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1
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Vairappan B, Ts R, Ram AK, Mohan P, Pottakkat B. NOSTRIN is an emerging positive regulator of decompensated cirrhotic patients with portal hypertension. Dig Liver Dis 2025; 57:427-435. [PMID: 39294044 DOI: 10.1016/j.dld.2024.08.050] [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: 05/29/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND AND AIMS Decreased nitric oxide (NO) bioavailability in a cirrhotic liver contributes to high intrahepatic vascular resistance (IHVR) and portal hypertension (PHT). Nostrin is an inhibitory protein of NO synthesising enzyme endothelial NO synthase (eNOS), shown to increase in cirrhosis with PHT, however, the precise molecular mechanism is poorly documented. This study aimed to elucidate the role of Nostrin and associated derangement in hepatic NO generation in cirrhotic liver. Further, we investigate whether Nostrin could be a biomarker in the progression of cirrhosis. METHODS This study was conducted on sixty healthy subjects and 120 cirrhotic patients. In addition, liver tissue samples were collected from cirrhotic patients for the analysis of Nostrin, eNOS and inflammatory markers. RESULTS When compared to healthy controls, systemic levels of Nostrin and cGMP were elevated in compensated cirrhosis. In decompensated cirrhosis, further robust increases in Nostrin and cGMP were noted. Furthermore, Nostrin expression was considerably higher whilst reduced eNOS activity and hepatic cGMP levels in cirrhotic liver compared to control liver. CONCLUSIONS In cirrhotic patients, a robust increase in hepatic Nostrin expression may reduce eNOS activity and associated local NO generation. Furthermore, Blood Nostrin concentration was higher and parallel to disease severity and could be a key diagnostic and prognostic biomarker in cirrhotic patients with PHT.
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Affiliation(s)
- Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India.
| | | | - Amit Kumar Ram
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, JIPMER, Pondicherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, JIPMER, Pondicherry 605006, India
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2
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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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3
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Liu J, MacNaughtan J, Kerbert AJC, Portlock T, Martínez Gonzalez J, Jin Y, Clasen F, Habtesion A, Ji H, Jin Q, Phillips A, De Chiara F, Ingavle G, Jimenez C, Zaccherini G, Husi K, Rodriguez Gandia MA, Cordero P, Soeda J, McConaghy L, Oben J, Church K, Li JV, Wu H, Jalan A, Gines P, Solà E, Eaton S, Morgan C, Kowalski M, Green D, Gander A, Edwards LA, Cox IJ, Cortez-Pinto H, Avery T, Wiest R, Durand F, Caraceni P, Elosua R, Vila J, Pavesi M, Arroyo V, Davies N, Mookerjee RP, Vargas V, Sandeman S, Mehta G, Shoaie S, Marchesi J, Albillos A, Andreola F, Jalan R. Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis. Gut 2024; 73:1183-1198. [PMID: 38621924 DOI: 10.1136/gutjnl-2023-330699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 03/17/2024] [Indexed: 04/17/2024]
Abstract
OBJECTIVE Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER NCT03202498.
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Affiliation(s)
- Jinxia Liu
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jane MacNaughtan
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Annarein J C Kerbert
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Theo Portlock
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Javier Martínez Gonzalez
- Hospital Ramón y Cajal, IRYCIS, CIBEREHD, Universidad de Alcalá, Madrid, Spain
- Liver Unit, Hospital Vall d'Hebron, Universitat Autónoma, CIBERehd, Barcelona, Spain
| | - Yi Jin
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Frederick Clasen
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Abeba Habtesion
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Huoyan Ji
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Qin Jin
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Alexandra Phillips
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Francesco De Chiara
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Ganesh Ingavle
- Centre for Regenerative Medicine and Devices, School of Applied Sciences, University of Brighton, Brighton, UK
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune, India
| | - Cesar Jimenez
- Liver Unit, Hospital Vall d'Hebron, Universitat Autónoma, CIBERehd, Barcelona, Spain
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-related Diseases, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
| | - Katherine Husi
- Department of Gastroenterology, Inselspital University Hospital Bern, Bern, Switzerland
| | | | - Paul Cordero
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune, India
| | - Junpei Soeda
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Lynda McConaghy
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Jude Oben
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Karen Church
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Jia V Li
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Haifeng Wu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | | | - Pere Gines
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Faculty of Medicine and Health sciences, University of Barcelona, Barcelona, Spain
| | - Elsa Solà
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Faculty of Medicine and Health sciences, University of Barcelona, Barcelona, Spain
| | - Simon Eaton
- Institute of Child Health, University College London, London, UK
| | - Carrie Morgan
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Michal Kowalski
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Daniel Green
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Amir Gander
- Tissue Access for Patient Benefit, University College London, London, UK
| | - Lindsey A Edwards
- Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, Guy's Tower, Guy's Hospital, King's College London, London, UK
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - I Jane Cox
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | | | - Reiner Wiest
- UVCM Gastroenterology, University Bern, Bern, Switzerland
| | - Francois Durand
- Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, University paris Cité, Paris, France
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | | | - Marco Pavesi
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Nathan Davies
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Rajeshwar P Mookerjee
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Victor Vargas
- Liver Unit, Hospital Vall d'Hebron, Universitat Autónoma, CIBERehd, Barcelona, Spain
| | - Susan Sandeman
- Centre for Regenerative Medicine and Devices, School of Applied Sciences, University of Brighton, Brighton, UK
| | - Gautam Mehta
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Julian Marchesi
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, St Mary's Hospital, Imperial College London, London, UK
| | - Agustín Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramon y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Fausto Andreola
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
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4
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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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5
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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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6
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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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7
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Saeidinejad M, Elshabrawi A, Sriphoosanaphan S, Andreola F, Mehta G, Agarwal B, Jalan R. Novel Therapeutic Approaches in Treatment of Acute-on-Chronic Liver Failure. Semin Liver Dis 2023; 43:429-445. [PMID: 38101419 PMCID: PMC10723941 DOI: 10.1055/s-0043-1776773] [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] [Indexed: 12/17/2023]
Abstract
Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.
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Affiliation(s)
- MohammadMahdi Saeidinejad
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Ahmed Elshabrawi
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Endemic Hepatology and Gastroenterology Department, Mansoura University, Mansoura, Egypt
| | - Supachaya Sriphoosanaphan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok
| | - Fausto Andreola
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Gautam Mehta
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Banwari Agarwal
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Intensive Care Unit, Royal Free Hospital, London, United Kingdom
| | - Rajiv Jalan
- Liver Failure Group, Department of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Hepatology Department, Royal Free Hospital, London, United Kingdom
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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8
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Hernández OP, González CM, Reimers EG. Author's Reply: "Mean platelet volume is not a useful prognostic biomarker in patients with cirrhosis". Dig Liver Dis 2023; 55:1579-1580. [PMID: 37704510 DOI: 10.1016/j.dld.2023.08.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/15/2023]
Affiliation(s)
- Onán Pérez Hernández
- Servicio de Medicina Interna, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | | | - Emilio González Reimers
- Servicio de Medicina Interna, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
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9
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Butt MF, Jalan R. Review article: Emerging and current management of acute-on-chronic liver failure. Aliment Pharmacol Ther 2023; 58:774-794. [PMID: 37589507 DOI: 10.1111/apt.17659] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/02/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a clinically and pathophysiologically distinct condition from acutely decompensated cirrhosis and is characterised by systemic inflammation, extrahepatic organ failure, and high short-term mortality. AIMS To provide a narrative review of the diagnostic criteria, prognosis, epidemiology, and general management principles of ACLF. Four specific interventions that are explored in detail are intravenous albumin, extracorporeal liver assist devices, granulocyte-colony stimulating factor, and liver transplantation. METHODS We searched PubMed and Cochrane databases for articles published up to July 2023. RESULTS Approximately 35% of hospital inpatients with decompensated cirrhosis have ACLF. There is significant heterogeneity in the criteria used to diagnose ACLF; different definitions identify different phenotypes with varying mortality. Criteria established by the European Association for the Study of the Liver were developed in prospective patient cohorts and are, to-date, the most well validated internationally. Systemic haemodynamic instability, renal dysfunction, coagulopathy, neurological dysfunction, and respiratory failure are key considerations when managing ACLF in the intensive care unit. Apart from liver transplantation, there are no accepted evidence-based treatments for ACLF, but several different approaches are under investigation. CONCLUSION The recognition of ACLF as a distinct entity from acutely decompensated cirrhosis has allowed for better patient stratification in clinical settings, facilitating earlier engagement with the intensive care unit and liver transplantation teams. Research priorities over the next decade should focus on exploring novel treatment strategies with a particular focus on which, when, and how patients with ACLF should be treated.
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Affiliation(s)
- Mohsin F Butt
- Centre for Neuroscience, Trauma and Surgery, Wingate Institute of Neurogastroenterology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottinghamshire, UK
| | - Rajiv Jalan
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium, Barcelona, Spain
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10
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McConnell MJ, Iwakiri Y. Portal Hypertension in Alcohol-Associated Hepatitis. CURRENT HEPATOLOGY REPORTS 2023; 22:67-73. [PMCID: PMC10075503 DOI: 10.1007/s11901-023-00601-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/23/2023] [Indexed: 04/08/2023]
Abstract
Purpose of Review This review article will examine portal hypertension in alcoholic hepatitis (AH) from both a basic mechanistic and a clinical perspective. Recent Findings Alcoholic hepatitis is a major public health problem in the USA, accounting for over 300,000 hospital admissions in a recent year of data (Jinjuvadia et al. J Clin Gastroenterol. 60;49:506–511). Portal hypertension is a key consequence of AH and a driver of liver-related morbidity and mortality. Alcohol may directly mediate portal hypertension via multiple possible mechanisms, including increased portal inflow, increased intrahepatic vasoconstriction, inflammation, and changes in the liver vasculature such as perisinusoidal fibrosis and phlebosclerosis. Summary Portal hypertension is a key consequence of AH and a critical area for future research.
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Affiliation(s)
- Matthew J. McConnell
- grid.47100.320000000419368710Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520 USA
| | - Yasuko Iwakiri
- grid.47100.320000000419368710Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, 1080 LMP, 333 Cedar Street, New Haven, CT 06520 USA
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11
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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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12
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Pande G, Hatti M, Rai MK, Rai P, Kumar K, VP K, Nehra A, Kumar S, Ranjan Rout S, Mishra SK, Kumar D, Kumar U, Mishra P, Majeed A, Saraswat VA, Singh K, Singh H, Misra DP, Agarwal V. Response Guided Slow Infusion of Albumin, Vasoconstrictors and Furosemide Improves Ascites Mobilization and Survival in Acute on Chronic Liver Failure: A Proof-of-Concept Study. J Inflamm Res 2022; 15:5027-5039. [PMID: 36072778 PMCID: PMC9444030 DOI: 10.2147/jir.s377494] [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] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/13/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND AND AIMS Acute-on-chronic liver failure (ACLF) with increasing organ failure is associated with poor outcomes. Severely deranged systemic hemodynamics and decreased effective arterial blood volume contribute to tissue damage and organ failure. Response-guided therapy with albumin, vasoconstrictors, and furosemide may help overcome effective hypovolemia, improve diuresis and impact survival. METHODS In the observation cohort, 230 patients with ACLF (CANONIC criteria) with ascites (≥Grade II) and ACLF ≥Grade I were enrolled. A total of 136 patients (GROUP I) received response-guided (urine sodium >80mmol/day) slow albumin-furosemide infusion ± terlipressin (SAFI ± T), while 94 patients (GROUP II) received standard medical therapy. Twenty-eight-day survival, ascites mobilization (nil or grade 1), and adverse events were noted. In another mechanistic cohort (n = 40), laboratory evidences for improvement in various pathophysiological alterations; gut permeability, endotoxemia, cytokine storm, neutrophil dysfunction, and hemodynamic alterations following SAFI ± T/Noradrenaline (NAdr) were evaluated. RESULTS Age, gender, CLIF-C-ACLF, SOFA and MELD scores, ACLF grades and urine sodium were not different between the two groups in the observation cohort. Ascites was mobilized in 102/136 in GROUP I (SAFI ± T) and 23/94 in GROUP II (p < 0.05). Twenty-eight-day survival was significantly higher in GROUP I = 103/136 (75.7%) vs GROUP II = 50/94 (53.2%), (P = <0.001). All those who were unable to reach urine sodium >80 mmol/day died. Four patients in GROUP I developed scrotal gangrene. In the mechanistic cohort, 72% of patients survived with significant improvement in gut permeability, endotoxemia, serum cytokines, neutrophil dysfunction, and hemodynamic alterations. CONCLUSION Ascitic fluid mobilization by response-guided SAFI ± T/NAdr therapy improves survival by improving splanchnic and systemic hemodynamics, decreasing gut congestion, gut permeability, and endotoxemia, improving neutrophil functions, and reducing pro-inflammatory cytokines in circulation.
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Affiliation(s)
- Gaurav Pande
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Manjunath Hatti
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Mohit Kumar Rai
- Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Praveer Rai
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Kamlesh Kumar
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Krishna VP
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Abhimanyu Nehra
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sudeep Kumar
- Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Smarak Ranjan Rout
- Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sourav Kumar Mishra
- Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Dinesh Kumar
- Department of Advanced Spectroscopy and Imaging, Center of Biomedical Research, Lucknow, India
| | - Umesh Kumar
- Department of Advanced Spectroscopy and Imaging, Center of Biomedical Research, Lucknow, India
| | - Prabhaker Mishra
- Biostatistics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Abdul Majeed
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Vivek Anand Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Kritika Singh
- Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Harshit Singh
- Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Durga Prasanna Misra
- Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Vikas Agarwal
- Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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13
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Li M, Wang W, Cheng Y, Zhang X, Zhao N, Tan Y, Xie Q, Chai J, Pan Q. Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis. J Biol Chem 2022; 298:101543. [PMID: 34971708 PMCID: PMC8784341 DOI: 10.1016/j.jbc.2021.101543] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 12/15/2021] [Indexed: 01/05/2023] Open
Abstract
Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic anion-transporting polypeptide 3A1 (OATP3A1) is upregulated in cholestasis to promote bile acid efflux transport. We have previously shown that the growth factor fibroblast growth factor 19 and inflammatory mediator tumor necrosis factor α (TNFα) increased OATP3A1 mRNA levels in hepatoma peritoneal lavage cell/PRF/5 cell lines. However, the mechanism underlying TNFα-stimulated OATP3A1 expression in cholestasis is unknown. To address this, we collected plasma samples from control and obstructive cholestasis patients and used ELISA to detect TNFα levels. We found that the TNFα levels of plasma and hepatic mRNA transcripts were significantly increased in obstructive cholestatic patients relative to control patients. A significant positive correlation was also observed between plasma TNFα and liver OATP3A1 mRNA transcripts in patients with obstructive cholestasis. Further mechanism analysis revealed that recombinant TNFα induced OATP3A1 expression and activated NF-κB and extracellular signal-regulated kinase (ERK) signaling pathways as well as expression of related transcription factors p65 and specificity protein 1 (SP1). Dual-luciferase reporter and chromatin immunoprecipitation assays showed that recombinant TNFα upregulated the binding activities of NF-κB p65 and SP1 to the OATP3A1 promoter in peritoneal lavage cell/PRF/5 cells. These effects were diminished following the application of NF-κB and ERK inhibitors BAY11-7082 and PD98059. We conclude that TNFα stimulates hepatic OATP3A1 expression in human obstructive cholestasis by activating NF-κB p65 and ERK-SP1 signaling. These results suggest that TNFα-activated NF-κB p65 and ERK-SP1 signaling may be a potential target to ameliorate cholestasis-associated liver injury.
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Affiliation(s)
- Mingqiao Li
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Weihua Wang
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ying Cheng
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiaoxun Zhang
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Nan Zhao
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ya Tan
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Qiaoling Xie
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jin Chai
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China.
| | - Qiong Pan
- Cholestatic Liver Diseases Center and Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, China.
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14
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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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15
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Allaire M, Rudler M, Thabut D. Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…. Liver Int 2021; 41:1734-1743. [PMID: 34051060 DOI: 10.1111/liv.14977] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complication of cirrhosis which significantly contribute to morbidity and mortality. In this review, we aim to describe the consequences of both angiogenesis and inflammation in the pathogenesis of PHT and HCC, but also the difficulty to propose adapted treatment when PHT and HCC coexist in the same patients. METHODS Studies for review in this article were retrieved from the PubMed database using literature published in English until March 2021. RESULTS Portal hypertension occurs secondary to an increase of intrahepatic vascular resistances, the opening of portosystemic collateral vessels and the formation of neovessels, related to vascular endothelial growth factor (VEGF). Recently, bacterial translocation-mediated inflammation was also identified as a major contributor to PHT. Interestingly, VEGF and chronic inflammation also contribute to HCC occurrence. As PHT and HCC often coexist in the same patient, management of PHT and its related complications as well as HCC treatment appear more complex. Indeed, PHT-related complications such as significant ascites may hamper the access to HCC treatment and the presence of HCC is also independently associated with poor prognosis in patients with acute variceal bleeding related to PHT. Due to their respective mechanism of action, the combination of Atezolizumab and Bevacizumab for advanced HCC may impact the level of PHT and its related complications and to date, no real-life data are available. CONSLUSIONS Appropriate evaluation and treatment of PHT remains a major issue in order to improve the outcome of HCC patients.
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Affiliation(s)
- Manon Allaire
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,Inserm U1149, Centre de Recherche sur l'Inflammation, France Faculté de Médecine Xavier Bichat, Université Paris Diderot, Paris, France
| | - Marika Rudler
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Dominique Thabut
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
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16
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Transition to decompensation and acute-on-chronic liver failure: Role of predisposing factors and precipitating events. J Hepatol 2021; 75 Suppl 1:S36-S48. [PMID: 34039491 DOI: 10.1016/j.jhep.2020.12.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 12/08/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022]
Abstract
The transition from compensated to decompensated cirrhosis results from a complex interplay of predisposing and precipitating factors and represents an inflection point in the probability of a patient surviving. With the progression of cirrhosis, patients accumulate multiple disorders (e.g. altered liver architecture, portal hypertension, local and systemic inflammation, bacterial translocation, gut dysbiosis, kidney vasoconstriction) that predispose them to decompensation. On the background of these factors, precipitating events (e.g. bacterial infection, alcoholic hepatitis, variceal haemorrhage, drug-induced liver injury, flare of liver disease) lead to acute decompensation (ascites, hepatic encephalopathy, variceal bleeding, jaundice) and/or organ failures, which characterise acute-on-chronic liver failure. In this review paper, we will discuss the current hypotheses and latest evidences regarding predisposing and precipitating factors associated with the transition to decompensated liver disease.
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17
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Jalan R, D'Amico G, Trebicka J, Moreau R, Angeli P, Arroyo V. New clinical and pathophysiological perspectives defining the trajectory of cirrhosis. J Hepatol 2021; 75 Suppl 1:S14-S26. [PMID: 34039485 DOI: 10.1016/j.jhep.2021.01.018] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023]
Abstract
Traditionally, the complications of cirrhosis, namely variceal bleeding, ascites and hepatic encephalopathy, were thought to result predominantly from circulatory dysfunction and altered organ perfusion arising as a result of portal hypertension. Over the past 20 years, large, international prospective studies have indicated the importance of systemic inflammation and organ immunopathology as additional determinants of organ dysfunction in cirrhosis, which not only manifests in the liver, brain, circulation and the kidneys, but also the immune system, gut, muscles, adrenal glands, reproductive organs, heart and lungs. This review provides an overview of the traditional and emerging concepts around the initiation and maintenance of organ dysfunction in cirrhosis and proposes a new paradigm based upon a better understanding of acute decompensation of cirrhosis. The interaction between the traditional concepts and the emerging perspectives remains a matter of great interest and the basis for future research.
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Affiliation(s)
- Rajiv Jalan
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom.
| | - Gennaro D'Amico
- Gastroenterology Unit, Ospedale Cervello and University of Palermo, Italy
| | - Jonel Trebicka
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; JW Goethe University Hospital, Frankfurt, Germany
| | - Richard Moreau
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; APHP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France; Inserm, Université de Paris, Centre de Recherche sur L'Inflammation, Paris, France
| | - Paolo Angeli
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; University of Padova, Padova, Italy
| | - Vicente Arroyo
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain
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18
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Van der Merwe S, Chokshi S, Bernsmeier C, Albillos A. The multifactorial mechanisms of bacterial infection in decompensated cirrhosis. J Hepatol 2021; 75 Suppl 1:S82-S100. [PMID: 34039494 DOI: 10.1016/j.jhep.2020.11.029] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/17/2020] [Accepted: 11/20/2020] [Indexed: 02/08/2023]
Abstract
Infections, due to a dysfunctional immune response, pose a great risk to patients with decompensated cirrhosis and herald the beginning of the terminal phase of this disease. Infections typically result from breaches in innate immune barriers and inadequate clearance by immune cells. This leads to bacterial and bacterial product translocation to the systemic circulation, which is already primed by ongoing hepatic inflammation in patients with cirrhosis, who are particularly prone to developing organ failure in the presence of an infection. Early identification of bacterial infection, along with the prompt use of appropriate antibiotics, have reduced the mortality associated with certain infections in patients with decompensated cirrhosis. Judicious use of antibiotic therapy remains imperative given the emergence of multidrug-resistant infections in the cirrhotic population. Important research over the last few years has identified molecular targets on immune cells that may enhance their function, and theoretically prevent infections. Clinical trials are ongoing to delineate the beneficial effects of targeted molecules from their off-target effects. Herein, we review the mechanisms that predispose patients with cirrhosis to bacterial infections, the clinical implications of infections and potential targets for the prevention or treatment of infections in this vulnerable population.
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Affiliation(s)
- Schalk Van der Merwe
- Department of Gastroenterology and Hepatology, University hospital, Leuven, Belgium; Laboratory of Hepatology, University of Leuven, Belgium.
| | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London, UK; Division of Transplantation, Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College, London, United Kingdom
| | - Christine Bernsmeier
- Department of Biomedicine, University of Basel, Switzerland; University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Agustin Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBEREHD, Universidad de Alcalá, Madrid, Spain
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19
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Chang Y, Suk KT, Jeong SW, Yoo JJ, Kim SG, Kim YS, Lee SH, Kim HS, Kang SH, Baik SK, Kim DJ, Kim MY, Jang JY. Application of Hepatic Venous Pressure Gradient to Predict Prognosis in Cirrhotic Patients with a Low Model for End-Stage Liver Disease Score. Diagnostics (Basel) 2020; 10:805. [PMID: 33050413 PMCID: PMC7599657 DOI: 10.3390/diagnostics10100805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/30/2020] [Accepted: 10/08/2020] [Indexed: 12/23/2022] Open
Abstract
UNLABELLED : Background/aim: We aimed to derive a model representing the dynamic status of cirrhosis and to discriminate patients with poor prognosis even if the Model for End-Stage Liver Disease (MELD) score is low. METHODS This study retrospectively enrolled 700 cirrhotic patients with a MELD score of less than 20 who underwent hepatic venous pressure gradient (HVPG) measurement. A model named H6C score (= HVPG + 6 × CTP score) to predict overall survival was derived and internal and external validations were conducted with the derivation and validation cohorts. RESULTS The H6C score using the HVPG was developed based on a multivariate Cox regression analysis. The H6C score showed a great predictive power for overall survival with a time-dependent AUC of 0.733, which was superior to that of a MELD of 0.602. In patients with viral etiology, the performance of the H6C score was much improved with a time-dependent AUC of 0.850 and was consistently superior to that of the MELD (0.748). Patients with an H6C score below 45 demonstrated an excellent overall survival with a 5-year survival rate of 91.5%. Whereas, patients with an H6C score above 64 showed a dismal prognosis with a 5-year survival rate of 51.1%. The performance of the H6C score was further verified to be excellent in the validation cohort. CONCLUSION This new model using the HVPG provides an excellent predictive power in cirrhotic patients, especially with viral etiology. In patients with H6C above 64, it would be wise to consider early liver transplantation to positively impact long-term survival, even when the MELD score is low.
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Affiliation(s)
- Young Chang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (S.W.J.)
| | - Ki Tae Suk
- Department of Internal Medicine, Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon 24252, Korea; (K.T.S); (D.J.K.)
| | - Soung Won Jeong
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (S.W.J.)
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (J.-J.Y.); (S.G.K.); (Y.S.K.)
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (J.-J.Y.); (S.G.K.); (Y.S.K.)
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon 14584, Korea; (J.-J.Y.); (S.G.K.); (Y.S.K.)
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.H.L.); (H.S.K.)
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan 31151, Korea; (S.H.L.); (H.S.K.)
| | - Seong Hee Kang
- Department of Internal Medicine, Yonsei University, Wonju College of Medicine, Wonju 26426, Korea; (S.H.K.); (S.K.B.)
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University, Wonju College of Medicine, Wonju 26426, Korea; (S.H.K.); (S.K.B.)
| | - Dong Joon Kim
- Department of Internal Medicine, Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon 24252, Korea; (K.T.S); (D.J.K.)
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University, Wonju College of Medicine, Wonju 26426, Korea; (S.H.K.); (S.K.B.)
| | - Jae Young Jang
- Department of Internal Medicine, Institute for Digestive Research, Digestive Disease Center, Soonchunhyang University College of Medicine, Seoul 04401, Korea; (Y.C.); (S.W.J.)
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20
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Praktiknjo M, Monteiro S, Grandt J, Kimer N, Madsen JL, Werge MP, William P, Brol MJ, Turco L, Schierwagen R, Chang J, Klein S, Uschner FE, Welsch C, Moreau R, Schepis F, Bendtsen F, Gluud LL, Møller S, Trebicka J. Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure. Liver Int 2020; 40:1457-1466. [PMID: 32162397 DOI: 10.1111/liv.14433] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 02/17/2020] [Accepted: 03/02/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality and systemic inflammation (SI). Recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal hypertension and their impact on ACLF development remains unclear. The aim of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fatal ACLF development in cirrhosis. RESULTS At inclusion, hemodynamic measures including cardiac index (CI) and hepatic venous pressure gradient of 208 patients were measured. Patients were followed prospectively for fatal ACLF development (primary endpoint). SI was assessed by proinflammatory markers such as interleukins (ILs) 6 and 8 and soluble IL-33 receptor (sIL-33R). Patients were divided according to CI (<3.2; 3.2-4.2; >4.2 L/min/m2 ) in hypo- (n = 84), normo- (n = 69) and hyperdynamic group (n = 55). After a median follow-up of 3 years, the highest risk of fatal ACLF was seen in hyperdynamic (35%) and hypodynamic patients (25%) compared with normodynamic (14%) (P = .011). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an independent predictor of fatal ACLF development. CONCLUSIONS Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic state is strongly associated with SI, which is an independent predictor of development of fatal ACLF.
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Affiliation(s)
| | - Sofia Monteiro
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.,Department of Medicine, Hospital Pedro Hispano, Matosinhos, Portugal
| | - Josephine Grandt
- Gastrounit Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Nina Kimer
- Gastrounit Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Jan L Madsen
- Department of Clinical Physiology and Nuclear Medicine, 239 Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mikkel P Werge
- Gastrounit Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Peter William
- Gastrounit Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Maximilian J Brol
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Laura Turco
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria di Modena and University of Modena and Reggio Emilia, Modena, Italy
| | - Robert Schierwagen
- Department of Internal Medicine I, J.W.Goethe University Hospital, Frankfurt, Germany
| | - Johannes Chang
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Sabine Klein
- Department of Internal Medicine I, J.W.Goethe University Hospital, Frankfurt, Germany
| | - Frank E Uschner
- Department of Internal Medicine I, J.W.Goethe University Hospital, Frankfurt, Germany
| | - Christoph Welsch
- Department of Internal Medicine I, J.W.Goethe University Hospital, Frankfurt, Germany
| | - Richard Moreau
- Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Département Hospitalo-Universitaire UNITY, Clichy, France.,Centre de Recherche sur l'Inflammation, Unité Mixte de Recherche, Institut National de la Santé et de la Recherche Médicale and Université Paris Diderot, Paris, France
| | - Filippo Schepis
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria di Modena and University of Modena and Reggio Emilia, Modena, Italy
| | - Flemming Bendtsen
- Gastrounit Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Lise L Gluud
- Gastrounit Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, 239 Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Jonel Trebicka
- Department of Internal Medicine I, J.W.Goethe University Hospital, Frankfurt, Germany.,European Foundation for Study of Chronic Liver Failure, Barcelona, Spain.,Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.,Institute of Bioengineering Catalunya, Barcelona, Spain
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21
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Qi W, Wang B, Yang M, Zhu L, Hu S, Sun H. The implementation of drug reposition for alcoholic hepatitis based on a sub-pathway integration strategy. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:208. [PMID: 32309355 PMCID: PMC7154418 DOI: 10.21037/atm.2020.01.36] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Alcoholic hepatitis (AH) is one of the most severe forms of liver disease. The therapies which are currently available are not entirely effective, and thus novel therapies are urgently needed. However, the development of these novel therapies is limited due to incomplete information about the molecular mechanisms involved in AH. Methods The microarray data (GSE28619) was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between the AH and the control samples were identified using the significant analysis of microarrays (SAM) method. Metabolic sub-pathways were identified using the SubpathwayMiner R package. Cell Counting Kit-8 (CCK-8) was used to evaluate the cell viability of AML-12 cells treated with different concentrations of ethanol or riboflavin. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were employed to show the hepatocyte function. Results A total of 1,041 genes were determined to be expressed differentially. We then identified 11 metabolic sub-pathways that could be involved in the development of AH. This was followed by a final integrated analysis of the sub-pathways involved in AH as well as the sub-pathways involved in the drug-affected cases. The final integration results led to the identification of 64 small molecular drugs. A potential novel drug (riboflavin) involved in the fatty acid metabolism pathway was identified for further investigation. Riboflavin at the 60 nM for 24 h could reverse ethanol-induced AML-12 cell injury and could markedly decrease ALT and AST activity. The decrease in the activities of these two enzymes was observed in a dose-dependent manner when it was compared to ethanol alone, which suggests that riboflavin has a protective effect against liver cell injury caused by alcoholism. Conclusions To summarize, the candidate agents which are identified in the present study might give practitioners insight into the development of novel therapeutic approaches for AH.
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Affiliation(s)
- Wei Qi
- College of Pharmacy, College of Pharmacy, Harbin Medical University, Harbin 150001, China.,Department of Inorganic Chemistry and Physical Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150001, China
| | - Bing Wang
- Qingdao Women and Children Hospital, Qingdao 266011, China
| | - Ming Yang
- College of Pharmacy, College of Pharmacy, Harbin Medical University, Harbin 150001, China
| | - Lin Zhu
- The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Sen Hu
- College of Pharmacy, College of Pharmacy, Harbin Medical University, Harbin 150001, China
| | - Hui Sun
- College of Pharmacy, College of Pharmacy, Harbin Medical University, Harbin 150001, China.,Pharmaceutical Experiment Teaching Center, College of Pharmacy, Harbin Medical University, Harbin 150001, China
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22
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Jalan R, Perricone G, Moreau R, Arroyo V, Williams R. Acute-on-Chronic Liver Failure: A New Disease or an Old One Hiding in Plain Sight? Clin Liver Dis (Hoboken) 2020; 15:S45-S51. [PMID: 32140213 PMCID: PMC7050950 DOI: 10.1002/cld.859] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 06/24/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Rajiv Jalan
- Liver Failure GroupUCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free HospitalLondonUnited Kingdom
| | - Giovanni Perricone
- Liver Failure GroupUCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free HospitalLondonUnited Kingdom,Hepatology and Gastroenterology UnitAzienda Socio‐Sanitaria Territoriale Grande Ospedale Metropolitano NiguardaMilanItaly
| | - Richard Moreau
- Inserm, U1149, Centre de Recherche sur l’InflammationUMRS1149, Université de Paris, Service d’Hépatologie, Hôpital Beaujon, Assistance Publique‐Hôpitaux de ParisClichyFrance
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver FailureBarcelonaSpain
| | - Roger Williams
- Institute of HepatologyFoundation for Liver ResearchLondonUnited Kingdom,Faculty of Life Sciences and MedicineKing’s CollegeLondonUnited Kingdom
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23
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Kim D, Thangavelu M, Baek JS, Kim HS, Choi MJ, Cho HH, Song JE, Khang G. Fabrication of POX/PLGA Scaffold for the Potential Application of Tissue Engineering and Cell Transplantation. Macromol Res 2019. [DOI: 10.1007/s13233-020-8030-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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24
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Majeed MB, Agrawal R, Attar BM, Abu Omar Y, Gandhi SR. Safety and Efficacy of Infliximab in Severe Alcoholic Hepatitis: A Systematic Review. Cureus 2019; 11:e5082. [PMID: 31516791 PMCID: PMC6721913 DOI: 10.7759/cureus.5082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 07/04/2019] [Indexed: 12/13/2022] Open
Abstract
Severe alcoholic hepatitis (SAH) is associated with significant morbidity and mortality, yet the treatment options available are very limited. Past studies have evaluated the efficacy of infliximab in such patients; however, they were limited by sample size. Our aim was to perform a systematic review of these studies to assess the role of infliximab in patients with SAH. We conducted a literature search using electronic database engines including Ovid, PubMed, Scopus, MEDLINE and Cochrane Library from inception to October 2018 to identify published articles addressing outcomes in patients treated for alcoholic hepatitis with infliximab. The primary outcome reviewed was one-month mortality. Secondary outcomes included rate and type of infection; cause of mortality; levels of aspartate aminotransferase, alanine aminotransferase, bilirubin and tumor necrosis factor-α; and Maddrey discriminant function. Five studies including two randomized controlled trials and three case series were included in our analysis with a total sample size of 70 patients. One-month mortality ranged from 10% to 17% in patients who received a single dose of infliximab with or without prednisone compared to 38% in patients who received three doses of infliximab in combination with prednisone. A single dose of infliximab was associated with an infection rate of 10% to 26% in contrast to an 89% rate with three doses of infliximab. Infliximab, when used in a single dose, could potentially be an alternative agent for the management of SAH in a large group of patients who have contraindications such as gastrointestinal bleeding, uncontrolled diabetes or an active hepatitis infection. It might also have a role in the prevention of hepatorenal syndrome. There is a need for larger trials to evaluate the role of infliximab in a cohort of patients who are not candidates for prednisolone therapy.
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Affiliation(s)
- Muhammad B Majeed
- Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
| | - Rohit Agrawal
- Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
| | - Bashar M Attar
- Gastroenterology and Hepatology, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
| | - Yazan Abu Omar
- Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
| | - Seema R Gandhi
- Gastroenterology and Hepatology, John H. Stroger, Jr. Hospital of Cook County, Chicago, USA
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25
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Jing ZT, Liu W, Xue CR, Wu SX, Chen WN, Lin XJ, Lin X. AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury. Am J Physiol Gastrointest Liver Physiol 2019; 316:G387-G396. [PMID: 30629471 DOI: 10.1152/ajpgi.00350.2018] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.
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Affiliation(s)
- Zhen-Tang Jing
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Wei Liu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University , Fuzhou , China
| | - Chao-Rong Xue
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Shu-Xiang Wu
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Wan-Nan Chen
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University , Fuzhou , China
| | - Xin-Jian Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University , Fuzhou , China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University , Fuzhou , China
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26
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Gustot T, Jalan R. Acute-on-chronic liver failure in patients with alcohol-related liver disease. J Hepatol 2019; 70:319-327. [PMID: 30658733 DOI: 10.1016/j.jhep.2018.12.008] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 12/11/2018] [Indexed: 12/16/2022]
Abstract
The spectrum of alcohol-related liver diseases (ALD) includes steatosis, steatohepatitis, progressive liver fibrosis, and cirrhosis. Acute-on-chronic liver failure (ACLF) is a recently defined entity that occurs in patients with chronic liver diseases and is characterised by acute decompensation, organ failures and a high risk of short-term mortality. Active alcohol consumption, alcoholic hepatitis and bacterial infections are the most frequent events precipitating the development of ACLF in the context of ALD (ALD-ACLF). The specific management of this entity remains unknown and the place of salvage liver transplantation controversial. This overview details the current knowledge on specific aspects of epidemiology, pathophysiology, prognosis and management of ALD-ACLF.
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Affiliation(s)
- Thierry Gustot
- Dept. Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Hospital, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Inserm Unité 1149, Centre de Recherche sur l'inflammation (CRI), Paris, France; UMR S_1149, Université Paris Diderot, Paris, France; The EASL-CLIF Consortium, European Foundation-CLIF, Barcelona, Spain.
| | - Rajiv Jalan
- The EASL-CLIF Consortium, European Foundation-CLIF, Barcelona, Spain; Liver Failure Group, Insitute for Liver and Digestive Health, University College London, London, UK
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27
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A return to harmful alcohol consumption impacts on portal hemodynamic changes following alcoholic hepatitis. Eur J Gastroenterol Hepatol 2018; 30:967-974. [PMID: 29727387 DOI: 10.1097/meg.0000000000001148] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Increased hepatic venous pressure gradient (HVPG) plays a role in the clinical manifestations of alcoholic hepatitis (AH). The evolution of HVPG and the influence of alcohol use in the intermediate term are unclear. AIM The aim of this study was to explore HVPG modifications following AH taking into consideration alcohol use and clinical manifestations. PATIENTS AND METHODS Patients with AH (n=37; age 52 years; model for end-stage liver disease: 18.5; Maddrey score: 43) and chronic excessive drinkers with compensated cirrhosis (n=19; age: 54 years; model for end-stage liver disease: 9.2) underwent HVPG measurement and liver biopsy. Ten long-standing abstinent alcoholic cirrhotics served as controls. After discharge, patients were monitored for alcohol use and clinical complications, with repeated HVPG after a median duration of 100 days. Inflammation was determined using plasma C-reactive protein. RESULTS At baseline, compared with chronic excessive drinkers and alcoholic cirrhotics, patients with AH had increased HVPG (18.1±0.6 vs. 13.8±1.4 vs. 15±1.3 mmHg, P<0.05). During follow-up, patients who became abstinent or reported occasional drinking were more likely to achieve a greater than 20% reduction in HVPG compared with those returning to harmful alcohol (45 vs. 0%, P<0.01), and suffered from fewer complications (25 vs. 68%, P<0.03). High baseline C-reactive protein levels correlated to the Maddrey (r=0.38), but no relationship was observed between changes in inflammation and HVPG. CONCLUSION Elevated HVPG is a feature of AH, with a clinically significant reduction in values in abstinent or occasional drinkers after weeks of follow-up. A return to harmful alcohol has a negative impact on portal hemodynamics and associated clinical complications.
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28
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Lopetuso LR, Mocci G, Marzo M, D'Aversa F, Rapaccini GL, Guidi L, Armuzzi A, Gasbarrini A, Papa A. Harmful Effects and Potential Benefits of Anti-Tumor Necrosis Factor (TNF)-α on the Liver. Int J Mol Sci 2018; 19:E2199. [PMID: 30060508 PMCID: PMC6121684 DOI: 10.3390/ijms19082199] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 07/19/2018] [Accepted: 07/24/2018] [Indexed: 02/08/2023] Open
Abstract
Anti-tumor necrosis factor (TNF)-α agents represent an effective treatment for chronic inflammatory diseases. However, some concerns about their potentially undesirable effects on liver function have been reported. On the other hand, evidence of their therapeutic effects on certain liver diseases is accumulating. Many data showed the safety of anti-TNF-α in patients with chronic hepatitis B and C and in liver transplanted patients even if a strict follow-up and prophylaxis are recommended in well-defined subgroups. On the other side, anti-TNF-α-induced liver injury is not a rare event. However, it is often reversible after anti-TNF-α withdrawal. Anti-TNF-α agents have been tested in advanced stages of severe alcoholic hepatitis and non-alcoholic fatty liver disease. Limited data on the efficacy of anti-TNF-α in patients with autoimmune hepatitis and primary biliary cholangitis are also available. In this review, we explored the hepatic safety concerns in patients receiving anti-TNF-α agents with and without pre-existent hepatic diseases. In addition, the available evidence on their potential benefits in the treatment of specific hepatic diseases is discussed.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Giammarco Mocci
- Gastroenterology Unit, Brotzu Hospital, 09121 Cagliari, Italy.
| | - Manuela Marzo
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Francesca D'Aversa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Gian Lodovico Rapaccini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Luisa Guidi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Alessandro Armuzzi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
| | - Alfredo Papa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, 00168 Roma, Italy.
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29
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Talal AH, Venuto CS, Younis I. Assessment of Hepatic Impairment and Implications for Pharmacokinetics of Substance Use Treatment. Clin Pharmacol Drug Dev 2018; 6:206-212. [PMID: 28263464 DOI: 10.1002/cpdd.336] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 12/30/2016] [Indexed: 12/12/2022]
Abstract
Although the liver is the primary site of metabolism and biliary excretion for many medications, data are limited on the liver's pharmacokinetic abilities in cirrhosis. Cirrhosis develops through collagen deposition, eventually culminating in end-stage liver disease that compromises hepatic drug metabolism. Consequently, the US Food and Drug Administration (FDA) recommends evaluating the pharmacokinetics of medications in subjects with hepatic impairment if hepatic metabolism constitutes more than 20% of their elimination or if they have a narrow therapeutic range. A variety of noninvasive indices and radiologic procedures can be employed to assess hepatic drug metabolism and excretion. The Child-Pugh score is the most commonly used scale for assessing hepatic impairment among drugs submitted for US FDA approval. The score, originally developed to guide operative mortality in patients undergoing hepatic resection, has not been modified since its inception 5 decades ago. Furthermore, the score was not originally intended to be a guide for potential dose modification in patients with hepatic impairment. These reasons, in combination with the availability of a variety of new imaging modalities and an enhanced understanding of hepatic biology, should foster the development of novel methods to assess the effect of hepatic impairment on liver drug metabolism.
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Affiliation(s)
- Andrew H Talal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University at Buffalo, Buffalo, NY, USA
| | - Charles S Venuto
- Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY, USA.,AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences; School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Islam Younis
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
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30
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Slack A, Hogan BJ, Wendon J. Acute Hepatic Failure. LIVER ANESTHESIOLOGY AND CRITICAL CARE MEDICINE 2018. [PMCID: PMC7121978 DOI: 10.1007/978-3-319-64298-7_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Balasubramanian V, Mehta G, Jones H, Sharma V, Davies NA, Jalan R, Mookerjee RP. Post-Transcriptional Regulation of Hepatic DDAH1 with TNF Blockade Leads to Improved eNOS Function and Reduced Portal Pressure In Cirrhotic Rats. Sci Rep 2017; 7:17900. [PMID: 29263339 PMCID: PMC5738445 DOI: 10.1038/s41598-017-18094-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 11/13/2017] [Indexed: 12/19/2022] Open
Abstract
Portal hypertension (PH) is a major cause of morbidity and mortality in chronic liver disease. Infection and inflammation play a role in potentiating PH and pro-inflammatory cytokines, including TNF, are associated with severity of PH. In this study, cirrhotic bile duct ligated (BDL) rats with PH were treated with Infliximab (IFX, a monoclonal antibody against TNF) and its impact on modulation of vascular tone was assessed. BDL rats had increased TNF and NFkB compared to sham operated rats, and their reduction by IFX was associated with a reduction in portal pressure. IFX treatment also reduced hepatic oxidative stress, and biochemical markers of hepatic inflammation and injury. IFX treatment was associated with an improvement in eNOS activity and increased l-arginine/ADMA ratio and DDAH1 expression. In vitro analysis of HepG2 hepatocytes showed that DDAH1 protein expression is reduced by oxidative stress, and this is in part mediated by post-transcriptional regulation by the 3′UTR. This study supports a role for the DDAH1/ADMA axis on the effect of inflammation and oxidative stress in PH and provides insight for new therapies.
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Affiliation(s)
- V Balasubramanian
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - G Mehta
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - H Jones
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - V Sharma
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - N A Davies
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - R Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - R P Mookerjee
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.
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Kao JT, Yu CJ, Feng CL, Tsai SM, Chen YL, Wu YY. IL-6 significantly correlates with p-STAT3 expression and presents high variceal bleeding with mortality in cirrhotic patients: A cross-sectional study. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2017; 50:286-296. [PMID: 25899133 DOI: 10.1016/j.jmii.2015.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 02/06/2015] [Accepted: 03/05/2015] [Indexed: 01/27/2023]
Abstract
BACKGROUND/PURPOSE Effective mediators activate downstream transducers regulating inflammation and angiogenesis. Correlation among mediators IL-6, IL-27, TNF-α, and VEGF with STAT proteins at diverse clinical-pathologic stages of cirrhotic patients remains limited. METHODS Plasma mediators were assayed from 158 naïve liver cirrhosis (LC-total group) and 144 non-LC individuals. The LC-total group included 69 hepatitis B virus-infected (LC-HBV) patients, 40 hepatitis C virus-infected (LC-HCV) patients, and 49 patients without HBV-/HCV- infection (LC-NBNC). Another 144 non-LC individuals comprised 54 healthy persons (HG) and 90 chronic hepatitis patients (CH-total) as the control group. To correlate with plasma mediators, 52 paired liver tissues (CH: 41 and LC: 11 cases) served for p-STAT1 and p-STAT3 immunostaining. RESULTS Although IL-6, IL-27, TNF-α, and VEGF were expressed significantly in CH-total versus HG (p = 0.011, p < 0.001, p = 0.007, p = 0.004, respectively) and overall viral hepatitis patients versus HG (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively), only IL-6 presented the strongest correlation in cirrhotic patients than noncirrhotic patients (LC-HBV vs. HG, p < 0.001, vs. CH-HBV, p = 0.001; LC-HCV vs. HG, p = 0.001, vs. CH-HCV, p = 0.031; LC-NBNC vs. HG, p < 0.001). Over-expressed IL-6 linked with poorer liver function (albumin: r = -0.346, p < 0.001; bilirubin: r = 0.271, p = 0.001; INR: r = 0.308, p < 0.001; Child-Turcotte-Pugh Classification C vs. A or B, p = 0.001, p = 0.007, respectively), variceal severity (p = 0.045), and bleeding (p = 0.047), as well as patients' mortality (p = 0.005). Furthermore, plasma IL-6 significantly correlated with tissues p-STAT3 expression (r = 0.737, p = 0.010) (IL-27: r = 0.078, p = 0.820; TNF-α: r = -0.145, p = 0.670; VEGF: r = 0.142, p = 0.678) in cirrhotic patients than noncirrhotic patients. CONCLUSION Over-expression of IL-6 reflects hepatic dysfunction and varices bleeding with mortality, as well as correlates p-STAT3 expression in cirrhotic patients.
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Affiliation(s)
- Jung-Ta Kao
- School of Medicine, China Medical University, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Ju Yu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Lung Feng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shu-Mei Tsai
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yao-Li Chen
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ying Wu
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
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Lipopolysaccharide-Induced Neutrophil Dysfunction Following Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS) Insertion is Associated with Organ Failure and Mortality. Sci Rep 2017; 7:40157. [PMID: 28051160 PMCID: PMC5209675 DOI: 10.1038/srep40157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/02/2016] [Indexed: 12/22/2022] Open
Abstract
Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised. The objective of this study was to characterise neutrophil function, LPS and cytokine concentrations within the splanchnic circulation of alcoholic cirrhotic patients undergoing TIPSS insertion for variceal haemorrhage and correlate this with outcome. 26 patients with alcoholic cirrhosis and variceal haemorrhage were studied prior to and 1-hour after TIPSS insertion. Neutrophil function, LPS and cytokine concentrations were determined in arterial, hepatic venous (HV) and portal venous blood (PV). Significantly higher LPS concentrations and neutrophil reactive oxidant species (ROS) production were observed in PV vs HV blood. Cross-incubation of HV plasma with PV neutrophils resulted in reduced ROS production. Insertion of TIPSS was associated with a significant increase in arterial LPS concentrations and deterioration in neutrophil phagocytosis. Number of organ failures and arterial IL-6 concentrations at presentation were associated with increased mortality. The portal circulation has a distinct immunological milieu characterised by a pathological neutrophil phenotype and an anti-inflammatory cytokine profile associated with heightened LPS levels. TIPSS insertion renders this neutrophil functional defect systemic, associated with an increase in arterial LPS and a susceptibility to sepsis.
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Bertino G, Privitera G, Purrello F, Demma S, Crisafulli E, Spadaro L, Koukias N, Tsochatzis EA. Emerging hepatic syndromes: pathophysiology, diagnosis and treatment. Intern Emerg Med 2016; 11:905-16. [PMID: 27273018 DOI: 10.1007/s11739-016-1478-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 05/25/2016] [Indexed: 12/11/2022]
Abstract
Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. In this article, we review the current understanding on the pathophysiology, the diagnostic criteria and the available therapeutic options for patients with emerging hepatic syndromes in cirrhosis, namely the hepatorenal, hepato-adrenal and hepatopulmonary syndrome. The hepatorenal syndrome is a well-recognized complication of advanced cirrhosis and is usually associated with an accelerated course to death unless liver transplantation is performed. The hepatopulmonary syndrome is often missed in the evaluation of patients with cirrhosis; however, early recognition is essential for the efficient management of individual patients. The hepato-adrenal syndrome, although not fully characterized, offers an exciting field for research and potential therapeutic interventions.
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Affiliation(s)
- Gaetano Bertino
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Graziella Privitera
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Francesco Purrello
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Shirin Demma
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Emanuele Crisafulli
- Hepatology Unit, Department of Clinical and Experimental Medicine, University of Catania, Policlinico "G. Rodolico", Catania, Italy
| | - Luisa Spadaro
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi-Nesima, Catania, Italy
| | - Nikolaos Koukias
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and UCL, London, UK.
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Thomsen KL, Møller HJ, Graversen JH, Magnusson NE, Moestrup SK, Vilstrup H, Grønbæk H. Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats. World J Hepatol 2016; 8:726-730. [PMID: 27330681 PMCID: PMC4911506 DOI: 10.4254/wjh.v8.i17.726] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 04/26/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats.
METHODS: Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate (0.02 mg/kg) or free dexamethasone (0.02 or 1 mg/kg) 24 h prior to lipopolysaccharide (LPS) (2.5 mg/kg intraperitoneal). We measured plasma concentrations of tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6) 2 h post-LPS and liver mRNAs and serum concentrations of the rat acute phase protein α-2-macroglobulin (α-2-M) 24 h after LPS. Also, plasma concentrations of alanine aminotransferase and bilirubin were measured at termination of the study. Spleen weight served as an indicator of systemic steroid effects.
RESULTS: The conjugate halved the α-2-M liver mRNA (3.3 ± 0.6 vs 6.8 ± 1.1, P < 0.01) and serum protein (201 ± 48 μg/mL vs 389 ± 67 μg/mL, P = 0.04) after LPS compared to low dose dexamethasone treated animals, while none of the free dexamethasone doses had an effect on liver mRNA or serum levels of α-2-M. Also, the conjugate reduced TNF-α (7208 ± 1977 pg/mL vs 21583 ± 7117 pg/mL, P = 0.03) and IL-6 (15685 ± 3779 pg/mL vs 25715 ± 4036 pg/mL, P = 0.03) compared to the low dose dexamethasone. The high dose dexamethasone dose decreased the spleen weight (421 ± 11 mg vs 465 ± 12 mg, P < 0.05) compared to controls, an effect not seen in any other group.
CONCLUSION: Low-dose anti-CD163-dexamethasone conjugate effectively decreased the hepatic acute phase response to LPS. This indicates an anti-inflammatory potential of the conjugate in vivo.
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Mookerjee RP, Pavesi M, Thomsen KL, Mehta G, Macnaughtan J, Bendtsen F, Coenraad M, Sperl J, Gines P, Moreau R, Arroyo V, Jalan R. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol 2016; 64:574-82. [PMID: 26519600 DOI: 10.1016/j.jhep.2015.10.018] [Citation(s) in RCA: 183] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 10/14/2015] [Accepted: 10/19/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Non-selective beta blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation and high mortality. As NSBBs may have beneficial effects on gut motility and permeability and, systemic inflammation, the aims of this prospective, observational study were to determine whether ongoing use of NSBBs reduced 28-day mortality in ACLF patients. METHODS The study was performed in 349 patients with ACLF included in the CANONIC study, which is a prospective observational investigation in hospitalized cirrhotic patients with acute deterioration. The data about the use of NSBBs, its type and dosage was specifically recorded. Patient characteristics at enrollment significantly associated with treatment and mortality were taken into account as potential confounders to adjust for treatment effect. A logistic regression model was fitted. RESULTS 164 (47%) ACLF patients received NSBBs whereas 185 patients did not. Although the CLIF-C ACLF scores were similar at presentation, more patients in the NSBB treated group had lower grades of ACLF (p=0.047) at presentation and significantly more patients improved. Forty patients (24.4%) died in NSBB treated group compared with 63 patients (34.1%) (p=0.048) [estimated risk-reduction 0.596 (95%CI: 0.361-0.985; p=0.0436)]. This improvement in survival was associated with a significantly lower white cell count (NSBB: 8.5 (5.8); no NSBB: 10.8 (6.6); p=0.002). No long-term improvement in survival was observed. CONCLUSIONS This study shows for the first time that ongoing treatment with NSBBs in cirrhosis is safe and reduces the mortality if they develop ACLF. Careful thought should be given before stopping NSBBs in cirrhotic patients.
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Affiliation(s)
- Rajeshwar P Mookerjee
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom
| | - Marco Pavesi
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium
| | - Karen Louise Thomsen
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom
| | - Gautam Mehta
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom
| | - Jane Macnaughtan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom
| | - Flemming Bendtsen
- Department of Gastroenterology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Minneke Coenraad
- Department of Gastroenterology-Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan Sperl
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Pere Gines
- Liver Unit, Hospital Clínic de Barcelona, University de Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Centro d'Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain
| | - Richard Moreau
- Inserm, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMRS1149, Université Paris Diderot-Paris 7, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; Laboratoire d'Excellence Inflamex, PRES Sorbonne Paris Cité, Paris, France
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom.
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Abstract
Acute-on-chronic liver failure combines an acute deterioration in liver function in an individual with pre-existing chronic liver disease and hepatic and extrahepatic organ failures, and is associated with substantial short-term mortality. Common precipitants include bacterial and viral infections, alcoholic hepatitis, and surgery, but in more than 40% of patients, no precipitating event is identified. Systemic inflammation and susceptibility to infection are characteristic pathophysiological features. A new diagnostic score, the Chronic Liver Failure Consortium (CLIF-C) organ failure score, has been developed for classification and prognostic assessment of patients with acute-on-chronic liver failure. Disease can be reversed in many patients, and thus clinical management focuses upon the identification and treatment of the precipitant while providing multiorgan-supportive care that addresses the complex pattern of physiological disturbance in critically ill patients with liver disease. Liver transplantation is a highly effective intervention in some specific cases, but recipient identification, organ availability, timing of transplantation, and high resource use are barriers to more widespread application. Recognition of acute-on-chronic liver failure as a clinically and pathophysiologically distinct syndrome with defined diagnostic and prognostic criteria will help to encourage the development of new management pathways and interventions to address the unacceptably high mortality.
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Affiliation(s)
- William Bernal
- Liver Intensive Therapy Unit, King's College Hospital, London, UK.
| | - Rajiv Jalan
- Liver Failure Group, Division of Medicine, University College London, London, UK; Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK; Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
| | - Alberto Quaglia
- Histopathology Section, Institute of Liver Studies, King's College Hospital, London, UK
| | - Kenneth Simpson
- Department of Hepatology, University of Edinburgh, Edinburgh, UK
| | - Julia Wendon
- Liver Intensive Therapy Unit, King's College Hospital, London, UK
| | - Andrew Burroughs
- Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK; Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK
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de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63:743-752. [PMID: 26047908 DOI: 10.1016/j.jhep.2015.07.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 05/14/2015] [Accepted: 05/27/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Roberto de Franchis
- Department of Biomedical and Clinical Sciences, University of Milan, Gastroenterology Unit, Luigi Sacco University Hospital, Milan, Italy.
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Rachakonda V, Gabbert C, Raina A, Li H, Malik S, DeLany JP, Behari J. Stratification of risk of death in severe acute alcoholic hepatitis using a panel of adipokines and cytokines. Alcohol Clin Exp Res 2015; 38:2712-21. [PMID: 25421508 DOI: 10.1111/acer.12558] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 08/29/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Dysregulated adipose tissue metabolism has been implicated in the pathogenesis of alcoholic liver disease in murine models. We aimed to characterize serum markers of adipose tissue metabolism and inflammation in patients with severe acute alcoholic hepatitis (AAH) and determine their utility to predict survival in severe AAH. METHODS A prospective, case-control study design was used. Seventy-six patients hospitalized with severe AAH and 25 ambulatory patients with alcoholic cirrhosis as controls were included. Serum samples were collected for biochemical analyses. Patients were followed for 180 days after enrollment to determine the survival. RESULTS AAH patients exhibited higher serum glycerol and free fatty acid levels, suggesting enhanced adipose tissue triglyceride hydrolysis. Patients with AAH demonstrated a distinct serum lipidomic profile compared with alcoholic cirrhosis but not in systemic and adipose-specific insulin resistance. AAH patients had higher serum resistin and plasmin activation inhibitor-1 levels, while serum leptin was decreased. Serum levels of the prolipolytic cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-15 were significantly higher in AAH patients. Only 53% of AAH patients survived 180 days after admission, while all cirrhotic patients were alive at the end of the study period. Among patients with severe AAH, white blood cell count, hemoglobin, resistin, IL-6 and TNF-α were associated with 180-day survival, and all 5 markers demonstrated accuracy by area under receiver-operator curve analysis. Serum IL-6 levels ≥38.66 pg/ml most precisely identified deaths in severe AAH. Patients with IL-6 ≥ 38.66 pg/ml had significantly decreased mean survival compared to those with lower levels. CONCLUSIONS AAH patients demonstrate evidence of increased adipose tissue lipolysis and altered serum lipidomic profile compared with alcoholic cirrhosis patients. IL-6 may be a useful biomarker to risk stratify severe AAH patients at the highest risk of mortality.
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Affiliation(s)
- Vikrant Rachakonda
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Kao JT, Feng CL, Yu CJ, Tsai SM, Hsu PN, Chen YL, Wu YY. IL-6, through p-STAT3 rather than p-STAT1, activates hepatocarcinogenesis and affects survival of hepatocellular carcinoma patients: a cohort study. BMC Gastroenterol 2015; 15:50. [PMID: 25908103 PMCID: PMC4424593 DOI: 10.1186/s12876-015-0283-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 04/08/2015] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Biologic activities of functional mediators activate downstream transducers regulating inflammation and carcinogenesis. Correlation among mediators (IL-6, IL-27, TNF-α, and VEGF) with STAT proteins at diverse clinical-pathologic stages of hepatocellular carcinoma (HCC) remains limited. METHODS Serum mediators assayed from 147 untreated HCC cases (HCC-total group) included 70 HBV-infected (HCC-HBV group), 64 HCV-infected (HCC-HCV group), and 13 without HBV-/HCV-infection (HCC-NBNC group). Another 156 non-HCC individuals comprised 54 healthy individuals (HG) and 102 chronic hepatitis patients (CH-total group) as control group. To correlate with serum mediators, 86-paired liver tissues (CH: 52 and HCC: 34 cases) served for p-STATs proteins immunostain. RESULTS Although four mediators (IL-6, IL-27, TNF-α, and VEGF) significantly over-expressed, IL-6 presented the strongest correlation in HCC-total versus CH-total or HG groups (HCC-total versus CH-total: P < 0.001; HCC-total versus HG: P < 0.001). Over-expressed IL-6 concentration linked with poor liver function (Albumin: r = -0.383, P < 0.001; Bilirubin: r = 0.280, P = 0.001; INR: r = 0.299, P < 0.001; AST: 0.212, P = 0.016), tumor progression (TNM system: r = 0.370; P < 0.001), clinical condition severity (BCLC system: r = 0.471; P < 0.001; terminal- versus early-stage HCC, P = 0.001; advanced- versus early-stage HCC, P = 0.007; terminal- versus intermediate- stage HCC P = 0.003; advanced- versus intermediate-stage HCC P = 0.019), and 6-month mortality (P = 0.024). Likewise, serum IL-6 (r = 0.501, P = 0.003) as compared to IL-27 (r = 0.052, P = 0.770), TNF-α (r = 0.019, P = 0.917), and VEGF (r = 0.096, P = 0.595) expression reflected positive correlation with activation of tissues p-STAT3 rather than p-STAT1. CONCLUSIONS Serum IL-6, through p-STAT3 rather than p-STAT1 signal pathway, affected hepatic function, tumor progression, and determine HCC patient survival.
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Affiliation(s)
- Jung-Ta Kao
- School of Medicine, China Medical University, Taichung, Taiwan.
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
- Department of Internal Medicine, Division of Hepato-Gastroenterology, China Medical University Hospital, Taichung, Taiwan.
| | - Chun-Lung Feng
- Department of Internal Medicine, Division of Hepato-Gastroenterology, China Medical University Hospital, Taichung, Taiwan.
| | - Cheng-Ju Yu
- Department of Internal Medicine, Division of Hepato-Gastroenterology, China Medical University Hospital, Taichung, Taiwan.
| | - Shu-Mei Tsai
- Graduate Institute of Clinical Medical Science, Chang Gung University, Tao-Yuan, Taiwan.
| | - Ping-Ning Hsu
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Yao-Li Chen
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan.
| | - Yi-Ying Wu
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, 404, Taiwan.
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Abstract
Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.
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Lin BY, Zhou L, Geng L, Zheng ZY, Jia JJ, Zhang J, Yao J, Zheng SS. High neutrophil-lymphocyte ratio indicates poor prognosis for acute-on-chronic liver failure after liver transplantation. World J Gastroenterol 2015; 21:3317-3324. [PMID: 25805939 PMCID: PMC4363762 DOI: 10.3748/wjg.v21.i11.3317] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 10/14/2014] [Accepted: 12/22/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the significance of pre-transplant neutrophil-lymphocyte ratio (NLR) in determining the prognosis of liver transplant (LT) recipients with acute-on-chronic liver failure (ACLF).
METHODS: Data were collected from the liver transplantation data bank. The NLR values and other conventional inflammatory markers were evaluated for their ability to predict the prognosis of 153 patients with ACLF after LT. The NLR cut-off value was based on a receiver operating characteristic curve analysis. A Kaplan-Meier curve analysis and univariate and multivariate Cox regression models were used to define the independent risk factors for poor outcomes.
RESULTS: The optimal NLR cut-off value was 4.6. Out of 153 patients, 83 (54.2%) had an NLR ≥ 4.6. The 1-, 3-, and 5-year overall survival rates were 94.3%, 92.5% and 92.5%, respectively, in the normal NLR group and 74.7%, 71.8% and 69.8%, respectively, in patients with high NLRs (P < 0.001). Furthermore, there was a significant difference in infectious complications after LT between the high and normal NLR groups. There were no significant differences for other complications. In the multivariate Cox regression model, a high NLR was defined as a significant predictor of poor outcomes for LT.
CONCLUSION: A high NLR is a convenient and available predictor for prognosis of LT patients and can potentially optimize the current criteria for LT in ACLF.
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Mehta G, Mookerjee RP, Sharma V, Jalan R. Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure. Liver Int 2015; 35:724-34. [PMID: 24703488 DOI: 10.1111/liv.12559] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 03/28/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is characterized by acute deterioration of cirrhosis, systemic inflammation and multi-organ failure. Inflammation is also key to the pathobiology of portal hypertension. This study aims to define the relationship between systemic and hepatic haemodynamics in patients with ACLF. METHODS Sixty patients with alcoholic cirrhosis were prospectively enrolled - stable cirrhosis (SC, n = 27), acute decompensation without ACLF (AD, n = 14) and ACLF (n = 19) - and managed with standard therapy. Systemic and hepatic haemodynamic studies were performed, and patients were followed up for 3 months. Plasma norepinephrine, cytokine profile, nitrate/nitrite and malondialdehyde levels were measured. RESULTS Three-month mortality was as follows: SC - none; AD - 14%; ACLF - 47.2% (P < 0.001). Mean arterial pressure was lowest in the ACLF group (P < 0.001). ACLF patients had significantly higher hepatic vein pressure gradient (HVPG), while the hepatic blood flow was markedly reduced with an increase in intrahepatic resistance, which predicted mortality (AUROC: 0.87, P < 0.0001). In ACLF, the severity of intrahepatic resistance correlated with markers of inflammatory response, norepinephrine levels, creatinine levels and severity of encephalopathy. Modelling data showed that the high norepinephrine levels in ACLF may contribute to the right shift of the HVPG-hepatic blood flow relationship and its levels correlated with inflammatory markers and mortality (AUROC: 0.90; P < 0.0001). CONCLUSIONS The disturbances in systemic and hepatic haemodynamics in alcohol-related ACLF are associated with dysregulated inflammation, multi-organ failure and marked activation of the sympathetic nervous system. These abnormalities predict high mortality rates in alcohol-related ACLF patients.
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Affiliation(s)
- Gautam Mehta
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, NW3 2PF, London
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Adebayo D, Morabito V, Davenport A, Jalan R. Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. Kidney Int 2014; 87:509-15. [PMID: 25296092 PMCID: PMC4346614 DOI: 10.1038/ki.2014.338] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Revised: 04/17/2014] [Accepted: 04/17/2014] [Indexed: 12/13/2022]
Abstract
The short-term mortality of cirrhotic patients who develop renal dysfunction remains unacceptably high, and as such the treatment of this condition is an unmet need. Although features of kidney injury are well recognized in these patients, the pathophysiology is complex and not completely understood. Improved understanding of the pathophysiological mechanisms involved in renal dysfunction occurring on a background of cirrhosis is key to developing effective treatment strategies to improve survival. Renal dysfunction due to hepatorenal syndrome (HRS) is characteristic of cirrhosis. Our current understanding is that HRS is functional in nature and occurs as a consequence of hemodynamic changes associated with portal hypertension. However, there is evidence in the literature suggesting that, histologically, the kidneys are not always normal in the vast majority of patients who present with renal dysfunction on the background of cirrhosis. Furthermore, there is emerging data implicating nonvasomotor mechanisms in the pathophysiology of renal dysfunction in cirrhosis. This mini-review aims to present the evidence suggesting that factors other than hemodynamic dysregulation have an important role in the development of this major complication for patients with progressive cirrhosis.
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Affiliation(s)
- Danielle Adebayo
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK
| | - Vincenzo Morabito
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK
| | - Andrew Davenport
- UCL Centre for Nephrology, Royal Free London NHS Foundation Trust, London, UK
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK
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Mehta G, Gustot T, Mookerjee RP, Garcia-Pagan JC, Fallon MB, Shah VH, Moreau R, Jalan R. Inflammation and portal hypertension - the undiscovered country. J Hepatol 2014; 61:155-63. [PMID: 24657399 DOI: 10.1016/j.jhep.2014.03.014] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 02/10/2014] [Accepted: 03/10/2014] [Indexed: 12/12/2022]
Abstract
Portal hypertension has traditionally been viewed as a progressive process, involving ultrastructural changes including fibrosis, nodule formation, and vascular thrombosis, leading to increased intrahepatic resistance to flow. However, it is increasingly recognized that a significant component of this vascular resistance results from a dynamic process, regulated by complex interactions between the injured hepatocyte, the sinusoidal endothelial cell, the Kupffer cell and the hepatic stellate cell, which impact on sinusoidal calibre. Recent findings suggest these haemodynamic findings are most marked in patients with superimposed inflammation. The precise mechanisms for vascular dysfunction in cirrhosis with superimposed inflammation remain to be fully elucidated but several studies over the past decade have started to generate the hypothesis that inflammation may be a key mediator of the pathogenesis and severity of portal hypertension in this context. This review provides a comprehensive overview of the biological mechanisms for inflammation playing a key role in the severity of portal hypertension, and illustrates potential novel therapies that act by modifying these processes.
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Affiliation(s)
- Gautam Mehta
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Campus, London NW3 2PF, United Kingdom
| | - Thierry Gustot
- Laboratory of Experimental Gastroenterology, ULB, Brussels, Belgium; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, ULB, Brussels, Belgium
| | - Rajeshwar P Mookerjee
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Campus, London NW3 2PF, United Kingdom
| | - Juan Carlos Garcia-Pagan
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Michael B Fallon
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 4.234, Houston, TX 77030-1501, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Richard Moreau
- INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Paris/Clichy, France; Université Paris-Diderot, Paris 7, UMR-S773, Paris, France; Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Campus, London NW3 2PF, United Kingdom.
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Papastergiou V, Burroughs AK, Tsochatzis EA. Prognosis and treatment of patients with acute alcoholic hepatitis. Expert Rev Gastroenterol Hepatol 2014; 8:471-86. [PMID: 24716632 DOI: 10.1586/17474124.2014.903800] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Despite alcoholic hepatitis (AH) is the most acute manifestation of alcohol-related liver disease, its treatment remains controversial. Corticosteroids, given either as monotherapy or together with N-acetylecysteine, have been associated with a moderate short-term survival benefit in patients with severe disease. The Maddrey's discriminant function; Glasgow alcoholic hepatitis score; age, bilirubin, INR and creatinine score; and the Model for end-stage liver disease have been proposed for stratifying prognosis in AH enabling selection of the patients to treat. Definition of treatment non-responders using the Lille model after 7 days of therapy may prevent a detrimental impact of prolonged corticosteroids. Pentoxifylline is an effective alternative reducing the occurrence of hepatorenal syndrome. Emerging evidence supports use of liver transplantation in a strictly selected subset of corticosteroid non-responders.
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Affiliation(s)
- Vassilios Papastergiou
- The Royal Free Sheila Sherlock Liver Centre and UCL Institute of Liver and Digestive Health, Royal Free Hospital and UCL, London, UK
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Yang AM, Wen LL, Yang CS, Wang SC, Chen CS, Bair MJ. Interleukin 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients. Kaohsiung J Med Sci 2014; 30:291-8. [PMID: 24835349 DOI: 10.1016/j.kjms.2014.02.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 02/24/2014] [Accepted: 12/11/2013] [Indexed: 12/20/2022] Open
Abstract
Alcoholic liver cirrhosis is a severe form of alcohol-related liver damage. More than 95% of heavy drinkers develop a fatty liver, but only 35% of them develop cirrhosis. We postulate that genetic factors may play a role in this difference. Genetic polymorphisms of the cytokine genes may influence Kupffer cells cytokine genes expression. In this study, we evaluated the promoter polymorphisms of interleukin (IL) 1β, IL 6, IL 10, and tumor necrosis factor alpha (TNFα) and aimed to clarify the association between the polymorphisms and the disease. Forty alcoholic patients with liver cirrhosis and 64 healthy volunteers were included in our investigation. Genotyping on IL 1β -511 T>C, IL 6 -572 G>C, IL 10 -819 C>T, IL 10 -1082 G>A, and TNFα -308 G>A was done. Another 36 patients with recurrent alcoholic pancreatitis were included as an additional control group. Genotyping on IL 10 -819 C>T and IL 10 -1082 G>A was done. The polymorphisms on IL 1 and IL 6 showed no significant association. The p value for TNFα -308 G>A was 0.028 in comparison with healthy volunteers. Although the p value was less than 0.05, it did not reach significance after Bonferroni correction. The p values for IL 10 -819 C>T and IL 10 -1082 G>A were respectively 0.031 and 0.026 in healthy volunteers and 0.028 and 0.023 in the alcoholic pancreatitis group. The results also did not reach significance after Bonferroni correction. Among the participants with the GCC haplotype, healthy volunteers had p = 0.027 (p < 0.05) and an odds ratio (OR) of 0.124 [confidence interval (95%) CI, 0.015-0.997], whereas the alcoholic pancreatitis group had p = 0.023 (p < 0.05) and an OR of 0.106 (95% CI, 0.012-0.912). The odds ratio of people having one ATA haplotype was 6.233 (95% CI, 0.739-52.547) in healthy volunteers and 6.588 (95% CI, 0.727-59.679) in the alcoholic pancreatitis group; the corresponding rate was 10.521 (95% CI, 1.252-88.440) and 12.833 (95% CI 1.408-117.008) for people with two ATA haplotypes. The p values in these groups were 0.031 (p < 0.05) and 0.028 (p < 0.05), respectively. The presence of a GCC haplotype could have protective effect against alcoholic liver disease, whereas the presence of an ATA haplotype could predispose carriers to the disease. The IL 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients.
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Affiliation(s)
- An-Ming Yang
- Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan; Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Li-Li Wen
- Department of Laboratory Medicine, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Chang-Shyue Yang
- Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Sun-Chong Wang
- Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Chien-Sheng Chen
- Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Ming-Jong Bair
- Department of Internal Medicine, Mackay Memorial Hospital, Taitung Branch, Taitung, Taiwan.
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Abenavoli L, Milic N, Rouabhia S, Addolorato G. Pharmacotherapy of acute alcoholic hepatitis in clinical practice. World J Gastroenterol 2014; 20:2159-67. [PMID: 24605014 PMCID: PMC3942820 DOI: 10.3748/wjg.v20.i9.2159] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 01/02/2014] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Severe alcoholic hepatitis (AH) is an acute form of alcohol induced liver disease with a poor prognosis that is seen in the patients who consume large quantities of alcohol. The diagnosis of AH is based on the appropriate alcohol intake history and is supported with clinical and histological features, and several scoring systems. Glucocorticoids are the mainstay for treating severe AH with pentoxifylline used as an alternative to steroids in addition to total alcohol abstinence. Liver transplantation is a possible therapeutic option for severe AH. Among the anti-craving medications able to improve abstinence rate, baclofen seems to be effective and safe in the alcoholic patients affected by severe liver damage.
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Rosselli M, MacNaughtan J, Jalan R, Pinzani M. Beyond scoring: a modern interpretation of disease progression in chronic liver disease. Gut 2013; 62:1234-41. [PMID: 23645629 DOI: 10.1136/gutjnl-2012-302826] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Matteo Rosselli
- Division of Medicine, University College London, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
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50
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[Management of severe alcoholic hepatitis]. Wien Med Wochenschr 2013; 164:3-8. [PMID: 23842647 DOI: 10.1007/s10354-013-0221-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 06/03/2013] [Indexed: 12/14/2022]
Abstract
Severe alcoholic hepatitis is still associated with high mortality and presence of liver failure manifested by jaundice, coagulopathy and encephalopathy is a poor prognostic indicator. The management of these patients includes at first hand several supportive measures as treatment of alcohol withdrawal, administration of fluid and vitamins and admission to an intensive care unit in the unstable patient. Glucocorticoids have been since decades the most intensively studied therapy in alcoholic hepatitis and are effective in certain subgroups. Indication for such a therapy is usually defined on a Maddrey Discriminant Function > 32. The Lille score at day 7 is used to decide whether corticosteroid therapy should be stopped or continued for a 1 month course. Nutritional supplementation is also likely to be beneficial. The main progress in better understanding its pathophysiology has come from cytokine studies. Various proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα) or interleukin-1 (IL-1) have been proposed to play a role in this disease. This advancement has recently led to pilot studies investigating anti-TNF drugs such as pentoxifylline, infliximab (anti-TNF antibody) or etanercept in the treatment of this disease. These studies revealed besides for pentoxifylline rather negative results. Despite this fact, targeting of certain cytokines such as IL-1 remains an attractive treatment concept for this devastating disorder in the future.
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