{"title":"Influence of Sex in the Development of Liver Diseases.","authors":"Jie-Wen Zhang, Nan Zhang, Yi Lyu, Xu-Feng Zhang","doi":"10.1055/a-2516-0261","DOIUrl":"10.1055/a-2516-0261","url":null,"abstract":"<p><p>The liver is a sexually dimorphic organ. Sex differences in prevalence, progression, prognosis, and treatment prevail in most liver diseases, and the mechanism of how liver diseases act differently among male versus female patients has not been fully elucidated. Biological sex differences in normal physiology and disease arise principally from sex hormones and/or sex chromosomes. Sex hormones contribute to the development and progression of most liver diseases, with estrogen- and androgen-mediated signaling pathways mechanistically involved. In addition, genetic factors in sex chromosomes have recently been found to contribute to the sex disparity of many liver diseases, which might explain, to some extent, the difference in gene expression pattern, immune response, and xenobiotic metabolism between men and women. Although increasing evidence suggests that sex is one of the most important modulators of disease prevalence and outcomes, at present, basic and clinical studies have long been sex unbalanced, with female subjects underestimated. As such, this review focuses on sex disparities of liver diseases and summarizes the current understanding of sex-specific mechanisms, including sex hormones, sex chromosomes, etc. We anticipate that understanding sex-specific pathogenesis will aid in promoting personalized therapies for liver disease among male versus female patients.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"15-32"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984359","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}
{"title":"Alcohol Plus Additional Risk Factors: Rodent Model of Liver Injury.","authors":"Qixiang Wu, Dashuai Yang, Chixiang Liu, Tao Xu","doi":"10.1055/a-2490-4278","DOIUrl":"10.1055/a-2490-4278","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD), primarily caused by chronic excessive alcohol consumption, is a leading cause of chronic liver disease worldwide. ALD includes alcohol-associated steatotic liver, alcohol-associated hepatitis (AH), fibrosis, cirrhosis, and can even progress to hepatocellular carcinoma (HCC). Existing research indicates that the risk factors of ALD are quite numerous. In addition to drinking patterns, factors such as aldehyde dehydrogenase 2 (ALDH2) deficiency, smoking, medication administration, high-fat diet (HFD), hepatitis virus infection, and disruption of circadian rhythms can also increase susceptibility to ALD. However, there is limited understanding regarding the exacerbation of liver injury by alcohol plus additional risk factors. This review presents rodent models of EtOH + \"X,\" which simulate the synergistic effects of alcohol and additional risk factors in causing liver injury. These models offer a further exploration of the interactions between alcohol and additional risk factors, advancing the simulation of human ALD and providing a more reliable platform for studying disease mechanisms and exploring therapeutic interventions. We summarize the modeling methods, relevant indicators of liver injury, and focus on the targets of the synergistic effects as well as the associated mechanisms.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"81-98"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885388","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}
Tao Liu, FeiYu Zhang, Yue Feng, PanShiLi Han, YanHang Gao
{"title":"Alcohol-Metabolizing Enzymes, Liver Diseases and Cancer.","authors":"Tao Liu, FeiYu Zhang, Yue Feng, PanShiLi Han, YanHang Gao","doi":"10.1055/a-2551-3320","DOIUrl":"10.1055/a-2551-3320","url":null,"abstract":"<p><p>Alcohol is generally believed to be metabolized in the liver by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and to a much lesser extent cytochrome P450 2E1 (CYP2E1) and other enzymes. Recent studies suggest that gut also play important roles in the promotion of alcohol metabolism. ADH, ALDH, and CYP2E1 have several polymorphisms that markedly impact alcohol metabolism. These alcohol-metabolizing enzymes not only affect alcohol-associated liver disease (ALD), but may also modulate the pathogenesis of other liver diseases and cancer in the absence of alcohol consumption. In this review, we discuss alcohol metabolism and the roles of alcohol-metabolizing enzymes in the pathogenesis of ALD, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction and alcohol-associated liver disease, viral hepatitis, and liver cancer. We also discuss how alcohol-metabolizing enzymes may affect endogenous ethanol production, and how ethanol metabolism in the gut affects liver disease and cancer. Directions for future research on the roles of alcohol-metabolizing enzymes in liver disease and cancer are also elaborated.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"99-113"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743659","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}
Abid A Anwar, Nidhi Jalan-Sakrikar, Robert C Huebert
{"title":"LncRNAs, RNA Therapeutics, and Emerging Technologies in Liver Pathobiology.","authors":"Abid A Anwar, Nidhi Jalan-Sakrikar, Robert C Huebert","doi":"10.1055/a-2490-1921","DOIUrl":"10.1055/a-2490-1921","url":null,"abstract":"<p><p>The field of ribonucleic acid (RNA) biology has revealed an array of noncoding RNA species, particularly long noncoding RNAs (lncRNAs), which play crucial roles in liver disease pathogenesis. This review explores the diverse functions of lncRNAs in liver pathology, including metabolic-associated steatotic liver disease, hepatocellular carcinoma, alcohol-related liver disease, and cholangiopathies such as primary sclerosing cholangitis and cholangiocarcinoma. We highlight key lncRNAs that regulate lipid metabolism, inflammation, fibrosis, and oncogenesis in the liver, demonstrating their diagnostic and therapeutic potential. Emerging RNA-based therapies, such as mRNA therapy, RNA interference, and antisense oligonucleotides, offer approaches to modulate lncRNA activity and address liver disease at a molecular level. Advances in sequencing technologies and bioinformatics pipelines are simultaneously enabling the identification and functional characterization of novel lncRNAs, driving innovation in personalized medicine. In conclusion, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in liver disease and emphasizes the need for further research into their regulatory mechanisms and clinical applications.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"1-14"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740448","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}
{"title":"Fontan-Associated Liver Disease.","authors":"Moira B Hilscher, Jonathan N Johnson","doi":"10.1055/a-2556-4897","DOIUrl":"10.1055/a-2556-4897","url":null,"abstract":"<p><p>Fontan-associated liver disease (FALD) occurs in all patients who have undergone Fontan palliation for functional single ventricle congenital heart defects. While liver fibrosis is universal in patients who have undergone Fontan palliation, FALD may lead to more serious consequences including portal hypertension, cirrhosis, and hepatocellular carcinoma. Scientific studies of the pathophysiology and clinical management of FALD have been limited to date by the heterogeneous nature of the disease, relatively small population of patients with Fontan physiology, and inaccuracy of noninvasive staging tests. As survival after the Fontan procedure improves, the population of adults with Fontan physiology is growing, leading to more severe extracardiac complications related to the Fontan circulation and growing demand for heart and liver transplantation. The accurate evaluation, staging, and management of FALD comprises a clinical challenge which requires expert multidisciplinary input.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"114-128"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625993","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}
Wagner Ramírez-Quesada, Edilmar Alvarado-Tapias, Sarah Shalaby, Virginia Hernández-Gea
{"title":"Recompensation in Cirrhosis: Biomarkers and Strategies.","authors":"Wagner Ramírez-Quesada, Edilmar Alvarado-Tapias, Sarah Shalaby, Virginia Hernández-Gea","doi":"10.1055/a-2542-9930","DOIUrl":"10.1055/a-2542-9930","url":null,"abstract":"<p><p>The onset of decompensation in advanced chronic liver disease (ACLD) is a hallmark in natural history, with a poor prognosis and a significantly increased liver-related mortality. Etiological treatments for viral hepatitis or abstinence in cirrhosis due to alcohol abuse have demonstrated that some patients experience partial to complete clinical and analytical improvement, a stage termed \"recompensation.\" Although recompensation is primarily defined clinically based on treatable etiologies, it is still evolving for conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the need for specific biomarkers in hepatic recompensation, no biomarkers have been thoroughly studied in this context. Biomarkers identified in compensated ACLD (cACLD) following etiological treatment might be explored for recompensation. Although the pathophysiology mechanisms underlying the hepatic recompensation remain unclear, understanding the mechanism involved in cirrhosis decompensation could help identify potential targets for recompensation. This review provides an update on the hepatic recompensation concept, examines the existing data on invasive and non-invasive biomarkers, mainly in cACLD after cure, that could be raised in recompensation, and explores future therapeutic targets for the hepatic recompensation process.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"129-143"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781122","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}
Julian Pohl, Dimitrios Aretakis, Frank Tacke, Cornelius Engelmann, Michael Sigal
{"title":"Role of Intestinal Barrier Disruption to Acute-on-Chronic Liver Failure.","authors":"Julian Pohl, Dimitrios Aretakis, Frank Tacke, Cornelius Engelmann, Michael Sigal","doi":"10.1055/a-2516-2361","DOIUrl":"10.1055/a-2516-2361","url":null,"abstract":"<p><p>Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut-liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut-liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"52-65"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625996","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}
Laura Sererols-Viñas, Gemma Garcia-Vicién, Paloma Ruiz-Blázquez, Ting-Fang Lee, Youngmin A Lee, Ester Gonzalez-Sanchez, Javier Vaquero, Anna Moles, Aveline Filliol, Silvia Affò
{"title":"Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer.","authors":"Laura Sererols-Viñas, Gemma Garcia-Vicién, Paloma Ruiz-Blázquez, Ting-Fang Lee, Youngmin A Lee, Ester Gonzalez-Sanchez, Javier Vaquero, Anna Moles, Aveline Filliol, Silvia Affò","doi":"10.1055/a-2551-0724","DOIUrl":"10.1055/a-2551-0724","url":null,"abstract":"<p><p>Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis, and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer-associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for antifibrotic and antitumor interventions.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"33-51"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568075","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}
Sasha-Jane Abi-Aad, Mark Lovell, Racha T Khalaf, Ronald J Sokol
{"title":"Pathogenesis and Management of Intestinal Failure-Associated Liver Disease.","authors":"Sasha-Jane Abi-Aad, Mark Lovell, Racha T Khalaf, Ronald J Sokol","doi":"10.1055/a-2545-7370","DOIUrl":"10.1055/a-2545-7370","url":null,"abstract":"<p><p>Long-term parenteral nutrition (PN) has considerably improved the management of intestinal failure (IF) in children and adults, particularly those with short bowel syndrome; however, it carries a significant risk of hepatotoxicity, specifically, intestinal failure-associated liver disease (IFALD), also known as PN-associated liver disease. This review provides an update on the latest understanding of IFALD pathogenesis, emerging therapies, and ongoing challenges in the management of this complication. A number of factors are associated with the development of IFALD. PN lipid emulsions, phytosterol exposure, bacterial dysbiosis, an altered gut-liver axis, and episodes of sepsis disrupt bile acid homeostasis and promote liver inflammation in the active phase of IFALD, favoring the development of PN-associated cholestasis (PNAC) and the more chronic form of steatohepatitis with fibrosis. Based on the identification of pathophysiological pathways, potential therapies are being studied in preclinical and clinical trials, including lipid emulsion modifications; targeted therapies such as Farnesoid X receptor (FXR) and liver receptor homolog 1 (LRH-1) agonists, tumor necrosis factor inhibitors, glucagon-like peptide-2 analogs; microbiome modulation; and supplementation with choline and antioxidants. In conclusion, the pathogenesis of IFALD is complex, and PN dependence and liver injury remain challenging, particularly in patients with IF who cannot advance to enteral nutrition and be weaned off PN.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":"66-80"},"PeriodicalIF":4.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524432","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":"Preface (Introduction).","authors":"Ashwani K Singal","doi":"10.1055/a-2541-3502","DOIUrl":"https://doi.org/10.1055/a-2541-3502","url":null,"abstract":"<p><p>Not applicable.</p>","PeriodicalId":21724,"journal":{"name":"Seminars in liver disease","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459456","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}