1
|
Tatscher E, Mady S, Fickert P. Emerging Targets for the Treatment of Primary Sclerosing Cholangitis. Semin Liver Dis 2025. [PMID: 40418973 DOI: 10.1055/a-2601-9426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/28/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, progressive cholestatic disease of unknown etiology and characterized by inflammation and stricturing of intrahepatic and/or extrahepatic bile ducts. This process leads to bile duct scarring, progressive liver fibrosis, and end-stage liver disease. PSC is often associated with a specific form of inflammatory bowel disease and patients face a significant risk of developing cholangiocarcinoma and colorectal cancer. The clinical course of PSC can differ significantly between subtypes and affected individuals, representing a major obstacle to successful medical treatment trials. Numerous innovative therapeutic targets have been identified and, at least in part, explored, including nuclear and membrane receptors regulating bile acid metabolism and transport, modulation of gut microbiota, and signaling molecules involved in liver inflammation and fibrosis. Successful drug testing in preclinical PSC models as well as positive signals from some clinical studies justify hope. However, no medical treatment has so far been proven to improve transplant-free survival or overall survival in PSC patients. Disease-modifying drugs are urgently awaited. Despite ongoing efforts to improve study designs and implement treatment trials for novel drug targets, a central breakthrough has not yet been convincingly achieved. This situation might change in the near future. This article summarizes current research efforts aimed at developing medical treatments for PSC.
Collapse
Affiliation(s)
- Elisabeth Tatscher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Samy Mady
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| |
Collapse
|
2
|
Niu D, Wu X, Zhang Y, Wang X, Shiu-Hin Chan D, Jing S, Wong CY, Wang W, Leung CH. Tailoring obeticholic acid activity by iridium(III) complex conjugation to develop a farnesoid X receptor probe. J Adv Res 2025; 71:307-316. [PMID: 39490736 DOI: 10.1016/j.jare.2024.10.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 09/27/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024] Open
Abstract
INTRODUCTION The farnesoid X receptor (FXR) is a crucial regulator in the intestine, maintaining bile acid homeostasis. Inhibiting intestinal FXR shows promise in managing inflammatory bowel and liver diseases by reducing bile acid accumulation. Additionally, changes in FXR expression could serve as a potential biomarker for intestinal diseases. Therefore, developing an imaging probe for FXR holds significant potential for the early detection, simultaneous treatment, and monitoring of FXR-related diseases. OBJECTIVES The study aimed to develop a bioimaging probe for FXR by conjugating obeticholic acid (OCA), an FXR agonist, to an iridium(III) complex, and to investigate its application for targeting FXR in intestinal cells. METHODS OCA was conjugated to an iridium(III) complex to generate the novel complex 1. The effect of complex 1 on FXR activity, nuclear translocation, and downstream targets was investigated in intestinal epithelial cells using various biochemical and cellular assays. Additionally, the photophysical properties of complex 1 were assessed for FXR imaging. RESULTS Complex 1 retained the desirable photophysical properties for monitoring FXR in intestinal cells while reversing OCA's activity from agonistic to antagonistic. It disrupted FXR-RXR heterodimerization, inhibited FXR nuclear translocation, and downregulated downstream targets responsible for bile acid absorption, transport, and metabolism in intestinal epithelial cells. CONCLUSION The study successfully developed an imaging probe and modulator of FXR by conjugating OCA to an iridium(III) complex. Complex 1 retained the favorable photophysical properties of the iridium(III) complex, while reversing OCA's activity from agonistic to antagonistic. The findings highlight the exciting application of using metals to tailor the activity of nuclear receptor modulators in living systems.
Collapse
Affiliation(s)
- Dou Niu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Xiaolei Wu
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Yuxin Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Xueliang Wang
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China
| | | | - Shaozhen Jing
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China
| | - Chun-Yuen Wong
- Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China
| | - Wanhe Wang
- Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi 710072, China.
| | - Chung-Hang Leung
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
| |
Collapse
|
3
|
Pohl J, Aretakis D, Tacke F, Engelmann C, Sigal M. Role of Intestinal Barrier Disruption to Acute-on-Chronic Liver Failure. Semin Liver Dis 2025; 45:52-65. [PMID: 40081417 DOI: 10.1055/a-2516-2361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
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.
Collapse
Affiliation(s)
- Julian Pohl
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Dimitrios Aretakis
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| |
Collapse
|
4
|
Porada M, Bułdak Ł. From Pathophysiology to Practice: Evolving Pharmacological Therapies, Clinical Complications, and Pharmacogenetic Considerations in Portal Hypertension. Metabolites 2025; 15:72. [PMID: 39997697 PMCID: PMC11857179 DOI: 10.3390/metabo15020072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/07/2025] [Accepted: 01/18/2025] [Indexed: 02/26/2025] Open
Abstract
Background: Portal hypertension is a major complication of chronic liver diseases, leading to serious issues such as esophageal variceal bleeding. The increase in portal vein pressure is driven by both an organic component and a functional component, including tonic contraction of hepatic stellate cells. These processes result in a pathological rise in intrahepatic vascular resistance, stemming from partial impairment of hepatic microcirculation, which is further exacerbated by abnormalities in extrahepatic vessels, including increased portal blood flow. Objectives: This review aims to provide a comprehensive overview of the evolving pharmacological therapies for portal hypertension, with consideration and discussion of pathophysiological mechanisms, clinical complications, and pharmacogenetic considerations, highlighting potential directions for future research. Methods: A review of recent literature was performed to evaluate current knowledge and potential therapeutic strategies in portal hypertension. Results: For over 35 years, non-selective beta-blockers have been the cornerstone therapy for portal hypertension by reducing portal vein inflow as an extrahepatic target, effectively preventing decompensation and variceal hemorrhages. However, since not all patients exhibit an adequate response to non-selective beta-blockers (NSBBs), and some may not tolerate NSBBs, alternative or adjunctive therapies that enhance the effects of NSBBs on portal pressure are being investigated in preclinical and early clinical studies. Conclusions: A better understanding of pharmacogenetic factors and pathophysiological mechanisms could lead to more individualized and effective treatments for portal hypertension. These insights highlight potential directions for future research.
Collapse
Affiliation(s)
- Michał Porada
- Students’ Scientific Society, Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland;
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
| |
Collapse
|
5
|
Wang X, Ning C, Cheng X, Wu Z, Wu D, Ding X, Ju C, Zhou Z, Wan L, Zhao W, Shi P. The N-terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism. Animal Model Exp Med 2025; 8:114-125. [PMID: 39731223 PMCID: PMC11798734 DOI: 10.1002/ame2.12506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 10/07/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND The emerging incidence of pathogenic liver conditions is turning into a major concern for global health. Induction of pyroptosis in hepatocytes instigates cellular disintegration, which in turn liberates substantial quantities of pro-inflammatory intracellular substances, thereby accelerating the advancement of liver fibrosis. Consequently, directing therapeutic efforts towards inhibiting pyroptosis could potentially serve as an innovative approach in managing inflammation related chronic hepatic disorders. METHODS GSDMD-NTki/wt mice and Alb-creki/wt mice were generated using CRISPR/Cas9 technology. After crossing the two strains together, we induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis. We analyzed differentially expressed genes by RNA sequencing and explored their biological functions. The efficacy of obeticholic acid (OCA) in the treatment of liver fibrosis was assessed. RESULTS Doxycycline-treated GSDMD-NTki/wt × Alb-creki/wt mice showed severe liver damage, vacuolation of hepatocytes, increased collagen fibers, and accumulation of lipid droplets. The expression of liver fibrosis related genes was greatly increased in the doxycycline-treated mouse liver compared with untreated mouse liver. RNA-sequencing showed that upregulated differentially expressed genes were involved in inflammatory responses, cell activation, and metabolic processes. Treatment with OCA alleviated the liver fibrosis, with reduced ALT and AST levels seen in the GSDMD-NTki/wt × Alb-creki/wt mice. CONCLUSIONS We successfully constructed a novel mouse model for liver fibrosis. This GSDMD-NT-induced fibrosis may be mediated by abnormal lipid metabolism. Our results demonstrated that we successfully constructed a mouse model of liver fibrosis, and GSDMD-NT induced fibrosis by mediating lipid metabolism.
Collapse
Affiliation(s)
- Xue Wang
- GemPharmatech Chengdu Co., Ltd.ChengduChina
| | | | | | | | - Dongbo Wu
- Center of Infectious DiseasesWest China Hospital, Sichuan UniversityChengduChina
| | | | - Cunxiang Ju
- Gempharmatech Shanghai Co., Ltd.ShanghaiChina
| | - Zhihang Zhou
- Department of Gastroenterologythe Second Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Lingfeng Wan
- Fatty Liver Disease Center of Integrated Chinese and Western MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjingChina
| | - Wei Zhao
- School of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
- Department of Clinical Biochemistry, School of Laboratory MedicineChengdu Medical CollegeChengduChina
| | - Peiliang Shi
- GemPharmatech Chengdu Co., Ltd.ChengduChina
- GemPharmatech Co., Ltd.GuangdongChina
| |
Collapse
|
6
|
Fuchs CD, Simbrunner B, Baumgartner M, Campbell C, Reiberger T, Trauner M. Bile acid metabolism and signalling in liver disease. J Hepatol 2025; 82:134-153. [PMID: 39349254 DOI: 10.1016/j.jhep.2024.09.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/12/2024] [Accepted: 09/17/2024] [Indexed: 10/02/2024]
Abstract
Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.
Collapse
Affiliation(s)
- Claudia D Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Maximillian Baumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Clarissa Campbell
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
7
|
Ratziu V. Cirrhose métabolique : une entité en plein essor. BULLETIN DE L'ACADÉMIE NATIONALE DE MÉDECINE 2024. [DOI: 10.1016/j.banm.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
8
|
Tajima K, Miuma S, Miyaaki H, Matsuo S, Shimakura A, Mori T, Takahashi K, Nakao Y, Fukushima M, Haraguchi M, Sasaki R, Ozawa E, Nakao K. Total bile acids levels as a stratification tool for screening portopulmonary hypertension in patients with decompensated cirrhosis. Hepatol Res 2024; 54:1049-1059. [PMID: 38779914 DOI: 10.1111/hepr.14059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 05/01/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024]
Abstract
AIM Echocardiography is necessary for portopulmonary hypertension diagnosis, and identifying patients with cirrhosis who require it is challenging. In this study, we aimed to investigate the utility of the total bile acid (TBA) levels as a screening tool for identifying patients with decompensated cirrhosis who should undergo echocardiography for portopulmonary hypertension diagnosis. METHODS We evaluated 135 patients with decompensated cirrhosis who underwent liver transplantation. Subsequently, factors contributing to tricuspid regurgitation pressure gradient (TRPG) elevation (≥30 mmHg) were analyzed using preoperative data, including the TBA levels. RESULTS The median age of patients was 58 years (61 women), and 45 and 90 patients had Child-Turcotte-Pugh grades of B and C, respectively. The median TRPG level was 21 mmHg, and 17 patients (12.6%) showed TRPG elevation. Multiple logistic regression analysis revealed that elevated TBA (odds ratio 4.322; p = 0.013) and main pulmonary artery diameter ≥33 mm (odds ratio 4.333; p = 0.016) were significantly associated with TRPG elevation. The TBA cut-off value (167.7 μmol/L) showed a high diagnostic performance, with 70.6% sensitivity and 64.4% specificity. Ursodeoxycholic acid (UDCA) administration increased the TBA levels dose-dependently. Analysis stratified by UDCA use revealed that in patients not taking UDCA (n = 59), elevated TBA levels and younger age significantly contributed to TRPG elevation. However, in those taking UDCA (n = 76), this contribution disappeared, suggesting that UDCA consumption reduced TBA levels' efficiency in diagnosing TRPG elevation. CONCLUSIONS The TBA levels may be a potential screening tool for TRPG elevation; however, caution is warranted when interpreting cases treated with UDCA.
Collapse
Affiliation(s)
- Kazuaki Tajima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoshi Matsuo
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akane Shimakura
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomotaka Mori
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kosuke Takahashi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yasuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masanori Fukushima
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Eisuke Ozawa
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| |
Collapse
|
9
|
Qian S, Wang X, Chen Y, Zai Q, He Y. Inflammation in Steatotic Liver Diseases: Pathogenesis and Therapeutic Targets. Semin Liver Dis 2024; 44:319-332. [PMID: 38838739 DOI: 10.1055/a-2338-9261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Abstract
Alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), two main types of steatotic liver disease (SLDs), are characterized by a wide spectrum of several different liver disorders, including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Multiple immune cell-mediated inflammatory responses not only orchestrate the killing and removal of infected/damaged cells but also exacerbate the development of SLDs when excessive or persistent inflammation occurs. In recent years, single-cell and spatial transcriptome analyses have revealed the heterogeneity of liver-infiltrated immune cells in ALD and MASLD, revealing a new immunopathological picture of SLDs. In this review, we will emphasize the roles of several key immune cells in the pathogenesis of ALD and MASLD and discuss inflammation-based approaches for effective SLD intervention. In conclusion, the study of immunological mechanisms, especially highly specific immune cell population functions, may provide novel therapeutic opportunities for this life-threatening disease.
Collapse
Affiliation(s)
- Shengying Qian
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaolin Wang
- Department of Infectious Diseases, Shanghai Jiao Tong University School of Medicine, Ruijin Hospital, Shanghai, China
| | - Yingfen Chen
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Qiuhong Zai
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yong He
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
10
|
Xiong A, Lu L, Jiang K, Wang X, Chen Y, Wang X, Zhang W, Zhuge Y, Huang W, Li L, Liao Q, Yang F, Liu P, Ding L, Wang Z, Yang L. Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome. Arch Toxicol 2024; 98:2557-2576. [PMID: 38703205 DOI: 10.1007/s00204-024-03762-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/10/2024] [Indexed: 05/06/2024]
Abstract
Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50 mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.
Collapse
Affiliation(s)
- Aizhen Xiong
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China.
- Shanghai R & D Center for Standardization of Traditional Chinese Medicines, Shanghai, 201210, China.
| | - Longhui Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China
| | - Kaiyuan Jiang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China
| | - Xiaoning Wang
- E-Institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yan Chen
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China
| | - Xunjiang Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China
| | - Wei Zhang
- Department of Gastroenterology, The Drum Tower Hospital of Nanjing, Affiliated to Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Yuzheng Zhuge
- Department of Gastroenterology, The Drum Tower Hospital of Nanjing, Affiliated to Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA
| | - Lujin Li
- Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China
| | - Qi Liao
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China
| | - Fan Yang
- Department of Obstetrics and Gynecology, and Shanghai Key Laboratory of Gynecologic Oncology Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Ping Liu
- E-Institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lili Ding
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China.
- Shanghai R & D Center for Standardization of Traditional Chinese Medicines, Shanghai, 201210, China.
| | - Zhengtao Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China.
- Shanghai R & D Center for Standardization of Traditional Chinese Medicines, Shanghai, 201210, China.
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China.
- Shanghai R & D Center for Standardization of Traditional Chinese Medicines, Shanghai, 201210, China.
| |
Collapse
|
11
|
Guixé-Muntet S, Quesada-Vázquez S, Gracia-Sancho J. Pathophysiology and therapeutic options for cirrhotic portal hypertension. Lancet Gastroenterol Hepatol 2024; 9:646-663. [PMID: 38642564 DOI: 10.1016/s2468-1253(23)00438-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 04/22/2024]
Abstract
Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. Data also suggest that the phenotype of hepatic cells could be further impaired due to the altered mechanical properties of the cirrhotic liver itself, creating a deleterious cycle that worsens portal hypertension in the advanced stages of liver disease. In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options.
Collapse
Affiliation(s)
- Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sergio Quesada-Vázquez
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
| |
Collapse
|
12
|
Simbrunner B, Hofer BS, Schwabl P, Zinober K, Petrenko O, Fuchs C, Semmler G, Marculescu R, Mandorfer M, Datz C, Trauner M, Reiberger T. FXR-FGF19 signaling in the gut-liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence. Hepatol Int 2024; 18:929-942. [PMID: 38332428 PMCID: PMC11126514 DOI: 10.1007/s12072-023-10636-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 12/22/2023] [Indexed: 02/10/2024]
Abstract
BACKGROUND AND AIMS Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut-liver axis and their link to disease severity in patients with cirrhosis. METHODS Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured. RESULTS Systemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = -0.512, p < 0.001) and BA (r = -0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls. CONCLUSIONS FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut-liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis. CLINICAL TRIAL NUMBER NCT03267615.
Collapse
Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
| | - Benedikt S Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
| | - Kerstin Zinober
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Oleksandr Petrenko
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
| | - Claudia Fuchs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Rodrig Marculescu
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital, Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
- CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria.
| |
Collapse
|
13
|
Bendixen SM, Jakobsgaard PR, Hansen D, Hejn KH, Terkelsen MK, Bjerre FA, Thulesen AP, Eriksen NG, Hallenborg P, Geng Y, Dam TV, Larsen FT, Wernberg CW, Vijayathurai J, Scott EAH, Marcher AB, Detlefsen S, Grøntved L, Dimke H, Berdeaux R, de Aguiar Vallim TQ, Olinga P, Lauridsen MM, Krag A, Blagoev B, Ravnskjaer K. Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module. J Hepatol 2024; 80:467-481. [PMID: 37972658 DOI: 10.1016/j.jhep.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 10/06/2023] [Accepted: 11/07/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND & AIMS Metabolic dysfunction-associated steatohepatitis (MASH) is linked to insulin resistance and type 2 diabetes and marked by hepatic inflammation, microvascular dysfunction, and fibrosis, impairing liver function and aggravating metabolic derangements. The liver homeostatic interactions disrupted in MASH are still poorly understood. We aimed to elucidate the plasticity and changing interactions of non-parenchymal cells associated with advanced MASH. METHODS We characterized a diet-induced mouse model of advanced MASH at single-cell resolution and validated findings by assaying chromatin accessibility, bioimaging murine and human livers, and via functional experiments in vivo and in vitro. RESULTS The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile acid receptor NR1H4/FXR and HSC-specific GS-protein-coupled receptors (GSPCRs) capable of preserving stellate cell quiescence. Accompanying HSC activation, we further observed the attenuation of HSC Gdf2 expression, and a MASH-associated expansion of a CD207-positive macrophage population likely derived from both incoming monocytes and Kupffer cells. CONCLUSION We conclude that HSC-expressed NR1H4 and GSPCRs of the healthy liver integrate postprandial cues, which sustain HSC quiescence and, through paracrine signals, overall sinusoidal health. Hence HSC activation in MASH not only drives fibrogenesis but may desensitize the hepatic sinusoid to liver homeostatic signals. IMPACT AND IMPLICATIONS Homeostatic interactions between hepatic cell types and their deterioration in metabolic dysfunction-associated steatohepatitis are poorly characterized. In our current single cell-resolved study of advanced murine metabolic dysfunction-associated steatohepatitis, we identified a quiescence-associated hepatic stellate cell-signaling module with potential to preserve normal sinusoid function. As expression levels of its constituents are conserved in the human liver, stimulation of the identified signaling module is a promising therapeutic strategy to restore sinusoid function in chronic liver disease.
Collapse
Affiliation(s)
- Sofie M Bendixen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Peter R Jakobsgaard
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Daniel Hansen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Kamilla H Hejn
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Mike K Terkelsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Frederik A Bjerre
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Annemette P Thulesen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Niels G Eriksen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Philip Hallenborg
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Yana Geng
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands
| | - Trine V Dam
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Frederik T Larsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Charlotte W Wernberg
- Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark; Department of Gastroenterology and Hepatology, University Hospital of South Denmark Esbjerg, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Janusa Vijayathurai
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Emma A H Scott
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Ann-Britt Marcher
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark
| | - Lars Grøntved
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Henrik Dimke
- Department of Molecular Medicine, University of Southern Denmark, Denmark; Department of Nephrology, Odense University Hospital, Denmark
| | - Rebecca Berdeaux
- Department of Integrative Biology and Pharmacology, McGovern Medical School, UT Health Houston, USA
| | - Thomas Q de Aguiar Vallim
- Department of Medicine, Division of Cardiology, University of California, Los Angeles, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, USA
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands
| | - Mette M Lauridsen
- Department of Gastroenterology and Hepatology, University Hospital of South Denmark Esbjerg, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Blagoy Blagoev
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark
| | - Kim Ravnskjaer
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark.
| |
Collapse
|
14
|
Zhao J, Li B, Zhang K, Zhu Z. The effect and safety of obeticholic acid for patients with nonalcoholic steatohepatitis: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2024; 103:e37271. [PMID: 38363900 PMCID: PMC10869096 DOI: 10.1097/md.0000000000037271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 01/24/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) is one of the primary causes of chronic liver disease worldwide. Obeticholic acid (OCA), a potent farnesoid X nuclear receptor activator, has shown promise for treating NASH-related fibrosis due to its anti-fibrotic effects. This study aimed to examine the efficacy of OCA for patients with NASH as well as to investigate its impact on dyslipidemia. METHOD A search of databases including PubMed, Embase, and Cochrane Library from January 1, 2010, to November 1, 2022, was conducted to identify systematic reviews of randomized controlled trials involving NASH patients. Inclusion criteria comprised randomized controlled trials that specifically addressed NASH as diagnosed through magnetic resonance imaging, computed tomography, or histology. The results were then categorized, with consideration given to both biochemical and histological outcomes. RESULT Five NASH studies were ultimately selected for further analysis. In terms of biochemical indicators, patients receiving OCA treatment showed improvements in alanine transaminase (mean difference: -19.48, 95% confidence interval [CI]: -24.39 to 14.58; P < .05) and aspartate aminotransferase (mean difference: -9.22, 95% CI: -12.70 to 5.74; P < .05). As for histological improvement, OCA treatment reduced fibrosis (odds ratio [OR]: 1.95, 95% CI: 1.47-2.59; P = .001) and steatosis (OR: 1.95, 95% CI: 1.47-2.59; P = .001). No significant differences were observed regarding adverse events (1.44, 95% CI: 0.57-3.62; P > .001). Regarding dyslipidemia, mean differences between total cholesterol and low-density lipoprotein were found to be high (0.33, 95% CI: 0.01-0.64, P < .05; 0.39, 95% CI: 0.04-0.73, P < .05). In the case of pruritus, OCA achieved a high OR (3.22, 95% CI: 2.22-4.74) compared with placebo. CONCLUSION OCA also reduced several liver test markers compared to placebo, including the biochemical indicators alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase, and improved hepatocellular ballooning, fibrosis, steatosis, and lobular inflammation. Although the incidence of adverse events did not significantly differ between OCA and placebo groups among NASH patients, OCA treatment was found to elevate total cholesterol and low-density lipoprotein levels, and the reported severity of pruritus increased with higher doses of OCA.
Collapse
Affiliation(s)
- Jie Zhao
- Department of Nephrology, Zibo Central Hospital, Zibo, China
| | - Baozhen Li
- Department of Gastroenterology, Zibo Central Hospital, Zibo, China
| | - Kai Zhang
- Shandong Drug and Food Vocational College, Weihai, China
| | - Zhiyong Zhu
- Department of Nephrology, Zibo Central Hospital, Zibo, China
| |
Collapse
|
15
|
Sheng JY, Meng ZF, Li Q, Yang YS. Recent advances in promising drugs for primary prevention of gastroesophageal variceal bleeding with cirrhotic portal hypertension. Hepatobiliary Pancreat Dis Int 2024; 23:4-13. [PMID: 37580228 DOI: 10.1016/j.hbpd.2023.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 08/01/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Gastroesophageal variceal bleeding is one of the most severe complications of patients with cirrhosis. Although primary prevention drugs, including non-selective β-blockers, have effectively reduced the incidence of bleeding, their efficacy is limited due to side effects and related contraindications. With recent advances in precision medicine, precise drug treatment provides better treatment efficacy. DATA SOURCES Literature search was conducted in PubMed, MEDLINE and Web of Science for relevant articles published up to May 2022. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/. RESULTS The in-depth understanding of the pathogenesis and advances of portal hypertension has enabled the discovery of multiple molecular targets for promising drugs. According to the site of action, these drugs could be classified into four classes: intrahepatic, extrahepatic, both intrahepatic and extrahepatic targets and others. All these classes of drugs offer advantages over traditional treatments in prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension. CONCLUSIONS This review classified and summarized the promising drugs, which prevent gastroesophageal variceal bleeding by targeting specific markers of pathogenesis of portal hypertension, demonstrating the significance of using the precision medicine strategy to discover and develop promising drugs for the primary prevention of gastroesophageal variceal bleeding in patients with cirrhotic portal hypertension.
Collapse
Affiliation(s)
- Ji-Yao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China; Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, the Second Hospital of Jilin University, Changchun 130041, China
| | - Zi-Fan Meng
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China; Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, the Second Hospital of Jilin University, Changchun 130041, China
| | - Qiao Li
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China
| | - Yong-Sheng Yang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Hospital of Jilin University, Changchun 130041, China; Jilin Engineering Laboratory for Translational Medicine of Hepatobiliary and Pancreatic Diseases, the Second Hospital of Jilin University, Changchun 130041, China.
| |
Collapse
|
16
|
Madir A, Grgurevic I, Tsochatzis EA, Pinzani M. Portal hypertension in patients with nonalcoholic fatty liver disease: Current knowledge and challenges. World J Gastroenterol 2024; 30:290-307. [PMID: 38313235 PMCID: PMC10835535 DOI: 10.3748/wjg.v30.i4.290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 01/26/2024] Open
Abstract
Portal hypertension (PH) has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease (NAFLD). However, recent studies have provided evidence that PH may develop in earlier stages of NAFLD, suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis. The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning, leading to the compression of liver sinusoids. External compression and intra-luminal obstacles cause mechanical forces such as strain, shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways, resulting in endothelial dysfunction and the development of fibrosis. The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD. Thus, current diagnostic methods such as hepatic venous pressure gradient (HVPG) measurement tend to underestimate portal pressure (PP) in NAFLD patients, who might decompensate below the HVPG threshold of 10 mmHg, which is traditionally considered the most relevant indicator of clinically significant portal hypertension (CSPH). This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients. In theory, the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component, but more investigations are needed to test its clinical utility for this indication. Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment. Lifestyle change remains the cornerstone of the treatment of PH in NAFLD, together with correcting the components of metabolic syndrome, using nonselective beta blockers, whereas emerging candidate drugs require more robust confirmation from clinical trials.
Collapse
Affiliation(s)
- Anita Madir
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Zagreb 10000, Croatia
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb 10000, Croatia
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and University College London, London NW3 2PF, United Kingdom
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and University College London, London NW3 2PF, United Kingdom
| |
Collapse
|
17
|
Fernández-Iglesias A, Gracia-Sancho J. Role of liver sinusoidal endothelial cells in the diagnosis and treatment of liver diseases. SINUSOIDAL CELLS IN LIVER DISEASES 2024:467-481. [DOI: 10.1016/b978-0-323-95262-0.00023-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
18
|
Kwanten W(WJ, Francque SM. The liver sinusoid in chronic liver disease: NAFLD and NASH. SINUSOIDAL CELLS IN LIVER DISEASES 2024:263-284. [DOI: 10.1016/b978-0-323-95262-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
19
|
Effenberger M, Grander C, Grabherr F, Tilg H. Nonalcoholic Fatty Liver Disease and the Intestinal Microbiome: An Inseparable Link. J Clin Transl Hepatol 2023; 11:1498-1507. [PMID: 38161503 PMCID: PMC10752805 DOI: 10.14218/jcth.2023.00069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 04/21/2023] [Accepted: 07/18/2023] [Indexed: 01/03/2024] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) particularly affects patients with type 2 diabetes and obesity. The incidence of NAFLD has increased significantly over the last decades and is now pandemically across the globe. It is a complex systemic disease comprising hepatic lipid accumulation, inflammation, lipotoxicity, gut dysbiosis, and insulin resistance as main features and with the potential to progress to cirrhosis and hepatocellular carcinoma (HCC). In numerous animal and human studies the gut microbiota plays a key role in the pathogenesis of NAFLD, NAFLD-cirrhosis and NAFLD-associated HCC. Lipotoxicity is the driver of inflammation, insulin resistance, and liver injury. Likewise, western diet, obesity, and metabolic disorders may alter the gut microbiota, which activates innate and adaptive immune responses and fuels hereby hepatic and systemic inflammation. Indigestible carbohydrates are fermented by the gut microbiota to produce important metabolites, such as short-chain fatty acids and succinate. Numerous animal and human studies suggested a pivotal role of these metabolites in the progression of NAFLD and its comorbidities. Though, modification of the gut microbiota and/or the metabolites could even be beneficial in patients with NAFLD, NAFLD-cirrhosis, and NAFLD-associated HCC. In this review we collect the evidence that exogenous and endogenous hits drive liver injury in NAFLD and propel liver fibrosis and the progressing to advanced disease stages. NAFLD can be seen as the product of a complex interplay between gut microbiota, the immune response and metabolism. Thus, the challenge will be to understand its pathogenesis and to develop new therapeutic strategies.
Collapse
Affiliation(s)
- Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| |
Collapse
|
20
|
Mohammed OS, Attia HG, Mohamed BMSA, Elbaset MA, Fayed HM. Current investigations for liver fibrosis treatment: between repurposing the FDA-approved drugs and the other emerging approaches. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2023; 26:11808. [PMID: 38022905 PMCID: PMC10662312 DOI: 10.3389/jpps.2023.11808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023]
Abstract
Long-term liver injuries lead to hepatic fibrosis, often progressing into cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. There is currently no effective therapy available for liver fibrosis. Thus, continuous investigations for anti-fibrotic therapy are ongoing. The main theme of anti-fibrotic investigation during recent years is the rationale-based selection of treatment molecules according to the current understanding of the pathology of the disease. The research efforts are mainly toward repurposing current FDA-approved drugs targeting etiological molecular factors involved in developing liver fibrosis. In parallel, investigations also focus on experimental small molecules with evidence to hinder or reverse the fibrosis. Natural compounds, immunological, and genetic approaches have shown significant encouraging effects. This review summarizes the efficacy and safety of current under-investigation antifibrosis medications targeting various molecular targets, as well as the properties of antifibrosis medications, mainly in phase II and III clinical trials.
Collapse
Affiliation(s)
- Omima S. Mohammed
- Department of Microbiology, College of Medicine, Najran University, Najran, Saudi Arabia
| | - Hany G. Attia
- Department of Pharmacognosy, College of Pharmacy, Najran University, Najran, Saudi Arabia
| | - Bassim M. S. A. Mohamed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Marawan A. Elbaset
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Hany M. Fayed
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| |
Collapse
|
21
|
Sanyal AJ, Ratziu V, Loomba R, Anstee QM, Kowdley KV, Rinella ME, Sheikh MY, Trotter JF, Knapple W, Lawitz EJ, Abdelmalek MF, Newsome PN, Boursier J, Mathurin P, Dufour JF, Berrey MM, Shiff SJ, Sawhney S, Capozza T, Leyva R, Harrison SA, Younossi ZM. Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2023; 79:1110-1120. [PMID: 37517454 DOI: 10.1016/j.jhep.2023.07.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/30/2023] [Accepted: 07/06/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND & AIMS Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for the treatment of pre-cirrhotic liver fibrosis due to non-alcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase III REGENERATE trial of OCA for the treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8,000 total patient-years' exposure with nearly 1,000 participants receiving study drug for >4 years. METHODS Digitized whole-slide images were evaluated independently by panels of three pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) ≥1 stage improvement in fibrosis with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events. RESULTS Prespecified efficacy analyses included 931 participants. The proportion of participants achieving a ≥1 stage improvement in fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs. 9.6% for placebo (p <0.0001). More participants receiving OCA 25 mg vs. placebo achieved NASH resolution with no worsening of fibrosis (6.5% vs. 3.5%, respectively; p = 0.093). Histology data in a larger population of 1,607 participants supported these results. Safety data included 2,477 participants. The incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups. CONCLUSIONS These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. These data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH. IMPACT AND IMPLICATIONS Patients with non-alcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in participants in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit of OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit: risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.
Collapse
Affiliation(s)
- Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.
| | - Vlad Ratziu
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Institute for Cardiometabolism and Nutrition, Paris, France
| | - Rohit Loomba
- University of California, San Diego, La Jolla, CA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | | | - Mary E Rinella
- University of Chicago, Pritzker School of Medicine, Chicago, IL, USA
| | | | | | | | - Eric J Lawitz
- Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Philip N Newsome
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | - Jérôme Boursier
- Angers University Hospital, Angers University, Angers, France
| | | | | | | | | | | | | | - Rina Leyva
- Intercept Pharmaceuticals, Morristown, NJ, USA
| | | | - Zobair M Younossi
- Beatty Liver and Obesity Research Program, Center for Liver Diseases, Inova Medicine, Falls Church, VA, USA
| |
Collapse
|
22
|
Adorini L, Trauner M. FXR agonists in NASH treatment. J Hepatol 2023; 79:1317-1331. [PMID: 37562746 DOI: 10.1016/j.jhep.2023.07.034] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/19/2023] [Accepted: 07/16/2023] [Indexed: 08/12/2023]
Abstract
The farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor highly expressed in the liver and intestine, regulates the expression of genes involved in cholesterol and bile acid homeostasis, hepatic gluconeogenesis, lipogenesis, inflammation and fibrosis, in addition to controlling intestinal barrier integrity, preventing bacterial translocation and maintaining gut microbiota eubiosis. Non-alcoholic steatohepatitis (NASH), an advanced stage of non-alcoholic fatty liver disease, is characterized by hepatic steatosis, hepatocyte damage (ballooning) and inflammation, leading to fibrosis, cirrhosis and hepatocellular carcinoma. NASH represents a major unmet medical need, but no pharmacological treatments have yet been approved. The pleiotropic mechanisms involved in NASH development offer a range of therapeutic opportunities and among them FXR activation has emerged as an established pharmacological target. Various FXR agonists with different physicochemical properties, which can be broadly classified as BA derivatives, non-BA-derived steroidal FXR agonists, non-steroidal FXR agonists, and partial FXR agonists, are in advanced clinical development. In this review we will summarize key preclinical and clinical features of the most advanced FXR agonists and critically evaluate their potential in NASH treatment.
Collapse
Affiliation(s)
- Luciano Adorini
- Intercept Pharmaceuticals Inc., 305 Madison Ave., Morristown, NJ 07960, USA.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
| |
Collapse
|
23
|
Jagdish RK, Roy A, Kumar K, Premkumar M, Sharma M, Rao PN, Reddy DN, Kulkarni AV. Pathophysiology and management of liver cirrhosis: from portal hypertension to acute-on-chronic liver failure. Front Med (Lausanne) 2023; 10:1060073. [PMID: 37396918 PMCID: PMC10311004 DOI: 10.3389/fmed.2023.1060073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 05/19/2023] [Indexed: 07/04/2023] Open
Abstract
Cirrhosis transcends various progressive stages from compensation to decompensation driven by the severity of portal hypertension. The downstream effect of increasing portal hypertension severity leads to various pathophysiological pathways, which result in the cardinal complications of cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. Additionally, the severity of portal hypertension is the central driver for further advanced complications of hyperdynamic circulation, hepatorenal syndrome, and cirrhotic cardiomyopathy. The management of these individual complications has specific nuances which have undergone significant developments. In contrast to the classical natural history of cirrhosis and its complications which follows an insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill course with high short-term mortality unless intervened at the early stages. The management of ACLF involves specific interventions, which have quickly evolved in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF.
Collapse
Affiliation(s)
- Rakesh Kumar Jagdish
- Department of Hepatology, Gastroenterology and Liver Transplant Medicine, Metro Hospital, Noida, India
| | - Akash Roy
- Department of Gastroenterology, Institute of Gastrosciences and Liver Transplantation, Apollo Hospitals, Kolkata, India
| | - Karan Kumar
- Department of Hepatology, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Madhumita Premkumar
- Department of Hepatology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Mithun Sharma
- Department of Hepatology, Asian Institute of Gastroenterology (AIG) Hospitals, Hyderabad, India
| | - Padaki Nagaraja Rao
- Department of Hepatology, Asian Institute of Gastroenterology (AIG) Hospitals, Hyderabad, India
| | - Duvvur Nageshwar Reddy
- Department of Hepatology, Asian Institute of Gastroenterology (AIG) Hospitals, Hyderabad, India
| | - Anand V. Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology (AIG) Hospitals, Hyderabad, India
| |
Collapse
|
24
|
Liu J, Sun J, Yu J, Chen H, Zhang D, Zhang T, Ma Y, Zou C, Zhang Z, Ma L, Yu X. Gut microbiome determines therapeutic effects of OCA on NAFLD by modulating bile acid metabolism. NPJ Biofilms Microbiomes 2023; 9:29. [PMID: 37258543 DOI: 10.1038/s41522-023-00399-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 05/18/2023] [Indexed: 06/02/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, had no approved pharmacological agents yet. Obeticholic acid (OCA), a novel bile acid derivative, was demonstrated to ameliorate NAFLD-related manifestations. Regarding the role of gut-liver axis in liver disease development, this study aimed to explore the potential role of gut microbiota in the treatment of OCA in NAFLD mice induced by the high-fat diet (HFD). Antibiotic-induced microbiome depletion (AIMD) and fecal microbiota transplantation (FMT) confirmed the critical role of gut microbiota in OCA treatment for NAFLD by effectively alleviating histopathological lesions and restoring liver function impaired by HFD. Metagenomic analysis indicated that OCA intervention in HFD mice remarkably increased the abundance of Akkermansia muciniphila, Bifidobacterium spp., Bacteroides spp., Alistipes spp., Lactobacillus spp., Streptococcus thermophilus, and Parasutterella excrementihominis. Targeted metabolomics analysis indicated that OCA could modulate host bile acids pool by reducing levels of serum hydrophobic cholic acid (CA) and chenodeoxycholic acid (CDCA), and increasing levels of serum-conjugated bile acids, such as taurodeoxycholic acid (TDCA) and tauroursodesoxycholic acid (TUDCA) in the HFD-fed mice. Strong correlations were observed between differentially abundant microbes and the shifted bile acids. Furthermore, bacteria enriched by OCA intervention exhibited much greater potential in encoding 7alpha-hydroxysteroid dehydrogenase (7α-HSDs) producing secondary bile acids rather than bile salt hydrolases (BSHs) mainly responsible for primary bile acid deconjugation. In conclusion, this study demonstrated that OCA intervention altered gut microbiota composition with specially enriched gut microbes modulating host bile acids, thus effectively alleviating NAFLD in the mice.
Collapse
Affiliation(s)
- Jianjun Liu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Biomedical Engineering, Kunming Medical University, Kunming, Yunnan, 650500, China
| | - Jiayi Sun
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Jiangkun Yu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China.
| | - Hang Chen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Dan Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Tao Zhang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
| | - Yicheng Ma
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
| | - Chenggang Zou
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
| | - Zhigang Zhang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China.
| | - Lanqing Ma
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, Yunnan, 650032, China.
| | - Xue Yu
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
| |
Collapse
|
25
|
Xu H, Xu Z, Long S, Li Z, Jiang J, Zhou Q, Huang X, Wu X, Wei W, Li X. The role of the gut microbiome and its metabolites in cerebrovascular diseases. Front Microbiol 2023; 14:1097148. [PMID: 37125201 PMCID: PMC10140324 DOI: 10.3389/fmicb.2023.1097148] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 03/23/2023] [Indexed: 05/02/2023] Open
Abstract
The gut microbiome is critically involved in maintaining normal physiological function in the host. Recent studies have revealed that alterations in the gut microbiome contribute to the development and progression of cerebrovascular disease via the microbiota-gut-brain axis (MGBA). As a broad communication network in the human body, MGBA has been demonstrated to have significant interactions with various factors, such as brain structure and function, nervous system diseases, etc. It is also believed that the species and composition of gut microbiota and its metabolites are intrinsically linked to vascular inflammation and immune responses. In fact, in fecal microbiota transplantation (FMT) research, specific gut microbiota and downstream-related metabolites have been proven to not only participate in various physiological processes of human body, but also affect the occurrence and development of cerebrovascular diseases directly or indirectly through systemic inflammatory immune response. Due to the high mortality and disability rate of cerebrovascular diseases, new treatments to improve intestinal dysbacteriosis have gradually attracted widespread attention to better ameliorate the poor prognosis of cerebrovascular diseases in a non-invasive way. This review summarizes the latest advances in the gut microbiome and cerebrovascular disease research and reveals the profound impact of gut microbiota dysbiosis and its metabolites on cerebrovascular diseases. At the same time, we elucidated molecular mechanisms whereby gut microbial metabolites regulate the expression of specific interleukins in inflammatory immune responses. Moreover, we further discuss the feasibility of novel therapeutic strategies targeting the gut microbiota to improve the outcome of patients with cerebrovascular diseases. Finally, we provide new insights for standardized diagnosis and treatment of cerebrovascular diseases.
Collapse
Affiliation(s)
- Hongyu Xu
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Ziyue Xu
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Shengrong Long
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Zhengwei Li
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Jiazhi Jiang
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Qiangqiang Zhou
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Xiaopeng Huang
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Xiaohui Wu
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Wei Wei
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| | - Xiang Li
- Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
- Brain Research Center, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
| |
Collapse
|
26
|
Idalsoaga F, Ayares G, Díaz LA, Arnold J, Ayala-Valverde M, Hudson D, Arrese M, Arab JP. Current and emerging therapies for alcohol-associated hepatitis. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:35-46. [PMID: 39959695 PMCID: PMC11792060 DOI: 10.1016/j.livres.2023.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 01/16/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
Alcohol-related liver disease (ALD) encompasses a spectrum of diseases caused by excessive alcohol consumption. ALD includes hepatic steatosis, steatohepatitis, variable degrees of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH), the latter being the most severe acute form of the disease. Severe AH is associated with high mortality (reaching up to 30%-50%) at 90 days. The cornerstone of ALD, and particularly AH, treatment continues to be abstinence, accompanied by support measures such as nutritional supplementation and management of alcohol withdrawal syndrome (AWS). In severe AH with model for end-stage liver disease (MELD) score ≥21, corticosteroids can be used, especially MELD score between 25 and 39, where the highest benefit is achieved. Other key aspects of treatment include the early identification of infections and their associated management and the proper identification of potential candidates for liver transplantation. The development of new therapies based on the pathophysiology and mechanisms of liver injury are underway. This includes the modulation and management of the innate immune response, gut dysbiosis, bacterial translocation, and bacteria-derived products from the intestine. These hold promise for the future of AH treatment.
Collapse
Affiliation(s)
- Francisco Idalsoaga
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gustavo Ayares
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis Antonio Díaz
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jorge Arnold
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - María Ayala-Valverde
- Internal Medicine Service, Hospital El Pino, Critical Patient Unit, Clinica Davila, Santiago, Chile
| | - David Hudson
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Pablo Arab
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Schulich School of Medicine, Western University, London, Ontario, Canada
- Alimentiv, London, Ontario, Canada
| |
Collapse
|
27
|
Nevens F, Trauner M, Manns MP. Primary biliary cholangitis as a roadmap for the development of novel treatments for cholestatic liver diseases †. J Hepatol 2023; 78:430-441. [PMID: 36272496 DOI: 10.1016/j.jhep.2022.10.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022]
Abstract
The discovery of nuclear receptors and transporters has contributed to the development of new drugs for the treatment of cholestatic liver diseases. Particular progress has been made in the development of second-line therapies for PBC. These new drugs can be separated into compounds primarily targeting cholestasis, molecules targeting fibrogenesis and molecules with immune-mediated action. Finally, drugs aimed at symptom relief (pruritus and fatigue) are also under investigation. Obeticholic acid is currently the only approved second-line therapy for PBC. Drugs in the late phase of clinical development include peroxisome proliferator-activated receptor agonists, norursodeoxycholic acid and NADPH oxidase 1/4 inhibitors.
Collapse
Affiliation(s)
- Frederik Nevens
- Department of Gastroenterology and Hepatology, University Hospital KU Leuven, Belgium; Centre of ERN RARE-LIVER.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Austria; Centre of ERN RARE-LIVER
| | - Michael P Manns
- Hannover Medical School, Hannover, Germany; Centre of ERN RARE-LIVER
| |
Collapse
|
28
|
Thakral N, Deutsch-Link S, Singal AK. Therapeutic Pipeline in Alcohol-Associated Liver Disease. Semin Liver Dis 2023; 43:60-76. [PMID: 36572032 PMCID: PMC11503467 DOI: 10.1055/s-0042-1759614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.
Collapse
Affiliation(s)
- Nimish Thakral
- Division of Gastroenterology and Hepatology, University of Kentucky, Lexington, Kentucky
| | - Sasha Deutsch-Link
- Department of Medicine, University of North Carolina at Chapel Hill, North Carolina
| | - Ashwani K. Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
- Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota
| |
Collapse
|
29
|
Felli E, Nulan Y, Selicean S, Wang C, Gracia-Sancho J, Bosch J. Emerging Therapeutic Targets for Portal Hypertension. CURRENT HEPATOLOGY REPORTS 2023; 22:51-66. [PMID: 36908849 PMCID: PMC9988810 DOI: 10.1007/s11901-023-00598-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 01/18/2023] [Indexed: 02/13/2023]
Abstract
Purpose of Review Portal hypertension is responsible of the main complications of cirrhosis, which carries a high mortality. Recent treatments have improved prognosis, but this is still far from ideal. This paper reviews new potential therapeutic targets unveiled by advances of key pathophysiologic processes. Recent Findings Recent research highlighted the importance of suppressing etiologic factors and a safe lifestyle and outlined new mechanisms modulating portal pressure. These include intrahepatic abnormalities linked to inflammation, fibrogenesis, vascular occlusion, parenchymal extinction, and angiogenesis; impaired regeneration; increased hepatic vascular tone due to sinusoidal endothelial dysfunction with insufficient NO availability; and paracrine liver cell crosstalk. Moreover, pathways such as the gut-liver axis modulate splanchnic vasodilatation and systemic inflammation, exacerbate liver fibrosis, and are being targeted by therapy. We have summarized studies of new agents addressing these targets. Summary New agents, alone or in combination, allow acting in complementary mechanisms offering a more profound effect on portal hypertension while simultaneously limiting disease progression and favoring regression of fibrosis and of cirrhosis. Major changes in treatment paradigms are anticipated.
Collapse
Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Yelidousi Nulan
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Sonia Selicean
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Cong Wang
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
- Department for BioMedical Research, Hepatology, University of Bern, 3012 Bern, Switzerland
- Liver Vascular Biology Research Group, CIBEREHD, IDIBAPS Research Institute, 08036 Barcelona, Spain
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland
| |
Collapse
|
30
|
Bile acids and their receptors in regulation of gut health and diseases. Prog Lipid Res 2023; 89:101210. [PMID: 36577494 DOI: 10.1016/j.plipres.2022.101210] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/26/2022]
Abstract
It is well established that bile acids play important roles in lipid metabolism. In recent decades, bile acids have also been shown to function as signaling molecules via interacting with various receptors. Bile acids circulate continuously through the enterohepatic circulation and go through microbial transformation by gut microbes, and thus bile acids metabolism has profound effects on the liver and intestinal tissues as well as the gut microbiota. Farnesoid X receptor and G protein-coupled bile acid receptor 1 are two pivotal bile acid receptors that highly expressed in the intestinal tissues, and they have emerged as pivotal regulators in bile acids metabolism, innate immunity and inflammatory responses. There is considerable interest in manipulating the metabolism of bile acids and the expression of bile acid receptors as this may be a promising strategy to regulate intestinal health and disease. This review aims to summarize the roles of bile acids and their receptors in regulation of gut health and diseases.
Collapse
|
31
|
The Mechanisms of Systemic Inflammatory and Immunosuppressive Acute-on-Chronic Liver Failure and Application Prospect of Single-Cell Sequencing. J Immunol Res 2022; 2022:5091275. [PMID: 36387424 PMCID: PMC9646330 DOI: 10.1155/2022/5091275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 01/24/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a complex clinical syndrome, and patients often have high short-term mortality. It occurs with intense systemic inflammation, often accompanied by a proinflammatory event (such as infection or alcoholic hepatitis), and is closely related to single or multiple organ failure. Liver inflammation begins when innate immune cells (such as Kupffer cells (KCs)) are activated by binding of pathogen-associated molecular patterns (PAMPs) from pathogenic microorganisms or damage-associated molecular patterns (DAMPs) of host origin to their pattern recognition receptors (PRRs). Activated KCs can secrete inflammatory factors as well as chemokines and recruit bone marrow-derived cells such as neutrophils and monocytes to the liver to enhance the inflammatory process. Bacterial translocation may contribute to ACLF when there are no obvious precipitating events. Immunometabolism plays an important role in the process (including mitochondrial dysfunction, amino acid metabolism, and lipid metabolism). The late stage of ACLF is mainly characterized by immunosuppression. In this process, the dysfunction of monocyte and macrophage is reflected in the downregulation of HLA-DR and upregulation of MER tyrosine kinase (MERTK), which weakens the antigen presentation function and reduces the secretion of inflammatory cytokines. We also describe the specific function of bacterial translocation and the gut-liver axis in the process of ACLF. Finally, we also describe the transcriptomics in HBV-ACLF and the recent progress of single-cell RNA sequencing as well as its potential application in the study of ACLF in the future, in order to gain a deeper understanding of ACLF in terms of single-cell gene expression.
Collapse
|
32
|
Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab 2022; 34:1700-1718. [PMID: 36208625 DOI: 10.1016/j.cmet.2022.09.017] [Citation(s) in RCA: 308] [Impact Index Per Article: 102.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/17/2022] [Accepted: 09/16/2022] [Indexed: 02/07/2023]
Abstract
Bidirectional crosstalk along the gut-liver axis controls gastrointestinal health and disease and exploits environmental and host mediators. Nutrients, microbial antigens, metabolites, and bile acids regulate metabolism and immune responses in the gut and liver, which reciprocally shape microbial community structure and function. Perturbation of such host-microbe interactions is observed in a variety of experimental liver diseases and is facilitated by an impaired intestinal barrier, which is fueling hepatic inflammation and disease progression. Clinical evidence describes perturbation of the gut-liver crosstalk in non-alcoholic fatty liver disease, alcoholic liver disease, and primary sclerosing cholangitis. In liver cirrhosis, a common sequela of these diseases, the intestinal microbiota and microbial pathogen-associated molecular patterns constitute liver inflammation and clinical complications, such as hepatic encephalopathy. Understanding the intricate metabolic interplay between the gut and liver in health and disease opens an avenue for targeted therapies in the future, which is probed in controlled clinical trials.
Collapse
Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University, Innsbruck, Austria.
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University, Innsbruck, Austria
| | - Michael Trauner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University, Vienna, Austria
| |
Collapse
|
33
|
Liu CH, Bowlus CL. Treatment of Primary Biliary Cholangitis: First-Line and Second-Line Therapies. Clin Liver Dis 2022; 26:705-726. [PMID: 36270725 DOI: 10.1016/j.cld.2022.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis (PBC) is an autoimmune disease of the interlobular bile ducts leading to secondary damage of hepatocytes and may progress to cirrhosis and liver failure. The first-line treatment is ursodeoxycholic acid; up to 40% of patients do not have an adequate response and remain at risk of disease progression. Obeticholic acid has been conditionally approved for the treatment of PBC as add-on therapy and bezafibrate has shown similar efficacy in this group of patients. Several new therapies are in development and may further add to the treatment options available to patients with PBC.
Collapse
Affiliation(s)
- Chung-Heng Liu
- Drexel University College of Medicine, 2900 W Queen Ln, Philadelphia, PA 19129 USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA.
| |
Collapse
|
34
|
Buchanan-Peart KA, Levy C. Novel Therapies in Primary Biliary Cholangitis: What Is in the Pipeline? Clin Liver Dis 2022; 26:747-764. [PMID: 36270727 DOI: 10.1016/j.cld.2022.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Primary biliary cholangitis is a chronic autoimmune disease characterized by inflammation and the progressive destruction of small intrahepatic bile ducts. Current first-line treatment includes ursodeoxycholic acid; however, a significant number of patients have an inadequate response to therapy. These patients are at risk of liver failure requiring liver transplantation and experience a poor quality of life due to refractory symptoms. This manuscript aims to shed light on the current and prospective treatment options that may slow disease progression and improve these patients' symptoms.
Collapse
Affiliation(s)
- Keri-Ann Buchanan-Peart
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, 1500 Northwest 12th Avenue, Suite 1101-E, Miami, FL 33136, USA; Department of Internal Medicine, Jackson Memorial Hospital, 1611 NW 12th Avenue, Miami, FL 33136, USA
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, 1500 Northwest 12th Avenue, Suite 1101-E, Miami, FL 33136, USA.
| |
Collapse
|
35
|
De Vincentis A, D'Amato D, Cristoferi L, Gerussi A, Malinverno F, Lleo A, Colapietro F, Marra F, Galli A, Fiorini C, Coco B, Brunetto M, Niro GA, Cotugno R, Saitta C, Cozzolongo R, Losito F, Giannini EG, Labanca S, Marzioni M, Marconi G, Morgando A, Pellicano R, Vanni E, Cazzagon N, Floreani A, Chessa L, Morelli O, Muratori L, Pellicelli A, Pompili M, Ponziani F, Tortora A, Rosina F, Russello M, Cannavò M, Simone L, Storato S, Viganò M, Abenavoli L, D'Antò M, De Gasperi E, Distefano M, Scifo G, Zolfino T, Calvaruso V, Cuccorese G, Palitti VP, Sacco R, Bertino G, Frazzetto E, Alvaro D, Mulinacci G, Palermo A, Scaravaglio M, Terracciani F, Galati G, Ronca V, Zuin M, Claar E, Izzi A, Picardi A, Invernizzi P, Vespasiani‐Gentilucci U, Carbone M. Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid. Liver Int 2022; 42:2453-2465. [PMID: 35932095 PMCID: PMC9804305 DOI: 10.1111/liv.15386] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/24/2022] [Accepted: 06/23/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. METHODS Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. CONCLUSIONS An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.
Collapse
Affiliation(s)
| | - Daphne D'Amato
- Gastroenterology Unit, Città della salute e della scienzaTurinItaly
| | - Laura Cristoferi
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | - Alessio Gerussi
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | - Federica Malinverno
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | - Ana Lleo
- Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCSHumanitas UniversityMilanItaly
| | - Francesca Colapietro
- Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCSHumanitas UniversityMilanItaly
| | - Fabio Marra
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical MedicineUniversity of FirenzeFirenzeItaly
| | - Andrea Galli
- Department of Experimental and Clinical Biochemical SciencesUniversity of FlorenceFlorenceItaly
| | - Cecilia Fiorini
- Department of Experimental and Clinical Biochemical SciencesUniversity of FlorenceFlorenceItaly
| | - Barbara Coco
- Hepatology Unit, University Hospital of PisaPisaItaly
| | | | - Grazia Anna Niro
- Gastroenterology Unit, Fondazione Casa Sollievo Della Sofferenza IRCCSSan Giovanni RotondoItaly
| | - Rosa Cotugno
- Gastroenterology Unit, Fondazione Casa Sollievo Della Sofferenza IRCCSSan Giovanni RotondoItaly
| | - Carlo Saitta
- Division of Medicine and HepatologyUniversity Hospital of Messina “Policlinico G. Martino”MessinaItaly
| | - Raffaele Cozzolongo
- Gastroenterology UnitNational Institute of Gastroenterology “S de Bellis” Research HospitalCastellana GrotteItaly
| | - Francesco Losito
- Gastroenterology UnitNational Institute of Gastroenterology “S de Bellis” Research HospitalCastellana GrotteItaly
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal MedicineUniversity of Genova, IRCCS Ospedale Policlinico San MartinoGenovaItaly
| | - Sara Labanca
- Gastroenterology Unit, Department of Internal MedicineUniversity of Genova, IRCCS Ospedale Policlinico San MartinoGenovaItaly
| | - Marco Marzioni
- Clinic of Gastroenterology and HepatologyUniversità Politecnica delle MarcheAnconaItaly
| | - Giulia Marconi
- Clinic of Gastroenterology and HepatologyUniversità Politecnica delle MarcheAnconaItaly
| | - Anna Morgando
- Gastroenterology Unit, Città della salute e della scienzaTurinItaly
| | | | - Ester Vanni
- Gastroenterology Unit, Città della salute e della scienzaTurinItaly
| | - Nora Cazzagon
- Gastroenterology Unit, Department of Surgery, Oncology and GastroenterologyPadua University HospitalPaduaItaly
| | - Annarosa Floreani
- Gastroenterology Unit, Department of Surgery, Oncology and GastroenterologyPadua University HospitalPaduaItaly
| | - Luchino Chessa
- Liver Unit, University Hospital of CagliariCagliariItaly
| | - Olivia Morelli
- Clinic of Gastroenterology and Hepatology, Department of MedicineUniversità degli Studi di PerugiaPerugiaItaly
| | - Luigi Muratori
- DIMEC Università di Bologna, Policlinico di Sant'OrsolaBolognaItaly
| | | | - Maurizio Pompili
- Internal Medicine and Hepatology Unit, Policlinico GemelliSapienza UniversityRomeItaly
| | - Francesca Ponziani
- Internal Medicine and Hepatology Unit, Policlinico GemelliSapienza UniversityRomeItaly
| | - Annalisa Tortora
- Internal Medicine and Hepatology Unit, Policlinico GemelliSapienza UniversityRomeItaly
| | | | | | | | - Loredana Simone
- Department of GastroenterologyUniversity Hospital Sant'AnnaFerraraItaly
| | - Silvia Storato
- IRCCS Sacro Cuore Institute Don Calabria, GastroenterologyNegrarItaly
| | - Mauro Viganò
- Hepatology Unit, San Giuseppe HospitalMilanItaly
| | - Ludovico Abenavoli
- Department of Health SciencesUniversity “Magna Graecia” of CatanzaroItaly
| | - Maria D'Antò
- Hepatology Unit, Santa Maria delle Grazie HospitalPozzuoliItaly
| | - Elisabetta De Gasperi
- Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico – Division of Gastroenterology and Hepatology – CRC “A.M. and A. Migliavacca” Center for Liver DiseaseMilanItaly
| | - Marco Distefano
- Department of Infectious DiseasesUmberto I HospitalSyracuseItaly
| | - Gaetano Scifo
- Department of Infectious DiseasesUmberto I HospitalSyracuseItaly
| | - Teresa Zolfino
- Department of GastroenterologyBrotzu HospitalCagliariItaly
| | | | | | | | | | - Gaetano Bertino
- Gastroenterology and Hepatology UnitUniversity Hospital Policlinico Vittorio EmanueleCataniaItaly
| | - Evelise Frazzetto
- Gastroenterology and Hepatology UnitUniversity Hospital Policlinico Vittorio EmanueleCataniaItaly
| | - Domenico Alvaro
- Department of Translational and Precision MedicineUniversity La SapienzaRomeItaly
| | - Giacomo Mulinacci
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | - Andrea Palermo
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | - Miki Scaravaglio
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | | | - Giovanni Galati
- Internal Medicine and HepatologyUniversity Campus Bio‐Medico of RomeRomeItaly
| | - Vincenzo Ronca
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | - Massimo Zuin
- Liver and Gastroenterology Unit, Department of Health SciencesUniversita’ degli Studi di MilanoMilanItaly
- ASST Santi Paolo e CarloUniversity Hospital San PaoloMilanItaly
| | | | - Antonio Izzi
- Department of Infectious DiseasesD. Cotugno HospitalNapoliItaly
| | - Antonio Picardi
- Internal Medicine and HepatologyUniversity Campus Bio‐Medico of RomeRomeItaly
| | - Pietro Invernizzi
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| | | | - Marco Carbone
- Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and SurgeryUniversity of Milano‐Bicocca, European Reference Network on Hepatological Diseases (ERN RARE‐LIVER), San Gerardo HospitalMonzaItaly
| |
Collapse
|
36
|
Lonardo A, Mantovani A, Targher G, Baffy G. Nonalcoholic Fatty Liver Disease and Chronic Kidney Disease: Epidemiology, Pathogenesis, and Clinical and Research Implications. Int J Mol Sci 2022; 23:13320. [PMID: 36362108 PMCID: PMC9654863 DOI: 10.3390/ijms232113320] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, affecting up to ~30% of adult populations. NAFLD defines a spectrum of progressive liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, which often occur in close and bidirectional associations with metabolic disorders. Chronic kidney disease (CKD) is characterized by anatomic and/or functional renal damage, ultimately resulting in a reduced glomerular filtration rate. The physiological axis linking the liver and kidneys often passes unnoticed until clinically significant portal hypertension, as a major complication of cirrhosis, becomes apparent in the form of ascites, refractory ascites, or hepatorenal syndrome. However, the extensive evidence accumulated since 2008 indicates that noncirrhotic NAFLD is associated with a higher risk of incident CKD, independent of obesity, type 2 diabetes, and other common renal risk factors. In addition, subclinical portal hypertension has been demonstrated to occur in noncirrhotic NAFLD, with a potential adverse impact on renal vasoregulation. However, the mechanisms underlying this association remain unexplored to a substantial extent. With this background, in this review we discuss the current evidence showing a strong association between NAFLD and the risk of CKD, and the putative biological mechanisms underpinning this association. We also discuss in depth the potential pathogenic role of the hepatorenal reflex, which may be triggered by subclinical portal hypertension and is a poorly investigated but promising research topic. Finally, we address emerging pharmacotherapies for NAFLD that may also beneficially affect the risk of developing CKD in individuals with NAFLD.
Collapse
Affiliation(s)
- Amedeo Lonardo
- Division of Internal Medicine, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, 37126 Verona, Italy
| | - Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02130, USA
| |
Collapse
|
37
|
Nababan SHH, Lesmana CRA. Portal Hypertension in Nonalcoholic Fatty Liver Disease: From Pathogenesis to Clinical Practice. J Clin Transl Hepatol 2022; 10:979-985. [PMID: 36304507 PMCID: PMC9547264 DOI: 10.14218/jcth.2021.00593] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/05/2022] [Accepted: 06/06/2022] [Indexed: 12/04/2022] Open
Abstract
Portal hypertension in nonalcoholic fatty liver disease (NAFLD) mostly occur in cirrhotic stage. However, several experimental and clinical studies showed evidence of portal hypertension in NAFLD without significant or advance fibrosis. This early development of portal hypertension in NAFLD is associated with liver sinusoidal contraction by hepatocellular lipid accumulation and ballooning, which is also accompanied by capillarization and dysfunction of liver sinusoidal endothelial cells. Both of these impaired mechanical and molecular components can cause an increase in intrahepatic vascular resistance which lead to the increase of portal pressure in the absence of significant liver fibrosis. Extrahepatic factors such as insulin resistance and gut dysbiosis may also contribute to liver sinusoidal endothelial dysfunction and early portal hypertension in NAFLD. The clinical impact of early portal hypertension in NAFLD is still unclear. However, clinical tools for diagnosis and monitoring of portal hypertension in NAFLD are being investigated to predict high-risk patients and to guide therapy.
Collapse
Affiliation(s)
- Saut Horas H. Nababan
- Hepatobiliary Division, Department of Internal Medicine, Dr Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Gastrointestinal Cancer Center, MRCCC Siloam Semanggi Hospital, Jakarta, Indonesia
| | - Cosmas Rinaldi Adithya Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Dr Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Gastrointestinal Cancer Center, MRCCC Siloam Semanggi Hospital, Jakarta, Indonesia
- Digestive Disease & GI Oncology Center, Medistra Hospital, Jakarta, Indonesia
| |
Collapse
|
38
|
Yang JY, Liu MJ, Lv L, Guo JR, He KY, Zhang H, Wang KK, Cui CY, Yan BZ, Du DD, Wang JH, Ding Q, Liu GL, Xu ZX, Jian YP. Metformin alleviates irradiation-induced intestinal injury by activation of FXR in intestinal epithelia. Front Microbiol 2022; 13:932294. [PMID: 36312920 PMCID: PMC9608595 DOI: 10.3389/fmicb.2022.932294] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 09/21/2022] [Indexed: 11/30/2022] Open
Abstract
Abdominal irradiation (IR) destroys the intestinal mucosal barrier, leading to severe intestinal infection. There is an urgent need to find safe and effective treatments to reduce IR-induced intestinal injury. In this study, we reported that metformin protected mice from abdominal IR-induced intestinal injury by improving the composition and diversity of intestinal flora. The elimination of intestinal microbiota (Abx) abrogated the protective effects of metformin on irradiated mice. We further characterized that treatment of metformin increased the murine intestinal abundance of Lactobacillus, which mediated the radioprotective effect. The administration of Lactobacillus or fecal microbiota transplantation (FMT) into Abx mice considerably lessened IR-induced intestinal damage and restored the radioprotective function of metformin in Abx mice. In addition, applying the murine intestinal organoid model, we demonstrated that IR inhibited the formation of intestinal organoids, and metformin alone bore no protective effect on organoids after IR. However, a combination of metformin and Lactobacillus or Lactobacillus alone displayed a strong radioprotection on the organoid formation. We demonstrated that metformin/Lactobacillus activated the farnesoid X receptor (FXR) signaling in intestinal epithelial cells and hence upregulated tight junction proteins and mucins in intestinal epithelia, increased the number of goblet cells, and augmented the mucus layer thickness to maintain the integrity of intestinal epithelial barrier, which eventually contributed to reduced radiation intestinal injury. In addition, we found that Lactobacillus abundance was significantly increased in the intestine of patients receiving metformin while undergoing abdominal radiotherapy and the abundance was negatively correlated with the diarrhea duration of patients. In conclusion, our results demonstrate that metformin possesses a protective effect on IR-induced intestinal injury by upregulating the abundance of Lactobacillus in the intestine.
Collapse
Affiliation(s)
- Jing-Yu Yang
- School of Life Sciences, Henan University, Kaifeng, China
| | - Meng-Jie Liu
- School of Life Sciences, Henan University, Kaifeng, China
| | - Lin Lv
- Department of Medical Oncology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jin-Rong Guo
- School of Life Sciences, Henan University, Kaifeng, China
| | - Kai-Yue He
- School of Life Sciences, Henan University, Kaifeng, China
| | - Hong Zhang
- School of Life Sciences, Henan University, Kaifeng, China
| | - Ke-Ke Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Cui-Yun Cui
- Department of Blood Transfusion, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Bei-Zhan Yan
- Department of Blood Transfusion, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Dan-Dan Du
- Department of Internal Medicine, Ningjin County People's Hospital, Dezhou, China
| | - Jin-Hua Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Qiang Ding
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Guo-Long Liu
- Department of Medical Oncology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- *Correspondence: Guo-Long Liu
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, China
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
- Zhi-Xiang Xu
| | - Yong-Ping Jian
- School of Life Sciences, Henan University, Kaifeng, China
- Yong-Ping Jian
| |
Collapse
|
39
|
Sakiani S, Heller T, Koh C. Current and investigational drugs in early clinical development for portal hypertension. Front Med (Lausanne) 2022; 9:974182. [PMID: 36300180 PMCID: PMC9589453 DOI: 10.3389/fmed.2022.974182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The development of portal hypertension leads to a majority of complications associated with chronic liver disease. Therefore, adequate treatment of portal hypertension is crucial in the management of such patients. Current treatment options are limited and consist mainly of medications that decrease the hyperdynamic circulation, such as non-selective beta blockers, and treatment of hypervolemia with diuretics. Despite these options, mortality rates have not improved over the last two decades. Newer, more effective treatment options are necessary to help improve survival and quality of life in these patients. Areas covered Multiple preclinical models and clinical studies have demonstrated potential efficacy of a variety of new treatment modalities. We introduce treatment options including the use of vasodilation promotors, vasoconstriction inhibitors, anticoagulants, antiangiogenics, and anti-inflammatory drugs. We examine the most recent studies for treatment options within these drug classes and offer insights as to which show the most promise in this field. Methodology Published studies that identified novel medical treatment options of portal hypertension were searched using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Clinical trials listed in Clinicaltrials.gov were also searched with a focus on more recent and ongoing studies, including those with completed recruitment. Searching with key terms including "portal hypertension" as well as individually searching specific treatment medications that were listed in other publications was carried out. Finally, current societal guidelines and recent review articles relevant to the management of portal hypertension were evaluated, and listed references of interest were included. Conclusion Many ongoing early phase studies demonstrate promising results and may shape the field of portal hypertension management in future. As concrete results become available, larger RCTs will be required before making definitive conclusions regarding safety and efficacy and whether or not they can be incorporated into routine clinical practice. Statins, anticoagulants, and PDE inhibitors have been among the most studied and appear to be most promising.
Collapse
Affiliation(s)
- Sasan Sakiani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Baltimore, MD, United States
| | - Theo Heller
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christopher Koh
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| |
Collapse
|
40
|
Liu Y, Liu T, Zhao X, Gao Y. New insights into the bile acid-based regulatory mechanisms and therapeutic perspectives in alcohol-related liver disease. Cell Mol Life Sci 2022; 79:486. [PMID: 35978227 PMCID: PMC11073206 DOI: 10.1007/s00018-022-04509-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/27/2022]
Abstract
Cholestasis is a key causative factor in alcohol-related liver disease (ALD) and variable degrees of cholestasis occur in all stages of ALD. However, the pathogenetic mechanisms and biomarkers associated with cholestasis are not well characterized. Cholestatic disease is marked by the disruption of bile acids (BA) transport and homeostasis. Consequently, in both human and experimental ALD, the disease shows a direct correlation with an imbalance in BA equilibrium, which in turn may also affect the severity of the disease. Modulation of BA metabolism or signaling pathways is increasingly considered as a potential therapeutic strategy for ALD in humans. In this paper, we highlight the key advances made in the past two decades in characterizing the molecular regulatory mechanisms of BA synthesis, enterohepatic circulation, and BA homeostasis. We summarize recent insights into the nature of the linkage between BA dysregulation and ALD, including the abnormal expression of genes involved in BA metabolism, abnormal changes in receptors that regulate BA metabolism, and disturbance in the gut flora engaged in BA metabolism caused by alcohol consumption. Additionally, we provide novel perspectives on the changes in BAs in various stages of ALD. Finally, we propose potential pharmacological therapies for ALD targeting BA metabolism and signaling.
Collapse
Affiliation(s)
- Yali Liu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, China
| | - Tao Liu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, China
| | - Xu Zhao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, China
| | - Yanhang Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, China.
- Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
41
|
Santopaolo F, Coppola G, Giuli L, Gasbarrini A, Ponziani FR. Influence of Gut–Liver Axis on Portal Hypertension in Advanced Chronic Liver Disease: The Gut Microbiome as a New Protagonist in Therapeutic Management. MICROBIOLOGY RESEARCH 2022; 13:539-555. [DOI: 10.3390/microbiolres13030038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Clinically significant portal hypertension is associated with most complications of advanced chronic liver disease (ACLD), including variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. Gut dysbiosis is a hallmark of ACLD with portal hypertension and consists of the overgrowth of potentially pathogenic bacteria and a decrease in autochthonous bacteria; additionally, congestion makes the intestinal barrier more permeable to bacteria and their products, which contributes to the development of complications through inflammatory mechanisms. This review summarizes current knowledge on the role of the gut–liver axis in the pathogenesis of portal hypertension, with a focus on therapies targeting portal hypertension and the gut microbiota. The modulation of the gut microbiota on several levels represents a major challenge in the upcoming years; in-depth characterization of the molecular and microbiological mechanisms linking the gut–liver axis to portal hypertension in a bidirectional relationship could pave the way to the identification of new therapeutic targets for innovative therapies in the management of ACLD.
Collapse
Affiliation(s)
- Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Lucia Giuli
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| |
Collapse
|
42
|
Duan S, Li X, Fan G, Liu R. Targeting bile acid signaling for the treatment of liver diseases: From bench to bed. Biomed Pharmacother 2022; 152:113154. [PMID: 35653887 DOI: 10.1016/j.biopha.2022.113154] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/13/2022] [Accepted: 05/15/2022] [Indexed: 11/02/2022] Open
Abstract
Liver diseases and related complications have become one of the leading causes of morbidity and mortality worldwide, yet effective medicine or approved treatment approach is still limited. Thus, novel therapy is urgently required to prevent or at least slow down the growing burden of liver transplantation or even death caused by malignant liver diseases. As the irreplaceable modulator of hepatic and intestinal signaling cascades, bile acids (BAs) play complex physiological as well as pathological roles in regulating energy and immune homeostasis in various liver diseases, including but not limited to metabolic diseases and cholangiopathies, making them highly attractive therapeutic targets. In the current review, recent progress in the research of enterohepatic circulation of BAs and potential therapeutic targets of BAs signaling, especially the development of currently available treatments, including agonizts of FXR and TGR5, analogs of FGF19, inhibitors of ASBT, and the regulation of gut microbiome through fecal microbiota transplantation were extensively summarized. Their protective effects, molecular mechanisms, and outcomes of clinical trials were highlighted. The structural features of these candidates and perspectives for their future development were further discussed. In conclusion, we believe that pharmacological therapies targeting BAs signaling represent promising and efficient strategies for the treatment of complex and multifactorial liver disorders.
Collapse
Affiliation(s)
- Shuni Duan
- School of Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Guifang Fan
- School of Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Runping Liu
- School of Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
| |
Collapse
|
43
|
Panzitt K, Zollner G, Marschall HU, Wagner M. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol 2022; 552:111678. [PMID: 35605722 DOI: 10.1016/j.mce.2022.111678] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/25/2022]
Abstract
The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
Collapse
Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
| |
Collapse
|
44
|
Kulkarni AV, Rabiee A, Mohanty A. Management of Portal Hypertension. J Clin Exp Hepatol 2022; 12:1184-1199. [PMID: 35814519 PMCID: PMC9257868 DOI: 10.1016/j.jceh.2022.03.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Portal hypertension is the cause of the clinical complications associated with cirrhosis. The primary complications of portal hypertension are ascites, acute variceal bleed, and hepatic encephalopathy. Hepatic venous pressure gradient measurement remains the gold standard test for diagnosing cirrhosis-related portal hypertension. Hepatic venous pressure gradient more than 10 mmHg is associated with an increased risk of complications and is termed clinically significant portal hypertension (CSPH). Clinical, laboratory, and imaging methods can also aid in diagnosing CSPH non-invasively. Recently, deep learning methods have been demonstrated to diagnose CSPH effectively. The management of portal hypertension is always individualized and is dependent on the etiology, the availability of therapies, and the degree of portal hypertension complications. In this review, we discuss the diagnosis and management of cirrhosis-related portal hypertension in detail. Also, we highlight the history of portal hypertension and future research areas in portal hypertension.
Collapse
Key Words
- ACLF, acute-on-chronic liver failure
- AKI, acute kidney injury
- APRI, AST to platelet ratio
- AST, aspartate transaminase
- BB, Beta blocker
- BRTO, balloon occluded retrograde transvenous obliteration
- CKD, chronic kidney disease
- CSPH, clinically significant portal hypertension
- CT, computed tomography
- GFR, glomerular filtration rate
- GOV, gastrpoesopahegal varices
- HE, hepatic encephalopathy
- HRS, hepatorenal syndrome
- HVPG, hepatic venous pressure gradient
- ICG, indocyanine green
- LOLA, l-ornithine l-aspartate
- NAFLD, Non-alcoholic fatty liver disease
- SBP, spontaneous bacterial peritonitis
- SGLT2I, sodium glucose co-transporter 2 inhibitors
- SSM, splenic stiffness measurement
- TE, transient elastography
- TIPS, transjugular intrahepatic portosystemic shunt
- VITRO, von Willebrand factor to platelet counts
- acute kidney injury
- ascites
- hemodynamics
- history
- vasoconstrictors
Collapse
Affiliation(s)
| | | | - Arpan Mohanty
- Boston University School of Medicine, Boston, MA, USA
| |
Collapse
|
45
|
Wang T, Rong X, Zhao C. Circadian Rhythms Coordinated With Gut Microbiota Partially Account for Individual Differences in Hepatitis B-Related Cirrhosis. Front Cell Infect Microbiol 2022; 12:936815. [PMID: 35846774 PMCID: PMC9283756 DOI: 10.3389/fcimb.2022.936815] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Cirrhosis is the end stage of chronic liver diseases like chronic hepatitis B. In China, hepatitis B accounts for around 60% of cases of cirrhosis. So far, clinical and laboratory indexes for the early diagnosis of cirrhosis are far from satisfactory. Nevertheless, there haven't been specific drugs for cirrhosis. Thus, it is quite necessary to uncover more specific factors which play their roles in cirrhosis and figure out the possible therapeutic targets. Among emerging factors taking part in the initiation and progression of cirrhosis, gut microbiota might be a pivot of systemic factors like metabolism and immune and different organs like gut and liver. Discovery of detailed molecular mechanism in gut microbiota and gut liver axis leads to a more promising prospect of developing new drugs intervening in these pathways. Time-based medication regimen has been proofed to be helpful in hormonotherapy, especially in the use of glucocorticoid. Thus, circadian rhythms, though haven't been strongly linked to hepatitis B and its complications, are still pivotal to various pathophysiological progresses. Gut microbiota as a potential effective factor of circadian rhythms has also received increasing attentions. Here, our work, restricting cirrhosis to the post-hepatitis B one, is aimed to summarize how circadian rhythms and hepatitis B-related cirrhosis can intersect via gut microbiota, and to throw new insights on the development of new and time-based therapies for hepatitis B-related cirrhosis and other cirrhosis.
Collapse
Affiliation(s)
- Tongyao Wang
- Ministry of Education (MOE)/National Health Commission (NHC)/Chinese Academy of Medical Science (CAMS) Key Lab of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xingyu Rong
- Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Chao Zhao
- Ministry of Education (MOE)/National Health Commission (NHC)/Chinese Academy of Medical Science (CAMS) Key Lab of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai, China
| |
Collapse
|
46
|
Rodrigues SG, Mendoza YP, Bosch J. Investigational drugs in early clinical development for portal hypertension. Expert Opin Investig Drugs 2022; 31:825-842. [PMID: 35758843 DOI: 10.1080/13543784.2022.2095259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Advanced chronic liver disease is considered a reversible condition after removal of the primary aetiological factor. This has led to a paradigm shift in which portal hypertension (PH) is a reversible complication of cirrhosis. The pharmacologic management of PH is centered on finding targets to modify the natural history of cirrhosis and PH. AREAS COVERED This paper offers an overview of the use of pharmacological strategies in early clinical development that modify PH. Papers included were selected from searching clinical trials sites and PubMed from the last 10 years. EXPERT OPINION A paradigm shift has generated a new concept of PH in cirrhosis as a reversible complication of a potentially curable disease. Decreasing portal pressure to prevent decompensation and further complications of cirrhosis that may lead liver transplantation or death is a goal. Therapeutic strategies also aspire achieve total or partial regression of fibrosis thus eliminating the need for treatment or screening of PH.
Collapse
Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Yuly P Mendoza
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.,Graduate School for Health Sciences (GHS), University of Bern
| | - Jaime Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| |
Collapse
|
47
|
Abstract
Initially a condition that received limited recognition and whose clinical impact was controversial, non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease. Although there are no approved therapies, major breakthroughs, which will be reviewed here, have paved the way for future therapeutic successes. The unmet medical need in NASH is no longer disputed, and progress in the understanding of its pathogenesis has resulted in the identification of many pharmacological targets. Key surrogate outcomes for therapeutic trials are now accepted by regulatory agencies, thus creating a path for drug registration. A set of non-invasive measurements enabled early-stage trials to be conducted expeditiously, thus providing early indications on the biological and possibly clinical actions of therapeutic candidates. This generated efficacy results for a number of highly promising compounds that are now in late-stage development. Intense research aimed at further improving the assessment of histological endpoints and in developing non-invasive predictive biomarkers is underway. This will help improve the design and feasibility of successful trials, ultimately providing patients with therapeutic options that can change the course of the disease.
Collapse
|
48
|
Miao L, Targher G, Byrne CD, Valenti L, Qi X, Zheng M. Portal hypertension in nonalcoholic fatty liver disease: Challenges and perspectives. PORTAL HYPERTENSION & CIRRHOSIS 2022; 1:57-65. [DOI: 10.1002/poh2.8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 04/21/2022] [Indexed: 04/16/2025]
Abstract
AbstractNonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. NAFLD‐related cirrhosis is often complicated by portal hypertension (PHT). Recent evidence showed that portal venous pressure (PVP) starts to rise in the early stages of NAFLD, even in absence of advanced fibrosis or cirrhosis. However, the precise pathological mechanisms of this process are still poorly understood. Lipid accumulation, hepatocellular ballooning, sinusoidal endothelial cell dysfunction, capillarization, microthrombosis, increased angiogenesis, and pericellular fibrosis may all be involved in the early development of increased PVP in NAFLD. Direct measurement of PHT is invasive and impractical in noncirrhotic NAFLD individuals and may also underestimate its severity. Thus, the development and validation of noninvasive and more accurate measurements, including new serum biomarkers, scoring models, and imaging techniques (such as ultrasonography, elastography, and magnetic resonance imaging), are urgently needed. Owing to the increasing morbidity, challenges in the prevention and management of PHT in NAFLD are unprecedented. This review article aims to briefly discuss these challenges and summarizes the mechanisms, diagnosis, and emerging therapies for PHT in people with NAFLD.
Collapse
Affiliation(s)
- Lei Miao
- Department of Gastroenterology The Second Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang China
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine University and Azienda Ospedaliera Universitaria Integrata of Verona Verona Italy
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, Southampton General Hospital University Hospital Southampton Southampton UK
| | - Luca Valenti
- Translational Medicine, Department of Transfusion Medicine and Hematology Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico Milano Italy
- Department of Pathophysiology and Transplantation Università degli Studi di Milano Milano Italy
| | - Xiaolong Qi
- CHESS Center, Institute of Portal Hypertension The First Hospital of Lanzhou University Lanzhou Gansu China
| | - Ming‐Hua Zheng
- Department of Hepatology, NAFLD Research Center The First Affiliated Hospital of Wenzhou Medical University Wenzhou Zhejiang China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province Wenzhou Zhejiang China
| |
Collapse
|
49
|
Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity. Cell Mol Gastroenterol Hepatol 2022; 14:271-293. [PMID: 35526796 PMCID: PMC9218579 DOI: 10.1016/j.jcmgh.2022.04.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 04/21/2022] [Accepted: 04/26/2022] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS Excessive acetaminophen (APAP) intake causes oxidative stress and inflammation, leading to fatal hepatotoxicity; however, the mechanism remains unclear. This study aims to explore the protective effects and detailed mechanisms of sirtuin 6 (SIRT6) in the defense against APAP-induced hepatotoxicity. METHODS Hepatocyte-specific SIRT6 knockout mice, farnesoid X receptor (FXR) knockout mice, and mice with genetic or pharmacological activation of SIRT6 were subjected to APAP to evaluate the critical role of SIRT6 in the pathogenesis of acute liver injury. RNA sequences were used to investigate molecular mechanisms underlying this process. RESULTS Hepatic SIRT6 expression was substantially reduced in the patients and mice with acute liver injury. The deletion of SIRT6 in mice and mice primary hepatocytes led to high N-acetyl-p-benzo-quinoneimine and low glutathione levels in the liver, thereby enhancing APAP overdose-induced liver injury, manifested as increased hepatic centrilobular necrosis, oxidative stress, and inflammation. Conversely, overexpression or pharmacological activation of SIRT6 enhanced glutathione and decreased N-acetyl-p-benzo-quinoneimine, thus alleviating APAP-induced hepatotoxicity via normalization of liver damage, inflammatory infiltration, and oxidative stress. Our molecular analysis revealed that FXR is regulated by SIRT6, which is associated with the pathological progression of ALI. Mechanistically, SIRT6 deacetylates FXR and elevates FXR transcriptional activity. FXR ablation in mice and mice primary hepatocytes prominently blunted SIRT6 overexpression and activation-mediated ameliorative effects. Conversely, pharmacological activation of FXR mitigated APAP-induced hepatotoxicity in SIRT6 knockout mice. CONCLUSIONS Our current study suggests that SIRT6 plays a crucial role in APAP-induced hepatotoxicity, and pharmacological activation of SIRT6 may represent a novel therapeutic strategy for APAP overdose-induced liver injury.
Collapse
|
50
|
Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis 2022; 54:598-613. [PMID: 34344577 DOI: 10.1016/j.dld.2021.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed. In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.
Collapse
Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, PR China.
| |
Collapse
|