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Kasuga R, Chu PS, Kanai T, Nakamoto N. Current insights into pathogenesis and anti-inflammatory treatment strategies for severe alcohol-associated hepatitis: focus on neutrophil-targeted therapies. Hepatol Res 2025. [PMID: 40357883 DOI: 10.1111/hepr.14206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2025] [Revised: 04/18/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025]
Abstract
Alcohol-associated hepatitis (AH) is the leading cause of liver-related mortality, with severe alcohol-associated hepatitis (SAH) showing a short-term mortality rate of 20%-50% even in developed countries. Corticosteroids are the only evidence-based pharmacologic treatment, but their efficacy is limited to short-term survival, with 30%-40% of patients achieving a complete response. Early liver transplantation (LT) has been explored as a salvage therapy for steroid-refractory SAH, but its feasibility is restricted by ethical concerns and donor shortages, particularly in Japan. In the absence of LT eligibility, patients are often left with the best supportive care, underscoring the urgent need for alternative salvage therapies. Recent studies have explored selective anti-inflammatory strategies targeting proinflammatory cytokines, such as TNFα and IL-1β. However, clinical trials have yet to demonstrate sufficient efficacy to outweigh the increased risk of infection. Granulocyte colony-stimulating factor (G-CSF) therapy has been investigated for its potential to promote liver regeneration, but its efficacy remains inconsistent across populations. Neutrophil-targeted therapies, including granulocyte-monocyte/macrophage apheresis (GMA), have emerged as a novel approach. Our recent pilot study demonstrated improved survival in patients with steroid-refractory SAH treated with GMA, supporting its potential as a safe and effective anti-inflammatory therapy. This review summarizes the latest advances in the treatment of SAH and emphasizes the need for novel salvage therapies to address unmet needs in steroid-refractory cases. Further research is essential to validate these new therapies and to optimize treatment strategies to improve the long-term prognosis of SAH.
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Affiliation(s)
- Ryosuke Kasuga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Po-Sung Chu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Rady ED, Anouti A, Mitchell MC, Cotter TG. Current Clinical Trials for Alcohol-Associated Hepatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00116-6. [PMID: 40254132 DOI: 10.1016/j.ajpath.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 03/22/2025] [Accepted: 03/28/2025] [Indexed: 04/22/2025]
Abstract
Alcohol-associated hepatitis (AH) is a severe form of alcohol-associated liver disease characterized by acute-onset jaundice and liver failure. AH carries a high mortality risk, particularly in severe cases. Although glucocorticoids have been the primary pharmacologic intervention for decades, their use is limited by a lack of long-term efficacy and significant side effects and relative contraindications. For patients who do not respond to glucocorticoids, early liver transplantation is a life-saving option; only a few patients qualify for this intervention, however. In recent years, advances in translational medicine have uncovered key mechanisms in AH pathophysiology, including microbiome interactions, proinflammatory signaling, and disruptions in hepatocyte function. These insights have led to the exploration of innovative pharmacologic treatments, targeting pathways such as the gut-liver axis, oxidative stress, inflammation, and liver regeneration. Despite promising results from ongoing clinical trials, several challenges persist, including low patient recruitment and retention rates, heterogeneity in trial design, and the lack of standardized endpoints. This review assesses the current pharmacologic landscape of AH, emphasizing emerging therapies and the ongoing challenges in AH clinical trials.
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Affiliation(s)
- Elias D Rady
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Ahmad Anouti
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Thomas G Cotter
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas.
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3
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Vergis N, Patel V, Bogdanowicz K, Czyzewska-Khan J, Keshinro R, Fiorentino F, Day E, Middleton P, Atkinson S, Tranah T, Cross M, Babalis D, Foster N, Lord E, Quaglia A, Lloyd J, Goldin R, Rosenberg W, Parker R, Richardson P, Masson S, Whitehouse G, Sieberhagan C, Patch D, Naoumov N, Dhanda A, Forrest E, Thursz M. IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab. Clin Gastroenterol Hepatol 2025; 23:797-807.e5. [PMID: 39181422 DOI: 10.1016/j.cgh.2024.07.025] [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: 12/14/2023] [Revised: 06/18/2024] [Accepted: 07/05/2024] [Indexed: 08/27/2024]
Abstract
BACKGROUND AND AIMS Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1β has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1β, in the treatment of patients with AH. METHODS Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ClinicalTrials.gov, Number: NCT03775109.
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Affiliation(s)
- Nikhil Vergis
- Division of Digestive Diseases, Imperial College London, London, United Kingdom
| | - Vishal Patel
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom; Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, United Kingdom; Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Karolina Bogdanowicz
- Imperial College Clinical Trials Unit, Faculty of Medicine, Imperial College Lon London, United Kingdom
| | - Justyna Czyzewska-Khan
- Imperial College Clinical Trials Unit, Faculty of Medicine, Imperial College Lon London, United Kingdom
| | - Rosemary Keshinro
- Imperial College Clinical Trials Unit, Faculty of Medicine, Imperial College Lon London, United Kingdom
| | - Francesca Fiorentino
- Imperial College Clinical Trials Unit, Faculty of Medicine, Imperial College Lon London, United Kingdom; Nightingale-Saunders Clinical Trials and Epidemiology Unit, King's Clinical Trials Unit, King's College London, United Kingdom
| | - Emily Day
- Imperial College Clinical Trials Unit, Faculty of Medicine, Imperial College Lon London, United Kingdom
| | - Paul Middleton
- Division of Digestive Diseases, Imperial College London, London, United Kingdom
| | - Stephen Atkinson
- Division of Digestive Diseases, Imperial College London, London, United Kingdom
| | - Thomas Tranah
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom; Roger Williams Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Mary Cross
- Imperial College Clinical Trials Unit, Faculty of Medicine, Imperial College Lon London, United Kingdom
| | - Daphne Babalis
- Imperial College Clinical Trials Unit, Faculty of Medicine, Imperial College Lon London, United Kingdom
| | - Neil Foster
- Patient partner, Department of Metabolism, Digestion & Reproduction, Imperial College, London
| | - Emma Lord
- Division of Digestive Diseases, Imperial College London, London, United Kingdom
| | - Alberto Quaglia
- Department of Cellular Pathology, UCL Cancer Institute, Royal Free Hospital, London, United Kingdom
| | - Josephine Lloyd
- North West London Pathology, Charing Cross Hospital, London, United Kingdom
| | - Robert Goldin
- Division of Digestive Diseases, Imperial College London, London, United Kingdom
| | - William Rosenberg
- Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Richard Parker
- Leeds Liver Unit, St James' Hospital, Leeds, United Kingdom
| | - Paul Richardson
- Hepatology Department, Liverpool University Hospitals NHS Trust, Liverpool, United Kingdom
| | - Steven Masson
- Translational and Clinical Research Unit, Faculty of Medical Sciences, Newcastle University Medical School, Newcastle upon Tyne, United Kingdom
| | - Gavin Whitehouse
- Gastroenterology Department, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom
| | - Cyril Sieberhagan
- Hepatology Department, Liverpool University Hospitals NHS Trust, Liverpool, United Kingdom
| | - David Patch
- Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | | | - Ashwin Dhanda
- Hepatology Research Group, Faculty of Health, University of Plymouth, Plymouth, United Kingdom
| | - Ewan Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, University of Glasgow, Glasgow, United Kingdom
| | - Mark Thursz
- Division of Digestive Diseases, Imperial College London, London, United Kingdom.
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Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [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: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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Alvarado-Tapias E, Pose E, Gratacós-Ginès J, Clemente-Sánchez A, López-Pelayo H, Bataller R. Alcohol-associated liver disease: Natural history, management and novel targeted therapies. Clin Mol Hepatol 2025; 31:S112-S133. [PMID: 39481875 PMCID: PMC11925442 DOI: 10.3350/cmh.2024.0709] [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: 08/24/2024] [Revised: 10/29/2024] [Accepted: 10/29/2024] [Indexed: 11/03/2024] Open
Abstract
Alcohol consumption is a leading cause of preventable morbidity and mortality worldwide and the primary cause of advanced liver disease. Alcohol use disorder is a chronic, frequently relapsing condition characterized by persistent alcohol consumption despite its negative consequences. Alcohol-associated liver disease (ALD) encompasses a series of stages, from fatty liver (steatosis) to inflammation (steatohepatitis), fibrosis, and, ultimately, liver cirrhosis and its complications. The development of ALD is complex, involving both genetic and environmental factors, yet the exact mechanisms at play remain unclear. Alcohol-associated hepatitis (AH), a severe form of ALD, presents with sudden jaundice and liver failure. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD to stop the progression of the disease, making alcohol abstinence the most effective way to improve prognosis across all stages of ALD. For patients with advanced ALD who do not respond to medical therapy, liver transplantation is the only option that can improve prognosis. Recently, AH has become an early indication for liver transplantation in non-responders to medical treatment, showing promising results in carefully selected patients. This review provides an update on the epidemiology, natural history, pathogenesis, and current treatments for ALD. A deeper insight into novel targeted therapies investigated for AH focusing on new pathophysiologically-based agents is also discussed, including anti-inflammatory and antioxidative stress drugs, gut-liver axis modulators, and hepatocyte regenerative molecules.
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Affiliation(s)
- Edilmar Alvarado-Tapias
- Department of Gastroenterology and Hepatology, Hospital of Santa Creu and Sant Pau, Autonomus University of Barcelona, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Madrid, Spain
| | - Elisa Pose
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Madrid, Spain
- Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Jordi Gratacós-Ginès
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Madrid, Spain
- Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ana Clemente-Sánchez
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Madrid, Spain
- Department of Gastroenterology and Hepatology, Hospital General Universitario Gregorio Marañón (IiSGM), Madrid, Spain
| | - Hugo López-Pelayo
- Addictions Unit, Psychiatry and Psychology Service, ICN, Hospital Clinic Barcelona, Barcelona; Health and Addictions Research Group, IDIBAPS, Barcelona, Spain
| | - Ramón Bataller
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Madrid, Spain
- Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Davis BC, Lin KC, Shahub S, Ramasubramanya A, Fagan A, Muthukumar S, Prasad S, Bajaj JS. A novel sweat sensor detects inflammatory differential rhythmicity patterns in inpatients and outpatients with cirrhosis. NPJ Digit Med 2024; 7:382. [PMID: 39733165 DOI: 10.1038/s41746-024-01404-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/20/2024] [Indexed: 12/30/2024] Open
Abstract
Patients with cirrhosis have high systemic inflammation (TNFα, CRP, and IL-6) that is associated with poor outcomes. These biomarkers need continuous non-invasive monitoring, which is difficult with blood. We studied the AWARE sweat-sensor to measure these in passively expressed sweat in healthy people (N = 12) and cirrhosis (N = 32, 10 outpatients/22 inpatients) for 3 days. Blood CRP, TNFα, IL6, levels, and liver function and quality of life were measured. We found that CRP, TNFα, and IL6 were correlated in sweat and serum among both groups and were evaluated in inpatients versus outpatients/controls. IL6 is associated with lower transplant-free survival. Sweat monitoring nocturnal CRP/IL6 elevations in cirrhosis versus controls. Outpatients with cirrhosis had inflammation levels that elevated during the evening and peaked towards the early night periods. The levels start to fall much later at night and early morning. These data suggest that further investigation of continuous measurement of sweat biomarkers in cirrhosis is warranted.
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Affiliation(s)
- Brian C Davis
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA
| | - Kai-Chun Lin
- University of Texas at Dallas, Richardson, TX, USA
| | - Sarah Shahub
- University of Texas at Dallas, Richardson, TX, USA
| | | | - Andrew Fagan
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA
| | | | | | - Jasmohan S Bajaj
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA.
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7
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Xia N, Xue H, Li Y, Liu J, Lou Y, Li S, Wang Y, Lu J, Chen X. Potential Mechanisms and Effects of Dai Bai Jie Ethanol Extract in Preventing Acute Alcoholic Liver Injury. Curr Issues Mol Biol 2024; 47:3. [PMID: 39852118 PMCID: PMC11763393 DOI: 10.3390/cimb47010003] [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: 11/23/2024] [Revised: 12/17/2024] [Accepted: 12/20/2024] [Indexed: 01/26/2025] Open
Abstract
This study investigated the protective effect of Dai Bai Jie (DBJ) extract against acute alcoholic liver injury (AALI) and elucidated its potential mechanism. The total saponin level in the DBJ extracts was measured using vanillin-chloroform acid colorimetry. To observe the preventive and protective effects of DBJ on AML-12 cells in an ethanol environment, the effective components of DBJ were identified. An alcohol-induced AALI mouse model was used to evaluate the efficacy of DBJ against AALI. For this purpose, alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) levels were assessed, liver function indices and oxidative and inflammatory markers were determined, and histopathological examinations were performed. Mechanistic investigations were conducted using RT-qPCR assays and immunohistochemical analysis to determine the protective effects of DBJ. The samples (DBJ-1, DBJ-2, and DBJ-3) were obtained by extracting DBJ with water, 50% ethanol, and 95% ethanol, yielding total saponin contents of 5.35%, 6.64%, and 11.83%, respectively. DBJ-3 was isolated and purified, and its components were identified by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). DBJ-3 had the greatest effect on cell viability in an ethanol environment. Moreover, DBJ-3 reduced inflammatory infiltration, liver cell degeneration, and hemorrhage, while increasing ADH and ALDH levels in liver tissues. Additionally, DBJ-3 considerably decreased the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and triglyceride (TG) levels. DBJ-3 reduced malondialdehyde (MDA), reactive oxygen species (ROS), and inflammatory factors, such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), while increasing superoxide dismutase (SOD) and glutathione S-transferase (GST) activities. Furthermore, DBJ-3 significantly increased alcohol dehydrogenase 1b (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) expression at the gene and protein levels within alcohol metabolism pathways and reduced the nuclear factor kappa-B (NF-κB) gene and protein levels. These findings suggest that DBJ-3 can prevent AALI by enhancing alcohol metabolism via the regulation of ADH1B and ALDH2 and the modulation of the NF-κB pathway to improve antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Niantong Xia
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Hongwei Xue
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yihang Li
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Jinghong 666100, China;
| | - Jia Liu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yang Lou
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Shuyang Li
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Yutian Wang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Juan Lu
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
| | - Xi Chen
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao Di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China; (N.X.); (H.X.); (J.L.); (Y.L.); (S.L.); (Y.W.)
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Jinghong 666100, China;
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8
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Mullish BH, Thursz MR. Alcohol-associated liver disease: Emerging therapeutic strategies. Hepatology 2024; 80:1372-1389. [PMID: 38922808 DOI: 10.1097/hep.0000000000000986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024]
Abstract
The large and growing burden of alcohol-associated liver disease-and the considerable burden of morbidity and mortality associated with it-has been a drive toward ongoing research into novel strategies for its treatment, with a particular focus upon alcohol-associated hepatitis (AH). Management of alcohol-use disorder forms the central pillar of alcohol-associated liver disease care, with evidence-based psychological and pharmacological approaches being well established, and certain models demonstrating improved clinical outcomes when hepatology and addiction services are co-located. Corticosteroids have previously been used somewhat indiscriminately in patients with severe AH, but effective tools now exist to assess early response (and limit futile ongoing exposure). Techniques to predict risk of corticosteroid-related infection are also available, although current clinical strategies to mitigate this risk are limited. A variety of novel therapeutic approaches to AH are at different phases of trials and evidence gathering, with some of the most promising signals related to cytokine manipulation, epigenetic modulation, and targeting of the gut microbiota (ie, by means of fecal microbiota transplant). While remaining an ongoing source of debate, early liver transplant in severe AH has grown in interest and acceptability over the past decade as evidence supporting its efficacy builds, in the process challenging paradigms about mandatory pretransplant sobriety periods. However, uncertainty remains regarding the optimal selection criteria, and whether liver transplant has a role for only a highly limited proportion of patients with AH or more widespread application. This review aims to provide an overview of this fast-moving field.
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Affiliation(s)
- Benjamin H Mullish
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
- Department of Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Mark R Thursz
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
- Department of Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
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9
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Anouti A, Kerr TA, Mitchell MC, Cotter TG. Advances in the management of alcohol-associated liver disease. Gastroenterol Rep (Oxf) 2024; 12:goae097. [PMID: 39502523 PMCID: PMC11537353 DOI: 10.1093/gastro/goae097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 11/08/2024] Open
Abstract
Alcohol-associated liver disease (ALD) is a significant global health challenge, encompassing a spectrum from steatotic liver disease to cirrhosis and alcohol-associated hepatitis, and contributed to 25% of global cirrhosis deaths in 2019. The identification of both modifiable (e.g. heavy drinking, metabolic syndromes) and non-modifiable risk factors (e.g. genetic predispositions) is crucial for effective disease management. Alcohol use assessment and treatment, by using both behavioral therapy and pharmacotherapeutic modalities, nutrition support, and optimization of liver disease modifiers, form the cornerstone of management. Advances in medical therapies, such as fecal microbiota transplantation and novel agents such as IL-22, are being explored for their therapeutic potential. A unifying theme in ALD care is the need for a personalized approach to management, accounting for the spectrum of the disease and individual patient characteristics, to tailor interventions effectively. Finally, it is essential to address the challenges to effective ALD treatment, including socioeconomic, logistical, and stigma-related barriers, to improve patient outcomes. This review discusses the current knowledge on ALD, including epidemiology, pathophysiology, risk factors, and management strategies, highlighting the critical role of integrated care models.
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Affiliation(s)
- Ahmad Anouti
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Thomas A Kerr
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Thomas G Cotter
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
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10
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Taru V, Szabo G, Mehal W, Reiberger T. Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation. J Hepatol 2024; 81:895-910. [PMID: 38908436 PMCID: PMC11881887 DOI: 10.1016/j.jhep.2024.06.016] [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: 02/18/2024] [Revised: 05/23/2024] [Accepted: 06/17/2024] [Indexed: 06/24/2024]
Abstract
Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting in liver fibrosis, cirrhosis, portal hypertension and liver failure. Thus, an improved understanding of inflammasomes - as key molecular drivers of liver injury - may result in the development of novel diagnostic or prognostic biomarkers and effective therapeutics. In liver disease, innate immune cells respond to hepatic insults by activating cell-intrinsic inflammasomes via toll-like receptors and NF-κB, and by releasing pro-inflammatory cytokines (such as IL-1β, IL-18, TNF-α and IL-6). Subsequently, cells of the adaptive immune system are recruited to fuel hepatic inflammation and hepatic parenchymal cells may undergo gasdermin D-mediated programmed cell death, termed pyroptosis. With liver disease progression, there is a shift towards a type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation may also occur at extrahepatic sites, such as the white adipose tissue in MASH (metabolic dysfunction-associated steatohepatitis). In end-stage liver disease, flares of inflammation (e.g., in severe alcohol-related hepatitis) that spark on a dysfunctional immune system, contribute to inflammasome-mediated liver injury and potentially result in organ dysfunction/failure, as seen in ACLF (acute-on-chronic liver failure). This review provides an overview of current concepts regarding inflammasome activation in liver disease progression, with a focus on related biomarkers and therapeutic approaches that are being developed for patients with liver disease.
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Affiliation(s)
- Vlad Taru
- 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; Iuliu Hatieganu University of Medicine and Pharmacy, 4(th) Dept. of Internal Medicine, Cluj-Napoca, Romania
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Wajahat Mehal
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; West Haven Veterans Medical Center, West Haven, CT, USA.
| | - Thomas Reiberger
- 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; Center for Molecular Medicine (CeMM) of the Austrian Academy of Science, Vienna, Austria
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11
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Unagolla JM, Das S, Flanagan R, Oehler M, Menon JU. Targeting chronic liver diseases: Molecular markers, drug delivery strategies and future perspectives. Int J Pharm 2024; 660:124381. [PMID: 38917958 PMCID: PMC11246230 DOI: 10.1016/j.ijpharm.2024.124381] [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: 01/28/2024] [Revised: 06/10/2024] [Accepted: 06/22/2024] [Indexed: 06/27/2024]
Abstract
Chronic liver inflammation, a pervasive global health issue, results in millions of annual deaths due to its progression from fibrosis to the more severe forms of cirrhosis and hepatocellular carcinoma (HCC). This insidious condition stems from diverse factors such as obesity, genetic conditions, alcohol abuse, viral infections, autoimmune diseases, and toxic accumulation, manifesting as chronic liver diseases (CLDs) such as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), alcoholic liver disease (ALD), viral hepatitis, drug-induced liver injury, and autoimmune hepatitis. Late detection of CLDs necessitates effective treatments to inhibit and potentially reverse disease progression. However, current therapies exhibit limitations in consistency and safety. A potential breakthrough lies in nanoparticle-based drug delivery strategies, offering targeted delivery to specific liver cell types, such as hepatocytes, Kupffer cells, and hepatic stellate cells. This review explores molecular targets for CLD treatment, ongoing clinical trials, recent advances in nanoparticle-based drug delivery, and the future outlook of this research field. Early intervention is crucial for chronic liver disease. Having a comprehensive understanding of current treatments, molecular biomarkers and novel nanoparticle-based drug delivery strategies can have enormous impact in guiding future strategies for the prevention and treatment of CLDs.
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Affiliation(s)
- Janitha M Unagolla
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Subarna Das
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Riley Flanagan
- Department of Chemical Engineering, University of Rhode Island, Kingston, RI 02881, USA
| | - Marin Oehler
- Department of Biomedical Engineering, College of Engineering, University of Rhode Island, Kingston, RI 02881, USA
| | - Jyothi U Menon
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA; Department of Chemical Engineering, University of Rhode Island, Kingston, RI 02881, USA.
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12
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Harshal R. Severe Alcoholic Hepatitis-optimizing Medical Management: Whether we need a Liver Transplant. ANNALS OF CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2024; 8:006-016. [DOI: 10.29328/journal.acgh.1001045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Severe alcoholic hepatitis is an ethical and clinical conundrum, wherein a liver transplant is often recommended. The adequacy of medical treatment versus the risk of recidivism after transplant is often debated. Complete recovery in 26 of 27 patients with severe alcoholic hepatitis was observed, and hence the data was retrospectively analysed. Methods: 27 patients, with severe alcoholic hepatitis, with Maddrey's discriminant function between 59.7 to 165.2 (mean 107.53), from June 2017 to May 2022, were followed up for between 11 months to 6 years. INR ranged from 1.99 to 3.7 (mean 2.709), and bilirubin was between 7.6 to 37.01, (mean 20.859). 8 patients had pre-existing liver cirrhosis. All patients received probiotics, nutritional support, physical rehabilitation, saturated fat (clarified butter/ desi ghee) supplementation, and anti-oxidant support. At 90 days, total bilirubin improved to between 1.0 to 6.8 (mean 2.625). ALT (Alanine Transaminase/ SGPT) ranged from 65 to 550 (mean ALT – 197); and AST (Aspartate Transaminase / SGOT) ranged from 58 to 810 (mean AST – 271.51). Both the AST and ALT were near normal after 90 days. One patient died due to bacterial pneumonia and sepsis; the remaining 26 patients made a complete recovery. All patients including those with diagnosed liver cirrhosis, had complete resolution of their ascites, and near-normal liver function. At the last outpatient visit, none had ascites, edema, or encephalopathy, and had normal albumin levels and INR values. Conclusion: Probiotics, nutrition, a saturated fat diet, and exercise; all have shown benefits in patients with severe alcoholic hepatitis when tested individually. Concomitant use of all the above has not been reported in the treatment of alcoholic hepatitis. The role of nutrition alone versus the contribution of nutritional deficiencies and the role of gut-derived endotoxemia need to be studied in detail. How to identify patients who need a transplant, if it is needed at all, remains a challenge.
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13
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Feng D, Hwang S, Guillot A, Wang Y, Guan Y, Chen C, Maccioni L, Gao B. Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets. Cell Mol Gastroenterol Hepatol 2024; 18:101352. [PMID: 38697358 PMCID: PMC11234022 DOI: 10.1016/j.jcmgh.2024.04.009] [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: 01/09/2024] [Revised: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 05/05/2024]
Abstract
Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.
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Affiliation(s)
- Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Yang Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Cheng Chen
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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14
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Scarlata GGM, Colaci C, Scarcella M, Dallio M, Federico A, Boccuto L, Abenavoli L. The Role of Cytokines in the Pathogenesis and Treatment of Alcoholic Liver Disease. Diseases 2024; 12:69. [PMID: 38667527 PMCID: PMC11048950 DOI: 10.3390/diseases12040069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of chronic liver disease. This term covers a broad spectrum of liver lesions, from simple steatosis to alcoholic hepatitis and cirrhosis. The pathogenesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. The accumulation of pro-inflammatory cytokines and the reduction of anti-inflammatory cytokines promote the development and progression of ALD. To date, there are no targeted therapies to counter the progression of chronic alcohol-related liver disease and prevent acute liver failure. Corticosteroids reduce mortality by acting on the hepatic-systemic inflammation. On the other hand, several studies analyzed the effect of inhibiting pro-inflammatory cytokines and stimulating anti-inflammatory cytokines as potential therapeutic targets in ALD. This narrative review aims to clarify the role of the main cytokines involved in the pathogenesis and treatment of ALD.
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Affiliation(s)
| | - Carmen Colaci
- Department of Health Sciences, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy; (G.G.M.S.); (C.C.)
| | - Marialaura Scarcella
- Anesthesia, Intensive Care and Nutritional Science, Azienda Ospedaliera “Santa Maria”, Via Tristano di Joannuccio, 05100 Terni, Italy;
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.D.); (A.F.)
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.D.); (A.F.)
| | - Luigi Boccuto
- Healthcare Genetics and Genomics Doctoral Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC 29634, USA;
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, Viale Europa, 88100 Catanzaro, Italy; (G.G.M.S.); (C.C.)
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15
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Duan F, Liu C, Chang C, Song S, Zhai H, Cheng J, Yang S. Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis. THE AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE 2024; 50:191-206. [PMID: 38011683 DOI: 10.1080/00952990.2023.2266117] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 11/29/2023]
Abstract
Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.
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Affiliation(s)
- Fangfang Duan
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chen Liu
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chunyan Chang
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shanshan Song
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hang Zhai
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jun Cheng
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Song Yang
- Division 3, Department of Hepatology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Division 2, Department of Hepatology, The Fourth People's Hospital of Qinghai Province, Xining, China
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16
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Fligor SC, Tsikis ST, Hirsch TI, Jain A, Sun L, Rockowitz S, Gura KM, Puder M. Inflammation drives pathogenesis of early intestinal failure-associated liver disease. Sci Rep 2024; 14:4240. [PMID: 38378873 PMCID: PMC10879484 DOI: 10.1038/s41598-024-54675-9] [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: 07/26/2023] [Accepted: 02/15/2024] [Indexed: 02/22/2024] Open
Abstract
Patients with intestinal failure who receive long-term parenteral nutrition (PN) often develop intestinal failure-associated liver disease (IFALD). Although there are identified risk factors, the early pathogenesis is poorly understood and treatment options are limited. Here, we perform a transcriptomic analysis of liver tissue in a large animal IFALD model to generate mechanistic insights and identify therapeutic targets. Preterm Yorkshire piglets were provided PN or bottle-fed with sow-milk replacer for 14 days. Compared to bottle-fed controls, piglets receiving PN developed biochemical cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9 mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Analysis identified 747 differentially expressed genes (343 upregulated and 404 downregulated) with an adjusted P < 0.05 and a fold-change of > |1|. Enriched canonical pathways were identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progression. Potential therapeutics including infliximab, glucocorticoids, statins, and obeticholic acid were identified as predicted upstream master regulators that may reverse the PN-induced gene dysregulation. The early driver of IFALD in neonates may be inflammation with an immature liver; identified therapeutics that target the inflammatory response in the liver should be investigated as potential treatments.
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Affiliation(s)
- Scott C Fligor
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Savas T Tsikis
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Thomas I Hirsch
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, USA
| | - Ashish Jain
- Research Computing, Information Technology, Boston Children's Hospital, Boston, MA, USA
| | - Liang Sun
- Research Computing, Information Technology, Boston Children's Hospital, Boston, MA, USA
| | - Shira Rockowitz
- Harvard Medical School, Boston, MA, USA
- Research Computing, Information Technology, Boston Children's Hospital, Boston, MA, USA
- Division of Genetics and Genomics, and the Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA
| | - Kathleen M Gura
- Harvard Medical School, Boston, MA, USA
- Department of Pharmacy and the Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - Mark Puder
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, MA, 02115, USA.
- Harvard Medical School, Boston, MA, USA.
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17
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Yang DK, Tungalag T, Kang HS. Bulbils of Aerial Yam Attenuate Ethanol-Induced Hepatotoxicity in HepG2 Cells through Inhibition of Oxidative Stress by Activation of the Nuclear Factor Erythroid-2-Related Factor 2 Signaling Pathway. Nutrients 2024; 16:542. [PMID: 38398866 PMCID: PMC10892442 DOI: 10.3390/nu16040542] [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: 12/27/2023] [Revised: 02/08/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
Bulbil of yam (BY) extract contains various active compounds possessing many pharmacological properties. However, little is known about the effect and underlying mechanism of BY extract on ethanol-induced liver damage. The present study explored the beneficial potential of BY extract on ethanol-induced hepatotoxicity. To evaluate its effectiveness, ethanol-induced HepG2 liver cells were pretreated with BY extract. BY extract effectively rescued cells from ethanol treatment through inhibition of apoptotic cell death as well as inhibiting expression of mitogen-activated protein kinase (MAPK) proteins as stress inducers. BY extract increased the expression of typical antioxidants. Furthermore, BY extract significantly inhibited mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which are major ROS-inducing factors. Finally, as an underlying mechanism of the protective effects of BY extract on ethanol-induced liver damage, it activated Nrf2 protein through translocation from the cytosol to the nucleus, which in turn activated its target oxidative stress suppressor genes. Collectively, our findings demonstrate that BY extract has potential antioxidative effects in ethanol-induced liver cells and contributes to the establishment of a treatment strategy for alcohol-derived liver injuries.
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Affiliation(s)
- Dong Kwon Yang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Jeollabuk-do, Republic of Korea; (D.K.Y.); (T.T.)
| | - Tsendsuren Tungalag
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Jeollabuk-do, Republic of Korea; (D.K.Y.); (T.T.)
- Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Jeollabuk-do, Republic of Korea
| | - Hyung-Sub Kang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Jeollabuk-do, Republic of Korea; (D.K.Y.); (T.T.)
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18
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Shearer J, Johnson A, Masson S. Improving survival in alcohol-related hepatitis: what's new? Frontline Gastroenterol 2024; 15:42-49. [PMID: 38487555 PMCID: PMC10935532 DOI: 10.1136/flgastro-2022-102362] [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: 04/24/2023] [Accepted: 06/21/2023] [Indexed: 03/17/2024] Open
Abstract
Alcohol-related hepatitis (AH) is the most florid presentation of alcohol-related liver disease and carries a high short-term and long-term mortality rate. Specific treatment options remain inadequate. The current management approach for AH focuses on early identification, careful screening and treatment of infection, as well as identification of those patients who may benefit from corticosteroid therapy based on validated prognostic scoring systems. In recent years, there has been growing interest in exploring novel therapies for AH, which may offer alternative treatment options beyond the traditional approaches. Additionally, early liver transplantation (LT) has emerged as a promising option in selected cases with growing evidence supporting its role. In this review, we will discuss the current evidence base for the assessment and treatment of AH, and how these advances are shaping practice to improve outcomes in the UK.
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Affiliation(s)
- Jessica Shearer
- Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Amy Johnson
- Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Steven Masson
- Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, UK
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19
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Hernández-Évole H, Jiménez-Esquivel N, Pose E, Bataller R. Alcohol-associated liver disease: Epidemiology and management. Ann Hepatol 2024; 29:101162. [PMID: 37832648 DOI: 10.1016/j.aohep.2023.101162] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023]
Abstract
Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. Alcohol-associated hepatitis (AH) is a severe clinical presentation of ALD, which is characterized by abrupt jaundice and clinical decompensations of liver disease. AH occurs in a percentage of patients with underlying ALD and active alcohol consumption. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population. In this regard, alcohol cessation remains the first-line treatment in all stages of alcohol disease. In patients with advanced ALD nonresponding to medical therapy, liver transplantation is the only approach that improves prognosis, and it should be considered in patients with decompensated cirrhosis. In the last years, AH has emerged as a new indication of early liver transplantation in non-responders to medical therapy, with promising results in highly selected patients. In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.
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Affiliation(s)
- Helena Hernández-Évole
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Natalia Jiménez-Esquivel
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elisa Pose
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ramón Bataller
- Liver Unit, Hospital Clinic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
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20
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Jophlin LL, Singal AK, Bataller R, Wong RJ, Sauer BG, Terrault NA, Shah VH. ACG Clinical Guideline: Alcohol-Associated Liver Disease. Am J Gastroenterol 2024; 119:30-54. [PMID: 38174913 PMCID: PMC11040545 DOI: 10.14309/ajg.0000000000002572] [Citation(s) in RCA: 54] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 10/04/2023] [Indexed: 01/05/2024]
Abstract
ABSTRACT Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful alcohol use as the primary risk factor, increasing alcohol use over the past decade has resulted in rapid growth of the ALD-related healthcare burden. The spectrum of ALD ranges from early asymptomatic liver injury to advanced disease with decompensation and portal hypertension. Compared with those with other etiologies of liver disease, patients with ALD progress faster and more often present at an advanced stage. A unique phenotype of advanced disease is alcohol-associated hepatitis (AH) presenting with rapid onset or worsening of jaundice, and acute on chronic liver failure in severe forms conveying a 1-month mortality risk of 20%-50%. The model for end stage disease score is the most accurate score to stratify AH severity (>20 defined as severe disease). Corticosteroids are currently the only available therapeutic with proven efficacy for patients with severe AH, providing survival benefit at 1 month in 50%-60% of patients. Abstinence of alcohol use, a crucial determinant of long-term outcomes, is challenging to achieve in ALD patients with concurrent alcohol use disorder (AUD). As patients with ALD are rarely treated for AUD, strategies are needed to overcome barriers to AUD treatment in patients with ALD and to promote a multidisciplinary integrated care model with hepatology, addiction medicine providers, and social workers to comprehensively manage the dual pathologies of liver disease and of AUD. Liver transplantation, a definitive treatment option in patients with advanced cirrhosis, should be considered in selected patients with AH, who are unresponsive to medical therapy and have a low risk of relapse to posttransplant alcohol use. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the American College of Gastroenterology Practice Parameters Committee.
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Affiliation(s)
- Loretta L. Jophlin
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville Health, Louisville, Kentucky, USA
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, University of South Dakota, Sioux Falls, South Dakota, USA
| | - Ramon Bataller
- Liver Unit, Department of Digestive and Metabolic Diseases, Hospital Clinic, Barcelona, Spain
| | - Robert J. Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | - Bryan G. Sauer
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA
| | - Norah A. Terrault
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Baweja S, Mittal A, Thangariyal S, Subudhi PD, Gautam S, Kaul R. Unveiling the effect of estrogen receptors in alcoholic liver disease: A novel outlook. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:333-341. [PMID: 39958778 PMCID: PMC11791908 DOI: 10.1016/j.livres.2023.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/19/2023] [Accepted: 10/23/2023] [Indexed: 01/11/2025]
Abstract
Alcoholic liver disease (ALD) has a multifaceted development, progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis, irreversible liver damage that can even result in hepatocellular carcinoma. The prevalence of ALD is increasing globally, particularly among middle-aged adults. Gender-based studies have revealed that ALD affects more men; however, disease progression differs between men and women. Despite this, the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism, particularly with estrogen and estrogen receptors (ERs) in ALD, remains poor. This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs. Chronic alcohol consumption affects the immune response, and whether estrogen has any contributory effect remains inadequately studied. This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling. The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD, the development of effective therapeutic approaches, and better disease management in both men and women, as ALD remains a major public health concern.
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Affiliation(s)
- Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashmit Mittal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Swati Thangariyal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - P. Debishree Subudhi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shivani Gautam
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rashmi Kaul
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA
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22
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Condon S, Jophlin LL. Past, Present, and Future Therapies for Alcohol-associated Hepatitis. Clin Ther 2023; 45:1171-1176. [PMID: 37980219 PMCID: PMC10842010 DOI: 10.1016/j.clinthera.2023.10.013] [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: 07/13/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 11/20/2023]
Abstract
PURPOSE Alcohol-associated hepatitis (AH) is a unique presentation of cholestatic steatohepatitis with liver dysfunction and malaise preceded by heavy alcohol intake. Although AH exists on a spectrum, in its most severe form, 28-day mortality approaches 50%. Clinical trials of therapeutic interventions over the last 50 years have yielded few durable therapies, none of which convey benefit beyond the short term. METHODS A qualitative systematic review was performed via searches of PubMed, the International Clinical Trials Registry Platform, and ClinicalTrials.gov for therapeutic interventions for AH. FINDINGS Prior to 2005, clinical trial results for AH were identified within PubMed. From 2005 to the present, trials were well catalogued within online registries and included information regarding trial status (eg, complete, terminated, actively enrolling). Most clinical trials for AH have used existing medications broadly targeting pathogenic themes of AH (eg, inflammation, cell death) in an off-label manner. The trend of initially promising pilot studies answered by larger trials showing lack of efficacy or safety signals have ended the hopes of many new therapeutics. The emergence of theragnostics to identify patients who may benefit from existing therapies and trials of agents with novel mechanisms of action, including epigenetic modifications and hyaluronic acid signaling targeted to AH pathogenesis, are currently under investigation. IMPLICATIONS This review of AH treatments details the historical interventions and clinical trials that have led to the current treatment algorithm and active studies shaping the therapeutic pipeline for AH.
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Affiliation(s)
- Sally Condon
- Department of Medicine, Division of Gastroenterology Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA
| | - Loretta L Jophlin
- Department of Medicine, Division of Gastroenterology Hepatology and Nutrition, University of Louisville, Louisville, Kentucky, USA.
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23
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Wang Y, Shi C, Guo J, Zhang Y, Gong Z. Distinct Types of Cell Death and Implications in Liver Diseases: An Overview of Mechanisms and Application. J Clin Transl Hepatol 2023; 11:1413-1424. [PMID: 37719956 PMCID: PMC10500292 DOI: 10.14218/jcth.2023.00132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/17/2023] [Accepted: 07/12/2023] [Indexed: 09/19/2023] Open
Abstract
Cell death is associated with a variety of liver diseases, and hepatocyte death is a core factor in the occurrence and progression of liver diseases. In recent years, new cell death modes have been identified, and certain biomarkers have been detected in the circulation during various cell death modes that mediate liver injury. In this review, cell death modes associated with liver diseases are summarized, including some cell death modes that have emerged in recent years. We described the mechanisms associated with liver diseases and summarized recent applications of targeting cell death in liver diseases. It provides new ideas for the diagnosis and treatment of liver diseases. In addition, multiple cell death modes can contribute to the same liver disease. Different cell death modes are not isolated, and they interact with each other in liver diseases. Future studies may focus on exploring the regulation between various cell death response pathways in liver diseases.
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Affiliation(s)
- Yukun Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chunxia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jin Guo
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yanqiong Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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24
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Sawada K, Chung H, Softic S, Moreno-Fernandez ME, Divanovic S. The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease. Cell Metab 2023; 35:1852-1871. [PMID: 37939656 PMCID: PMC10680147 DOI: 10.1016/j.cmet.2023.10.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 11/10/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.
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Affiliation(s)
- Keisuke Sawada
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Hak Chung
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Samir Softic
- Department of Pediatrics and Gastroenterology, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Maria E Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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25
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Zhang S, Zeng Y, Wang B, Li J, Hu C, Weng Z, Wang Z. Reduction of alcohol-induced mitochondrial damage with ginsenoside Rg1 studied by atomic force microscopy. Micron 2023; 174:103522. [PMID: 37572500 DOI: 10.1016/j.micron.2023.103522] [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: 06/15/2023] [Revised: 07/23/2023] [Accepted: 08/01/2023] [Indexed: 08/14/2023]
Abstract
The quantification of mitochondrial morphology and mechanical properties is useful for the diagnosis and treatment of mitochondrial and alcoholic liver disease. In this study, the effects of ginsenoside Rg1 (G-Rg1) on the morphology and mechanical properties of mitochondria that had suffered alcohol-induced damage were investigated under near-physiological conditions. Additionally, the morphological and mechanical properties of mitochondria were quantified through atomic force microscopy. Atomic force microscopy revealed that alcohol-induced significant morphological changes in mitochondria. Compared with that of the mitochondria of normal hepatocytes, the average surface area of the damaged mitochondria was found to have increased significantly under the influence of alcohol. Furthermore, the mitochondrial area tended to be normal under the action of G-Rg1, whilst other parameters (length, width and perimeter) were significantly different from those of the mitochondria with the alcohol-induced damage. Simultaneously, alcohol significantly reduced the adhesion and elastic modulus of mitochondria, whilst the adhesion and elastic modulus of mitochondria in the G-Rg1 treatment group were closer to the values of normal mitochondria. This study overall showed that G-Rg1 could effectively alleviate the swelling and anomalous mechanical properties of mitochondria induced by alcohol.
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Affiliation(s)
- Shengli Zhang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China; Zhongshan Institute of hangchun University of Science and Technology, Zhongshan 528400, China; Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Yi Zeng
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China; Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Bowei Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China; Zhongshan Institute of hangchun University of Science and Technology, Zhongshan 528400, China; Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Jiani Li
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China; Zhongshan Institute of hangchun University of Science and Technology, Zhongshan 528400, China; Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Cuihua Hu
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China; Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China
| | - Zhankun Weng
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China; Zhongshan Institute of hangchun University of Science and Technology, Zhongshan 528400, China.
| | - Zuobin Wang
- International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China; Zhongshan Institute of hangchun University of Science and Technology, Zhongshan 528400, China; Ministry of Education Key Laboratory for Cross-Scale Micro and Nano Manufacturing, Changchun University of Science and Technology, Changchun 130022, China; JR3CN & IRAC, University of Bedfordshire, Luton LU1 3JU, UK.
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26
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Tilg H, Adolph TE, Tacke F. Therapeutic modulation of the liver immune microenvironment. Hepatology 2023; 78:1581-1601. [PMID: 37057876 DOI: 10.1097/hep.0000000000000386] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/14/2023] [Indexed: 04/15/2023]
Abstract
Inflammation is a hallmark of progressive liver diseases such as chronic viral or immune-mediated hepatitis, alcohol-associated liver disease, and NAFLD. Preclinical and clinical studies have provided robust evidence that cytokines and related cellular stress sensors in innate and adaptive immunity orchestrate hepatic disease processes. Unresolved inflammation and liver injury result in hepatic scarring, fibrosis, and cirrhosis, which may culminate in HCC. Liver diseases are accompanied by gut dysbiosis and a bloom of pathobionts, fueling hepatic inflammation. Anti-inflammatory strategies are extensively used to treat human immune-mediated conditions beyond the liver, while evidence for immunomodulatory therapies and cell therapy-based strategies in liver diseases is only emerging. The development and establishment of novel immunomodulatory therapies for chronic liver diseases has been dampened by several clinical challenges, such as invasive monitoring of therapeutic efficacy with liver biopsy in clinical trials and risk of DILI in several studies. Such aspects prevented advancements of novel medical therapies for chronic inflammatory liver diseases. New concepts modulating the liver immune environment are studied and eagerly awaited to improve the management of chronic liver diseases in the future.
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Affiliation(s)
- Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
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27
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Kasper P, Lang S, Steffen HM, Demir M. Management of alcoholic hepatitis: A clinical perspective. Liver Int 2023; 43:2078-2095. [PMID: 37605624 DOI: 10.1111/liv.15701] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/11/2023] [Accepted: 08/07/2023] [Indexed: 08/23/2023]
Abstract
Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol-associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short-term mortality. During the COVID-19 pandemic, rates of alcohol-associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol-associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short-term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology-based therapeutic approaches include anti-inflammatory agents, modifications of the gut-liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient-centred treatment approaches to improve prognosis.
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Affiliation(s)
- Philipp Kasper
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Sonja Lang
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hans-Michael Steffen
- Clinic for Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Münevver Demir
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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28
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Wang Y, Chen Q, Wu S, Sun X, Yin R, Ouyang Z, Yin H, Wei Y. Amelioration of ethanol-induced oxidative stress and alcoholic liver disease by in vivo RNAi targeting Cyp2e1. Acta Pharm Sin B 2023; 13:3906-3918. [PMID: 37719371 PMCID: PMC10502278 DOI: 10.1016/j.apsb.2023.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/16/2022] [Accepted: 12/10/2022] [Indexed: 09/19/2023] Open
Abstract
Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.
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Affiliation(s)
- Yalan Wang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Qiubing Chen
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Shuang Wu
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Xinyu Sun
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Zhen Ouyang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Hao Yin
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- RNA Institute, Wuhan University, Wuhan 430072, China
- Wuhan Research Centre for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430010, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
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29
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Germani G, D’Arcangelo F, Grasso M, Burra P. Advances and Controversies in Acute Alcohol-Related Hepatitis: From Medical Therapy to Liver Transplantation. Life (Basel) 2023; 13:1802. [PMID: 37763206 PMCID: PMC10532507 DOI: 10.3390/life13091802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Alcohol-related hepatitis (AH) is a clinical syndrome characterized by recent-onset jaundice in the context of alcohol consumption. In patients with severe AH "unresponsive" to steroid therapy, mortality rates exceed 70% within six months. According to European and American guidelines, liver transplantation (LT) may be considered in highly selected patients who do not respond to medical therapy. The aim of this narrative review is to summarize current knowledge from medical therapy to liver transplantation in acute alcohol-related hepatitis. Due to the impossibility to guarantee six-month abstinence, LT for AH is controversial. Principal concerns are related to organ scarcity in the subset of stigma of "alcohol use disorder" (AUD) and the risk of relapse to alcohol use after LT. Return to alcohol use after LT is a complex issue that cannot be assessed as a yes/no variable with heterogeneous results among studies. In conclusion, present data indicate that well-selected patients have excellent outcomes, with survival rates of up to 100% at 24 and 36 months after LT. Behavioral therapy, ongoing psychological support, and strong family support seem essential to improve long-term outcomes after LT and reduce the risk in relapse of alcohol use.
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Affiliation(s)
- Giacomo Germani
- Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy
| | - Francesca D’Arcangelo
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Marco Grasso
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
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30
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Desregulación inmunológica y fisiopatología del consumo de alcohol y la enfermedad hepática alcohólica. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2023; 88:136-154. [DOI: 10.1016/j.rgmx.2023.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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31
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Yang K, Ryu T, Chung BS. A Meta-Analysis of Preclinical Studies to Investigate the Effect of Panax ginseng on Alcohol-Associated Liver Disease. Antioxidants (Basel) 2023; 12:841. [PMID: 37107216 PMCID: PMC10135056 DOI: 10.3390/antiox12040841] [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: 02/21/2023] [Revised: 03/14/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Alcohol-associated liver disease (ALD) has become a major global concern, but the development of effective drugs remains a challenge despite numerous preclinical and clinical pieces of research on the effects of natural compounds. To address this, a meta-analysis was conducted on the efficacy of Panax ginseng for ALD based on preclinical studies. We identified 18 relevant studies from PubMed, Web of Science, and Cochrane Library database and evaluated their methodological quality using the Systematic Review Centre for Laboratory animal Experimentation tool. We analyzed the data using I2, p-values, and fixed effects models to assess overall efficacy and heterogeneity. The results of the meta-analysis suggested that Panax ginseng treatment is effective in reducing the levels of inflammatory markers associated with hepatic injury caused by ALD in animal experiments. Additionally, the administration of Panax ginseng was found to down-regulate inflammatory cytokines and attenuate lipid metabolism in ALD. Moreover, Panax ginseng markedly improved the antioxidant systems in ALD. Therefore, we concluded that Panax ginseng has the potential to be a promising therapeutic agent for ALD. Further research is needed to confirm these findings and to determine the optimal dosage and duration of treatment for patients with ALD.
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Affiliation(s)
- Keungmo Yang
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Tom Ryu
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, College of Medicine, Soonchunhyang University, Seoul 04401, Republic of Korea
| | - Beom Sun Chung
- Department of Anatomy, College of Medicine, Yonsei University Wonju, Wonju 26426, Republic of Korea
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32
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Ryu T, Kim K, Choi SE, Chung KPS, Jeong WI. New insights in the pathogenesis of alcohol-related liver disease: The metabolic, immunologic, and neurologic pathways ☆. LIVER RESEARCH 2023; 7:1-8. [PMID: 39959703 PMCID: PMC11791844 DOI: 10.1016/j.livres.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/04/2022] [Accepted: 09/28/2022] [Indexed: 02/16/2023]
Abstract
Alcohol-related liver disease (ALD) became an important health issue worldwide. Following chronic alcohol consumption, the development of ALD might be caused by metabolic and immunologic factors, such as reactive oxygen species (ROS) and pro-inflammatory cytokines. For example, hepatic cytochrome P450 2E1 enzyme increases ROS production and stimulates de novo lipogenesis after alcohol exposure. In addition, damage- and pathogen-associated molecular patterns stimulate their specific receptors in non-parenchymal cells, including Kupffer cells, hepatic stellate cells (HSCs), and lymphocytes, which result in hepatocyte death and infiltration of pro-inflammatory cells (e.g., neutrophils and macrophages) in the liver. Moreover, our studies have suggested the novel involvement of neurologic signaling pathways (e.g., endocannabinoid and glutamate) through the metabolic synapse between hepatocytes and HSCs in the development of alcohol-related hepatic steatosis. Additionally, agouti-related protein and beta2-adrenergic receptors aggravate hepatic steatosis. Furthermore, organ-crosstalk has emerged as a critical issue in ALD. Chronic alcohol consumption induces dysbiosis and barrier disruption in the gut, leading to endotoxin leakage into the portal circulation, or lipolysis-mediated transport of triglycerides from the adipose tissue to the liver. In summary, this review addresses multiple pathogeneses of ALD, provides novel neurologic signaling pathways, and emphasizes the importance of organ-crosstalk in the development of ALD.
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Affiliation(s)
- Tom Ryu
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Kyurae Kim
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Sung Eun Choi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Katherine Po Sin Chung
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
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Martinez-Castillo M, Altamirano-Mendoza I, Sánchez-Valle S, García-Islas L, Sánchez-Barragán M, Hernández-Santillán M, Hernández-Barragán A, Pérez-Hernández J, Higuera-de la Tijera F, Gutierrez-Reyes G. Immune dysregulation and pathophysiology of alcohol consumption and alcoholic liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2023; 88:136-154. [PMID: 36973122 DOI: 10.1016/j.rgmxen.2023.03.003] [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] [Received: 07/10/2022] [Accepted: 01/13/2023] [Indexed: 03/28/2023] Open
Abstract
Alcoholic liver disease (ALD) is a clinical-pathologic entity caused by the chronic excessive consumption of alcohol. The disease includes a broad spectrum of anomalies at the cellular and tissual level that can cause acute-on-chronic (alcoholic hepatitis) or chronic (fibrosis, cirrhosis, hepatocellular cancer) injury, having a great impact on morbidity and mortality worldwide. Alcohol is metabolized mainly in the liver. During alcohol metabolism, toxic metabolites, such as acetaldehyde and oxygen reactive species, are produced. At the intestinal level, alcohol consumption can cause dysbiosis and alter intestinal permeability, promoting the translocation of bacterial products and causing the production of inflammatory cytokines in the liver, perpetuating local inflammation during the progression of ALD. Different study groups have reported systemic inflammatory response disturbances, but reports containing a compendium of the cytokines and cells involved in the pathophysiology of the disease, from the early stages, are difficult to find. In the present review article, the role of the inflammatory mediators involved in ALD progression are described, from risky patterns of alcohol consumption to advanced stages of the disease, with the aim of understanding the involvement of immune dysregulation in the pathophysiology of ALD.
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Wu X, Fan X, Miyata T, Kim A, Cajigas-Du Ross CK, Ray S, Huang E, Taiwo M, Arya R, Wu J, Nagy LE. Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease. ANNUAL REVIEW OF PATHOLOGY 2023; 18:411-438. [PMID: 36270295 PMCID: PMC10060166 DOI: 10.1146/annurev-pathmechdis-031521-030435] [Citation(s) in RCA: 117] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis of ALD. We also summarize current understanding of innate immune responses, liver sinusoidal endothelial cell dysfunction and hepatic stellate cell activation, and gut-liver and adipose-liver cross talk in response to ethanol. In addition,we describe the current potential therapeutic targets and clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory responses, and targeting gut microbiota, for the treatment of ALD.
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Affiliation(s)
- Xiaoqin Wu
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Xiude Fan
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Tatsunori Miyata
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Adam Kim
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Christina K Cajigas-Du Ross
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Semanti Ray
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Emily Huang
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Moyinoluwa Taiwo
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Rakesh Arya
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
| | - Jianguo Wu
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Laura E Nagy
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio, USA;
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio, USA
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Im GY. Emerging Biomarkers in Alcohol-associated Hepatitis. J Clin Exp Hepatol 2023; 13:103-115. [PMID: 36647419 PMCID: PMC9840081 DOI: 10.1016/j.jceh.2022.07.246] [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: 03/13/2022] [Revised: 07/14/2022] [Accepted: 07/17/2022] [Indexed: 01/19/2023] Open
Abstract
Alcohol-associated hepatitis (AH) is a clinical syndrome of jaundice, abdominal pain, and anorexia due to prolonged heavy alcohol intake. AH is associated with changes in gene expression, cytokines, immune response, and the gut microbiome. There are limited biomarkers to diagnose and prognosticate in AH, but several non-invasive biomarkers are emerging. In this review, clinical risk-stratifying algorithms, promising AH biomarkers like cytokeratin-18 fragments, genetic polymorphisms, and microRNAs will be reviewed.
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Key Words
- AH, Alcohol-associated hepatitis
- ALD, alcohol-associated liver disease
- ASCA, anti–Saccharomyces cerevisiae antibodies
- AUC, area under the curve
- FGF, fibroblast growth factor
- GAHS, Glasgow alcohol-associated hepatitis score
- HCC, hepatocellular carcinoma
- MELD, model for end-stage liver disease
- NASH, non-alcohol-associated steatohepatitis
- PPV, positive predictive value
- PT, prothrombin time
- VCTE, vibration-controlled transient elastography
- alcohol-associated hepatitis
- biomarkers
- cytokines
- miRNAs, MicroRNAs
- microRNA
- microbiome
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Affiliation(s)
- Gene Y. Im
- Icahn School of Medicine at Mount Sinai, Division of Liver Diseases, Recanati/Miller Transplantation Institute, New York, NY, USA
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Adekunle AD, Adejumo A, Singal AK. Therapeutic targets in alcohol-associated liver disease: progress and challenges. Therap Adv Gastroenterol 2023; 16:17562848231170946. [PMID: 37187673 PMCID: PMC10176580 DOI: 10.1177/17562848231170946] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Alcohol-associated liver disease (ALD) is a complex disease with rapidly increasing prevalence. Although there are promising therapeutic targets on the horizon, none of the newer targets is currently close to an Food and Drug Administration approval. Strategies are needed to overcome challenges in study designs and conducting clinical trials and provide impetus to the field of drug development in the landscape of ALD and alcoholic hepatitis. Management of ALD is complex and should include therapies to achieve and maintain alcohol abstinence, preferably delivered by a multidisciplinary team. Although associated with clear mortality benefit in select patients, the use of early liver transplantation still requires refinement to create uniformity in selection protocols across transplant centers. There is also a need for reliable noninvasive biomarkers for prognostication. Last but not the least, strategies are urgently needed to implement integrated multidisciplinary care models for treating the dual pathology of alcohol use disorder and of liver disease for improving the long-term outcomes of patients with ALD.
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Affiliation(s)
- Ayooluwatomiwa Deborah Adekunle
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
| | - Adeyinka Adejumo
- Department of Internal Medicine, St. Luke’s
Hospital, Chesterfield, Missouri, USA
- Division of Hepatology, University of
Pittsburgh Medical Center, Pittsburgh, PA, USA
- Division of Transplant Hepatology, University
of South Dakota Sanford Medical School, Sioux Falls, SD
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Han J, Lee C, Hur J, Jung Y. Current Therapeutic Options and Potential of Mesenchymal Stem Cell Therapy for Alcoholic Liver Disease. Cells 2022; 12:22. [PMID: 36611816 PMCID: PMC9818513 DOI: 10.3390/cells12010022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/16/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The therapeutic efficiency of current therapies for ALD is limited, and there is no FDA-approved therapy for ALD at present. Various strategies targeting pathogenic events in the progression of ALD are being investigated in preclinical and clinical trials. Recently, mesenchymal stem cells (MSCs) have emerged as a promising candidate for ALD treatment and have been tested in several clinical trials. MSC-released factors have captured attention, as they have the same therapeutic function as MSCs. Herein, we focus on current therapeutic options, recently proposed strategies, and their limitations in ALD treatment. Also, we review the therapeutic effects of MSCs and those of MSC-related secretory factors on ALD. Although accumulating evidence suggests the therapeutic potential of MSCs and related factors in ALD, the mechanisms underlying their actions in ALD have not been well studied. Further investigations of the detailed mechanisms underlying the therapeutic role of MSCs in ALD are required to expand MSC therapies to clinical applications. This review provides information on current or possible treatments for ALD and contributes to our understanding of the development of effective and safe treatments for ALD.
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Affiliation(s)
- Jinsol Han
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Chanbin Lee
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
| | - Jin Hur
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
- PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea
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Conde de la Rosa L, Goicoechea L, Torres S, Garcia-Ruiz C, Fernandez-Checa JC. Role of Oxidative Stress in Liver Disorders. LIVERS 2022; 2:283-314. [DOI: 10.3390/livers2040023] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Oxygen is vital for life as it is required for many different enzymatic reactions involved in intermediate metabolism and xenobiotic biotransformation. Moreover, oxygen consumption in the electron transport chain of mitochondria is used to drive the synthesis of ATP to meet the energetic demands of cells. However, toxic free radicals are generated as byproducts of molecular oxygen consumption. Oxidative stress ensues not only when the production of reactive oxygen species (ROS) exceeds the endogenous antioxidant defense mechanism of cells, but it can also occur as a consequence of an unbalance between antioxidant strategies. Given the important role of hepatocytes in the biotransformation and metabolism of xenobiotics, ROS production represents a critical event in liver physiology, and increasing evidence suggests that oxidative stress contributes to the development of many liver diseases. The present review, which is part of the special issue “Oxidant stress in Liver Diseases”, aims to provide an overview of the sources and targets of ROS in different liver diseases and highlights the pivotal role of oxidative stress in cell death. In addition, current antioxidant therapies as treatment options for such disorders and their limitations for future trial design are discussed.
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Affiliation(s)
- Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Leire Goicoechea
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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Alcohol-Related Liver Disease: An Overview on Pathophysiology, Diagnosis and Therapeutic Perspectives. Biomedicines 2022; 10:biomedicines10102530. [PMID: 36289791 PMCID: PMC9599689 DOI: 10.3390/biomedicines10102530] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/01/2022] [Accepted: 10/08/2022] [Indexed: 11/19/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to a spectrum of liver manifestations ranging from fatty liver diseases, steatohepatitis, and fibrosis/cirrhosis with chronic inflammation primarily due to excessive alcohol use. Currently, ALD is considered as one of the most prevalent causes of liver disease-associated mortality worldwide. Although the pathogenesis of ALD has been intensively investigated, the present understanding of its biomarkers in the context of early clinical diagnosis is not complete, and novel therapeutic targets that can significantly alleviate advanced forms of ALD are limited. While alcohol abstinence remains the primary therapeutic intervention for managing ALD, there are currently no approved medications for treating ALD. Furthermore, given the similarities and the differences between ALD and non-alcoholic fatty liver disease in terms of disease progression and underlying molecular mechanisms, numerous studies have demonstrated that many therapeutic interventions targeting several signaling pathways, including oxidative stress, inflammatory response, hormonal regulation, and hepatocyte death play a significant role in ALD treatment. Therefore, in this review, we summarized several key molecular targets and their modes of action in ALD progression. We also described the updated therapeutic options for ALD management with a particular emphasis on potentially novel signaling pathways.
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Chao X, Williams SN, Ding WX. Role of mechanistic target of rapamycin in autophagy and alcohol-associated liver disease. Am J Physiol Cell Physiol 2022; 323:C1100-C1111. [PMID: 36062877 PMCID: PMC9550572 DOI: 10.1152/ajpcell.00281.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/26/2022] [Accepted: 08/26/2022] [Indexed: 11/22/2022]
Abstract
Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase and a cellular sensor for nutrient and energy status, which is critical in regulating cell metabolism and growth by governing the anabolic (protein and lipid synthesis) and catabolic process (autophagy). Alcohol-associated liver disease (ALD) is a major chronic liver disease worldwide that carries a huge financial burden. The spectrum of the pathogenesis of ALD includes steatosis, fibrosis, inflammation, ductular reaction, and eventual hepatocellular carcinoma, which is closely associated with metabolic changes that are regulated by mTOR. In this review, we summarized recent progress of alcohol consumption on the changes of mTORC1 and mTORC2 activity, the potential mechanisms and possible impact of the mTORC1 changes on autophagy in ALD. We also discussed the potential beneficial effects and limitations of targeting mTORC1 against ALD.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Sha Neisha Williams
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
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Ballester MP, Sittner R, Jalan R. Alcohol and Acute-on-Chronic Liver Failure. J Clin Exp Hepatol 2022; 12:1360-1370. [PMID: 36157143 PMCID: PMC9499845 DOI: 10.1016/j.jceh.2021.12.010] [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: 11/07/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high short-term mortality. Alcohol is one of the leading causes of ACLF and the most frequently reported aetiology of underlying chronic liver disease. Among patients with alcoholic hepatitis (AH), ACLF is a frequent and severe complication. It is characterised by both immune dysfunction associated to an increased risk of infection and high-grade systemic inflammation that ultimately induce organ failure. Diagnosis and severity of ACLF determine AH prognosis, and therefore, ACLF prognostic scores should be used in severe AH with organ failure. Corticosteroids remain the first-line treatment for severe AH but they seem insufficient when ACLF is associated. Novel therapeutic targets to contain the excessive inflammatory response and reduce infection have been identified and are under investigation. With liver transplantation remaining one of the most effective therapies for severe AH and ACLF, adequate organ allocation represents a growing challenge. Hence, a clear understanding of the pathophysiology, clinical implications and management strategies of ACLF in AH is essential for hepatologists, which is narrated briefly in this review.
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Key Words
- ACLF, Acute-on-chronic liver failure
- AH, alcoholic hepatitis
- ALT, alanine aminotransferase
- APASL, Asian Pacific Association for the Study of the Liver
- AST, aspartate aminotransferase
- DAMPs, damage-associated molecular patterns
- EASL-CLIF, European Association for the Study of the Liver – Chronic Liver Failure Consortium
- GAHS, Glasgow alcoholic hepatitis score
- IL, interleukin
- INR, international normalised ratio
- MELD, model for end-stage liver disease
- NAC, N-acetylcysteine
- NACSELD, North American Consortium for the Study of End-Stage Liver Disease
- PAMPs, pathogen-associated molecular patterns
- TNF, tumour necrosis factor
- WGO, World Gastroenterology Organization
- acute-on-chronic liver failure
- alcoholic hepatitis
- cirrhosis
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Affiliation(s)
- Maria Pilar Ballester
- Digestive Disease Department, University Clinic Hospital of Valencia, Blasco Ibañez Av, 17, Valencia, 46010, Spain
- INCLIVA Biomedical Research Institute, Menéndez y Pelayo St., 4, Valencia, 46010, Spain
| | - Richard Sittner
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charitéplatz 1 Berlin, 10117, Germany
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Disease Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, United Kingdom
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and the European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) Consortium, Travessera de Gràcia St., 11, Barcelona, 08021, Spain
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Kaur B, Rosenblatt R, Sundaram V. Infections in Alcoholic Hepatitis. J Clin Transl Hepatol 2022; 10:718-725. [PMID: 36062291 PMCID: PMC9396323 DOI: 10.14218/jcth.2022.00024] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/11/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Severe alcoholic hepatitis (sAH) is defined by a modified discriminant function ≥32 or model for end-stage liver disease (MELD) >20. Patients with sAH are in an immunocompromised state attributed to cirrhosis-related immunoparesis and corticosteroid use. Individuals with sAH often develop severe infections that adversely impact short-term prognosis. Currently, the corticosteroid prednisolone is the only treatment with proven efficacy in sAH; however, the combination of corticosteroid treatment and altered host defense in sAH has been thought to increase the risk of acquiring of bacterial, opportunistic fungal, and viral infections. Newer studies have shown that corticosteroids do not increase occurrence of infections in those with sAH; unfortunately, the lack of response to corticosteroids may instead predispose to infection development. Prompt and appropriate antibiotic treatment is therefore essential to improving patient outcomes. This review highlights common infections and risk factors in patients with sAH. Additionally, current diagnostic, therapeutic, and prophylactic strategies in these patients are discussed.
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Affiliation(s)
- Bhupinder Kaur
- Internal Medicine Department, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Russell Rosenblatt
- Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Vinay Sundaram
- Department of Gastroenterology and Hepatology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Correspondence to: Vinay Sundaram, Department of Gastroenterology and Hepatology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8635W. Third Street, Suite 1060W, Los Angeles, CA 90048, USA. ORCID: https://orcid.org/0000-0002-1450-7756. Tel: +1-310-423-6000, Fax: +1-310-423-6086, E-mail:
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Rattan P, Shah VH. Review article: current and emerging therapies for acute alcohol-associated hepatitis. Aliment Pharmacol Ther 2022; 56:28-40. [PMID: 35567372 DOI: 10.1111/apt.16969] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/20/2022] [Accepted: 04/28/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Alcohol-associated hepatitis is an acute manifestation of alcohol-associated liver disease (ALD) and is associated with 30%-40% mortality at 28 days. Abstinence and corticosteroids are the mainstays of treatment, but the latter only improves short-term mortality, so new and improved therapies remain an unmet need. AIMS The aim was to review the pathophysiology of alcohol-associated hepatitis and how various targets can be used by current and emerging therapies as treatment. METHODS A thorough literature review was conducted on acute alcohol-associated hepatitis, current therapies and therapies under investigation. RESULTS With the increasing prevalence of alcohol use disorder and ALD, the burden of alcohol-associated hepatitis is also expected to rise. The current understanding of alcohol-associated hepatitis pathophysiology has led to clinical trials of several therapies involving IL-1 antagonism, modification of the gut microbiome and liver regeneration. CONCLUSIONS Corticosteroid therapy for alcohol-associated hepatitis is restricted in its applicability and has limited efficacy. Developing multidisciplinary, patient-centred care models based on digital health technologies, in combination with continued discovery of novel therapies using multiomics data and computational biology techniques will be necessary to tackle the increasing burden of alcohol-associated hepatitis.
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Affiliation(s)
- Puru Rattan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Tan J, Zhang J, Wang M, Wang Y, Dong M, Ma X, Sun B, Liu S, Zhao Z, Chen L, Jin W, Liu K, Xin Y, Zhuang L. DRAM1 increases the secretion of PKM2-enriched EVs from hepatocytes to promote macrophage activation and disease progression in ALD. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:375-389. [PMID: 35036051 PMCID: PMC8728309 DOI: 10.1016/j.omtn.2021.12.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 12/09/2021] [Indexed: 11/24/2022]
Abstract
DNA damage-regulated autophagy modulator 1 (DRAM1) could play important roles in inflammation and hepatic apoptosis, while its roles in alcohol-related liver disease (ALD), which is characterized by hepatic inflammation and apoptosis, are still unclear. In this study, we explored the expression, role, and mechanism of DRAM1 in ALD. Firstly, our results showed that DRAM1 was significantly increased in liver tissues of mice at the early stage of alcohol treatment. In addition, DRAM1 knockout reduced, and liver-specific overexpression of DRAM1 aggravated, alcohol-induced hepatic steatosis, injury, and expressions of M1 macrophage markers in mice. Furthermore, ethanol-induced DRAM1 of hepatic cells increased pyruvate kinase M2 (PKM2)-enriched extracellular vesicles (EVs), and ectosomes derived from hepatic cells with DRAM1 overexpression promoted macrophage activation. Mechanistic investigations showed that DRAM1 interacted with PKM2 and increased the PKM2 level in plasma membrane. At last, DRAM1 was significantly increased in liver tissues of ALD patients, and it was positively correlated with M1 macrophage markers. Taken together, this study revealed that ethanol-induced DRAM1 of hepatic cells could increase the PKM2-enriched EVs, promote macrophage activation, and aggravate the disease progression of ALD. These findings suggested that DRAM1 might be a potentially promising target for the therapy of ALD.
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Affiliation(s)
- Jie Tan
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Jie Zhang
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Mengke Wang
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Yifen Wang
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Mengzhen Dong
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Xuefeng Ma
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Baokai Sun
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Shousheng Liu
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Zhenzhen Zhao
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
| | - Lizhen Chen
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Wenwen Jin
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Kai Liu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Yongning Xin
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China
| | - Likun Zhuang
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China
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Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease. Int J Mol Sci 2022; 23:ijms23020774. [PMID: 35054960 PMCID: PMC8775426 DOI: 10.3390/ijms23020774] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD. Notably, oxidative changes in the liver have been recognized as a signature trait of ALD. Progression of ALD is linked to the generation of highly reactive free radicals by reactions involving ethanol and its metabolites. Furthermore, hepatic oxidative stress promotes tissue injury and, in turn, stimulates inflammatory responses in the liver, forming a pathological loop that promotes the progression of ALD. Accordingly, accumulating further knowledge on the relationship between oxidative stress and inflammation may help establish a viable therapeutic approach for treating ALD.
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46
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Chen DY, Lin CH, Chen HH, Tang KT. Association of tumor necrosis factor-α inhibitors and liver cirrhosis in patients with rheumatoid arthritis: A nationwide population-based nested case-control study. Int J Rheum Dis 2022; 25:327-334. [PMID: 34994523 DOI: 10.1111/1756-185x.14272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/29/2021] [Accepted: 12/20/2021] [Indexed: 11/29/2022]
Abstract
AIM Results from various studies are controversial regarding long-term hepatic effects of tumor necrosis factor (TNF)-α inhibitors. Here we aimed to investigate the development of liver cirrhosis with TNF-α inhibitors use in patients with rheumatoid arthritis (RA). METHOD This nested case-control study was based on the National Health Insurance Research Database (January 1, 2000 to December 31, 2008) of Taiwan. We identified 559 adult RA patients who developed liver cirrhosis, and 1055 matched control RA patients. TNF-α inhibitors of interest in the study period included adalimumab and etanercept. Multivariate logistic regression analysis for the development of liver cirrhosis with respect to use of TNF-α inhibitors was performed. RESULTS The incidence rate of liver cirrhosis was 274 per 100 000 person-years in newly diagnosed RA patients. We found the use of TNF-α inhibitors was not associated with the development of liver cirrhosis in RA patients (odds ratio 1.02, 95% confidence interval 0.61, 1.70) after adjustment for potential confounders. In addition, the finding was robust to an unobserved confounder. CONCLUSION We found no association between the use of TNF-α inhibitors and development of liver cirrhosis in RA patients.
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Affiliation(s)
- Der-Yuan Chen
- Translational Medicine Laboratory, China Medical University Hospital, Taichung, Taiwan.,Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Hsin-Hua Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.,Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan.,Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.,Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan
| | - Kuo-Tung Tang
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan.,Ph.D. Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
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Vergis N, Patel V, Bogdanowicz K, Czyzewska-Khan J, Fiorentino F, Day E, Cross M, Foster N, Lord E, Goldin R, Forrest E, Thursz M. IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo-controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis. Trials 2021; 22:792. [PMID: 34763711 PMCID: PMC8581959 DOI: 10.1186/s13063-021-05719-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1β antibody, canakinumab, in the treatment of AH. METHODS This is a multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the UK. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is the difference between groups in the proportion of patients demonstrating histological improvement and will compare histological appearances at baseline with appearances at 28 days to assign a category of "improved" or "not improved". Patients with evidence of ongoing disease activity will receive a second infusion of canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days. DISCUSSION This phase II study will explore the benefits of the IL-1β antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1β signalling may improve histology and survival for patients with AH. TRIAL REGISTRATION EudraCT 2017-003724-79 . Prospectively registered on 13 April 2018.
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Affiliation(s)
- N Vergis
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
| | - V Patel
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.,Institute of Hepatology London, Foundation for Liver Research, London, UK.,School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - K Bogdanowicz
- Imperial Clinical Trials Unit, Department of Surgery and Cancer, Imperial College, London, UK
| | - J Czyzewska-Khan
- Imperial Clinical Trials Unit, Department of Surgery and Cancer, Imperial College, London, UK
| | - F Fiorentino
- Imperial Clinical Trials Unit, Department of Surgery and Cancer, Imperial College, London, UK
| | - E Day
- Imperial Clinical Trials Unit, Department of Surgery and Cancer, Imperial College, London, UK
| | - M Cross
- Imperial Clinical Trials Unit, Department of Surgery and Cancer, Imperial College, London, UK
| | - N Foster
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - E Lord
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - R Goldin
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - E Forrest
- Glasgow Royal Infirmary and University of Glasgow, Glasgow, UK
| | - M Thursz
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
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48
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Kapila N, Gonzalez A, Rosado JM, Flocco G, Salomon F, Abusaif M, Hussain I, Moor MA, Modaresi-Esfeh J, Castro FJ. Safety of anti-TNF agents in patients with compensated cirrhosis: a case-control study. Therap Adv Gastroenterol 2021; 14:17562848211037094. [PMID: 34707687 PMCID: PMC8543557 DOI: 10.1177/17562848211037094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/06/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND There is limited data on the use of anti-TNF agents in patients with concomitant cirrhosis. The aim of this study is to assess the safety of anti-TNF agents in patients with compensated cirrhosis who used these medications for the treatment of an underlying rheumatologic condition or IBD. METHODS Multicenter, retrospective, matched, case-control study. A one to three case-control match was performed. Adults who received anti-TNF therapy were matched to three adults with cirrhosis who did not receive anti-TNF therapy. Patients were matched for etiology of cirrhosis, MELD-Na and age. Primary outcome was the development of hepatic decompensation. Secondary outcomes included development of infectious complications, hepatocellular carcinoma (HCC), extra-hepatic malignancy, and mortality. RESULTS Eighty patients with cirrhosis who received anti-TNF agents were matched with 240 controls. Median age was 57.2 years. Median MELD-Na for the anti-TNF cohort was seven and median MELD-Na for the controls was eight. The most common etiology of cirrhosis was NAFLD. Anti-TNF therapy did not increase risk of decompensation (HR: 0.91, 95% CI: 0.64-1.30, p = 0.61) nor influence the time to development of a decompensating event. Anti-TNF therapy did not increase the risk of hepatic mortality or need for liver transplantation (HR: 1.18, 95% CI: 0.55-2.53, p = 0.67). Anti-TNF therapy was not associated with an increased risk of serious infection (HR: 1.21, 95% CI: 0.68-2.17, p = 0.52), HCC (OR: 0.45, 95% CI: 0.13-1.57, p = 0.21), or extra-hepatic malignancy (OR: 0.82, 95% CI: 0.29-2.30, p = 0.71). CONCLUSIONS Anti-TNF agents in patients with compensated cirrhosis does not influence the risk of decompensation, serious infections, transplant free survival, or malignancy.
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Affiliation(s)
- Nikhil Kapila
- Department of Transplant, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL 33331, USA
| | - Adalberto Gonzalez
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL, USA
| | - Jose Melendez Rosado
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL, USA
| | - Gianina Flocco
- Digestive Diseases Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Fayssa Salomon
- Department of Internal Medicine, Cleveland Clinic Florida, Weston, FL, USA
| | - Mohammad Abusaif
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL, USA
| | - Ishtiaq Hussain
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL, USA
| | - Molly A. Moor
- Department of Medical and Population Health Sciences Research, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | | | - Fernando J. Castro
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL, USA
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Petagine L, Zariwala MG, Patel VB. Alcoholic liver disease: Current insights into cellular mechanisms. World J Biol Chem 2021; 12:87-103. [PMID: 34630912 PMCID: PMC8473419 DOI: 10.4331/wjbc.v12.i5.87] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/20/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality. Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level. Although the disease spectrum of ALD is widely recognized, the precise triggers for disease progression are still to be fully elucidated. Oxidative stress, mitochondrial dysfunction, gut dysbiosis and altered immune system response plays an important role in disease pathogenesis, triggering the activation of inflammatory pathways and apoptosis. Despite many recent clinical studies treatment options for ALD are limited, especially at the alcoholic hepatitis stage. We have therefore reviewed some of the key pathways involved in the pathogenesis of ALD and highlighted current trials for treating patients.
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Affiliation(s)
- Lucy Petagine
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Mohammed Gulrez Zariwala
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
| | - Vinood B Patel
- Center for Nutraceuticals, School of Life Sciences, University of Westminster, London W1W 6UW, United Kingdom
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Pohl K, Moodley P, Dhanda AD. Alcohol's Impact on the Gut and Liver. Nutrients 2021; 13:nu13093170. [PMID: 34579046 PMCID: PMC8472839 DOI: 10.3390/nu13093170] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022] Open
Abstract
Alcohol is inextricably linked with the digestive system. It is absorbed through the gut and metabolised by hepatocytes within the liver. Excessive alcohol use results in alterations to the gut microbiome and gut epithelial integrity. It contributes to important micronutrient deficiencies including short-chain fatty acids and trace elements that can influence immune function and lead to liver damage. In some people, long-term alcohol misuse results in liver disease progressing from fatty liver to cirrhosis and hepatocellular carcinoma, and results in over half of all deaths from chronic liver disease, over half a million globally per year. In this review, we will describe the effect of alcohol on the gut, the gut microbiome and liver function and structure, with a specific focus on micronutrients and areas for future research.
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Affiliation(s)
- Keith Pohl
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, UK; (K.P.); (P.M.)
- Hepatology Research Group, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
| | - Prebashan Moodley
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, UK; (K.P.); (P.M.)
- Hepatology Research Group, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
| | - Ashwin D. Dhanda
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth PL6 8DH, UK; (K.P.); (P.M.)
- Hepatology Research Group, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
- Correspondence: ; Tel.: +44-1752-432723
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