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Yamazaki T, Schnabl B. Acute alcohol-associated hepatitis: Latest findings in non-invasive biomarkers and treatment. Liver Int 2025; 45:e15608. [PMID: 37183549 PMCID: PMC10646153 DOI: 10.1111/liv.15608] [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: 02/16/2023] [Revised: 04/15/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023]
Abstract
Acute alcohol-associated hepatitis (AH) is a syndrome that occurs in heavy and long-term drinkers and results in severe jaundice and liver failure. The mortality rate in severe cases is 20%-50% at 28 days, and in cases that do not improve despite appropriately timed corticosteroid therapy, the mortality rate reaches 70% at 6 months. The only curative treatment is early liver transplantation, but less than 2% of patients with severe AH are eligible. In order to improve the prognosis, diagnostic tools are needed to detect appropriate cases at risk of severe conditions, and new therapies need to be developed that can replace corticosteroids. Recent research has revealed that the pathogenesis of AH involves a complex of factors, including changes in the gut microbiota, inflammatory and cytokine signalling, oxidative stress and mitochondrial dysfunction, and abnormalities in the hepatic regenerative capacity. Non-invasive diagnostic tools focusing on these specific pathologies have been reported in recent years. In addition, several novel agents targeting specific pathways are currently being developed and tested in clinical trials. This review will provide an overview of alcohol-associated hepatitis and focus on the latest diagnostic tools, particularly non-invasive biomarkers, and novel therapies.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Nagano, Matsumoto, Japan
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, California, San Diego, USA
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Liu S, Zhu K, Huang Y, Ye W, Wu J. PRDM16 in thermogenic adipocytes mediates an inter-organ protective signaling against alcohol-associated liver disease. Mol Cell Endocrinol 2025; 595:112407. [PMID: 39505231 DOI: 10.1016/j.mce.2024.112407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/31/2024] [Accepted: 11/02/2024] [Indexed: 11/08/2024]
Abstract
Alcohol-associated liver disease (ALD) is one of the major chronic liver diseases and despite the dire clinical needs and extensive research efforts, no effective therapies are available for late-stages of ALD except for liver transplantation. Adipose tissue dysfunction has been implicated in the progression of ALD. Furthermore, it has been previously suggested that thermogenic fat can be activated after alcohol consumption. In this study, increased thermogenic gene expression was detected in both classical brown adipose tissue and beige adipocytes in mice that were given alcohol challenges even when housed at thermoneutrality. In particular, higher expression level of Prdm16, the key transcriptional co-component for beige fat function, was observed in the subcutaneous fat of mice after alcohol challenges. The objective of the present study is to explore the functional significance of adipocyte PRDM16 in the context of ALD. Even though Prdm16 adipocyte-specific-deleted mice (Prdm16-adKO) did not show liver defects at the basal level, following two different alcohol challenge regimens, exacerbated ALD phenotypes were observed in Prdm16-adKO mice compared to that of the control Prdm16 fl/fl mice. Mechanistic investigation suggests that adipose dysfunction after alcohol abuse, including alcohol-induced changes in adipose lipolytic activity, fatty acid oxidation and adipokine levels, may render the worsened ALD phenotype in Prdm16-adKO mice. These results indicate PRDM16-mediated signaling in fat plays a protective role against liver injury caused by alcohol abuse, suggesting it may represent a potential therapeutic target against ALD.
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Affiliation(s)
- Shanshan Liu
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Kezhou Zhu
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Yunying Huang
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China
| | - Weilai Ye
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jun Wu
- Life Sciences Institute, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
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Simon L, Lin HY, Poret J, Vande Stouwe C, Ferguson TF, Welsh DA, Molina PE. Association of circulating adipokines with metabolic measures among people with HIV: Moderating effects of alcohol use. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:2281-2293. [PMID: 39424415 PMCID: PMC11631649 DOI: 10.1111/acer.15464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 08/27/2024] [Accepted: 09/25/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND People with HIV (PWH) are at increased risk for cardiometabolic comorbidities. We have reported that lifetime alcohol use among people with HIV (PWH) is associated with increased risk for metabolic syndrome. Dysfunctional adipose tissue and altered circulating adipokines mediate metabolic dysregulation. The objective of this study was to determine the associations of circulating adipokine concentration with metabolic measures, and the moderating effects of lifetime and recent alcohol use in PWH. METHODS This is a cross-sectional analysis of data from 357 PWH at their baseline visit of the longitudinal New Orleans Alcohol and HIV (NOAH) study. The concentrations of four circulating adipokines (adiponectin, leptin, resistin, and fatty acid-binding protein 4 [FABP4]) and their associations with five metabolic measures (triglycerides, cholesterol, Hemoglobin A1c, Homeostatic Model Assessment for Insulin Resistance, and metabolic syndrome) were examined. RESULTS Higher circulating adiponectin was associated with increased odds of normal triglyceride, cholesterol, and Hemoglobin A1c levels. Increased leptin and FABP4 concentrations were associated with decreased odds of normal triglyceride and cholesterol levels. Increased leptin and FABP4 concentrations were associated with increased odds of insulin resistance and meeting criteria for metabolic syndrome. Increased circulating resistin concentration was associated with decreased odds of normal triglyceride levels and increased odds of meeting criteria for metabolic syndrome. Additionally, among PWH with increased lifetime alcohol use, higher adiponectin concentration was associated with decreased odds of meeting criteria for metabolic syndrome. CONCLUSIONS These data suggest the interplay between adiponectin, leptin, FABP4, and resistin may contribute to metabolic stability among PWH. Moreover, lifetime, but not recent, alcohol use moderates the relationship between adipokines and metabolic measures. These data highlight the relevance of functional adipose tissue mass and associated circulating adipokine levels in maintaining metabolic homeostasis, and its moderation by lifetime alcohol consumption.
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Affiliation(s)
- Liz Simon
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Hui-Yi Lin
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Jonquil Poret
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Curtis Vande Stouwe
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Tekeda F. Ferguson
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Epidemiology Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - David A. Welsh
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Internal Medicine, Section of Pulmonary/Critical Care, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Patricia E. Molina
- Comprehensive Alcohol-HIV/AIDS Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
- Department of Physiology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
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Li W, Xia Y, Yang J, Sanyal AJ, Shah VH, Chalasani NP, Yu Q. Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis. Front Immunol 2024; 15:1377236. [PMID: 39640267 PMCID: PMC11617321 DOI: 10.3389/fimmu.2024.1377236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
Background Alcoholic hepatitis (AH) is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from w-6 and w-3 poly-unsaturated fatty acids (PUFAs). Currently, the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the w-6 and w-3 PUFA metabolic pathways and the impact of alcohol abstinence on profiles of PLMs and SPMs in AH patients are not well studied. Methods In this study, we used LC-MS/MS and ELISA to quantify levels of lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and inflammatory mediators. Furthermore, we conducted a longitudinal study to analyze the effects of alcohol abstinence on LMs over 6- and 12-month follow-ups. Results AH patients exhibited significantly higher plasma levels of w-6 PLMs (PGD2 and LTB4) and SPM RvE1 compared to HDCs or HCs. Conversely, the SPM LXA4 was significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity and various inflammatory cytokines. Particularly, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence.
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Affiliation(s)
- Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Ying Xia
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jing Yang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Arun J. Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Naga P. Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
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Ignat M, Stefanescu H. Non-Invasive Biomarkers for Differentiating Alcohol Associated Hepatitis from Acute Decompensation in Patients with ALD. J Clin Med 2024; 13:3747. [PMID: 38999313 PMCID: PMC11242687 DOI: 10.3390/jcm13133747] [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: 05/19/2024] [Revised: 06/17/2024] [Accepted: 06/22/2024] [Indexed: 07/14/2024] Open
Abstract
Alcohol-associated hepatitis (AH) is the most severe form of alcohol-related liver disease. The natural course of alcohol-related liver disease is influenced by heavy alcohol consumption and abstinence periods. Differentiating between AH and decompensated cirrhosis (DC) could be extremely challenging in clinical practice due to clinical and bioclinical similarities. The severity of AH is made on bioclinical grounds, the severe form necessitating corticotherapy treatment. Liver biopsy is still the standard of care for establishing the diagnosis in atypical presentations. The pathogenesis of AH is an interplay between gene expression, cytokine dysregulation, the immune system and the gut microbiota. Non-invasive tests are increasingly and widely used for the purpose of early diagnosis and reliable prognostication. The non-invasive tests are emerging in concordance with disease pathogenesis. In this review, we describe the non-invasive tools that can distinguish AH from DC. We outline the available cut-offs and their performance in diagnosis and prognosis, as well as in assessing the treatment response to corticotherapy. Promising circulating biomarkers like keratin 18, microRNAs and sphingolipids will be in the review.
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Affiliation(s)
- Mina Ignat
- Regional Institute of Gastroenterology and Hepatology "Prof. Dr. O. Fodor", 400394 Cluj-Napoca, Romania
- Faculty of Medicine, University of Medicine and Pharmacy "Iuliu Hatieganu", 400347 Cluj-Napoca, Romania
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology "Prof. Dr. O. Fodor", 400394 Cluj-Napoca, Romania
- Faculty of Medicine, University of Medicine and Pharmacy "Iuliu Hatieganu", 400347 Cluj-Napoca, Romania
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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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Kronborg TM, Gao Q, Trošt K, Ytting H, O’Connell MB, Werge MP, Thing M, Gluud LL, Hamberg O, Møller S, Moritz T, Bendtsen F, Kimer N. Low sphingolipid levels predict poor survival in patients with alcohol-related liver disease. JHEP Rep 2024; 6:100953. [PMID: 38283758 PMCID: PMC10820332 DOI: 10.1016/j.jhepr.2023.100953] [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: 05/03/2023] [Revised: 10/08/2023] [Accepted: 10/20/2023] [Indexed: 01/30/2024] Open
Abstract
Background & Aims Alcohol-related hepatitis (AH) and alcohol-related cirrhosis are grave conditions with poor prognoses. Altered hepatic lipid metabolism can impact disease development and varies between different alcohol-related liver diseases. Therefore, we aimed to investigate lipidomics and metabolomics at various stages of alcohol-related liver diseases and their correlation with survival. Methods Patients with newly diagnosed alcohol-related cirrhosis, who currently used alcohol (ALC-A), stable outpatients with decompensated alcohol-related cirrhosis with at least 8 weeks of alcohol abstinence (ALC), and patients with AH, were compared with each other and with healthy controls (HC). Circulating lipids and metabolites were analysed using HPLC and mass spectrometry. Results Forty patients with ALC, 95 with ALC-A, 30 with AH, and 42 HC provided plasma. Lipid levels changed according to disease severity, with generally lower levels in AH and cirrhosis than in the HC group; this was most pronounced for AH, followed by ALC-A. Nine out of 10 free fatty acids differed between cirrhosis groups by relative increases of 0.12-0.66 in ALC compared with the ALC-A group (p <0.0005). For metabolomics, total bile acids increased by 19.7, 31.3, and 80.4 in the ALC, ALC-A, and AH groups, respectively, compared with HC (all p <0.0001). Low sphingolipid ([d42:1] and [d41:1]) levels could not predict 180-day mortality (AUC = 0.73, p = 0.95 and AUC = 0.73, p = 0.95) more accurately than the model for end-stage liver disease score (AUC = 0.71), but did predict 90-day mortality (AUC d42:1 = 0.922, AUC d41:1 = 0.893; pd42:1 = 0.005, pd41:1 = 0.007) more accurately than the MELD score AUCMELD = 0.70, pMELD = 0.19). Conclusions Alcohol-related severe liver disease is characterised by low lipid levels progressing with severity of liver disease, especially low sphingomyelins, which also associate to poor prognoses. Impact and implications Lipidomics has the potential to diagnose and risk stratify patients with liver diseases. Lipidomics differed between patients with alcohol-related hepatitis and alcohol-related cirrhosis with and without recent alcohol use. Furthermore, lipidomics could predict short-term mortality and might be suitable as a prognostic tool in the future. Clinical Trials Registration Scientific Ethics Committee of the Capital Region of Denmark, journal no. H-21013476.
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Affiliation(s)
| | - Qian Gao
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kajetan Trošt
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henriette Ytting
- Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | | | - Mira Thing
- Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
| | - Lise Lotte Gluud
- Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
| | - Ole Hamberg
- Medical Department, University Hospital of Zealand, Koege, Denmark
| | - Søren Møller
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Centre for Functional and Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, Hvidovre, Denmark
| | - Thomas Moritz
- Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
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Pérez-Hernández O, González-Reimers E, García-Rodríguez A, Fernández-Rodríguez C, Abreu-González P, González-Pérez JM, Sánchez-Pérez MJ, Ferraz-Amaro I, Martín-González C. Value of inflammatory response and oxidative damage in the diagnosis of infections in severe alcoholic hepatitis. Eur J Intern Med 2024; 119:64-70. [PMID: 37586986 DOI: 10.1016/j.ejim.2023.08.005] [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: 06/10/2023] [Revised: 07/26/2023] [Accepted: 08/03/2023] [Indexed: 08/18/2023]
Abstract
Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p<0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon-gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000-1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections.
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Affiliation(s)
- Onán Pérez-Hernández
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Canary Islands, Spain
| | - Emilio González-Reimers
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Laguna, San Cristóbal de La Laguna, Canary Islands, Spain
| | - Alen García-Rodríguez
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Canary Islands, Spain
| | - Camino Fernández-Rodríguez
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Canary Islands, Spain
| | - Pedro Abreu-González
- Departamento de Ciencias Médicas Básicas, Unidad de Fisiología, Universidad de la Laguna, San Cristóbal de La Laguna, Canary Islands, Spain
| | - José María González-Pérez
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Canary Islands, Spain
| | - María José Sánchez-Pérez
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Canary Islands, Spain
| | - Iván Ferraz-Amaro
- Servicio de Reumatología, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Canary Islands, Spain
| | - Candelaria Martín-González
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Canary Islands, Spain; Departamento de Medicina Interna, Facultad de Medicina, Universidad de La Laguna, San Cristóbal de La Laguna, Canary Islands, Spain.
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Li W, Xia Y, Yang J, Sanyal AJ, Shah VH, Chalasani NP, Yu Q. Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.12.15.23300034. [PMID: 38168393 PMCID: PMC10760266 DOI: 10.1101/2023.12.15.23300034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Background Chronic excessive alcohol consumption leads to a spectrum of alcohol-associated liver diseases (ALD), including alcoholic hepatitis (AH). AH is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is an actively regulated process, primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from ω-6 and ω-3 poly-unsaturated fatty acids (PUFAs). We investigated the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the ω-6 and ω-3 PUFA metabolic pathways and examined the impact of alcohol abstinence on rectifying the dysregulated biosynthesis of PLMs and SPMs in AH patients. Methods LC-MS/MS and ELISA were used to quantify levels of bioactive lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and various markers of inflammatory cascade andmicrobial translocation. Furthermore, we conducted a longitudinal study to track changes in levels of LMs over 6- and 12-month follow-ups in AH patients who underwent alcohol abstinence. Results AH patients exhibited significantly higher plasma levels of ω-6 PLMs (PGD 2 and LTB 4 ) and SPM RvE1 compared to HDCs and/or HCs. Conversely, key SPMs such as LXA4, RvD1, and several precursors in the ω-3 pathway were significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity, clinical parameters, and various inflammatory cytokines. In particular, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score, suggesting its potential utility as an indicator of disease severity in AH patients. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence. Conclusion Our study reveals significant dysregulation in the levels of PLM metabolites and anti-inflammatory SPMs in both ω-6 and ω-3 PUFA pathways in AH patients. This disrupted biosynthesis, characterized by an overabundance of PLMs and a deficiency in SPMs, is linked to the heightened inflammation observed in AH patients. Importantly, our findings suggest an important role of alcohol abstinence in restoring the balance of these LMs and the potential therapeutic benefits of SPM supplements in alleviating the inflammatory cascade in AH patients.
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Birnbaum JA, Herman HS, Gao Q, Koenigsberg M, Sigal SH. The Prognostic Significance of the Platelet Count in Alcoholic Hepatitis. GASTRO HEP ADVANCES 2022; 2:8-15. [PMID: 39130158 PMCID: PMC11308416 DOI: 10.1016/j.gastha.2022.07.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 07/29/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Thrombocytopenia is present in up to 76% of patients with chronic liver disease, and lower platelet counts (PCs) are associated with greater severity of portal hypertension. In this study, we assess the relationship of PC in patients with a clinical diagnosis of severe alcoholic hepatitis (SAH) with clinical severity and response to corticosteroid (CS) therapy. Methods Clinical characteristics, treatment, and hospital outcomes for patients admitted with SAH were analyzed from an electronic health record system. Patients were categorized based on admission PC (k/uL) into 5 categories: <50, 50-99, 100-149, 150-199, and ≥200. Frequency of complications (acute kidney injury, ascites, and hepatic encephalopathy), length of stay, and admission to an intensive care unit were analyzed across PC categories. Characteristics of patients who did and did not receive at least 4 days of CS therapy were compared. Results Among 159 patients, 15 (9.4%) were in the PC < 50 category, 42 (26.4%) in PC 50-99, 51 (32%) in PC 100-149, 23 (14.5%) in PC 150-199, and 28 (17.6%) in PC ≥ 200. A higher admission PC was associated with greater white blood cell count, absolute neutrophil count, and total bilirubin (P < .05). Patients with higher PC on admission were more likely to receive steroids. PC was inversely associated with Lille score at treatment day 4 (P < .05). Conclusion A higher PC in SAH was associated with a greater inflammatory response and total bilirubin. Patients with a higher PC were more likely to receive CS and have a favorable treatment response.
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Affiliation(s)
| | | | - Qi Gao
- Albert Einstein College of Medicine, Bronx, New York
| | - Mordecai Koenigsberg
- Albert Einstein College of Medicine, Bronx, New York
- Department of Radiology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York
| | - Samuel H. Sigal
- Albert Einstein College of Medicine, Bronx, New York
- Division of Hepatology, Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York
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11
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Jophlin L, Singal AK. Liver Biopsy in Patients With Alcohol-Associated Liver Disease With Acute-on-Chronic Liver Failure. J Clin Exp Hepatol 2022; 12:544-550. [PMID: 35535109 PMCID: PMC9077173 DOI: 10.1016/j.jceh.2021.08.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/09/2021] [Indexed: 01/11/2023] Open
Abstract
Patients with alcohol-associated liver disease may develop severe forms of presentation of acute-on-chronic liver failure, with a high risk for short-term mortality. Alcoholic hepatitis should be suspected among patients with alcohol-associated liver disease who present with acute-on-chronic liver failure. In this review, we discuss the need and feasibility of liver biopsy in the diagnosis of alcoholic hepatitis and predicting its prognosis among decompensated patients with alcohol-associated liver disease and acute-on-chronic liver failure.
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Key Words
- AARC, Asia-Pacific ACLF Research Consortium
- ACLF
- ACLF, acute-on-chronic liver failure
- AH
- AH, alcoholic hepatitis
- AHHS, alcoholic hepatitis histologic score
- ALD
- ALD, alcohol-associated liver disease
- AUD, alcohol use disorder
- DF, discriminant function
- EUS, endoscopic ultrasound
- EtG, ethyl glucuronide
- NIAAA, National Institute on Alcoholism and Alcohol Abuse
- PEth, phosphatidylethanol
- SALVE, Study of Alcohol-related LiVer disease in Europe
- histology
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Affiliation(s)
- Loretta Jophlin
- Department of Gastroenterology and Hepatology, University of Louisville, Louisville, KY, USA
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, Department of Medicine, University of South Dakota Sanford School of Medicine, South Dakota, USA,Address for correspondence:. Ashwani K. Singal, Professor of Medicine, University of South Dakota Sanford School of Medicine, Transplant Hepatologist and Chief Clinical Research Affairs, Avera McKennan University Hospital Transplant Institute, Sioux Falls, SD, 57105, USA. Tel.: +605 322-8545; fax: +605 322 8536.
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12
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Morcuende A, Navarrete F, Nieto E, Manzanares J, Femenía T. Inflammatory Biomarkers in Addictive Disorders. Biomolecules 2021; 11:biom11121824. [PMID: 34944470 PMCID: PMC8699452 DOI: 10.3390/biom11121824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/23/2021] [Accepted: 11/30/2021] [Indexed: 12/21/2022] Open
Abstract
Substance use disorders are a group of diseases that are associated with social, professional, and family impairment and that represent a high socio-economic impact on the health systems of countries around the world. These disorders present a very complex diagnosis and treatment regimen due to the lack of suitable biomarkers supporting the correct diagnosis and classification and the difficulty of selecting effective therapies. Over the last few years, several studies have pointed out that these addictive disorders are associated with systemic and central nervous system inflammation, which could play a relevant role in the onset and progression of these diseases. Therefore, identifying different immune system components as biomarkers of such addictive disorders could be a crucial step to promote appropriate diagnosis and treatment. Thus, this work aims to provide an overview of the immune system alterations that may be biomarkers of various addictive disorders.
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Affiliation(s)
- Alvaro Morcuende
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
| | - Francisco Navarrete
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
- Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain
| | - Elena Nieto
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
| | - Jorge Manzanares
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
- Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain
| | - Teresa Femenía
- Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, Avda. de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; (A.M.); (F.N.); (E.N.); (J.M.)
- Red Temática de Investigación Cooperativa en Salud (RETICS), Red de Trastornos Adictivos, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-965-919-553
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13
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Gopal T, Ai W, Casey CA, Donohue TM, Saraswathi V. A review of the role of ethanol-induced adipose tissue dysfunction in alcohol-associated liver disease. Alcohol Clin Exp Res 2021; 45:1927-1939. [PMID: 34558087 PMCID: PMC9153937 DOI: 10.1111/acer.14698] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/14/2022]
Abstract
Alcohol-associated liver disease (AALD) encompasses a spectrum of liver diseases that includes simple steatosis, steatohepatitis, fibrosis, and cirrhosis. The adverse effects of alcohol in liver and the mechanisms by which ethanol (EtOH) promotes liver injury are well studied. Although liver is known to be the primary organ affected by EtOH exposure, alcohol's effects on other organs are also known to contribute significantly to the development of liver injury. It is becoming increasingly evident that adipose tissue (AT) is an important site of EtOH action. Both AT storage and secretory functions are altered by EtOH. For example, AT lipolysis, stimulated by EtOH, contributes to chronic alcohol-induced hepatic steatosis. Adipocytes secrete a wide variety of biologically active molecules known as adipokines. EtOH alters the secretion of these adipokines from AT, which include cytokines and chemokines that exert paracrine effects in liver. In addition, the level of EtOH-metabolizing enzymes, in particular, CYP2E1, rises in the AT of EtOH-fed mice, which promotes oxidative stress and/or inflammation in AT. Thus, AT dysfunction characterized by increased AT lipolysis and free fatty acid mobilization and altered secretion of adipokines can contribute to the severity of AALD. Of note, moderate EtOH exposure results in AT browning and activation of brown adipose tissue which, in turn, can promote thermogenesis. In this review article, we discuss the direct effects of EtOH consumption in AT and the mechanisms by which EtOH impacts the functions of AT, which, in turn, increases the severity of AALD in animal models and humans.
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Affiliation(s)
- Thiyagarajan Gopal
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Weilun Ai
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Carol A. Casey
- Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Terrence M. Donohue
- Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Viswanathan Saraswathi
- Department of Internal Medicine, Divisions of Diabetes, Endocrinology, and Metabolism
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
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14
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Mitra A, Myers L, Ahn J. Assessing the Severity and Prognosis of Alcoholic Hepatitis. Clin Liver Dis 2021; 25:585-593. [PMID: 34229841 DOI: 10.1016/j.cld.2021.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Acute alcoholic hepatitis is a clinical entity with significant consequences. Those with severe disease can have high short-term mortality, and considerations for liver transplant candidacy may be raised. Estimating prognosis and mortality is of the utmost importance, as it can guide decision making for corticosteroid therapy and help patients gain an understanding of their illness. Maddrey's discriminant function and MELD score are 2 commonly used static models validated to help estimate severity and prognosis in acute alcoholic hepatitis. This article reviews the 2 models and others used in this difficult setting to assess these patients and guide decision making.
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Affiliation(s)
- Arnab Mitra
- Division of Gastroenterology and Hepatology, Department of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, L461, Portland, OR 97239-3098, USA.
| | - Lauren Myers
- Division of Gastroenterology and Hepatology, Department of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, L461, Portland, OR 97239-3098, USA
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Department of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, L461, Portland, OR 97239-3098, USA
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15
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Arab JP, Arrese M, Singal AK. Diagnosis of Alcohol-Associated Hepatitis: When Is Liver Biopsy Required? Clin Liver Dis 2021; 25:571-584. [PMID: 34229840 DOI: 10.1016/j.cld.2021.03.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcohol-associated hepatitis (AH) is a unique clinical syndrome in patients with excessive and prolonged alcohol consumption, and negatively impacts the patient outcomes. Among patients with asymptomatic alcohol-associated liver disease with elevated liver enzymes and/or steatosis, liver biopsy is required to diagnose AH. Noninvasive assessment should be performed in these patients to determine risk of advanced fibrosis. In symptomatic patients with jaundice, liver biopsy is required when the clinical diagnosis is uncertain. Liver biopsy is not recommended to determine prognosis of patients with AH. Noninvasive biomarkers are emerging for diagnosis of and determining prognosis of patients with AH.
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Affiliation(s)
- Juan Pablo Arab
- Department of Gastroenterology and Hepatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Av Libertador Bernardo O'Higgins 340, Santiago, Región Metropolitana, Chile; Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marco Arrese
- Department of Gastroenterology and Hepatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Av Libertador Bernardo O'Higgins 340, Santiago, Región Metropolitana, Chile; Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ashwani K Singal
- University of South Dakota Sanford School of Medicine, McKennan University Hospital Transplant Institute, Cliff Ave., Sioux Falls, SD 57105, USA.
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16
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Abstract
Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated with a poor prognosis and its recovery relies mostly on abstinence. With alcohol use disorder being universally on the rise, the impact of alcoholic hepatitis on society and health-care costs is expected to increase significantly. Prognostic factors and liver biopsy can help with timely diagnosis, to determine eligibility and response to corticosteroids, and for prognostication and transplant referral. Although recent discoveries in the pathophysiology of alcoholic hepatitis are encouraging and could pave the way for novel treatment modalities, a multidisciplinary approach considering timely identification and treatment of liver-related complications, infectious and metabolic disease, malnutrition, and addiction counseling should be emphasized. Apart from proper selection of candidates, transplant programs should provide adequate post-transplant addiction support in order to make of early liver transplantation for alcoholic hepatitis the ultimate sobering experience in the next decade.
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Affiliation(s)
- Vikrant Rachakonda
- Division of Gastroenterology and Hepatology, Starzl Transplantation Institute, and Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Starzl Transplantation Institute, and Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, Starzl Transplantation Institute, and Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
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17
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Shipley LC, Kodali S, Singal AK. Recent updates on alcoholic hepatitis. Dig Liver Dis 2019; 51:761-768. [PMID: 31010745 DOI: 10.1016/j.dld.2019.03.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/17/2019] [Accepted: 03/22/2019] [Indexed: 02/07/2023]
Abstract
Alcoholic hepatitis (AH) is a unique clinical syndrome that affects patients with chronic and active harmful alcohol consumption, and is associated with a high mortality of up to 40% at 1 month from presentation. It is important to assess disease severity and prognosis at time of presentation to identify patients at risk for high mortality and potential candidates for specific therapies. The cornerstone therapy for AH is enteral nutrition and abstinence. Steroids remain the only pharmacological option for severe AH however, adverse effects and lack of long-term benefit limit their routine use. Early liver transplantation is a potential salvage therapy for select severe AH patients. This review article comprehensively covers recent advances on the clinical unmet needs in the field including newer therapies and therapeutic targets, role of liver transplantation, and emerging biomarkers throughout the disease process from diagnosis, assessing prognosis and disease severity, and predicting responsiveness to medical therapies for severe AH.
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Affiliation(s)
- Lindsey C Shipley
- University of South Dakota Sanford School of Medicine, United States; Avera Transplant Institute, United States
| | - Sudha Kodali
- Division of Gastroenterology and Hepatology, Methodist Hospital, Houston, TX, United States
| | - Ashwani K Singal
- Division of Gastroenterology and Hepatology, University of South Dakota, Avera McKennan University Health Center and Transplant Institute, Sioux Falls, SD 57105, United States.
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18
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Huo X, Sun X, Cao Z, Qiao J, Yang S, Meng X, Zhao Y. Optimal ratio of 18α- and 18β-glycyrrhizic acid for preventing alcoholic hepatitis in rats. Exp Ther Med 2019; 18:172-178. [PMID: 31258651 PMCID: PMC6566121 DOI: 10.3892/etm.2019.7572] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
The glycyrrhizic acid (GA) epimers 18α- and 18β-GA exert anti-inflammatory and hepatoprotective activities, which may help to protect against alcoholic liver disease, particularly alcoholic hepatitis (AH). The aim of the present study was to investigate the optimal ratio of 18α- and 18β-GA for preventing AH in rats. Different groups of rats were administered seven different ratios of 18α- and 18β-GA (10:0, 8:2, 6:4, 5:5, 4:6, 2:8 and 0:10; 10.83 mg/kg), vehicle control, or silymarin (22.75 mg/kg) as a positive control, followed by administration of 40% alcohol (10 ml/kg) once a day for four weeks. Subsequently, livers were isolated and routinely processed for histological examination. The serum levels of 23 cytokines and chemokines associated with AH were examined with a Bio-Plex 200 Luminex assay. It was revealed that all ratios of 18α- and 18β-GA prevented alcohol-induced liver injury, as evidenced by a lesser degree of histopathological changes in the liver as compared with those in the model group. Furthermore, the levels of 15 cytokines/chemokines were significantly altered after alcohol administration, which was significantly inhibited by, pre-treatment with different proportions of 18α- and 18β-GA, particularly at a ratio of 4:6, for most cytokines/chemokines associated with AH, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-7, IL-6, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-3α, macrophage- and granulocyte macrophage colony-stimulating factor, chemokine (C-X-C motif) ligand 1(GRO/KC), vascular endothelial growth factor and C-C motif chemokine ligand 5 (RANTES). Taken together, based on these results the optimal ratio of 18α- and 18β-GA to prevent AH in model rats was considered to be 4:6.
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Affiliation(s)
- Xiaowei Huo
- College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, Hebei 071002, P.R. China
| | - Xiaoke Sun
- College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, Hebei 071002, P.R. China
| | - Zepeng Cao
- College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, Hebei 071002, P.R. China
| | - Jingzhe Qiao
- Oncology Department, Hebei Yiling Hospital, Shijiazhuang, Hebei 050091, P.R. China
| | - Sa Yang
- College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, Hebei 071002, P.R. China
| | - Xiangbo Meng
- College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, Hebei 071002, P.R. China
| | - Yanyan Zhao
- College of Pharmaceutical Science, Key Laboratory of Pharmaceutical Quality Control of Hebei Province, Hebei University, Baoding, Hebei 071002, P.R. China
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19
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Shen H, Jiang L, Lin JD, Omary MB, Rui L. Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice. J Clin Invest 2019; 129:2305-2317. [PMID: 30888335 PMCID: PMC6546460 DOI: 10.1172/jci124376] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 03/14/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic alcohol consumption causes liver injury, inflammation and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a novel hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT, and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin that suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.
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Affiliation(s)
- Hong Shen
- Department of Molecular & Integrative Physiology
| | - Lin Jiang
- Department of Molecular & Integrative Physiology
| | - Jiandie D. Lin
- Life Sciences Institute and Department of Cell & Developmental Biology, and
| | - M. Bishr Omary
- Department of Molecular & Integrative Physiology
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Liangyou Rui
- Department of Molecular & Integrative Physiology
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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20
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Procopet B, Fischer P, Farcau O, Stefanescu H. Metabolomics: From liver chiromancy to personalized precision medicine in advanced chronic liver disease. World J Hepatol 2018; 10:371-378. [PMID: 29599900 PMCID: PMC5871857 DOI: 10.4254/wjh.v10.i3.371] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 01/19/2018] [Accepted: 01/29/2018] [Indexed: 02/06/2023] Open
Abstract
Currently there is a lack of accurate biomarkers for diagnosis and prognosis in advanced liver diseases. Either the occurrence of first decompensation, or diagnosis of acute on chronic liver failure, severe alcoholic hepatitis, or hepatocellular carcinoma (HCC), none of the available biomarkers are satisfactory. Metabolomics is the newest of omics, being much closer than the others to the actual phenotype and pathologic changes that characterizes a certain condition. It deals with a much wider spectrum of low molecular weight bio-compounds providing a powerful platform for discovering novel biomarkers and biochemical pathways to improve diagnostic, prognostication and therapy. Until now metabolomics was applied in a wide spectrum of liver conditions, but the findings were contradictory. This review proposes a synthesis of the existing evidences of metabolomics use in advanced chronic liver diseases, decompensated liver cirrhosis, severe alcoholic hepatitis and HCC.
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Affiliation(s)
- Bogdan Procopet
- 3 Medical Clinic, University of Medicine and Pharmacy, Cluj 400162, Romania
| | - Petra Fischer
- 3 Medical Clinic, University of Medicine and Pharmacy, Cluj 400162, Romania
| | - Oana Farcau
- 3 Medical Clinic, University of Medicine and Pharmacy, Cluj 400162, Romania
| | - Horia Stefanescu
- Hepatology Unit, Regional Institute of Gastroenterology and Hepatology, Cluj 400162, Romania.
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21
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22
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Abstract
Adipose tissue represents a large volume of biologically active tissue that exerts substantial systemic effects in health and disease. Alcohol consumption can profoundly disturb the normal functions of adipose tissue by inducing adipocyte death and altering secretion of adipokines, pro-inflammatory mediators and free fatty acids from adipose tissue, which have important direct and indirect effects on the pathogenesis of alcoholic liver disease (ALD). Cessation of alcohol intake quickly reverses inflammatory changes in adipose tissue, and pharmacological treatment that normalizes adipose tissue function improves experimental ALD. Obesity exacerbates liver injury induced by chronic or binge alcohol consumption, and obesity and alcohol can synergize to increase risk of ALD and progression. Physicians who care for individuals with ALD should be aware of the effects of adipose tissue dysfunction on liver function, and consider strategies to manage obesity and insulin resistance. This Review examines the effect of alcohol on adiposity and adipose tissue and the relationship between alcohol, adipose tissue and the liver.
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23
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Abnormalities of Lipoprotein Levels in Liver Cirrhosis: Clinical Relevance. Dig Dis Sci 2018; 63:16-26. [PMID: 29177578 DOI: 10.1007/s10620-017-4862-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 11/19/2017] [Indexed: 12/17/2022]
Abstract
Progressive lipoprotein impairment occurs in liver cirrhosis and is associated with increased morbidity and mortality. The present review aims to summarize the current evidence regarding the prognostic value of lipoprotein abnormalities in liver cirrhosis and to address the need of a better prognostic stratification of patients, including lipoprotein profile assessment. Low levels of lipoproteins are usual in cirrhosis. Much evidence supports the prognostic role of hypolipidemia in cirrhotic patients. In particular, hypocholesterolemia represents an independent predictor of survival in cirrhosis. In cirrhotic patients, lipoprotein impairment is associated with several complications: infections, malnutrition, adrenal function, and spur cell anemia. Alterations of liver function are associated with modifications of circulating lipids. Decreased levels of lipoproteins significantly impact the survival of cirrhotic patients and play an important role in the pathogenesis of some cirrhosis-related complications.
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24
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Li W, Amet T, Xing Y, Yang D, Liangpunsakul S, Puri P, Kamath P, Sanyal A, Shah V, Katz B, Radaeva S, Crabb D, Chalasani N, Yu Q. Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study. Hepatology 2017; 66:575-590. [PMID: 28466561 PMCID: PMC5548491 DOI: 10.1002/hep.29242] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/27/2017] [Accepted: 04/24/2017] [Indexed: 12/13/2022]
Abstract
Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma-induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. CONCLUSION AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).
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Affiliation(s)
- Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Tohti Amet
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yanyan Xing
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Dennis Yang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Puneet Puri
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Patrick Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Barry Katz
- Department of Biostatistics, Indiana University School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202
| | - Svetlana Radaeva
- National Institute of Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD
| | - David Crabb
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Internal Medicine, Eskenazi Health, Indianapolis, IN 46202
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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25
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Sidhu SS, Goyal O, Kishore H, Sidhu S. New paradigms in management of alcoholic hepatitis: a review. Hepatol Int 2017; 11:255-267. [PMID: 28247264 DOI: 10.1007/s12072-017-9790-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 02/08/2017] [Indexed: 12/12/2022]
Abstract
Severe alcoholic hepatitis (SAH) is defined by modified Maddrey discriminant function ≥32 or Model for End-Stage Liver Disease (MELD) >21 and/or hepatic encephalopathy. It has a 3-month mortality rate ≥30-70 %. Patients with severe alcoholic hepatitis need combined, i.e., static (MELD score) and dynamic (Lille's score), prognostication. Systemic inflammation and poor regeneration are hallmarks of SAH, rather than intrahepatic inflammation. SAH is characterized by dysregulated and uncontrolled systemic inflammatory response followed by weak compensatory antiinflammatory response that leads to increased susceptibility to infection and multiple organ failure. Massive necrosis of hepatocytes exceeds the proliferative capacity of hepatocytes. Liver progenitor cells proliferate to form narrow ductules which radiate out into the damaged liver parenchyma. Corticosteroids have been the standard-of-care therapy, albeit controversial. However, the recent Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial revealed that prednisolone was not associated with a significant reduction in 28-day mortality, with no improvement in outcomes at 90 days or 1 year. A paradigm shift from antiinflammatory therapy such as corticosteroids to liver regeneration treatment, e.g., granulocyte-colony stimulating factor, molecular targeted treatments, and fecal microbiota transplantation, for severe alcoholic hepatitis is taking place. Liver transplantation should be offered to select patients with severe alcoholic hepatitis who are nonresponsive to medical treatment.
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Affiliation(s)
- Sandeep Singh Sidhu
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India.
| | - Omesh Goyal
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Harsh Kishore
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
| | - Simran Sidhu
- Himalayan Institute of Medical Sciences, Dehradun, Uttarakhand, India
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26
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Fung P, Pyrsopoulos N. Emerging concepts in alcoholic hepatitis. World J Hepatol 2017; 9:567-585. [PMID: 28515843 PMCID: PMC5411952 DOI: 10.4254/wjh.v9.i12.567] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/21/2017] [Accepted: 03/12/2017] [Indexed: 02/06/2023] Open
Abstract
Severe alcoholic hepatitis is implicated as a costly, worldwide public health issue with high morbidity and mortality. The one-month survival for severe alcoholic hepatitis is low with mortality rates high as 30%-50%. Abstinence from alcohol is the recommended first-line treatment. Although corticosteroids remain as the current evidence based option for selected patients with discriminant function > 32, improvement of short-term survival rate may be the only benefit. Identification of individuals with risk factors for the development of severe alcoholic hepatitis may provide insight to the diverse clinical spectrum and prognosis of the disease. The understanding of the complex pathophysiologic processes of alcoholic hepatitis is the key to elucidating new therapeutic treatments. Newer research describes the use of gut microbiota modification, immune modulation, stimulation of liver regeneration, caspase inhibitors, farnesoid X receptors, and the extracorporeal liver assist device to aid in hepatocellular recovery. Liver transplantation can be considered as the last medical option for patients failing conventional medical interventions. Although the preliminary data is promising in patients with low risk of recividism, controversy remains due to organ scarcity. This review article comprehensively summarizes the epidemiology, pathophysiology, risk factors, and prognostic indicators of severe alcoholic hepatitis with a focus on the current and emerging therapeutics.
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Affiliation(s)
- Phoenix Fung
- Phoenix Fung, Nikolaos Pyrsopoulos, Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Phoenix Fung, Nikolaos Pyrsopoulos, Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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27
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Sugimoto K, Takei Y. Pathogenesis of alcoholic liver disease. Hepatol Res 2017; 47:70-79. [PMID: 27138729 DOI: 10.1111/hepr.12736] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 04/26/2016] [Accepted: 04/29/2016] [Indexed: 02/06/2023]
Abstract
Alcoholic liver disease (ALD) has become one of the most critical health problems in many countries, including Japan. Liver injury in ALD ranges from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular carcinoma. Many factors are thought to contribute to the development and progression of ALD, particularly insulin resistance, generation of reactive oxygen species during alcohol metabolism, adipokines from visceral adipose tissue, and endotoxin derived from the gut. Although the pathogenesis of ALD has been widely investigated, the precise mechanisms are yet to be elucidated and many questions remain. This article reviews the possible mechanisms for the development of ALD identified to date.
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Affiliation(s)
- Kazushi Sugimoto
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Mie, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Mie, Japan
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28
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Shasthry SM, Sarin SK. New treatment options for alcoholic hepatitis. World J Gastroenterol 2016; 22:3892-3906. [PMID: 27099434 PMCID: PMC4823241 DOI: 10.3748/wjg.v22.i15.3892] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/07/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using “Omics” platforms, newer options for patients with alcoholic hepatitis are expected soon.
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29
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Neuman MG, Maor Y, Nanau RM, Melzer E, Mell H, Opris M, Cohen L, Malnick S. Alcoholic Liver Disease: Role of Cytokines. Biomolecules 2015; 5:2023-2034. [PMID: 26343741 PMCID: PMC4598786 DOI: 10.3390/biom5032023] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 08/21/2015] [Accepted: 08/24/2015] [Indexed: 02/07/2023] Open
Abstract
The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, ON M5G 0A3, Canada.
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON M5G 0A3, Canada.
| | - Yaakov Maor
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot 76100, Israel.
| | - Radu M Nanau
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, ON M5G 0A3, Canada.
| | - Ehud Melzer
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot 76100, Israel.
| | - Haim Mell
- Israel Anti-Drug Authority, Jerusalem 91039, Israel.
| | - Mihai Opris
- In Vitro Drug Safety and Biotechnology, University of Toronto, Toronto, ON M5G 0A3, Canada.
- Casa de Ajutor Reciproc, Bucharest 031621, Romania.
| | - Lawrence Cohen
- Sunnybrook Health Sciences Centre and Department of Internal Medicine, University of Toronto, Toronto, ON M5G 0A3, Canada.
| | - Stephen Malnick
- Division of Gastroenterology, Kaplan Health Sciences Centre, Department of Medicine, Faculty of Medicine, Hebrew University, Rehovot 76100, Israel.
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30
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Carr RM, Correnti J. Insulin resistance in clinical and experimental alcoholic liver disease. Ann N Y Acad Sci 2015; 1353:1-20. [PMID: 25998863 DOI: 10.1111/nyas.12787] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Alcoholic liver disease (ALD) is the number one cause of liver failure worldwide; its management costs billions of healthcare dollars annually. Since the advent of the obesity epidemic, insulin resistance (IR) and diabetes have become common clinical findings in patients with ALD; and the development of IR predicts the progression from simple steatosis to cirrhosis in ALD patients. Both clinical and experimental data implicate the impairment of several mediators of insulin signaling in ALD, and experimental data suggest that insulin-sensitizing therapies improve liver histology. This review explores the contribution of impaired insulin signaling in ALD and summarizes the current understanding of the synergistic relationship between alcohol and nutrient excess in promoting hepatic inflammation and disease.
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Affiliation(s)
- Rotonya M Carr
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jason Correnti
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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31
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Liu N, Mu H, Liang CD, Zheng JM, Zhang J. Effect of norepinephrine on expression of leptin and leptin receptor in hepatic stellate cells. Shijie Huaren Xiaohua Zazhi 2015; 23:1052-1058. [DOI: 10.11569/wcjd.v23.i7.1052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of sympathetic neurotransmitter norepinephrine (NE) on the expression of leptin and leptin receptor in hepatic stellate cells (HSCs) in vitro.
METHODS: Different concentrations of NE were applied on HSCs for 24, 48 or 72 h. Immunohistochemical staining was used to detect the expression of α-smooth muscle actin (α-SMA) in activated HSCs. Western blot was used to detect the expression of leptin and soluble leptin receptor (sOB-R) proteins. Real-time PCR was used to examine the effect of NE on mRNA expression of leptin and sOB-R in HSCs.
RESULTS: Immunohistochemistry results showed that after 1, 10, or 100 μmol/L NE was used on HSCs, the expression of α-SMA increased significantly at 24 h (14.1 ± 4.4, 17.5 ± 5.2, 19.8 ± 4.1 vs 11.3 ± 4.5; P < 0.05), suggesting that NE could activate HSCs and promote their proliferation. When 10 μmol/L NE was applied for 24, 48 or 72 h, α-SMA expression gradually increased (17.5 ± 5.2; 18.5 ± 5.4; 19.2 ± 6.2, P < 0.05), indicating that NE induced HSC proliferation in a time-dependent manner. Western blot analysis showed that leptin protein expression was significantly higher in HSCs after treatment with 1, 10 and 100 μmol/L NE for 24 h compared with the control group (1.54 ± 0.08, 2.72 ± 0.09, 2.84 ± 0.18 vs 0.85 ± 0.12, P < 0.05); the expression of leptin receptor protein was also significantly higher than that in the control group (1.57 ± 0.18, 2.51 ± 0.17, 2.89 ± 0.19 vs 0.98 ± 0.15, P < 0.05). Real-time PCR was used to detect mRNA expression of leptin and leptin receptor, and the results showed that leptin mRNA expression was significantly higher than that in the control group (1.51 ± 0.08, 2.58 ± 0.09, 3.63 ± 0.12 vs 1.00 ± 0.07, P < 0.05); the expression of leptin receptor mRNA was also significantly higher than that in the control group (1.71 ± 0.08, 2.87 ± 0.10, 4.01 ± 0.14 vs 1.00 ± 0.08, P < 0.05).
CONCLUSION: The sympathetic neurotransmitter NE plays a role in the process of liver fibrosis possibly by promoting leptin and sOB-R expression in activated HSCs.
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