Metabolic abnormalities are recognized as risk factors for reflux esophagitis. Recently, the definition of MASLD and MetALD has been proposed. However, the effect of moderate alcohol consumption on its development remains unclear. We aimed to investigate independent risk factors for reflux esophagitis, including MASLD and MetALD.
Methods
The present multicenter observational cohort study enrolled 5441 consecutive health check-up examinees between 2008 and 2021. Participants were classified into the non-SLD, MASLD, or MetALD groups. Independent risk factors for reflux esophagitis were evaluated using multivariate Cox regression analysis. Directed acyclic graphs were constructed to identify direct risk factors for reflux esophagitis.
Results
Age, male sex, and hiatus hernia were independent risk factors for reflux esophagitis. MASLD (HR 1.1534, 95% CI 1.0069–1.3213, p = 0.0395) and MetALD (HR 1.9026, 95% CI 1.3554–2.6707, p = 0.0002) were also identified as independent risk factors compared to non-SLD. Furthermore, the MetALD group showed a significantly higher risk than the MASLD group (HR 1.6495, 95% CI 1.1668–2.3319, p = 0.0046). The cumulative incidence in the MetALD group was significantly higher than in the MASLD group (85.1/1000 vs. 55.8/1000 person-years, p = 0.0111). Directed acyclic graphs revealed that moderate alcohol consumption was identified as a direct risk factor for reflux esophagitis.
Conclusions
MASLD and MetALD were independent risk factors for reflux esophagitis. Patients with MetALD had a higher risk than patients with MASLD. Furthermore, moderate alcohol consumption was a direct risk factor for reflux esophagitis in patients with SLD. These findings highlight the importance of both MASLD and moderate alcohol consumption in the pathogenesis of reflux esophagitis.
目的：代谢异常被认为是反流性食管炎的危险因素。最近，人们提出了MASLD和MetALD的定义。然而，适度饮酒对其发展的影响尚不清楚。我们的目的是研究反流性食管炎的独立危险因素，包括MASLD和MetALD。方法：本多中心观察队列研究纳入了2008 - 2021年间5441名连续健康体检者。参与者被分为非sld、MASLD和MetALD组。采用多变量Cox回归分析评估反流性食管炎的独立危险因素。构建有向无环图以确定反流性食管炎的直接危险因素。结果：年龄、男性、裂孔疝是反流性食管炎的独立危险因素。与非sld相比，MASLD （HR 1.1534, 95% CI 1.0069-1.3213, p = 0.0395）和MetALD （HR 1.9026, 95% CI 1.3554-2.6707, p = 0.0002）也被认为是独立的危险因素。此外，MetALD组的风险明显高于MASLD组（HR 1.6495, 95% CI 1.1668-2.3319, p = 0.0046）。MetALD组的累积发病率显著高于MASLD组（85.1/1000 vs. 55.8/1000人年，p = 0.0111）。有向无环图显示，适量饮酒被确定为反流性食管炎的直接危险因素。结论：MASLD和MetALD是反流性食管炎的独立危险因素。MetALD患者比MASLD患者有更高的风险。此外，适度饮酒是SLD患者反流性食管炎的直接危险因素。这些发现强调了MASLD和适度饮酒在反流性食管炎发病机制中的重要性。
{"title":"MetALD Was a More Notable Independent Risk Factor for Reflux Esophagitis Than MASLD: A Multicenter Cohort Study Using Directed Acyclic Graphs","authors":"Hiroshi Tanaka, Shuhei Fukunaga, Michita Mukasa, Tomoyuki Nakane, Tomonori Cho, Shinpei Minami, Daiki Ohzono, Tomokazu Yoshio, Yusei Watanabe, Dan Nakano, Tsubasa Tsutsumi, Shinobu Yoshinaga, Ryuichi Nouno, Hidetoshi Takedatsu, Takumi Kawaguchi","doi":"10.1111/hepr.70028","DOIUrl":"10.1111/hepr.70028","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Metabolic abnormalities are recognized as risk factors for reflux esophagitis. Recently, the definition of MASLD and MetALD has been proposed. However, the effect of moderate alcohol consumption on its development remains unclear. We aimed to investigate independent risk factors for reflux esophagitis, including MASLD and MetALD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The present multicenter observational cohort study enrolled 5441 consecutive health check-up examinees between 2008 and 2021. Participants were classified into the non-SLD, MASLD, or MetALD groups. Independent risk factors for reflux esophagitis were evaluated using multivariate Cox regression analysis. Directed acyclic graphs were constructed to identify direct risk factors for reflux esophagitis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Age, male sex, and hiatus hernia were independent risk factors for reflux esophagitis. MASLD (HR 1.1534, 95% CI 1.0069–1.3213, <i>p</i> = 0.0395) and MetALD (HR 1.9026, 95% CI 1.3554–2.6707, <i>p</i> = 0.0002) were also identified as independent risk factors compared to non-SLD. Furthermore, the MetALD group showed a significantly higher risk than the MASLD group (HR 1.6495, 95% CI 1.1668–2.3319, <i>p</i> = 0.0046). The cumulative incidence in the MetALD group was significantly higher than in the MASLD group (85.1/1000 vs. 55.8/1000 person-years, <i>p</i> = 0.0111). Directed acyclic graphs revealed that moderate alcohol consumption was identified as a direct risk factor for reflux esophagitis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MASLD and MetALD were independent risk factors for reflux esophagitis. Patients with MetALD had a higher risk than patients with MASLD. Furthermore, moderate alcohol consumption was a direct risk factor for reflux esophagitis in patients with SLD. These findings highlight the importance of both MASLD and moderate alcohol consumption in the pathogenesis of reflux esophagitis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1610-1620"},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952035","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}
Víctor Merino, Carlos Abril, Gloria Segarra, Maria Pilar Ballester, Joan Tosca, Pilar Aguilar, Pascual Medina, Paloma Lluch
Background and Aims
The relationship between oxidative stress (OS) and hepatocellular carcinoma (HCC) is well known, influencing both, hepatocarcinogenesis and subsequent tumor progression. Less understood is its potential role in antitumor defense mechanisms. This study examines the production of OS in circulating leukocytes in HCC patients, its anti or pro-tumoral capacity, and its potential utility as a prognostic marker.
Approach and Results
The intracellular production of mitochondrial superoxide, total superoxide, hydrogen peroxide (H2O2), and glutathione was analyzed by flow cytometry in peripheral blood samples from 36 HCC patients and 18 HCC-free cirrhotic patients. Levels of mitochondrial superoxide in neutrophils and H2O2 in lymphocytes and neutrophils from HCC patients were higher than in the same cell populations from HCC-free cirrhotic patients (p < 0.05). Glutathione was higher in lymphocytes, monocytes, and neutrophils from HCC patients (p < 0.05). In HCC patients, for each 1000-unit increase in mitochondrial superoxide in lymphocytes, monocytes, and neutrophils, the risk of death is reduced by 49.4%, 49.5%, and 34.8%, respectively, demonstrating its role as a protective factor. A cutoff point in each leukocyte subset allowed the estimation of survival at 6 months and 1 year. Mitochondrial superoxide also proved to be a protective factor against disease progression (HR 0.314, 95% CI 0.113–0.872).
Conclusions
Circulating leukocytes in HCC patients exhibit increased OS compared to HCC-free cirrhotic patients. Specifically, the increase in mitochondrial OS in HCC patients shows a strong correlation with survival and could thus be considered a prognostic factor.
{"title":"Mitochondrial Oxidative Stress in Circulating Leukocytes as a Prognostic Marker in Hepatocellular Carcinoma","authors":"Víctor Merino, Carlos Abril, Gloria Segarra, Maria Pilar Ballester, Joan Tosca, Pilar Aguilar, Pascual Medina, Paloma Lluch","doi":"10.1111/hepr.70026","DOIUrl":"10.1111/hepr.70026","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The relationship between oxidative stress (OS) and hepatocellular carcinoma (HCC) is well known, influencing both, hepatocarcinogenesis and subsequent tumor progression. Less understood is its potential role in antitumor defense mechanisms. This study examines the production of OS in circulating leukocytes in HCC patients, its anti or pro-tumoral capacity, and its potential utility as a prognostic marker.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Approach and Results</h3>\u0000 \u0000 <p>The intracellular production of mitochondrial superoxide, total superoxide, hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), and glutathione was analyzed by flow cytometry in peripheral blood samples from 36 HCC patients and 18 HCC-free cirrhotic patients. Levels of mitochondrial superoxide in neutrophils and H<sub>2</sub>O<sub>2</sub> in lymphocytes and neutrophils from HCC patients were higher than in the same cell populations from HCC-free cirrhotic patients (<i>p</i> < 0.05). Glutathione was higher in lymphocytes, monocytes, and neutrophils from HCC patients (<i>p</i> < 0.05). In HCC patients, for each 1000-unit increase in mitochondrial superoxide in lymphocytes, monocytes, and neutrophils, the risk of death is reduced by 49.4%, 49.5%, and 34.8%, respectively, demonstrating its role as a protective factor. A cutoff point in each leukocyte subset allowed the estimation of survival at 6 months and 1 year. Mitochondrial superoxide also proved to be a protective factor against disease progression (HR 0.314, 95% CI 0.113–0.872).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Circulating leukocytes in HCC patients exhibit increased OS compared to HCC-free cirrhotic patients. Specifically, the increase in mitochondrial OS in HCC patients shows a strong correlation with survival and could thus be considered a prognostic factor.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1663-1674"},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952012","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":"Prediction of Metabolic, Cardiovascular, and Liver Health With Controlled Attenuation Parameter: A Potential Screening Tool for Preventive Hepatologists","authors":"Ajay kumar Mishra","doi":"10.1111/hepr.70025","DOIUrl":"10.1111/hepr.70025","url":null,"abstract":"","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1565-1567"},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952024","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}
Ming Lu, Yixin Zhao, Zhihong Liu, Yanrong Zhang, Jing Liu
Background
Canagliflozin shows anti-inflammatory and antioxidant properties. However, whether canagliflozin can mitigate metabolic dysfunction-associated steatotic liver disease (MASLD) by modulating mitochondrial dysfunction remains to be explored.
Methods
Canagliflozin was administered daily for MASLD mice at 10 mg/kg from Week 5 to Week 15. Biochemical assays were performed to assess serum triglyceride, total cholesterol, and liver damage markers. RT-qPCR was used to quantify the genes' expression involved in lipid synthesis and metabolism, whereas oil red O staining was utilized to visualize hepatic lipid accumulation. Western blot analysis was conducted to evaluate the expression of key proteins involved in mitochondrial damage and mitophagy.
Results
Canagliflozin treatment reduced liver hypertrophy, as shown by a lower liver weight/body weight ratio, and alleviated hepatic lipid accumulation with decreased triglyceride and total cholesterol levels. It improved the serum lipid profile by lowering low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol through inhibiting lipid metabolism genes, including Srebf1, Fasn, and Cd36. Canagliflozin also reduced oxidative stress, as shown by lower malondialdehyde levels, and restored superoxide dismutase and catalase activity. Mitochondrial function was improved with increased ATP production and mitochondrial DNA content. Additionally, canagliflozin activated Parkin/PINK1-mediated mitophagy, as evidenced by upregulation of key mitophagy-related proteins such as PINK1, Parkin, and Atg7, as well as enhanced colocalization of LC3 and TOM20.
Conclusion
Our results demonstrate that canagliflozin may effectively treat MASLD by reducing liver fat and oxidative stress and improving mitochondrial function. It could be a promising treatment option for MASLD, particularly in diabetic patients.
{"title":"Canagliflozin Alleviates Metabolic Dysfunction-Associated Steatotic Liver Disease via Mitochondrial Protection and Enhanced Mitophagy","authors":"Ming Lu, Yixin Zhao, Zhihong Liu, Yanrong Zhang, Jing Liu","doi":"10.1111/hepr.70021","DOIUrl":"10.1111/hepr.70021","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Canagliflozin shows anti-inflammatory and antioxidant properties. However, whether canagliflozin can mitigate metabolic dysfunction-associated steatotic liver disease (MASLD) by modulating mitochondrial dysfunction remains to be explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Canagliflozin was administered daily for MASLD mice at 10 mg/kg from Week 5 to Week 15. Biochemical assays were performed to assess serum triglyceride, total cholesterol, and liver damage markers. RT-qPCR was used to quantify the genes' expression involved in lipid synthesis and metabolism, whereas oil red O staining was utilized to visualize hepatic lipid accumulation. Western blot analysis was conducted to evaluate the expression of key proteins involved in mitochondrial damage and mitophagy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Canagliflozin treatment reduced liver hypertrophy, as shown by a lower liver weight/body weight ratio, and alleviated hepatic lipid accumulation with decreased triglyceride and total cholesterol levels. It improved the serum lipid profile by lowering low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol through inhibiting lipid metabolism genes, including Srebf1, Fasn, and Cd36. Canagliflozin also reduced oxidative stress, as shown by lower malondialdehyde levels, and restored superoxide dismutase and catalase activity. Mitochondrial function was improved with increased ATP production and mitochondrial DNA content. Additionally, canagliflozin activated Parkin/PINK1-mediated mitophagy, as evidenced by upregulation of key mitophagy-related proteins such as PINK1, Parkin, and Atg7, as well as enhanced colocalization of LC3 and TOM20.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results demonstrate that canagliflozin may effectively treat MASLD by reducing liver fat and oxidative stress and improving mitochondrial function. It could be a promising treatment option for MASLD, particularly in diabetic patients.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1598-1609"},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952051","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}
This study is aimed to evaluate the safety and outcomes of surgical resection in patients with hepatocellular carcinoma (HCC) treated with systemic therapy, address the therapeutic benefit, and identify candidates for surgery after systemic treatment.
Methods
This retrospective cohort study was conducted at seven high-volume centers in Japan, enrolling patients who underwent surgical resection for HCC after systemic drug therapy. Pre- and post-treatment resectability criteria and oncological outcomes (progression-free survival [PFS], overall survival [OS], pathological complete response [pCR], and postoperative complications) were analyzed.
Results
The cohort included 96 patients (mean age 68.3 years). The first-line systemic therapies were sorafenib, lenvatinib, atezolizumab plus bevacizumab, and durvalumab plus tremelimumab (n = 2/60/33/1, respectively). The pre-treatment oncological resectability criteria were R/BR1/BR2 (n = 8/42/46, respectively) and the pre-surgery criteria were R/BR1/BR2 (n = 13/41/42, respectively). Surgical procedures included 87 hepatectomies (42 major, 45 minor) and 9 non-hepatectomy procedures. The median PFS was 0.9 years with 1-, 2-, and 5-year PFS rates of 45.2%, 35.0%, and 25.6%, and the median OS was 4.0 years with 1-, 2-, and 5-year OS rates of 86.1%, 64.5%, and 39.9%, respectively. R0/1 resection rate was 83.3%, and pCR rate was 18.8%. Postoperative complications (Clavien-Dindo grade ≥ IIIa) occurred in 18.8%, with a 30-day mortality rate of 0% and a 90-day mortality rate of 4.2%. R0/1 resection was independently associated with better PFS and OS.
Conclusions
Surgical resection following systemic therapy demonstrated favorable safety and long-term outcomes in advanced HCC. R0/1 resection is a key determinant of the prognosis.
{"title":"Impact of Surgical Resection on Hepatocellular Carcinoma Following Systemic Drug Therapy: A Multicenter Retrospective Observational Study","authors":"Takamichi Ishii, Junichi Shindoh, Ikuo Nakamura, Seiko Hirono, Masaki Wakasugi, Akihiko Ichida, Takashi Hamada, Hajime Matsushima, Takahiro Nishio, Yukio Tokumitsu, Hidenori Takahashi, Yuji Morine, Shinichiro Yamada, Akiyoshi Nakakura, Susumu Eguchi, Kiyoshi Hasegawa, Etsuro Hatano","doi":"10.1111/hepr.70027","DOIUrl":"10.1111/hepr.70027","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study is aimed to evaluate the safety and outcomes of surgical resection in patients with hepatocellular carcinoma (HCC) treated with systemic therapy, address the therapeutic benefit, and identify candidates for surgery after systemic treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This retrospective cohort study was conducted at seven high-volume centers in Japan, enrolling patients who underwent surgical resection for HCC after systemic drug therapy. Pre- and post-treatment resectability criteria and oncological outcomes (progression-free survival [PFS], overall survival [OS], pathological complete response [pCR], and postoperative complications) were analyzed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The cohort included 96 patients (mean age 68.3 years). The first-line systemic therapies were sorafenib, lenvatinib, atezolizumab plus bevacizumab, and durvalumab plus tremelimumab (<i>n</i> = 2/60/33/1, respectively). The pre-treatment oncological resectability criteria were R/BR1/BR2 (<i>n</i> = 8/42/46, respectively) and the pre-surgery criteria were R/BR1/BR2 (<i>n</i> = 13/41/42, respectively). Surgical procedures included 87 hepatectomies (42 major, 45 minor) and 9 non-hepatectomy procedures. The median PFS was 0.9 years with 1-, 2-, and 5-year PFS rates of 45.2%, 35.0%, and 25.6%, and the median OS was 4.0 years with 1-, 2-, and 5-year OS rates of 86.1%, 64.5%, and 39.9%, respectively. R0/1 resection rate was 83.3%, and pCR rate was 18.8%. Postoperative complications (Clavien-Dindo grade ≥ IIIa) occurred in 18.8%, with a 30-day mortality rate of 0% and a 90-day mortality rate of 4.2%. R0/1 resection was independently associated with better PFS and OS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Surgical resection following systemic therapy demonstrated favorable safety and long-term outcomes in advanced HCC. R0/1 resection is a key determinant of the prognosis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1652-1662"},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952009","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}
To determine the impact of obesity on the prognosis of patients with liver cirrhosis.
Methods
This present retrospective observational study enrolled 482 patients without hepatocellular carcinoma (HCC). The patients were evaluated for obesity during the subsequent 8-year follow-up period. Obesity was defined as a body fat percentage of ≥ 25.8% for men and ≥ 36.5% for women as measured using a bioelectrical impedance analysis. After propensity score matching was adjusted for age, sex, etiology, and severity of liver disease, 185 patients were assigned to either the obese or nonobese group. The prognostic impact of obesity in patients with cirrhosis was evaluated by differentiating between liver-related and nonliver-related deaths.
Results
The median observation period was 4.2 years. The cumulative incidence of liver-related deaths was significantly higher in the nonobese group than in the obese group (P = 0.02), whereas there was no significant difference in the cumulative incidence of nonliver-related deaths between the obese and nonobese groups (P = 0.70). Multivariate competing risk analyses revealed that a nonviral etiology (hazard ratio [HR], 5.43), decompensated cirrhosis (HR, 5.22), sarcopenia (HR, 2.28), and obesity (HR, 0.49) were independently associated with liver-related death. Among patients with a nonviral etiology, female patients sarcopenia, and patients with decompensated cirrhosis, the cumulative incidence of liver-related death was significantly higher in nonobese patients than in obese patients (P < 0.01, 0.04, 0.03, and 0.01, respectively).
Conclusions
Obesity decreased liver-related death in patients with cirrhosis, particularly in female patients, patients with a nonviral etiology, and patients with sarcopenia.
{"title":"Obesity Decreases Liver-Related Death in Patients With Cirrhosis: A Retrospective Propensity Score-Matched Study","authors":"Kei Endo, Keisuke Kakisaka, Tamami Abe, Hiroaki Abe, Ippeki Nakaya, Takuya Watanabe, Akiko Suzuki, Yuichi Yoshida, Takayoshi Oikawa, Akio Miyasaka, Hidekatsu Kuroda, Takayuki Matsumoto","doi":"10.1111/hepr.70022","DOIUrl":"10.1111/hepr.70022","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To determine the impact of obesity on the prognosis of patients with liver cirrhosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This present retrospective observational study enrolled 482 patients without hepatocellular carcinoma (HCC). The patients were evaluated for obesity during the subsequent 8-year follow-up period. Obesity was defined as a body fat percentage of ≥ 25.8% for men and ≥ 36.5% for women as measured using a bioelectrical impedance analysis. After propensity score matching was adjusted for age, sex, etiology, and severity of liver disease, 185 patients were assigned to either the obese or nonobese group. The prognostic impact of obesity in patients with cirrhosis was evaluated by differentiating between liver-related and nonliver-related deaths.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The median observation period was 4.2 years. The cumulative incidence of liver-related deaths was significantly higher in the nonobese group than in the obese group (<i>P</i> = 0.02), whereas there was no significant difference in the cumulative incidence of nonliver-related deaths between the obese and nonobese groups (<i>P</i> = 0.70). Multivariate competing risk analyses revealed that a nonviral etiology (hazard ratio [HR], 5.43), decompensated cirrhosis (HR, 5.22), sarcopenia (HR, 2.28), and obesity (HR, 0.49) were independently associated with liver-related death. Among patients with a nonviral etiology, female patients sarcopenia, and patients with decompensated cirrhosis, the cumulative incidence of liver-related death was significantly higher in nonobese patients than in obese patients (<i>P</i> < 0.01, 0.04, 0.03, and 0.01, respectively).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Obesity decreased liver-related death in patients with cirrhosis, particularly in female patients, patients with a nonviral etiology, and patients with sarcopenia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1631-1641"},"PeriodicalIF":3.4,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952017","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}
This study aimed to evaluate the association between the efficacy of durvalumab plus tremelimumab (Dur/Tre) and metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with hepatocellular carcinoma (HCC).
Methods
A total of 239 patients with HCC who received Dur/Tre between March 2023 and October 2024 at multiple institutions in Japan were retrospectively analyzed. Patients were categorized into three groups based on underlying liver disease: viral-related HCC (n = 126), MASLD-related HCC (n = 30), and nonviral, non-MASLD HCC (n = 83).
Results
The overall response rates (ORR) were 17.5%, 16.7%, and 19.3% in viral-related HCC, MASLD-related HCC, and nonviral, non-MASLD HCC, respectively. The disease control rates (DCR) were 44.4%, 46.7%, and 51.8%, respectively. No significant differences in ORR (p = 0.6) or DCR (p = 0.9) were observed among the three groups. The median PFS was 3.7 months (95% CI, 2.8–4.9) in patients with viral-related HCC, 3.6 months (95% CI, 2.3–4.8) in patients with MASLD-related HCC, and 4.4 months (95% CI, 2.6–5.8) in patients with nonviral, non-MASLD HCC. The median OS was 14.4 months (95% CI, 9.8–NA) in patients with viral-related HCC and 11.0 months (95% CI, 6.4–NA) in patients with MASLD-related HCC, whereas it was not reached in patients with nonviral, non-MASLD HCC. No statistically significant differences in PFS (p = 1.0) and OS (p = 0.3) were found among the groups.
Conclusions
Dur/Tre showed comparable efficacy in MASLD-related HCC and other etiologies, warranting confirmation in larger cohorts.
{"title":"Association of Metabolic-Associated Steatotic Liver Disease With Clinical Outcomes of Durvalumab and Tremelimumab in Advanced Hepatocellular Carcinoma Patients: A Multicenter Study","authors":"Takeshi Hatanaka, Shigeo Shimose, Takanori Ito, Joji Tani, Tetsu Tomonari, Issei Saeki, Yasuto Takeuchi, Kyo Sasaki, Yuichi Honma, Ryu Sasaki, Naoki Yoshioka, Takehito Naito, Mamiko Takeuchi, Tetsuya Yasunaka, Masahiro Sakata, Hideki Iwamoto, Satoshi Itano, Yuki Kanayama, Tomotake Shirono, Norikazu Tanabe, Takafumi Yamamoto, Atsushi Naganuma, Sohji Nishina, Motoyuki Otsuka, Hideki Kobara, Taro Takami, Tetsuji Takayama, Takumi Kawaguchi, Hiroki Kawashima, Masaru Harada, Hisamitsu Miyaaki, Satoru Kakizaki, Hepatology InVestigator Experts in Japan (HIVE-J) Study Group","doi":"10.1111/hepr.70023","DOIUrl":"10.1111/hepr.70023","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study aimed to evaluate the association between the efficacy of durvalumab plus tremelimumab (Dur/Tre) and metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with hepatocellular carcinoma (HCC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 239 patients with HCC who received Dur/Tre between March 2023 and October 2024 at multiple institutions in Japan were retrospectively analyzed. Patients were categorized into three groups based on underlying liver disease: viral-related HCC (<i>n</i> = 126), MASLD-related HCC (<i>n</i> = 30), and nonviral, non-MASLD HCC (<i>n</i> = 83).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The overall response rates (ORR) were 17.5%, 16.7%, and 19.3% in viral-related HCC, MASLD-related HCC, and nonviral, non-MASLD HCC, respectively. The disease control rates (DCR) were 44.4%, 46.7%, and 51.8%, respectively. No significant differences in ORR (<i>p</i> = 0.6) or DCR (<i>p</i> = 0.9) were observed among the three groups. The median PFS was 3.7 months (95% CI, 2.8–4.9) in patients with viral-related HCC, 3.6 months (95% CI, 2.3–4.8) in patients with MASLD-related HCC, and 4.4 months (95% CI, 2.6–5.8) in patients with nonviral, non-MASLD HCC. The median OS was 14.4 months (95% CI, 9.8–NA) in patients with viral-related HCC and 11.0 months (95% CI, 6.4–NA) in patients with MASLD-related HCC, whereas it was not reached in patients with nonviral, non-MASLD HCC. No statistically significant differences in PFS (<i>p</i> = 1.0) and OS (<i>p</i> = 0.3) were found among the groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Dur/Tre showed comparable efficacy in MASLD-related HCC and other etiologies, warranting confirmation in larger cohorts.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1642-1651"},"PeriodicalIF":3.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951986","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}
Primary biliary cholangitis (PBC) is a chronic, slowly progressive, and autoimmune liver disease. This study aimed to establish the clinicopathological features that accurately predict long-term prognosis in patients with early-stage PBC.
Methods
The present long-term (8.8 years), multicenter, and retrospective investigation enrolled 274 treatment-naïve PBC patients who had undergone liver biopsy. Among them, 207 patients with albumin–bilirubin (ALBI) grade 1 were categorized as clinical early-stage, and 230 patients with Nakanuma stage 1/2 were classified as pathological early-stage. The prognostic factors related to the time to liver-related events (LRE) were statistically evaluated.
Results
Cox regression analysis identified Nakanuma bile duct loss score of ≥ 1 as a significant independent factor associated with LRE development in clinical early-stage PBC patients (hazard ratio [HR] 12.89, 95% confidence interval [95% CI] 1.60–103.96, P = 0.016). Kaplan–Meier testing revealed that the cumulative incidence of LRE was significantly higher in patients with bile duct loss score of ≥ 1 than in those with bile duct loss score 0 (log-rank test; P < 0.001). Similarly, bile duct loss score could predict LRE in pathological early-stage PBC patients, as confirmed by both multivariable Cox regression (HR 6.60, 95% CI 1.37–31.86, P = 0.019) and Kaplan–Meier (log-rank test; P < 0.001) analyses.
Conclusions
Nakanuma bile duct loss score may be a valuable prognostic indicator in the early clinical and pathological stages of PBC.
{"title":"Prognostic Significance of Bile Duct Loss in Early-Stage Primary Biliary Cholangitis: A Long-Term Observational Study","authors":"Taiki Okumura, Takefumi Kimura, Takanobu Iwadare, Shun-Ichi Wakabayashi, Hiroyuki Kobayashi, Yuki Yamashita, Satoru Joshita, Michiharu Komatsu, Naoki Tanaka, Akihiro Matsumoto, Tomoyuki Nakajima, Mai Iwaya, Masahiro Umemura, Kazuhito Kawata, Kenichi Harada, Takeji Umemura","doi":"10.1111/hepr.70018","DOIUrl":"10.1111/hepr.70018","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background & Aims</h3>\u0000 \u0000 <p>Primary biliary cholangitis (PBC) is a chronic, slowly progressive, and autoimmune liver disease. This study aimed to establish the clinicopathological features that accurately predict long-term prognosis in patients with early-stage PBC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The present long-term (8.8 years), multicenter, and retrospective investigation enrolled 274 treatment-naïve PBC patients who had undergone liver biopsy. Among them, 207 patients with albumin–bilirubin (ALBI) grade 1 were categorized as clinical early-stage, and 230 patients with Nakanuma stage 1/2 were classified as pathological early-stage. The prognostic factors related to the time to liver-related events (LRE) were statistically evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cox regression analysis identified Nakanuma bile duct loss score of ≥ 1 as a significant independent factor associated with LRE development in clinical early-stage PBC patients (hazard ratio [HR] 12.89, 95% confidence interval [95% CI] 1.60–103.96, <i>P</i> = 0.016). Kaplan–Meier testing revealed that the cumulative incidence of LRE was significantly higher in patients with bile duct loss score of ≥ 1 than in those with bile duct loss score 0 (log-rank test; <i>P</i> < 0.001). Similarly, bile duct loss score could predict LRE in pathological early-stage PBC patients, as confirmed by both multivariable Cox regression (HR 6.60, 95% CI 1.37–31.86, <i>P</i> = 0.019) and Kaplan–Meier (log-rank test; <i>P</i> < 0.001) analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Nakanuma bile duct loss score may be a valuable prognostic indicator in the early clinical and pathological stages of PBC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1621-1630"},"PeriodicalIF":3.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hepr.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882789","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}
Complete abstinence is the cornerstone of alcohol-related liver disease (ALD) management. However, many patients struggle to achieve or sustain abstinence, prompting growing interest in harm reduction strategies, particularly pharmacological interventions to reduce alcohol intake. Nalmefene, an opioid receptor modulator, has shown efficacy in reducing alcohol consumption among individuals with alcohol dependence. However, its effects on hepatic parameters in ALD have not been well studied in real-world settings.
Objective
To evaluate the efficacy and safety of nalmefene in patients with ALD, focusing on changes in alcohol consumption, liver function, and hepatic reserve capacity.
Methods
The present retrospective observational study included 21 patients with ALD who received nalmefene therapy at our institution between September 2019 and December 2023. Data on alcohol intake, liver function tests, hepatic reserve capacity, and alcohol use disorders identification test scores were collected at baseline and after 6 months of treatment. Adverse events were also recorded.
Results
Within 1 month of initiating nalmefene, significant reductions in heavy drinking days and total alcohol consumption were observed. These reductions were accompanied by improvements in liver function parameters. However, no statistically significant changes in hepatic reserve capacity were noted. Most adverse events were mild to moderate (Grade 1 or 2), and no serious adverse events occurred.
Conclusion
Nalmefene appears to be a safe and effective pharmacological option for reducing alcohol intake and improving liver function in patients with ALD. These findings support its use as part of a harm reduction approach for those unable to achieve complete abstinence.
{"title":"Initial Experience With Nalmefene in Alcohol-Related Liver Disease: A Real-World Retrospective Study","authors":"Junichi Hanatani, Tadashi Namisaki, Hiroaki Takaya, Shinya Sato, Masayoshi Takami, Hiroyuki Masuda, Yuki Tsuji, Norihisa Nishimura, Takashi Inoue, Akihiko Shibamoto, Satoshi Iwai, Yukihisa Fujinaga, Koh Kitagawa, Kosuke Kaji, Akira Mitoro, Kiyoshi Asada, Hitoshi Yoshiji","doi":"10.1111/hepr.70019","DOIUrl":"10.1111/hepr.70019","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Complete abstinence is the cornerstone of alcohol-related liver disease (ALD) management. However, many patients struggle to achieve or sustain abstinence, prompting growing interest in harm reduction strategies, particularly pharmacological interventions to reduce alcohol intake. Nalmefene, an opioid receptor modulator, has shown efficacy in reducing alcohol consumption among individuals with alcohol dependence. However, its effects on hepatic parameters in ALD have not been well studied in real-world settings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate the efficacy and safety of nalmefene in patients with ALD, focusing on changes in alcohol consumption, liver function, and hepatic reserve capacity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The present retrospective observational study included 21 patients with ALD who received nalmefene therapy at our institution between September 2019 and December 2023. Data on alcohol intake, liver function tests, hepatic reserve capacity, and alcohol use disorders identification test scores were collected at baseline and after 6 months of treatment. Adverse events were also recorded.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Within 1 month of initiating nalmefene, significant reductions in heavy drinking days and total alcohol consumption were observed. These reductions were accompanied by improvements in liver function parameters. However, no statistically significant changes in hepatic reserve capacity were noted. Most adverse events were mild to moderate (Grade 1 or 2), and no serious adverse events occurred.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Nalmefene appears to be a safe and effective pharmacological option for reducing alcohol intake and improving liver function in patients with ALD. These findings support its use as part of a harm reduction approach for those unable to achieve complete abstinence.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 12","pages":"1589-1597"},"PeriodicalIF":3.4,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862142","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}
The sex-determining region Y-box 9 (SOX9) plays a critical role in the development of intrahepatic bile ducts (IHBDs) during the embryonic stage. However, its role in postnatal IHBD maturation remains unclear. This study aimed to investigate the function of SOX9 in the postnatal development of the bile duct network, with particular emphasis on its role in structural organization.
Methods
Three-dimensional imaging analysis was conducted using a mouse model in which SOX9 deficiency is predominant after birth to assess the structural organization of IHBDs. Additionally, transcriptional profiling was performed in Sox9 conditional knockout (cKO) mice to elucidate mechanisms underlying abnormal IHBD morphogenesis.
Results
In Sox9 cKO mice, bile ductules were significantly reduced in the middle region at 1, 5, and 10 weeks, whereas a ductular reaction was observed in the peripheral region at 5 and 10 weeks, likely in response to cholestatic liver injury, compared to control mice. SOX9 was essential for IHBD maturation and structural organization, in particular, in establishing connections between bile ductules and also between bile ductules and bile canaliculi. Furthermore, transcriptome analysis of Sox9 cKO mice revealed activation of compensatory pathways involved in bile acid transport and metabolism, whereas intercellular adhesion pathways were downregulated.
Conclusions
These findings underscore the pivotal role of SOX9 in postnatal bile duct network development, demonstrating its critical involvement in maintaining structural organization. The results suggest that SOX9 plays a more substantial role in bile duct maturation than previously recognized, providing new insights into its regulatory mechanisms in liver development.
{"title":"SOX9 Is a Key Factor for the Postnatal Maturation of the Intrahepatic Bile Duct Network","authors":"Hiroki Hirao, Daiki Yoshii, Shigeyuki Esumi, Ahmad Adawy, Yukio Fujiwara, Masaki Honda, Yuji Yokouchi, Taizo Hibi, Yoshihiro Komohara","doi":"10.1111/hepr.70012","DOIUrl":"10.1111/hepr.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The sex-determining region Y-box 9 (SOX9) plays a critical role in the development of intrahepatic bile ducts (IHBDs) during the embryonic stage. However, its role in postnatal IHBD maturation remains unclear. This study aimed to investigate the function of SOX9 in the postnatal development of the bile duct network, with particular emphasis on its role in structural organization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Three-dimensional imaging analysis was conducted using a mouse model in which SOX9 deficiency is predominant after birth to assess the structural organization of IHBDs. Additionally, transcriptional profiling was performed in <i>Sox9</i> conditional knockout (cKO) mice to elucidate mechanisms underlying abnormal IHBD morphogenesis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In <i>Sox9</i> cKO mice, bile ductules were significantly reduced in the middle region at 1, 5, and 10 weeks, whereas a ductular reaction was observed in the peripheral region at 5 and 10 weeks, likely in response to cholestatic liver injury, compared to control mice. SOX9 was essential for IHBD maturation and structural organization, in particular, in establishing connections between bile ductules and also between bile ductules and bile canaliculi. Furthermore, transcriptome analysis of <i>Sox9</i> cKO mice revealed activation of compensatory pathways involved in bile acid transport and metabolism, whereas intercellular adhesion pathways were downregulated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings underscore the pivotal role of SOX9 in postnatal bile duct network development, demonstrating its critical involvement in maintaining structural organization. The results suggest that SOX9 plays a more substantial role in bile duct maturation than previously recognized, providing new insights into its regulatory mechanisms in liver development.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12987,"journal":{"name":"Hepatology Research","volume":"55 11","pages":"1541-1550"},"PeriodicalIF":3.4,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862144","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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