheTrp demonstrated a high and similar differentiating ability (area under the receiver-operating characteristic curve [ROC-AUC] > 0.9) in patients with mixed and cholestatic DILI compared with those in patients who recovered from DILI, suggesting that these three metabolites are biomarkers for mixed/cholestatic DILI. All or some of them demonstrated a substantially high differentiating ability (ROC-AUC > 0.8) in patients with mixed/cholestatic DILI compared with patients with other liver diseases, except for obstructive jaundice.
Conclusions
We identified novel DILI biomarkers that can be used to clinically assess patients with mixed/cholestatic DILI and to differentiate these patients from recovered patients and those with other liver diseases.
{"title":"Identification and Characterization of Three Novel Biomarkers for Mixed/Cholestatic Drug-Induced Liver Injury","authors":"Kosuke Saito, Tatehiro Kagawa, Keiji Tsuji, Yuji Kumagai, Ken Sato, Shotaro Sakisaka, Naoya Sakamoto, Mitsuhiko Aiso, Shunji Hirose, Nami Mori, Toshio Uraoka, Kazuhide Takata, Koji Ogawa, Kazuhiko Mori, Motonobu Sato, Takayoshi Nishiya, Kazuhiko Takamatsu, Noriaki Arakawa, Takashi Izumi, Ruri Kikura-Hanajiri, Yasuo Ohno, Yoshiro Saito, Hajime Takikawa","doi":"10.1111/hepr.70043","DOIUrl":"10.1111/hepr.70043","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study aimed to identify and establish novel biomarkers for human drug-induced liver injury (DILI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with DILI (<i>N</i> = 52) or other liver diseases (<i>N</i> = 486) and healthy participants (<i>N</i> = 60) were recruited from the hospitals enrolled in this study. Metabolomics was conducted using serum samples from patients with DILI and healthy participants to screen for candidate DILI biomarkers. Subsequently, the serum concentrations of the candidate biomarkers were determined using a validated assay to characterize their properties and evaluate their ability to differentiate the patients with DILI from those who recovered from DILI and those with other liver diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Three metabolites, pyroglutamylglycine (pyroGluGly), phenylalanine (Phe), and phenylalanyltryptophan (PheTrp), were identified as candidate DILI biomarkers. The serum concentrations of pyroGluGly, Phe, and PheTrp demonstrated a high and similar differentiating ability (area under the receiver-operating characteristic curve [ROC-AUC] > 0.9) in patients with mixed and cholestatic DILI compared with those in patients who recovered from DILI, suggesting that these three metabolites are biomarkers for mixed/cholestatic DILI. All or some of them demonstrated a substantially high differentiating ability (ROC-AUC > 0.8) in patients with mixed/cholestatic DILI compared with patients with other liver diseases, except for obstructive jaundice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified novel DILI biomarkers that can be used to clinically assess patients with mixed/cholestatic DILI and to differentiate these patients from recovered patients and those with other liver diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":"111-124"},"PeriodicalIF":3.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Which Cells Play a Protective Role in Primary Biliary Cholangitis: Dendritic Cells or Others?","authors":"Zhencheng Zhang, Zaixing Yang","doi":"10.1111/hepr.70045","DOIUrl":"10.1111/hepr.70045","url":null,"abstract":"","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bile acid (BA) signaling plays an important role in the pathogenesis of hepatic encephalopathy (HE), including covert (CHE) and overt HE (OHE). However, few studies have examined its clinical impact in patients with cirrhosis.
Methods
This retrospective study included patients with cirrhosis who underwent CHE assessment using a computer-aided neuropsychiatric test. BAs were quantified using liquid chromatography-tandem mass spectrometry. Patients were divided into high and low groups according to their BA levels. Independent factors, namely CHE, OHE development, and mortality, were assessed using logistic, Fine–Gray competing risk, and Cox proportional hazards regression models.
Results
Among the 189 patients, the median age was 71 years, 74.1% were male, and 28.0% were diagnosed with CHE. During a median follow-up period of 3.1 years, 15.9% (n = 30) developed OHE, and 33.3% (n = 63) died. Considering mortality as a competing risk, multivariable analysis identified a high conjugated primary BA level (subdistribution hazard ratio [HR] 3.44; 95% confidence interval [CI] 1.08–10.97) as an independent factor for OHE development. Additionally, a high non-conjugated primary BA level (odds ratio 2.18; 95% CI 1.06–4.46) was an independent factor of CHE. Furthermore, a high conjugated primary BA level (HR 2.06; 95% CI 1.11–3.83) was an independent predictor of mortality.
Conclusions
Elevated serum conjugated primary BA levels are an independent factor for OHE development and mortality in patients with cirrhosis. Additionally, elevated non-conjugated primary BA levels were an independent factor for CHE in these patients.
目的：胆汁酸（BA）信号在肝性脑病（HE）的发病机制中起重要作用，包括隐性（CHE）和显性（OHE）。然而，很少有研究考察其对肝硬化患者的临床影响。方法：本回顾性研究纳入了使用计算机辅助神经精神测试进行CHE评估的肝硬化患者。采用液相色谱-串联质谱法对BAs进行定量。根据BA水平将患者分为高、低两组。独立因素，即CHE、OHE发展和死亡率，采用logistic、Fine-Gray竞争风险和Cox比例风险回归模型进行评估。结果：189例患者中位年龄为71岁，男性占74.1%，诊断为CHE的比例为28.0%。在中位随访3.1年期间，15.9% （n = 30）发生OHE， 33.3% （n = 63）死亡。考虑到死亡率作为竞争风险，多变量分析确定高共轭原发性BA水平（亚分布风险比[HR] 3.44； 95%置信区间[CI] 1.08-10.97）是OHE发展的独立因素。此外，高非共轭原发性BA水平（优势比2.18;95% CI 1.06-4.46）是CHE的独立因素。此外，高共轭原发BA水平（HR 2.06; 95% CI 1.11-3.83）是死亡率的独立预测因子。结论：血清结合原发性BA水平升高是肝硬化患者OHE发展和死亡率的独立因素。此外，非共轭原发性BA水平升高是这些患者CHE的独立因素。
{"title":"Altered Serum Bile Acid Pattern as an Independent Factor for Covert and Overt Hepatic Encephalopathy in Patients With Cirrhosis","authors":"Takao Miwa, Hajime Ueda, Teruo Miyazaki, Akira Honda, Tadashi Ikegami, Shinji Unome, Tatsunori Hanai, Yohei Shirakami, Masahito Shimizu","doi":"10.1111/hepr.70036","DOIUrl":"10.1111/hepr.70036","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Bile acid (BA) signaling plays an important role in the pathogenesis of hepatic encephalopathy (HE), including covert (CHE) and overt HE (OHE). However, few studies have examined its clinical impact in patients with cirrhosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective study included patients with cirrhosis who underwent CHE assessment using a computer-aided neuropsychiatric test. BAs were quantified using liquid chromatography-tandem mass spectrometry. Patients were divided into high and low groups according to their BA levels. Independent factors, namely CHE, OHE development, and mortality, were assessed using logistic, Fine–Gray competing risk, and Cox proportional hazards regression models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the 189 patients, the median age was 71 years, 74.1% were male, and 28.0% were diagnosed with CHE. During a median follow-up period of 3.1 years, 15.9% (<i>n</i> = 30) developed OHE, and 33.3% (<i>n</i> = 63) died. Considering mortality as a competing risk, multivariable analysis identified a high conjugated primary BA level (subdistribution hazard ratio [HR] 3.44; 95% confidence interval [CI] 1.08–10.97) as an independent factor for OHE development. Additionally, a high non-conjugated primary BA level (odds ratio 2.18; 95% CI 1.06–4.46) was an independent factor of CHE. Furthermore, a high conjugated primary BA level (HR 2.06; 95% CI 1.11–3.83) was an independent predictor of mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Elevated serum conjugated primary BA levels are an independent factor for OHE development and mortality in patients with cirrhosis. Additionally, elevated non-conjugated primary BA levels were an independent factor for CHE in these patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":"60-69"},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Successful Retreatment of Glecaprevir-Pibrentasvir for Hepatitis C Virus Genotype 2a Infection in Patient Whose Cirrhosis Improved From Decompensation to Compensation After Sofosbuvir–Velpatasvir Therapy","authors":"Tatsuo Kanda, Ryota Masuzaki, Naoki Matsumoto, Reina Sasaki-Tanaka, Hirofumi Kogure","doi":"10.1111/hepr.70046","DOIUrl":"10.1111/hepr.70046","url":null,"abstract":"","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 2","pages":"253-255"},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic liver diseases (CLD) arising from various etiologies including viral hepatitis, excessive alcohol intake, alcoholic associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), are associated with persistent hepatic injury ultimately resulting in fibrosis. Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM). This pathological ECM deposition increases tissue stiffness, disrupts normal tissue architecture and impairs liver functions leading to cirrhosis which constitutes a major risk factor for the onset of hepatocellular carcinoma (HCC). The characteristics of the ECM in liver fibrosis have been extensively investigated, particularly with the use of recent proteomic approaches that provide a large overview of ECM changes during disease progression. Alongside large collagen fiber molecules, established as a hallmark of fibrotic tissues, numerous other matrix components are significantly altered. These include the fibulin family. These glycoproteins are distributed across various tissues and involved in numerous physiological processes including embryonic development and tissue repair. They are implicated in a range of pathological processes such as hypertrophic cardiomyopathy, chronic fibrotic disorders, and cancer. In healthy a liver, low levels of fibulins can be detected; however, the expression of a number of fibulin family members is markedly induced during the progression of fibrosis. Beyond their role in the organization and structure integrity of elastic fibers, their contribution to the pathogenesis of liver fibrosis and HCC remains poorly understood. The present review provides an up-to-date overview of the literature on fibulins in the context of chronic liver diseases with particular insights from new omics meta-analyses.
{"title":"Fibulin Family Members: New Players in Liver Fibrosis and Potential Biomarkers in Chronic Liver Diseases","authors":"Fidaa Bouezzedine, Célia Thomas, Nathalie Théret","doi":"10.1111/hepr.70032","DOIUrl":"10.1111/hepr.70032","url":null,"abstract":"<p>Chronic liver diseases (CLD) arising from various etiologies including viral hepatitis, excessive alcohol intake, alcoholic associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), are associated with persistent hepatic injury ultimately resulting in fibrosis. Liver fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM). This pathological ECM deposition increases tissue stiffness, disrupts normal tissue architecture and impairs liver functions leading to cirrhosis which constitutes a major risk factor for the onset of hepatocellular carcinoma (HCC). The characteristics of the ECM in liver fibrosis have been extensively investigated, particularly with the use of recent proteomic approaches that provide a large overview of ECM changes during disease progression. Alongside large collagen fiber molecules, established as a hallmark of fibrotic tissues, numerous other matrix components are significantly altered. These include the fibulin family. These glycoproteins are distributed across various tissues and involved in numerous physiological processes including embryonic development and tissue repair. They are implicated in a range of pathological processes such as hypertrophic cardiomyopathy, chronic fibrotic disorders, and cancer. In healthy a liver, low levels of fibulins can be detected; however, the expression of a number of fibulin family members is markedly induced during the progression of fibrosis. Beyond their role in the organization and structure integrity of elastic fibers, their contribution to the pathogenesis of liver fibrosis and HCC remains poorly understood. The present review provides an up-to-date overview of the literature on fibulins in the context of chronic liver diseases with particular insights from new omics meta-analyses.</p>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 11","pages":"1425-1436"},"PeriodicalIF":3.4,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Frailty is emerging as a prognostic factor in chronic liver disease (CLD). However, its clinical impact remains underexplored, particularly in Japan. This study aimed to evaluate the prognostic significance of frailty in Japanese patients with CLD. In addition, the prevalence and clinical characteristics of frailty in this population were assessed.
Methods
The present multicenter retrospective study included patients with CLD who were admitted to three institutions in Japan. Frailty was diagnosed based on a Clinical Frailty Scale score of > 4. Factors associated with prognosis and frailty were evaluated using Cox proportional hazards regression and logistic regression models, respectively.
Results
Of 715 patients (median [interquartile range] age, 67 [56–74] years; 354 [49.5%] male; 227 [38.7%] with viral hepatitis), frailty was identified in 137 (19.2%). During the median follow-up of 2.9 years, 221 patients (28%) died. Patients with frailty had significantly shorter survival than those without frailty (median 2.4 vs. 10.6 years, p < 0.001). Multivariable Cox regression analysis showed that frailty was an independent adverse factor for mortality (hazard ratio, 1.75; 95% confidence interval, 1.25–2.45; p = 0.001) in patients with CLD. Regarding determinants of frailty, multivariable logistic regression analysis showed that older age, hepatic encephalopathy, hypoalbuminemia, thrombocytopenia, and prolonged international normalized ratio were associated with frailty.
Conclusions
Frailty is prevalent in patients with CLD and independently predicts poor survival. Given its prognostic significance, frailty assessment should be incorporated for risk stratification, early intervention, and outcome improvement in patients with CLD.
{"title":"Frailty Is an Independent Predictor of Mortality in Japanese Patients With Chronic Liver Disease: A Multicenter Retrospective Cohort Study","authors":"Shinji Unome, Mikita Oi, Yuki Utakata, Takao Miwa, Masashi Aiba, Tatsunori Hanai, Makoto Shiraki, Yasuhiro Kawashima, Naoki Katsumura, Masahito Shimizu","doi":"10.1111/hepr.70042","DOIUrl":"10.1111/hepr.70042","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Frailty is emerging as a prognostic factor in chronic liver disease (CLD). However, its clinical impact remains underexplored, particularly in Japan. This study aimed to evaluate the prognostic significance of frailty in Japanese patients with CLD. In addition, the prevalence and clinical characteristics of frailty in this population were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The present multicenter retrospective study included patients with CLD who were admitted to three institutions in Japan. Frailty was diagnosed based on a Clinical Frailty Scale score of > 4. Factors associated with prognosis and frailty were evaluated using Cox proportional hazards regression and logistic regression models, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 715 patients (median [interquartile range] age, 67 [56–74] years; 354 [49.5%] male; 227 [38.7%] with viral hepatitis), frailty was identified in 137 (19.2%). During the median follow-up of 2.9 years, 221 patients (28%) died. Patients with frailty had significantly shorter survival than those without frailty (median 2.4 vs. 10.6 years, <i>p</i> < 0.001). Multivariable Cox regression analysis showed that frailty was an independent adverse factor for mortality (hazard ratio, 1.75; 95% confidence interval, 1.25–2.45; <i>p</i> = 0.001) in patients with CLD. Regarding determinants of frailty, multivariable logistic regression analysis showed that older age, hepatic encephalopathy, hypoalbuminemia, thrombocytopenia, and prolonged international normalized ratio were associated with frailty.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Frailty is prevalent in patients with CLD and independently predicts poor survival. Given its prognostic significance, frailty assessment should be incorporated for risk stratification, early intervention, and outcome improvement in patients with CLD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":"70-77"},"PeriodicalIF":3.4,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although direct-acting antivirals (DAAs) achieve high sustained virologic response (SVR) rates, the long-term outcomes of patients with hepatitis C virus (HCV)-related cirrhosis remain variable. Growth differentiation factor 15 (GDF15), a stress-induced cytokine, has emerged as a potential biomarker for liver disease progression. This study aimed to evaluate the prognostic value of serum GDF15 levels in predicting hepatocellular carcinoma (HCC), hepatic decompensation, and mortality in patients with HCV-related cirrhosis.
Methods
We retrospectively analyzed 196 patients with HCV-related cirrhosis who achieved SVR at 18 Japanese institutions. Serum GDF15 levels were measured at baseline (BL) and 24 weeks posttreatment (p24w). A previously validated cutoff of 1.75 ng/mL was applied. The clinical outcomes included HCC occurrence, hepatic decompensation, and all-cause mortality.
Results
During a median follow-up of 46.2 months, 75 patients developed HCC, 28 experienced hepatic decompensation, and 25 died. Hepatic decompensation occurred significantly less frequently in the BL GDF15-low group. Importantly, no deaths occurred in the GDF15-low group, whereas the 5-year survival rate in the GDF15-high group was 71.7%. Similar trends were observed for GDF15 levels at p24w. In the overall cohort, GDF15 was not significantly associated with incident HCC; among HCC-naïve patients, a nonsignificant trend toward lower 3-year HCC incidence was observed in the GDF15-low group.
Conclusions
Serum GDF15 is a promising prognostic biomarker for post-SVR outcomes in patients with HCV-related cirrhosis. Its ability to predict decompensation and mortality through a validated cutoff supports its use for risk stratification and long-term management in patients with chronic liver disease.
{"title":"Serum Growth Differentiation Factor 15 Can Be a Novel Biomarker to Predict the Prognosis of Patients With Hepatitis C Virus Cirrhosis After Virus Elimination","authors":"Yuta Myojin, Hayato Hikita, Yuki Tahata, Kenji Fukumoto, Seiya Kato, Yoichi Sasaki, Shusuke Kumazaki, Atsunori Tsuchiya, Masaru Enomoto, Daiki Miki, Hiroshi Yatsuhashi, Hidekatsu Kuroda, Yoshihito Uchida, Hitoshi Yoshiji, Taro Yamashita, Seiichi Mawatari, Nobuharu Tamaki, Hisamitsu Miyaaki, Yasuhiro Asahina, Goki Suda, Kentaro Matsuura, Yasunari Nakamoto, Yoichi Hiasa, Taro Takami, Kumiko Shirai, Kazuki Maesaka, Kazuhiro Murai, Yuki Makino, Yoshinobu Saito, Takahiro Kodama, Tomohide Tatsumi, Tetsuo Takehara","doi":"10.1111/hepr.70041","DOIUrl":"10.1111/hepr.70041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Although direct-acting antivirals (DAAs) achieve high sustained virologic response (SVR) rates, the long-term outcomes of patients with hepatitis C virus (HCV)-related cirrhosis remain variable. Growth differentiation factor 15 (GDF15), a stress-induced cytokine, has emerged as a potential biomarker for liver disease progression. This study aimed to evaluate the prognostic value of serum GDF15 levels in predicting hepatocellular carcinoma (HCC), hepatic decompensation, and mortality in patients with HCV-related cirrhosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively analyzed 196 patients with HCV-related cirrhosis who achieved SVR at 18 Japanese institutions. Serum GDF15 levels were measured at baseline (BL) and 24 weeks posttreatment (p24w). A previously validated cutoff of 1.75 ng/mL was applied. The clinical outcomes included HCC occurrence, hepatic decompensation, and all-cause mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During a median follow-up of 46.2 months, 75 patients developed HCC, 28 experienced hepatic decompensation, and 25 died. Hepatic decompensation occurred significantly less frequently in the BL GDF15-low group. Importantly, no deaths occurred in the GDF15-low group, whereas the 5-year survival rate in the GDF15-high group was 71.7%. Similar trends were observed for GDF15 levels at p24w. In the overall cohort, GDF15 was not significantly associated with incident HCC; among HCC-naïve patients, a nonsignificant trend toward lower 3-year HCC incidence was observed in the GDF15-low group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Serum GDF15 is a promising prognostic biomarker for post-SVR outcomes in patients with HCV-related cirrhosis. Its ability to predict decompensation and mortality through a validated cutoff supports its use for risk stratification and long-term management in patients with chronic liver disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":"21-32"},"PeriodicalIF":3.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuta Maruki, Yasushi Yatabe, Chiharu Mizoguchi, Kathleen Yasmin de Almeida, Aumkhae Sookprasert, Charuwan Akewanlop, Ming-Huang Chen, Ekaphop Sirachainan, Dao Van Tu, Rozita Abdul Malik, Chaiyut Charoentum, Hwoei Fen Soo Hoo, Suhana Yusak, Tsung-Hao Liu, Rangasamy Ramachandran, Patrapim Sunpaweravong, Pei Jye Voon, Najihah Abu Bakar, Junki Mizusawa, Hitomi Sumiyoshi Okuma, Kenichi Nakamura, Chigusa Morizane, Takuji Okusaka
Aim
Biliary tract cancers, including intrahepatic cholangiocarcinoma (ICC), are aggressive with limited treatment options and poor prognosis. Recent trials (TOPAZ-1, Keynote-966) showed improved survival with ICIs plus gemcitabine and cisplatin. Targeted therapies, including FGFR inhibitors, are promising for cholangiocarcinoma patients with FGFR2 gene fusions or rearrangements, although few reports exist on FGFR2 positivity and clinical data in Asia. This study aims to address this gap by evaluating FGFR2 fusions or rearrangements in intrahepatic and perihilar cholangiocarcinoma patients across Asia, providing insights into their clinical significance and potential therapeutic implications.
Methods
This multicenter study evaluated the frequency of FGFR2 rearrangements and fusion genes in ICC and perihilar cholangiocarcinoma across Asia (Thailand, Malaysia, Vietnam, and Taiwan) using fluorescence in situ hybridization (FISH) and comprehensive genomic profiling with the Todai OncoPanel2 (TOP2).
Results
Of 113 patients, 102 were eligible; FGFR2 rearrangements/fusions were found in 3.9% (4 cases) by FISH, all of which were also confirmed by the TOP2 panel, consistent with the Japanese PRELUDE study. Younger age was significantly associated with FGFR2 positivity (34.5 ± 3.17 vs. 62.69 ± 1.04; p = 0.0003), whereas no correlation was observed with hepatitis infection, alcohol use, or smoking history. Genomic profiling identified frequent mutations in TP53, KRAS, and ARID1A with notable regional variability. Patients treated with ICIs showed significantly longer progression-free survival compared to other therapies: ICI + cytotoxic (348 days, 95% CI: 0–897), platinum-based + GEM (240 days, 95% CI: 197–282), and other treatments (168 days, 95% CI: 11–325; p = 0.017).
Conclusion
The FGFR2 positivity rate in Asia is slightly lower but consistent with Japanese reports and is more common in younger patients with ICC. Distinct genetic alterations may characterize Asian populations.
目的：胆道肿瘤，包括肝内胆管癌（ICC），具有侵袭性，治疗方案有限，预后差。最近的试验（TOPAZ-1, Keynote-966）显示ICIs联合吉西他滨和顺铂可改善生存率。包括FGFR抑制剂在内的靶向治疗对于FGFR2基因融合或重排的胆管癌患者是有希望的，尽管在亚洲很少有关于FGFR2阳性和临床数据的报道。本研究旨在通过评估亚洲肝内和肝门周围胆管癌患者的FGFR2融合或重排来解决这一差距，为其临床意义和潜在的治疗意义提供见解。方法：这项多中心研究利用荧光原位杂交（FISH）和Todai OncoPanel2 （TOP2）的全面基因组图谱分析，评估了亚洲（泰国、马来西亚、越南和台湾）ICC和肝门周围胆管癌中FGFR2重排和融合基因的频率。结果：113例患者中，102例符合条件；FISH发现FGFR2重排/融合占3.9%（4例），所有这些也被TOP2小组证实，与日本PRELUDE研究一致。年龄较小与FGFR2阳性显著相关（34.5±3.17 vs 62.69±1.04;p = 0.0003），而与肝炎感染、饮酒或吸烟史无相关性。基因组分析鉴定了TP53、KRAS和ARID1A的频繁突变，具有显著的区域差异。与其他治疗方法相比，接受ICIs治疗的患者显示出更长的无进展生存期：ICI +细胞毒（348天，95% CI: 0-897），铂基+ GEM（240天，95% CI: 197-282）和其他治疗（168天，95% CI: 11-325; p = 0.017）。结论：亚洲的FGFR2阳性率略低，但与日本的报道一致，并且在年轻的ICC患者中更为常见。不同的基因改变可能是亚洲人群的特征。
{"title":"FGFR2 Fusions or Rearrangements in Young Intrahepatic and Perihilar Cholangiocarcinoma Patients: Key Genetic Insights From a Pan-Asian Study","authors":"Yuta Maruki, Yasushi Yatabe, Chiharu Mizoguchi, Kathleen Yasmin de Almeida, Aumkhae Sookprasert, Charuwan Akewanlop, Ming-Huang Chen, Ekaphop Sirachainan, Dao Van Tu, Rozita Abdul Malik, Chaiyut Charoentum, Hwoei Fen Soo Hoo, Suhana Yusak, Tsung-Hao Liu, Rangasamy Ramachandran, Patrapim Sunpaweravong, Pei Jye Voon, Najihah Abu Bakar, Junki Mizusawa, Hitomi Sumiyoshi Okuma, Kenichi Nakamura, Chigusa Morizane, Takuji Okusaka","doi":"10.1111/hepr.70031","DOIUrl":"10.1111/hepr.70031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Biliary tract cancers, including intrahepatic cholangiocarcinoma (ICC), are aggressive with limited treatment options and poor prognosis. Recent trials (TOPAZ-1, Keynote-966) showed improved survival with ICIs plus gemcitabine and cisplatin. Targeted therapies, including FGFR inhibitors, are promising for cholangiocarcinoma patients with <i>FGFR</i>2 gene fusions or rearrangements, although few reports exist on <i>FGFR</i>2 positivity and clinical data in Asia. This study aims to address this gap by evaluating <i>FGFR</i>2 fusions or rearrangements in intrahepatic and perihilar cholangiocarcinoma patients across Asia, providing insights into their clinical significance and potential therapeutic implications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This multicenter study evaluated the frequency of <i>FGFR</i>2 rearrangements and fusion genes in ICC and perihilar cholangiocarcinoma across Asia (Thailand, Malaysia, Vietnam, and Taiwan) using fluorescence in situ hybridization (FISH) and comprehensive genomic profiling with the Todai OncoPanel2 (TOP2).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 113 patients, 102 were eligible; <i>FGFR2</i> rearrangements/fusions were found in 3.9% (4 cases) by FISH, all of which were also confirmed by the TOP2 panel, consistent with the Japanese PRELUDE study. Younger age was significantly associated with <i>FGFR</i>2 positivity (34.5 ± 3.17 vs. 62.69 ± 1.04; <i>p</i> = 0.0003), whereas no correlation was observed with hepatitis infection, alcohol use, or smoking history. Genomic profiling identified frequent mutations in <i>TP</i>53, <i>KRAS</i>, and <i>ARID1A</i> with notable regional variability. Patients treated with ICIs showed significantly longer progression-free survival compared to other therapies: ICI + cytotoxic (348 days, 95% CI: 0–897), platinum-based + GEM (240 days, 95% CI: 197–282), and other treatments (168 days, 95% CI: 11–325; <i>p</i> = 0.017).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The <i>FGFR</i>2 positivity rate in Asia is slightly lower but consistent with Japanese reports and is more common in younger patients with ICC. Distinct genetic alterations may characterize Asian populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":"78-88"},"PeriodicalIF":3.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study examined mortality patterns and their association with liver fibrosis in Japanese patients with biopsy-confirmed metabolic dysfunction–associated steatotic liver disease (MASLD).
Methods
We analyzed 1104 MASLD-eligible individuals from the Suita SLD cohort (2004–2023). Mortality rates were assessed using Kaplan–Meier analysis and compared between patients with and without fibrosis (Stages 1–4 vs. 0) and between metabolic dysfunction–associated steatohepatitis (MASH) and non-MASH groups, adjusting for age and sex. Associations between fibrosis or inflammation levels and cause-specific mortality were also evaluated.
Results
Of the initial 1109 patients, 1104 met the MASLD criteria. Among these patients (544 men, 560 women; mean age: 57.2 years; mean follow-up period: 6.9 years), 93 patients died, primarily from hepatocellular carcinoma (HCC) (n = 17), liver failure (n = 16), extrahepatic malignancies (n = 17), cardio-cerebrovascular diseases (n = 7), and other causes (n = 36). Fibrosis was associated with higher all-cause (11.4% vs. 3.6%) and liver-related mortality (4.8% vs. 0%, both p < 0.0001), but not with nonliver-related mortality after adjustment. All-cause mortality was higher in the MASH group (11.2% vs. 2.6%, p < 0.0001), with increased risk of both liver- and nonliver-related deaths (adjusted hazard ratios: liver-related = 1.34 × 1017, 95% CI: NE, nonliver-related = 2.20, 95% confidence interval [CI]: 1.07–4.53).
Conclusion
HCC and extrahepatic malignancies were the leading causes of death in Japanese patients with MASLD. Liver fibrosis was a significant predictor of both all-cause and liver-related mortalities, but not nonliver-related mortality, highlighting its importance in follow-up strategies for MASLD. MASH may contribute to increased nonliver-related deaths. Further long-term studies are warranted.
{"title":"Association Between Liver Fibrosis and Cause-Specific Mortality in Japanese Patients With Biopsy-Confirmed Metabolic Dysfunction–Associated Steatotic Liver Disease: A Prospective Cohort Study / Liver Fibrosis and Mortality in Japanese MASLD","authors":"Kyoko Sakai, Toshihide Shima, Hirohisa Oya, Takahiro Miura, Shohei Amioka, Takahiro Nonaka, Shinsaku Fujiishi, Keiichiro Okuda, Kei Terasaki, Kohei Fukumoto, Yasuhide Mitsumoto, Masayuki Mizuno, Takeshi Okanoue","doi":"10.1111/hepr.70034","DOIUrl":"10.1111/hepr.70034","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study examined mortality patterns and their association with liver fibrosis in Japanese patients with biopsy-confirmed metabolic dysfunction–associated steatotic liver disease (MASLD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 1104 MASLD-eligible individuals from the Suita SLD cohort (2004–2023). Mortality rates were assessed using Kaplan–Meier analysis and compared between patients with and without fibrosis (Stages 1–4 vs. 0) and between metabolic dysfunction–associated steatohepatitis (MASH) and non-MASH groups, adjusting for age and sex. Associations between fibrosis or inflammation levels and cause-specific mortality were also evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of the initial 1109 patients, 1104 met the MASLD criteria. Among these patients (544 men, 560 women; mean age: 57.2 years; mean follow-up period: 6.9 years), 93 patients died, primarily from hepatocellular carcinoma (HCC) (<i>n</i> = 17), liver failure (<i>n</i> = 16), extrahepatic malignancies (<i>n</i> = 17), cardio-cerebrovascular diseases (<i>n</i> = 7), and other causes (<i>n</i> = 36). Fibrosis was associated with higher all-cause (11.4% vs. 3.6%) and liver-related mortality (4.8% vs. 0%, both <i>p</i> < 0.0001), but not with nonliver-related mortality after adjustment. All-cause mortality was higher in the MASH group (11.2% vs. 2.6%, <i>p</i> < 0.0001), with increased risk of both liver- and nonliver-related deaths (adjusted hazard ratios: liver-related = 1.34 × 10<sup>17</sup>, 95% CI: NE, nonliver-related = 2.20, 95% confidence interval [CI]: 1.07–4.53).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>HCC and extrahepatic malignancies were the leading causes of death in Japanese patients with MASLD. Liver fibrosis was a significant predictor of both all-cause and liver-related mortalities, but not nonliver-related mortality, highlighting its importance in follow-up strategies for MASLD. MASH may contribute to increased nonliver-related deaths. Further long-term studies are warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":"33-49"},"PeriodicalIF":3.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atezolizumab plus bevacizumab (Atezo+Bev) therapy is the preferred first-line treatment for advanced hepatocellular carcinoma (HCC). However, the efficacy of Atezo+Bev is limited in patients with a CRAFITY score of 2 (C-reactive protein ≥ 1 mg/dL and alpha-fetoprotein [AFP] ≥ 100 ng/mL). This study compared the efficacy and safety of lenvatinib and Atezo+Bev in these patients.
Methods
We retrospectively analyzed 774 patients treated with lenvatinib or Atezo+Bev as first-line treatment for advanced HCC between October 2020 and December 2023 across 11 hospitals in Japan. Among them, 90 patients (11.6%) had a CRAFITY score of 2. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profiles were compared.
Results
Baseline characteristics were similar, except tumor size and AFP levels, which were higher in the Atezo+Bev group. Median PFS was significantly longer in the lenvatinib group compared to the Atezo+Bev group (6.0 vs. 2.3 months; hazard ratio [HR]: 0.55, 95% confidence interval [CI]: 0.32–0.95]; p = 0.032). The median OS was not significantly different between the two groups (9.8 vs. 5.2 months; HR: 0.66, 95% CI: 0.41–1.08; p = 0.101). The DCR (62.0% vs. 30.0%; p = 0.003) and the occurrence of grade ≥ 3 treatment-related adverse events (46.0% vs. 20.0%; p = 0.014) were significantly higher in the lenvatinib group than in the Atezo+Bev group.
Conclusion
Lenvatinib provided a significantly longer PFS than Atezo+Bev in patients with HCC and a baseline CRAFITY score of 2, whereas OS did not significantly differ between the two groups. These findings may serve as a cornerstone for developing biomarker-based strategies in first-line treatment selection for this patient population.
{"title":"Lenvatinib Versus Atezolizumab Plus Bevacizumab as First-Line Treatment for Advanced Hepatocellular Carcinoma With a CRAFITY Score of 2: A Multi-Center Retrospective Study","authors":"Masayuki Ueno, Haruhiko Takeda, Atsushi Takai, Makoto Umeda, Hiroki Morimura, Shunsuke Okuyama, Norihiro Nishijima, Satoru Iwamoto, Shigeharu Nakano, Shu Nagatomo, Takeshi Seta, Tomoyuki Goto, Atsuyuki Ikeda, Takahisa Kayahara, Shin'ichi Miyamoto, Shujiro Yazumi, Taro Ueo, Yoshito Uenoyama, Kazuyoshi Matsumura, Masako Mishima, Tadashi Inuzuka, Yuji Eso, Ken Takahashi, Hiroyuki Marusawa, Yukio Osaki, Etsuro Hatano, Hiroshi Seno","doi":"10.1111/hepr.70040","DOIUrl":"10.1111/hepr.70040","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Atezolizumab plus bevacizumab (Atezo+Bev) therapy is the preferred first-line treatment for advanced hepatocellular carcinoma (HCC). However, the efficacy of Atezo+Bev is limited in patients with a CRAFITY score of 2 (C-reactive protein ≥ 1 mg/dL and alpha-fetoprotein [AFP] ≥ 100 ng/mL). This study compared the efficacy and safety of lenvatinib and Atezo+Bev in these patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We retrospectively analyzed 774 patients treated with lenvatinib or Atezo+Bev as first-line treatment for advanced HCC between October 2020 and December 2023 across 11 hospitals in Japan. Among them, 90 patients (11.6%) had a CRAFITY score of 2. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profiles were compared.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Baseline characteristics were similar, except tumor size and AFP levels, which were higher in the Atezo+Bev group. Median PFS was significantly longer in the lenvatinib group compared to the Atezo+Bev group (6.0 vs. 2.3 months; hazard ratio [HR]: 0.55, 95% confidence interval [CI]: 0.32–0.95]; <i>p</i> = 0.032). The median OS was not significantly different between the two groups (9.8 vs. 5.2 months; HR: 0.66, 95% CI: 0.41–1.08; <i>p</i> = 0.101). The DCR (62.0% vs. 30.0%; <i>p</i> = 0.003) and the occurrence of grade ≥ 3 treatment-related adverse events (46.0% vs. 20.0%; <i>p</i> = 0.014) were significantly higher in the lenvatinib group than in the Atezo+Bev group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Lenvatinib provided a significantly longer PFS than Atezo+Bev in patients with HCC and a baseline CRAFITY score of 2, whereas OS did not significantly differ between the two groups. These findings may serve as a cornerstone for developing biomarker-based strategies in first-line treatment selection for this patient population.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"56 1","pages":"100-110"},"PeriodicalIF":3.4,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145052890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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