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McGettigan B, Hernandez-Tejero M, Malhi H, Shah V. Immune Dysfunction and Infection Risk in Advanced Liver Disease. Gastroenterology 2025; 168:1085-1100. [PMID: 39927926 DOI: 10.1053/j.gastro.2024.08.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 02/11/2025]
Abstract
The risk of microbial infections is increased in cirrhosis and other forms of advanced liver disease such as alcohol-associated hepatitis. Such infections may precipitate new or further decompensation and death, especially in patients with clinical features of acute-on-chronic liver failure. The severe immune dysfunction or "immune paralysis" caused by advanced liver disease is associated with high short-term mortality. However, the pathogenic mechanisms underlying immune dysfunction and immunodeficiency are incompletely understood. Evidence to date suggests a complex, dynamic process that perturbs the physiological roles of the liver as a master regulator of systemic immunity and protector against noxious effects of exogenous molecules in the portal vein flowing from the gut. Thus, in cirrhosis and severe alcohol-associated hepatitis, the ability of hepatocytes and intrahepatic immune cells to balance normal context-dependent dichotomous responses of tolerance vs immune activation is lost. Contributing factors include loss of the gut barrier with translocation of microbial products through the portal vein, culminating in development of functional defects in innate and adaptive immune cells, and generation of immune-regulatory myeloid cells that permit microbial colonization and infection. This review addresses key evidence supporting the paradigm of immune dysfunction as a risk for microbial infections and identifies potential therapeutic targets for intervention. The primary focus is on cirrhosis-associated immune dysfunction and alcohol-associated liver disease, because the bulk of available data are from these 2 conditions.
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Affiliation(s)
- Brett McGettigan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Maria Hernandez-Tejero
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
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2
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Sun M, Yang Z, Tang F, Li F, Ye Q, Sun C, Liang J. Alcoholic cirrhosis-associated immune dysfunction: What does it imply for us? Ann Hepatol 2025:101927. [PMID: 40379022 DOI: 10.1016/j.aohep.2025.101927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/19/2025] [Accepted: 04/02/2025] [Indexed: 05/19/2025]
Abstract
Alcoholic cirrhosis is a leading cause of chronic advanced liver disease. With the gradual eradication of viral hepatitis and the rising levels of alcohol consumption, the incidence of alcoholic cirrhosis is expected to increase steadily. Alcohol is primarily metabolized in the gastrointestinal tract, producing toxic metabolites that enter the portal vein circulation and are subsequently transported to the liver. Excessive alcohol intake activates the microsomal ethanol oxidation system and disrupts the intestinal microbiota-driven microenvironment dictated by intestinal microbiota, and increase intestinal permeability, all of which trigger severe systemic inflammatory responses and impaired immune function. This phenomenon, known as cirrhosis-associated immune dysfunction (CAID), is closely linked to the severity of cirrhosis and can significantly influence disease progression, potentially leading to multi-organ failure. This narrative review sheds light on the relationship between alcoholic cirrhosis and CAID, focusing on tailored interventions to modify immune response and modulate gut microbiota composition in hopes of mitigating the development and deterioration of alcoholic cirrhosis.
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Affiliation(s)
- Mingyu Sun
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Ziyi Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Fei Tang
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Fenghui Li
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Qing Ye
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin 300308, China.
| | - Jing Liang
- Department of Hepatology, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China.
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McPherson S, Abbas N, Allison MED, Backhouse D, Boothman H, Cooksley T, Corless L, Crame T, Cross TJS, Henry J, Hogan B, Mansour D, McGinty G, McKinnon G, Patel J, Tavabie OD, Williams F, Hollywood C. Decompensated cirrhosis: an update of the BSG/BASL admission care bundle. Frontline Gastroenterol 2025:flgastro-2025-103074. [DOI: 10.1136/flgastro-2025-103074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/03/2025] Open
Abstract
Acute decompensated cirrhosis (DC) and acute-on-chronic liver failure are common reasons for hospital admission that have a high in-hospital mortality rate (10%–20%). Patients require a detailed assessment for precipitating factors and management of complications such as infections, ascites, acute kidney injury and hepatic encephalopathy. Multiple reports have demonstrated unwarranted variability in the care of patients with DC. In 2014, the British Society of Gastroenterology (BSG)/British Association for the Study of the Liver (BASL) DC care bundle (DCCB) was introduced to provide a structured approach for the management of patients with DC in the first 24 hours. Usage of the DCCB has been shown to improve care of patients with DC. However, despite evidence indicating the beneficial impact of the DCCB, overall usage across the UK was only 11.4% in a national audit. Our aim was to update the DCCB to incorporate recent advances in care and improve its usability and develop a strategy to improve its usage nationally. The updated bundle was developed by a multidisciplinary group of specialists from BSG, BASL and the Society for Acute Medicine with the quality of evidence supporting the bundle recommendations assessed using the Grading of Recommendation Assessment Development and Evaluation tool. Proposed minimum standards for audit were also developed. Finally, a strategy to promote usage of the bundle including education/training at a national and local level, improving accessibility for the bundle, and promotion of frameworks for use at an institutional level to improve and monitor utilisation of DCCB.
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Engelmann C, Zhang IW, Clària J. Mechanisms of immunity in acutely decompensated cirrhosis and acute-on-chronic liver failure. Liver Int 2025; 45:e15644. [PMID: 37365995 PMCID: PMC11815630 DOI: 10.1111/liv.15644] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/28/2023]
Abstract
The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.
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Affiliation(s)
- Cornelius Engelmann
- Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow‐KlinikumCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Berlin Institute of HealthBerlinGermany
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
| | - Ingrid W. Zhang
- Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow‐KlinikumCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Berlin Institute of HealthBerlinGermany
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols ChairBarcelonaSpain
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols ChairBarcelonaSpain
- Biochemistry and Molecular Genetics ServiceHospital Clínic‐IDIBAPS CIBERehdBarcelonaSpain
- Department of Biomedical SciencesUniversity of BarcelonaBarcelonaSpain
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Hackstein CP. Liver damage and immune responses. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:56-64. [PMID: 39793602 DOI: 10.1055/a-2365-3796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2025]
Abstract
Chronic liver disease (CLD) has massive systemic repercussions including major impacts on the body's immune system. Abnormalities in phenotype, function and numbers of various immune cell subsets have been established by a large number of clinical and pre-clinical studies. The loss of essential immune functions renders CLD-patients exceptionally susceptible to bacterial and viral infections and also impairs the efficacy of vaccination. Consequently, infections represent a major clinical issue causing significant morbidity and mortality in these patients. Mechanistically, the immune dysfunction associated with CLD results from the increased translocation of bacteria and bacterial cues from the intestine. These trigger a signaling axis around the cytokines IFN I and IL-10 in hepatic myeloid cells, which aside from impairing the function of the myeloid cells themselves, also has notable negative impacts on the functionality of other immune cells. T cells in CLD-patients and -models are especially affected by this signaling axis and display a variety of quantitative and qualitative defects. Due to the high clinical relevance, understanding the mechanisms underlaying CED-associated immune dysfunction is of critical importance to discover and develop new therapeutic targets.
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Affiliation(s)
- Carl-Philipp Hackstein
- Institut für Molekulare Immunologie, Technische Universität München, München, Germany
- Zentrum für Infektionsprävention (ZIP), Technische Universität München, Freising, Germany
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Wang D, Xiong J. Association between alcohol consumption levels and pelvic inflammatory disease: Findings from the NHANES 2013-2020. J Obstet Gynaecol Res 2025; 51:e16188. [PMID: 39676636 DOI: 10.1111/jog.16188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/02/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND AND AIM Pelvic inflammatory disease (PID) is a common and serious infection affecting women's reproductive health, which may result in severe consequences, such as infertility. This research is to investigate the association between alcohol consumption levels and the odds of PID prevalence, providing insights that could inform public health policies. METHODS AND RESULTS The U.S. National Health and Nutrition Examination Survey (NHANES) 2013-2020 is the data source. Multivariate logistic regression analysis, trend analysis, and curve fitting were employed to examine the associations between alcohol consumption levels and the odds of PID prevalence. Regarding subgroup analysis, we utilized the stratified analysis and interaction test to investigate the robustness of this association. Compared with participants who never consumed alcohol, alcohol consumption increased the odds of PID prevalence. The odds of PID prevalence increased with the increase in the level of alcohol consumption. In the fully adjusted model, compared to non-drinkers, the odds ratios (OR) for PID were 1.89 (95% CI: 1.23-2.92) for mild drinkers, 1.94 (95% CI: 1.24-3.04) for moderate drinkers, and 2.01 (95% CI: 1.27-3.19) for heavy drinkers, indicating an increased prevalence of PID by 89, 94, and 101%, respectively. This association was consistently observed across the study population. CONCLUSIONS Alcohol consumption levels were positively related to the odds of PID prevalence among adult females in the United States. Our results indicate that reducing alcohol consumption and cultivating good living habits will likely help prevent PID in the general population.
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Affiliation(s)
- Daji Wang
- School of First Clinical Medical, Xinxiang Medical University, Xinxiang, Henan, China
| | - Jianbo Xiong
- School of First Clinical Medical, Xinxiang Medical University, Xinxiang, Henan, China
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Li Y, Niu B, Liu J, Zhou H, Chen Z, Zhou Y, Wei Q, Jiao X, Mi Y, Li P. Bacterial infection adversely increases the risk of decompensation in patients with hepatitis B virus-related compensated cirrhosis: a retrospective study. BMC Infect Dis 2024; 24:1446. [PMID: 39695967 DOI: 10.1186/s12879-024-10306-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 12/04/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Hepatitis B virus related compensated cirrhosis generally has a favorable prognosis until decompensation occurs. Bacterial infections are prevalent in Hepatitis B virus related decompensated cirrhosis.Bacterial infection and decompensated hepatitis B cirrhosis are mutually reinforcing. And it also interacts with and promotes certain decompensation-related events. However, the impact of bacterial infections on the progression from compensated to decompensated cirrhosis in Hepatitis B patients remains unclear. METHODS We retrospectively analyzed the baseline characteristics of 1,011 patients with Hepatitis B virus related compensated cirrhosis. Using time-dependent regression analysis, we evaluated whether bacterial infections increase the risk of decompensation, defined as the occurrence of ascites, hepatic encephalopathy, or variceal bleeding. RESULTS A total of 1,011 patients were retrospectively analyzed over a median follow-up period of 79 months. Bacterial infections were observed in 89 patients (8.8%). Respiratory and urinary tract infections were the most common bacterial infections.Decompensation occurred in 44.9% of patients with bacterial infections, compared to 9% of those without BIs. Patients with bacterial infections had a higher risk of decompensation ([OR] 1.024; 95% CI 1.016-1.032; p < 0.001) than those without bacterial infections. CONCLUSION Our findings suggest that bacterial infections have a significant impact on the progression of hepatitis B virus related compensated cirrhosis, notably increasing the risk of decompensation.
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Affiliation(s)
- Yinglun Li
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Bin Niu
- Department of Infectious Diseases, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Jing Liu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Hui Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China
| | - Ze Chen
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Yibing Zhou
- Department of Scientific Research, Central Laboratory, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, 215500, China
| | - Qian Wei
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
| | - Xue Jiao
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
- Clinical School of the Second People's Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuqiang Mi
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China
- Tianjin Research Institute of Liver Diseases, Tianjin, China
| | - Ping Li
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin, China.
- Tianjin Research Institute of Liver Diseases, Tianjin, China.
- Second Department of Integrated Traditional Chinese and Western Medicine, Tianjin Second People's Hospital, Tianjin, China.
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McGettigan BM, A Osna N. Functional humoral immunity is crucial to outcomes in severe alcohol-associated hepatitis. Hepatology 2024:01515467-990000000-01004. [PMID: 39190687 DOI: 10.1097/hep.0000000000001079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Affiliation(s)
- Brett M McGettigan
- Division Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Natalia A Osna
- The Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
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Gromadzka G, Czerwińska J, Krzemińska E, Przybyłkowski A, Litwin T. Wilson's Disease-Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues. Int J Mol Sci 2024; 25:9034. [PMID: 39201720 PMCID: PMC11354778 DOI: 10.3390/ijms25169034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/11/2024] [Accepted: 08/13/2024] [Indexed: 09/03/2024] Open
Abstract
Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD.
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Affiliation(s)
- Grażyna Gromadzka
- Department of Biomedical Sciences, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University, Wóycickiego Street 1/3, 01-938 Warsaw, Poland
| | - Julia Czerwińska
- Students Scientific Association “Immunis”, Cardinal Stefan Wyszynski University, Dewajtis Street 5, 01-815 Warsaw, Poland
| | - Elżbieta Krzemińska
- Students Scientific Association “Immunis”, Cardinal Stefan Wyszynski University, Dewajtis Street 5, 01-815 Warsaw, Poland
| | - Adam Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland;
| | - Tomasz Litwin
- Second Department of Neurology, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Poland;
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Brujats A, Huerta A, Osuna-Gómez R, Guinart-Cuadra A, Ferrero-Gregori A, Pujol C, Soriano G, Poca M, Fajardo J, Escorsell A, Gallego A, Vidal S, Villanueva C, Alvarado-Tapias E. Immune Response and Risk of Decompensation following SARS-CoV-2 Infection in Outpatients with Advanced Chronic Liver Disease. Int J Mol Sci 2024; 25:8302. [PMID: 39125872 PMCID: PMC11312207 DOI: 10.3390/ijms25158302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Advanced chronic liver disease (ACLD) is associated with a wide spectrum of immune dysfunction. The clinical impact of SARS-CoV-2 on the development of decompensation and immune response in unvaccinated outpatients has not as yet been clearly defined. This study aimed to evaluate the clinical and immunological impact of SARS-CoV-2 on outpatients with ACLD. This is an observational case-control study, in which ACLD outpatients were included prospectively and consecutively and classified into two groups: SARS-CoV-2 infected and non-infected. Patients' baseline characteristics and infection data were collected and analyzed. Immunoglobulin G (IgG) levels against Spike 1 were evaluated. The primary endpoint was risk of liver decompensation during follow-up, assessed after propensity score matching and adjusted by Cox regression. Between October 2020 and July 2021, ACLD outpatients (n = 580) were identified, and 174 patients with clinical follow-up were included. SARS-CoV-2 infection incidence was 7.6% (n = 44). Risk of liver decompensation was significantly higher after infection (HR = 2.43 [1.01-5.86], p = 0.048) vs. non-infection. The time of IgG evaluation was similar in all patients (n = 74); IgG concentrations were significantly higher in compensated vs. decompensated patients (1.02 ± 0.35 pg/mL vs. 0.34 ± 0.16 pg/mL, p < 0.0001) and correlated with hemoglobin levels. The dysregulation of the innate immune response in patients with decompensated liver disease increased the risk of further decompensation following SARS-CoV-2, mainly due to a worsening of ascites.
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Affiliation(s)
- Anna Brujats
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Anna Huerta
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Rubén Osuna-Gómez
- Inflammatory Diseases Department, Institut Recerca Hospital de la Santa Creu i Sant Pau (IR Sant Pau), 08041 Barcelona, Spain; (A.G.-C.); (S.V.)
| | - Albert Guinart-Cuadra
- Inflammatory Diseases Department, Institut Recerca Hospital de la Santa Creu i Sant Pau (IR Sant Pau), 08041 Barcelona, Spain; (A.G.-C.); (S.V.)
| | - Andreu Ferrero-Gregori
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Clàudia Pujol
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - German Soriano
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Maria Poca
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Javier Fajardo
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Angels Escorsell
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Adolfo Gallego
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
| | - Silvia Vidal
- Inflammatory Diseases Department, Institut Recerca Hospital de la Santa Creu i Sant Pau (IR Sant Pau), 08041 Barcelona, Spain; (A.G.-C.); (S.V.)
| | - Càndid Villanueva
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Edilmar Alvarado-Tapias
- Department of Gastroenterology and Hepatology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Insitute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain; (A.B.); (A.H.); (A.F.-G.); (C.P.); (G.S.); (M.P.); (J.F.); (A.E.); (A.G.); (C.V.)
- Departament Medicina UAB, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Balazs I, Stadlbauer V. Circulating neutrophil anti-pathogen dysfunction in cirrhosis. JHEP Rep 2023; 5:100871. [PMID: 37822786 PMCID: PMC10562928 DOI: 10.1016/j.jhepr.2023.100871] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/16/2023] [Accepted: 07/22/2023] [Indexed: 10/13/2023] Open
Abstract
Neutrophils are the largest population of leucocytes and are among the first cells of the innate immune system to fight against intruding pathogens. In patients with cirrhosis, neutrophils exhibit altered functionality, including changes in phagocytic ability, bacterial killing, chemotaxis, degranulation, reactive oxygen species production and NET (neutrophil extracellular trap) formation. This results in their inability to mount an adequate antibacterial response and protect the individual from infection. Prognosis and survival in patients with cirrhosis are greatly influenced by the development of infectious complications. Multidrug-resistant bacterial infections in patients with cirrhosis are currently a growing problem worldwide; therefore, alternative methods for the prevention and treatment of bacterial infections in cirrhosis are urgently needed. The prevention and treatment of neutrophil dysfunction could be a potential way to protect patients from bacterial infections. However, the reasons for changes in neutrophil function in cirrhosis are still not completely understood, which limits the development of efficient therapeutic strategies. Both cellular and serum factors have been proposed to contribute to the functional impairment of neutrophils. Herein, we review the current knowledge on features and proposed causes of neutrophil dysfunction in cirrhosis, with a focus on current knowledge gaps and limitations, as well as opportunities for future investigations in this field.
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Affiliation(s)
- Irina Balazs
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Graz, Austria
- Center for Biomarker Research in Medicine (CBmed), Graz, Austria
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12
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Blohm JE, Panthula M, Aggarwal A, Swazo R, Ashoka A, Ainapurapu B. Fatal Disseminated Coccidioidomycosis in Cirrhosis: A case series. Am J Med 2023:S0002-9343(23)00245-0. [PMID: 37068575 DOI: 10.1016/j.amjmed.2023.04.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/06/2023] [Indexed: 04/19/2023]
Abstract
PURPOSE Coccidioidomycosis is endemic to the Southwest United States and Mexico. In this case series, we describe three cases occurring in the Southwest US of patients with disseminated coccidioidomycosis infection in cirrhosis, all with a miliary pattern present on chest imaging. METHODS This case series was performed conducting a review of patients' electronic health records and thorough review of the literature for coccidioidomycosis infection in patients with liver disease. RESULTS Three patients with different etiology of liver disease with MELD-Na scores greater than 20 had chest imaging findings indicative of a miliary pattern on presentation. Each patient subsequently had extensive infectious disease workup that showed evidence of disseminated coccidioidomycosis. All three patients clinically worsened and eventually died. CONCLUSIONS This case series highlights the severity of disseminated coccidioidomycosis in patients with cirrhosis in an endemic area, as well as potential early clues such as miliary patterns on chest imaging. A review of the literature found a significant connection between potential mechanisms describing why patients with cirrhosis have such adverse outcomes in the setting of disseminated coccidioidomycosis including cirrhosis-associated immune dysfunction and genetic defects in immune functioning.
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Affiliation(s)
| | | | - Avin Aggarwal
- University of Arizona College of Medicine-Tucson; Department of Medicine, Banner-University Medical Center, Tucson, Arizona
| | - Roberto Swazo
- Orlando Health Medical Group - Lung & Sleep Medicine; Orlando, FL
| | - Ankita Ashoka
- University of Arizona College of Medicine-Tucson; Department of Medicine, Banner-University Medical Center, Tucson, Arizona
| | - Bujji Ainapurapu
- University of Arizona College of Medicine-Tucson; Department of Medicine, Banner-University Medical Center, Tucson, Arizona.
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13
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Yu L, Yousuf S, Yousuf S, Yeh J, Biggins SW, Morishima C, Shyu I, O’Shea-Stone G, Eilers B, Waldum A, Copié V, Burkhead J. Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease. Hepatol Commun 2023; 7:e0076. [PMID: 36809345 PMCID: PMC9949837 DOI: 10.1097/hc9.0000000000000076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/17/2022] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND AND AIM Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways. METHODS We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 µg/dL for women or 70 µg/dL for men. RESULTS The prevalence of copper deficiency was 17% (N=31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%, p=0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1β. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18-9.82, p=0.023). CONCLUSIONS In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.
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Affiliation(s)
- Lei Yu
- Department of Medicine, Division of Gastroenterology and Center for Liver Investigation Fostering Discovery, University of Washington, Seattle, Washington, USA
| | - Sarim Yousuf
- College of Medicine, Ziauddin University, Karachi, Pakistan
| | - Shahrukh Yousuf
- Department of Medicine, Division of Gastroenterology and Center for Liver Investigation Fostering Discovery, University of Washington, Seattle, Washington, USA
| | - Jeffrey Yeh
- Department of Medicine, Division of Gastroenterology and Center for Liver Investigation Fostering Discovery, University of Washington, Seattle, Washington, USA
| | - Scott W. Biggins
- Department of Medicine, Division of Gastroenterology and Center for Liver Investigation Fostering Discovery, University of Washington, Seattle, Washington, USA
| | - Chihiro Morishima
- Department of Lab Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Irene Shyu
- Department of Lab Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Galen O’Shea-Stone
- Department of Chemistry, Montana State University, Bozeman, Montana, USA
| | - Brian Eilers
- Department of Chemistry, Montana State University, Bozeman, Montana, USA
| | - Annie Waldum
- Department of Chemistry, Montana State University, Bozeman, Montana, USA
| | - Valérie Copié
- Department of Chemistry, Montana State University, Bozeman, Montana, USA
| | - Jason Burkhead
- Department of Biological Sciences, University of Alaska Anchorage, Anchorage, Alaska, USA
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14
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Medina-Morales JE, Panayotova GG, Nguyen DT, Graviss EA, Prakash GS, Marsh JA, Simonishvili S, Shah Y, Ayorinde T, Qin Y, Jin L, Zoumpou T, Minze LJ, Paterno F, Amin A, Riddle GL, Ghobrial RM, Guarrera JV, Lunsford KE. Pre-transplant Biomarkers of Immune Dysfunction Improve Risk Assessment of Post-transplant Mortality Compared to Conventional Clinical Risk Scores. RESEARCH SQUARE 2023:rs.3.rs-2548184. [PMID: 36798404 PMCID: PMC9934742 DOI: 10.21203/rs.3.rs-2548184/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction There is a critical need to accurately stratify liver transplant (LT) candidates' risk of post-LT mortality prior to LT to optimize patient selection and avoid futility. Here, we compare previously described pre-LT clinical risk scores with the recently developed Liver Immune Frailty Index (LIFI) for prediction of post-LT mortality. LIFI measures immune dysregulation based on pre-LT plasma HCV IgG, MMP3 and Fractalkine. LIFI accurately predicts post-LT mortality, with LIFI-low corresponding to 1.4% 1-year post-LT mortality compared with 58.3% for LIFI-high (C-statistic=0.85). Methods LIFI was compared to MELD, MELD-Na, MELD 3.0, D-MELD, MELD-GRAIL, MELD-GRAIL-Na, UCLA-FRS, BAR, SOFT, P-SOFT, and LDRI scores on 289 LT recipients based on waitlist data at the time of LT. Survival, hazard of early post-LT death, and discrimination power (C-statistic) were assessed. Results LIFI showed superior discrimination (highest C-statistic) for post-LT mortality when compared to all other risk scores, irrespective of biologic MELD. On univariate analysis, the LIFI showed a significant correlation with mortality 6-months, as well as 1-, 3-, and 5-years. No other pre-LT scoring system significantly correlated with post-LT mortality. On bivariate adjusted analysis, African American race (p<0.05) and pre-LT cardiovascular disease (p=0.053) were associated with early- and long-term post-LT mortality. Patients who died within 1-yr following LT had a significantly higher incidence of infections, including 30-day and 90-day incidence of any infection, pneumonia, abdominal infections, and UTI (p<0.05). Conclusions LIFI, which measures pre-LT biomarkers of immune dysfunction, more accurately predicts risk of post-LT futility compared with current clinical predictive models. Pre-LT assessment of immune dysregulation may be critical in predicting mortality after LT and may optimize selection of candidates with lowest risk of futile outcomes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Yong Qin
- Rutgers New Jersey Medical School
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15
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Dukić M, Radonjić T, Jovanović I, Zdravković M, Todorović Z, Kraišnik N, Aranđelović B, Mandić O, Popadić V, Nikolić N, Klašnja S, Manojlović A, Divac A, Gačić J, Brajković M, Oprić S, Popović M, Branković M. Alcohol, Inflammation, and Microbiota in Alcoholic Liver Disease. Int J Mol Sci 2023; 24:ijms24043735. [PMID: 36835145 PMCID: PMC9966185 DOI: 10.3390/ijms24043735] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/17/2023] Open
Abstract
Alcoholic liver disease (ALD) is a consequence of excessive alcohol use. According to many studies, alcohol represents a significant socioeconomic and health risk factor in today's population. According to data from the World Health Organization, there are about 75 million people who have alcohol disorders, and it is well known that its use leads to serious health problems. ALD is a multimodality spectrum that includes alcoholic fatty liver disease (AFL) and alcoholic steatohepatitis (ASH), consequently leading to liver fibrosis and cirrhosis. In addition, the rapid progression of alcoholic liver disease can lead to alcoholic hepatitis (AH). Alcohol metabolism produces toxic metabolites that lead to tissue and organ damage through an inflammatory cascade that includes numerous cytokines, chemokines, and reactive oxygen species (ROS). In the process of inflammation, mediators are cells of the immune system, but also resident cells of the liver, such as hepatocytes, hepatic stellate cells, and Kupffer cells. These cells are activated by exogenous and endogenous antigens, which are called pathogen and damage-associated molecular patterns (PAMPs, DAMPs). Both are recognized by Toll-like receptors (TLRs), which activation triggers the inflammatory pathways. It has been proven that intestinal dysbiosis and disturbed integrity of the intestinal barrier perform a role in the promotion of inflammatory liver damage. These phenomena are also found in chronic excessive use of alcohol. The intestinal microbiota has an important role in maintaining the homeostasis of the organism, and its role in the treatment of ALD has been widely investigated. Prebiotics, probiotics, postbiotics, and symbiotics represent therapeutic interventions that can have a significant effect on the prevention and treatment of ALD.
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Affiliation(s)
- Marija Dukić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Tijana Radonjić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Igor Jovanović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Marija Zdravković
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Zoran Todorović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Nemanja Kraišnik
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Bojana Aranđelović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Olga Mandić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Višeslav Popadić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Novica Nikolić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Slobodan Klašnja
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Andrea Manojlović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Anica Divac
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Jasna Gačić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milica Brajković
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Svetlana Oprić
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Maja Popović
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
| | - Marija Branković
- University Hospital Medical Center Bežanijska Kosa, 11000 Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Correspondence: or
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16
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The Mechanisms of Systemic Inflammatory and Immunosuppressive Acute-on-Chronic Liver Failure and Application Prospect of Single-Cell Sequencing. J Immunol Res 2022; 2022:5091275. [PMID: 36387424 PMCID: PMC9646330 DOI: 10.1155/2022/5091275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 01/24/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a complex clinical syndrome, and patients often have high short-term mortality. It occurs with intense systemic inflammation, often accompanied by a proinflammatory event (such as infection or alcoholic hepatitis), and is closely related to single or multiple organ failure. Liver inflammation begins when innate immune cells (such as Kupffer cells (KCs)) are activated by binding of pathogen-associated molecular patterns (PAMPs) from pathogenic microorganisms or damage-associated molecular patterns (DAMPs) of host origin to their pattern recognition receptors (PRRs). Activated KCs can secrete inflammatory factors as well as chemokines and recruit bone marrow-derived cells such as neutrophils and monocytes to the liver to enhance the inflammatory process. Bacterial translocation may contribute to ACLF when there are no obvious precipitating events. Immunometabolism plays an important role in the process (including mitochondrial dysfunction, amino acid metabolism, and lipid metabolism). The late stage of ACLF is mainly characterized by immunosuppression. In this process, the dysfunction of monocyte and macrophage is reflected in the downregulation of HLA-DR and upregulation of MER tyrosine kinase (MERTK), which weakens the antigen presentation function and reduces the secretion of inflammatory cytokines. We also describe the specific function of bacterial translocation and the gut-liver axis in the process of ACLF. Finally, we also describe the transcriptomics in HBV-ACLF and the recent progress of single-cell RNA sequencing as well as its potential application in the study of ACLF in the future, in order to gain a deeper understanding of ACLF in terms of single-cell gene expression.
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17
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Sasaki-Tanaka R, Ray R, Moriyama M, Ray RB, Kanda T. Molecular Changes in Relation to Alcohol Consumption and Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23179679. [PMID: 36077080 PMCID: PMC9456124 DOI: 10.3390/ijms23179679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.
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Affiliation(s)
- Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
| | - Ranjit Ray
- Departments of Internal Medicine, and Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Ratna B. Ray
- Department of Pathology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
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18
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
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19
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Hasa E, Hartmann P, Schnabl B. Liver cirrhosis and immune dysfunction. Int Immunol 2022; 34:455-466. [PMID: 35792761 PMCID: PMC9447994 DOI: 10.1093/intimm/dxac030] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/27/2022] [Indexed: 01/05/2023] Open
Abstract
Cirrhosis is end-stage liver disease resulting from various etiologies and is a common cause of death worldwide. The progression from compensated to decompensated cirrhosis to acute-on-chronic liver failure (ACLF) is due to multiple factors, including continuation of alcohol use or continued exposure to other toxins, an imbalance of the gut microbiota (dysbiosis), increased gut permeability and a disrupted immune response. This disrupted immune response is also named cirrhosis-associated immune dysfunction, which is characterized by worsening systemic inflammation with concomitant immune paralysis, as liver disease deteriorates. This review highlights central immunologic events during the exacerbation of cirrhosis and characterizes the different immune cell populations involved therein.
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20
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Tranah TH, Kronsten VT, Shawcross DL. Implications and Management of Cirrhosis-Associated Immune Dysfunction Before and After Liver Transplantation. Liver Transpl 2022; 28:700-716. [PMID: 34738724 DOI: 10.1002/lt.26353] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 12/28/2022]
Abstract
Cirrhosis-associated immune dysfunction (CAID) describes a panacea of innate and adaptive deficits that result from the sequelae of cirrhotic portal hypertension that is similar in its manifestations regardless of etiology of chronic liver injury. CAID is associated with synchronous observations of dysregulated priming of innate immune effector cells that demonstrate a proinflammatory phenotype but are functionally impaired and unable to adequately prevent invading pathogens. CAID is mainly driven by gut-barrier dysfunction and is associated with deficits of microbial compartmentalization and homeostasis that lead to tonic activation, systemic inflammation, and exhaustion of innate-immune cells. CAID leads to a high frequency of bacterial and fungal infections in patients with cirrhosis that are often associated with acute decompensation of chronic liver disease and acute-on-chronic liver failure and carry a high mortality rate. Understanding the deficits of mucosal and systemic immunity in the context of chronic liver disease is essential to improving care for patients with cirrhosis, preventing precipitants of acute decompensation of cirrhosis, and improving morbidity and survival. In this review, we summarize the detailed dynamic immunological perturbations associated with advanced chronic liver disease and highlight the importance of recognizing immune dysregulation as a sequela of cirrhosis. Furthermore, we address the role of screening, prevention, and early treatment of infections in cirrhosis in improving patient outcomes in transplant and nontransplant settings.
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Affiliation(s)
- Thomas H Tranah
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
| | - Victoria T Kronsten
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
| | - Debbie L Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.,Institute of Liver Studies, King's College Hospital National Health Service Foundation Trust, London, UK
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21
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Xu H, Wang H. Immune cells in alcohol-related liver disease. LIVER RESEARCH 2022; 6:1-9. [PMID: 39959807 PMCID: PMC11791833 DOI: 10.1016/j.livres.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/18/2021] [Accepted: 01/07/2022] [Indexed: 11/24/2022]
Abstract
Alcohol-related liver disease (ALD), which is caused by excessive alcohol consumption, is one of the most common types of liver disease and a primary cause of hepatic injury, with a disease spectrum that includes steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Various lines of evidence have indicated that immune cells play a significant role in the inflammatory processes of ALD. On the one hand, the liver contains various resident immune cells that have been proven to perform different functions in ALD. For example, in the progression of the disease, Kupffer cells (KCs) are activated by lipopolysaccharide-Toll-like receptor 4 signaling and release various proinflammatory cytokines. Moreover, alcohol intake has been shown to depress the function of natural killer cells. Additionally, two types of unconventional T cells (natural killer T cells and mucosal-associated invariant T cells) are involved in the development of ALD. On the other hand, alcohol and many different cytokines stimulate the recruitment and infiltration of circulating immune cells (neutrophils, T cells, macrophages, and mast cells) into the liver. The neutrophils can produce proinflammatory mediators and cause the dysfunction of anti-infection processes. Additionally, alcohol intake can change the phenotype of T cells, resulting in their increased production of interleukin-17. Aside from KCs, infiltrating macrophages have also been observed in patients with ALD, but the roles of all of these cells in the progression of the disease have shown both similarities and differences. Additionally, the activated mast cells are also associated with the development of ALD. Herein, we review the diverse roles of the various immune cells in the progression of ALD.
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Affiliation(s)
- Honghai Xu
- Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
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22
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Albillos A, Martin-Mateos R, Van der Merwe S, Wiest R, Jalan R, Álvarez-Mon M. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 2022; 19:112-134. [PMID: 34703031 DOI: 10.1038/s41575-021-00520-7] [Citation(s) in RCA: 213] [Impact Index Per Article: 71.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 02/08/2023]
Abstract
The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.
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Affiliation(s)
- Agustín Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. .,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
| | - Rosa Martin-Mateos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Schalk Van der Merwe
- Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, University Inselspital, Bern, Switzerland
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Melchor Álvarez-Mon
- Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Department of Internal Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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23
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Acute-on-chronic liver failure in Egypt: an underestimated complication of liver cirrhosis. Eur J Gastroenterol Hepatol 2021; 33:e458-e463. [PMID: 33741801 DOI: 10.1097/meg.0000000000002132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a severe liver cirrhosis complication with high mortality rates. Despite that chronic liver diseases are prevalent in Egypt, there is no available data about patients with ACLF. We aimed to evaluate the pattern of ACLF in Egypt. METHODS This prospective cohort study included all patients with ACLF, according to the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver, admitted to Al-Rajhi liver Hospital, Egypt, between November 2018 and October 2019. We recorded data at admission, days 3, 7, 14 and 28, and calculated ACLF grades and Chronic Liver Failure Consortium scores until discharge or death. Kaplan-Meier survival analysis was used for survival analysis. RESULTS We analyzed 52 patients with ACLF. Liver cirrhosis was secondary to hepatitis C virus in 46 patients (88.9%), and hepatitis B virus in 4 (7.4%). The main ACLF precipitating factors were infection in 38 (73.1%) and variceal bleeding in 9 (17.3%). The most common infections were spontaneous bacterial peritonitis (44.7%) and chest infection (31.6%). The 28 and 90-day mortality rates were 86.5 and 96.2%. None of the patients who survived >28 days had ACLF 3 at admission or day 7. Among those who died <28 days, ACLF 3 was reported in 7 at admission and 19 on day 7. Living donor liver transplantation was not offered in any case. CONCLUSION In this study, the 28-day mortality rate was higher than in the literature. Egypt urgently needs to develop specific protocols for the proper management of ACLF.
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24
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Chebl RB, Tamim H, Sadat M, Qahtani S, Dabbagh T, Arabi YM. Outcomes of septic cirrhosis patients admitted to the intensive care unit: A retrospective cohort study. Medicine (Baltimore) 2021; 100:e27593. [PMID: 34797280 PMCID: PMC8601275 DOI: 10.1097/md.0000000000027593] [Citation(s) in RCA: 7] [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: 05/31/2021] [Accepted: 10/04/2021] [Indexed: 01/05/2023] Open
Abstract
The aim of this study is to examine the outcome of septic patients with cirrhosis admitted to the intensive care unit (ICU) and predictors of mortality.Single center, retrospective cohort study.The study was conducted in Intensive care Department of King Abdulaziz Medical City, Riyadh, Saudi Arabia.Data was extracted from a prospectively collected ICU database managed by a full time data collector. All patients with an admission diagnosis of sepsis according to the sepsis-3 definition were included from 2002 to 2017. Patients were categorized into 2 groups based on the presence or absence of cirrhosis.The primary outcome of the study was in-hospital mortality. Secondary outcomes included ICU mortality, ICU and hospital lengths of stay and mechanical ventilation duration.A total of 7906 patients were admitted to the ICU with sepsis during the study period, of whom 497 (6.29%) patients had cirrhosis. 64.78% of cirrhotic patients died during their hospital stay compared to 31.54% of non-cirrhotic. On multivariate analysis, cirrhosis patients were at greater odds of dying within their hospital stay as compared to non-cirrhosis patients (Odds ratio {OR} 2.53; 95% confidence interval {CI} 2.04 - 3.15) independent of co-morbidities, organ dysfunction or hemodynamic status. Among cirrhosis patients, elevated international normalization ratio (INR) (OR 1.69; 95% CI 1.29-2.23), hemodialysis (OR 3.09; 95% CI 1.76-5.42) and mechanical ventilation (OR 2.61; 95% CI 1.60-4.28) were the independent predictors of mortality.Septic cirrhosis patients admitted to the intensive care unit have greater odds of dying during their hospital stay. Among septic cirrhosis patients, elevated INR and the need for hemodialysis and mechanical ventilation were associated with increased mortality.
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Affiliation(s)
- Ralphe Bou Chebl
- Department of Emergency Medicine, American University of Beirut, Lebanon
| | - Hani Tamim
- Department of Emergency Medicine, American University of Beirut, Lebanon
| | - Musharaf Sadat
- Intensive Care Department, Ministry of National Guard Health Affairs, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia
| | - Saad Qahtani
- Intensive Care Department, Ministry of National Guard Health Affairs, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia
| | - Tarek Dabbagh
- Intensive Care Department, Ministry of National Guard Health Affairs, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia
| | - Yaseen M. Arabi
- Intensive Care Department, Ministry of National Guard Health Affairs, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia
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25
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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: 54] [Impact Index Per Article: 13.5] [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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26
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Malek A, Arias CA, Pankow S, Olmedo-Reneaum A, Barnett B. Bullous and Necrotic Skin Lesions in a Cirrhotic Patient. Clin Infect Dis 2021; 71:237-240. [PMID: 32578868 DOI: 10.1093/cid/ciz862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Alexandre Malek
- Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Cesar A Arias
- Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Center for Infectious Diseases, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.,Molecular Genetics and Antimicrobial Resistance Unit, International Center for Microbial Genomics, Universidad El Bosque, Bogota, Colombia
| | - Stephanie Pankow
- Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | | | - Ben Barnett
- Center for Antimicrobial Resistance and Microbial Genomics and Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
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27
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Knooihuizen SAI, Alexander NJ, Hopke A, Barros N, Viens A, Scherer A, Atallah NJ, Dagher Z, Irimia D, Chung RT, Mansour MK. Loss of Coordinated Neutrophil Responses to the Human Fungal Pathogen, Candida albicans, in Patients With Cirrhosis. Hepatol Commun 2021; 5:502-515. [PMID: 33681682 PMCID: PMC7917271 DOI: 10.1002/hep4.1645] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/02/2020] [Accepted: 10/26/2020] [Indexed: 12/31/2022] Open
Abstract
Neutrophils are the most abundant white blood cell in the body and are key participants in the defense against fungal infections. Fungal infections occur often in patients with cirrhosis and are associated with increased 30-day and 90-day mortality. Previous studies have shown that specific neutrophil functions are abnormal in patients with cirrhosis, although the extent of neutrophil dysfunction is not well understood. We tested the ability of neutrophils from 21 hospitalized patients with cirrhosis and 23 healthy control patients to kill Candida albicans, a common fungal pathogen in patients with cirrhosis. Using an assay, we also measured the ability of neutrophils to coordinate multicellular, synchronized control of C. albicans hyphae through a process known as swarming. We found that neutrophils from patients with cirrhosis have significantly decreased fungicidal capacity compared with healthy control neutrophils (53% vs. 74%, P < 0.0001) and diminished ability to control hyphal growth normalized as a ratio to healthy control (0.22 vs. 0.65, P < 0.0001). Moreover, serum from patients with cirrhosis decreases the ability of healthy control neutrophils to kill C. albicans (from 60% to 41%, P < 0.003). Circulating concentration of the inflammatory cytokines tumor necrosis factor α, interleukin-6, and interleukin-8 were found to be significantly elevated in patients with cirrhosis compared to healthy controls. Following pretreatment with granulocyte-colony stimulating factor and granulocyte-macrophage colony-stimulating factor, neutrophil function was restored to almost that of healthy controls. Conclusion: Our data establish profound neutrophil dysfunction against, and altered swarming to, C. albicans in patients with cirrhosis. This dysfunction can be partially reversed with cytokine augmentation ex vivo.
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Affiliation(s)
- Sally A I Knooihuizen
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA
| | | | - Alex Hopke
- Harvard Medical SchoolBostonMAUSA.,Department of SurgeryCenter for Engineering in MedicineMassachusetts General HospitalBostonMAUSA.,Shriners Burns HospitalBostonMAUSA
| | - Nicolas Barros
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Adam Viens
- Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Allison Scherer
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Natalie J Atallah
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Zeina Dagher
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
| | - Daniel Irimia
- Harvard Medical SchoolBostonMAUSA.,Department of SurgeryCenter for Engineering in MedicineMassachusetts General HospitalBostonMAUSA.,Shriners Burns HospitalBostonMAUSA
| | - Raymond T Chung
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Liver Center and Gastrointestinal DivisionMassachusetts General HospitalBostonMAUSA
| | - Michael K Mansour
- Department of MedicineMassachusetts General HospitalBostonMAUSA.,Harvard Medical SchoolBostonMAUSA.,Division of Infectious DiseasesMassachusetts General HospitalBostonMAUSA
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28
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Kedarisetty CK, Kumar A, Sarin SK. Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis. Semin Liver Dis 2021; 41:67-78. [PMID: 33764486 DOI: 10.1055/s-0040-1719177] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Alcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating factor (G-CSF) has been shown to favorably modulate the intrahepatic immune milieu and stimulate the regenerative potential of the liver. Initial studies have shown encouraging results with G-CSF in patients with severe alcoholic hepatitis. It has also been found to help steroid nonresponsive patients. There is, however, a need for careful selection of patients, regular dose monitoring and close observation for adverse events of G-CSF. In this review, we analyze the basis of the potential benefits, clinical studies, cautions and challenges in the use of G-CSF in alcoholic hepatitis.
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Affiliation(s)
- Chandan Kumar Kedarisetty
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.,Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Anupam Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.,Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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29
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Casulleras M, Zhang IW, López-Vicario C, Clària J. Leukocytes, Systemic Inflammation and Immunopathology in Acute-on-Chronic Liver Failure. Cells 2020; 9:E2632. [PMID: 33302342 PMCID: PMC7762372 DOI: 10.3390/cells9122632] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 11/20/2020] [Accepted: 12/01/2020] [Indexed: 02/06/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure(s) and high short-term mortality. ACLF frequently occurs in close temporal relationship to a precipitating event, such as acute alcoholic, drug-induced or viral hepatitis or bacterial infection and, in cases without precipitating events, probably related to intestinal translocation of bacterial products. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. This hyperinflammatory state ultimately impairs the host defensive mechanisms of immune cells, rendering ACLF patients immunocompromised and more vulnerable to secondary infections, and therefore to higher organ dysfunction and mortality. In this review, we describe the prevailing characteristics of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on cells of the innate immune system (i.e., monocytes and neutrophils), their triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]), their effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) and the consequences on tissue immunopathology. In addition, this review includes a chapter discussing new emerging therapies based on the modulation of leukocyte function by the administration of pleiotropic proteins such as albumin, Toll-like receptor 4 antagonists, interleukin-22 or stem cell therapy. Finally, the importance of finding an appropriate intervention that reduces inflammation without inducing immunosuppression is highlighted as one of the main therapeutic challenges in cirrhosis.
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Affiliation(s)
- Mireia Casulleras
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
| | - Ingrid W. Zhang
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
| | - Cristina López-Vicario
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
| | - Joan Clària
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS, 08036 Barcelona, Spain; (M.C.); (I.W.Z.)
- European Foundation for the Study of Chronic Liver Failure (EF Clif) and Grifols Chair, 08021 Barcelona, Spain
- Department of Biomedical Sciences, School of Medicine and Health Sciences, Universitat de Barcelona, 08036 Barcelona, Spain
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30
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Scarpellini E, Fagoonee S, Rinninella E, Rasetti C, Aquila I, Larussa T, Ricci P, Luzza F, Abenavoli L. Gut Microbiota and Liver Interaction through Immune System Cross-Talk: A Comprehensive Review at the Time of the SARS-CoV-2 Pandemic. J Clin Med 2020; 9:2488. [PMID: 32756323 PMCID: PMC7464500 DOI: 10.3390/jcm9082488] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The gut microbiota is a complex ecosystem containing bacteria, viruses, fungi, yeasts and other single-celled organisms. It is involved in the development and maintenance of both innate and systemic immunity of the body. Emerging evidence has shown its role in liver diseases through the immune system cross-talk. We review herein literature data regarding the triangular interaction between gut microbiota, immune system and liver in health and disease. METHODS We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials and case series using the following keywords and acronyms and their associations: gut microbiota, microbiome, gut virome, immunity, gastrointestinal-associated lymphoid tissue (GALT), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steato-hepatitis (NASH), alcoholic liver disease, liver cirrhosis, hepatocellular carcinoma. RESULTS The gut microbiota consists of microorganisms that educate our systemic immunity through GALT and non-GALT interactions. The latter maintain health but are also involved in the pathophysiology and in the outcome of several liver diseases, particularly those with metabolic, toxic or immune-mediated etiology. In this context, gut virome has an emerging role in liver diseases and needs to be further investigated, especially due to the link reported between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and hepatic dysfunctions. CONCLUSIONS Changes in gut microbiota composition and alterations in the immune system response are involved in the pathogenesis of metabolic and immune-mediated liver diseases.
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Affiliation(s)
- Emidio Scarpellini
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
- Department of Biomedical Sciences, KU Leuven, Gasthuisberg University Hospital, TARGID, 3000 Leuven, Belgium
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Center, 10121 Turin, Italy;
| | - Emanuele Rinninella
- Nephrology and Urology Department, Gastroenterology, Endocrinology, Fondazione Policlinico A, Clinical Nutrition Unit, Gemelli IRCCS, 00168 Rome, Italy;
- Institute of Medical Pathology, Catholic University of the Sacred Heart, 00168 Rome, Italy
| | - Carlo Rasetti
- Internal Medicine Unit, “Madonna del Soccorso” General Hospital, San Benedetto del, 63074 Tronto, Italy;
| | - Isabella Aquila
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Tiziana Larussa
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Pietrantonio Ricci
- Institute of Legal Medicine and Department of Surgical and Medical Sciences, University “Magna Graecia” of Catanzaro (UMG), 88100 Viale Europa, Italy; (I.A.); (P.R.)
| | - Francesco Luzza
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Græcia”, 88100 Catanzaro, Italy; (T.L.); (F.L.)
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31
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Sangineto M, Grabherr F, Adolph TE, Grander C, Reider S, Jaschke N, Mayr L, Schwärzler J, Dallio M, Moschen AR, Moschetta A, Sabbà C, Tilg H. Dimethyl fumarate ameliorates hepatic inflammation in alcohol related liver disease. Liver Int 2020; 40:1610-1619. [PMID: 32306456 PMCID: PMC7383968 DOI: 10.1111/liv.14483] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/25/2020] [Accepted: 04/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Alcohol-related liver disease (ALD) comprises different liver disorders which impose a health care issue. ALD and particularly alcoholic steatohepatitis, an acute inflammatory condition, cause a substantial morbidity and mortality as effective treatment options remain elusive. Inflammation in ALD is fuelled by macrophages (Kupffer cells [KCs]) which are activated by intestinal pathogen associated molecular patterns, eg lipopolysaccharide (LPS), disseminated beyond a defective intestinal barrier. We hypothesized that the immunomodulator dimethyl-fumarate (DMF), which is approved for the treatment of human inflammatory conditions such as multiple sclerosis or psoriasis, ameliorates the course of experimental ALD. METHODS Dimethyl-fumarate or vehicle was orally administered to wild-type mice receiving a Lieber-DeCarli diet containing 5% ethanol for 15 days. Liver injury, steatosis and inflammation were evaluated by histology, biochemical- and immunoassays. Moreover, we investigated a direct immunosuppressive effect of DMF on KCs and explored a potential impact on ethanol-induced intestinal barrier disruption. RESULTS Dimethyl-fumarate protected against ethanol-induced hepatic injury, steatosis and inflammation in mice. Specifically, we observed reduced hepatic triglyceride and ALT accumulation, reduced hepatic expression of inflammatory cytokines (Tnf-α, Il-1β, Cxcl1) and reduced abundance of neutrophils and macrophages in ethanol-fed and DMF-treated mice when compared to vehicle. DMF protected against ethanol-induced barrier disruption and abrogated systemic LPS concentration. In addition, DMF abolished LPS-induced cytokine responses of KCs. CONCLUSIONS Dimethyl-fumarate counteracts ethanol-induced barrier dysfunction, suppresses inflammatory responses of KCs and ameliorates hepatic inflammation and steatosis, hallmarks of experimental ALD. Our data indicates that DMF treatment might be beneficial in human ALD and respective clinical trials are eagerly awaited.
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Affiliation(s)
- Moris Sangineto
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Department of Interdisciplinary MedicineUniversity of BariBariItaly
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Simon Reider
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Christian Doppler Laboratory for Mucosal ImmunologyMedical University InnsbruckInnsbruckAustria
| | - Nikolai Jaschke
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Lisa Mayr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
| | - Marcello Dallio
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Department of Precision MedicineUniversity of Campania “L. Vanvitelli”NaplesItaly
| | - Alexander R. Moschen
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria,Christian Doppler Laboratory for Mucosal ImmunologyMedical University InnsbruckInnsbruckAustria
| | | | - Carlo Sabbà
- Department of Interdisciplinary MedicineUniversity of BariBariItaly
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & MetabolismMedical University InnsbruckInnsbruckAustria
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Abstract
Cirrhosis is a multisystemic disease wherein inflammatory responses originating from advanced liver disease and its sequelae affect distant compartments. Patients with cirrhosis are susceptible to bacterial infections, which may precipitate acute decompensation and acute-on-chronic liver failure, both of which are associated with high short-term mortality. Innate immune cells are an essential first line of defence against pathogens. Activation of liver macrophages (Kupffer cells) and resident mastocytes generate proinflammatory and vaso-permeating mediators that induce accumulation of neutrophils, lymphocytes, eosinophils and monocytes in the liver, and promote tissue damage. During cirrhosis progression, damage- and pathogen-associated molecular patterns activate immune cells and promote development of systemic inflammatory responses which may involve different tissues and compartments. The antibacterial function of circulating neutrophils and monocytes is gradually and severely impaired as cirrhosis worsens, contributing to disease progression. The mechanisms underlying impaired antimicrobial responses are complex and incompletely understood. This review focuses on the continuous and distinct perturbations arising in innate immune cells during cirrhosis, including their impact on disease progression, as well as reviewing potential therapeutic targets.
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Bernardi M, Angeli P, Claria J, Moreau R, Gines P, Jalan R, Caraceni P, Fernandez J, Gerbes AL, O'Brien AJ, Trebicka J, Thevenot T, Arroyo V. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut 2020; 69:1127-1138. [PMID: 32102926 PMCID: PMC7282556 DOI: 10.1136/gutjnl-2019-318843] [Citation(s) in RCA: 214] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 02/03/2020] [Accepted: 02/03/2020] [Indexed: 12/12/2022]
Abstract
The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.
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Affiliation(s)
- Mauro Bernardi
- Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, Padova, Italy,EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain
| | - Joan Claria
- EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain,Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red (CIBERehd) and Universitat de Barcelona, Barcelona, Spain
| | - Richard Moreau
- EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain,Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; Inserm, Université de Paris, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - Pere Gines
- Liver Unit, Hospital Clínic, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS) and Centro de Investigación Biomèdica en Red (CIBEREHD), Barcelona, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver Disease Health, University College London, Royal Free Hospital, London, UK
| | - Paolo Caraceni
- Unit of Semeiotica Medica, Policlinico S Orsola, Bologna; Department of Medical and Surgical Sciences, Alma Mater Studiorum – University of Bologna, Bologna, Italy
| | - Javier Fernandez
- EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain,Liver Unit, Hospital Clínic, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS) and Centro de Investigación Biomèdica en Red (CIBEREHD), Barcelona, Spain
| | - Alexander L Gerbes
- Department of Medicine II, Liver Centre Munich, University Hospital, LMU Munich, Munich, Germany
| | - Alastair J O'Brien
- Institute for Liver Disease Health, University College London, Royal Free Hospital, London, UK
| | - Jonel Trebicka
- EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain,Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany
| | - Thierry Thevenot
- Centre Hospitalier Universitaire de Besançon, Hôpital Jean Minjoz, Service d'Hépatologie et de Soins Intensifs Digestifs, Besançon, France
| | - Vicente Arroyo
- EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain
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Addolorato G, Abenavoli L, Dallio M, Federico A, Germani G, Gitto S, Leandro G, Loguercio C, Marra F, Stasi E. Alcohol associated liver disease 2020: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2020; 52:374-391. [PMID: 32001151 DOI: 10.1016/j.dld.2019.12.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 11/06/2019] [Accepted: 12/17/2019] [Indexed: 12/11/2022]
Abstract
Alcohol use disorder which includes alcohol abuse and dependence represents one of the leading risk factors for premature mortality in Europe and it is responsible of over 200 conditions, including neuropsychiatric disorders, chronic diseases, cancers and accidents leading to permanent disability. Alcohol use disorder represents the most common cause of liver damage in the Western world, with a wide spectrum of diseases ranging from steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. The present clinical practice guidelines by the Italian Association for the Study of the Liver (AISF) are focused on the current knowledge about epidemiology, pathophysiology, clinical features, diagnosis and treatment of alcohol associated liver disease, aiming to provide practical recommendations on the management of this complex pathological condition.
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Affiliation(s)
- Giovanni Addolorato
- Alcohol Use Disorder Unit, Division of Internal Medicine, Gastroenterology and Hepatology Unit, Catholic University of Rome, A. Gemelli Hospital, Rome, Italy; "Agostino Gemelli" Hospital Foundation - IRCCS, Rome, Italy.
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Marcello Dallio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessandro Federico
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Gioacchino Leandro
- National Institute of Gastroenterology "S. De Bellis" Research Hospital, Castellana Grotte, Italy
| | - Carmelina Loguercio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Italy; Research Center Denothe, University of Florence, Italy
| | - Elisa Stasi
- National Institute of Gastroenterology "S. De Bellis" Research Hospital, Castellana Grotte, Italy
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36
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Härmälä S, Parisinos CA, Shallcross L, O'Brien A, Hayward A. Effectiveness of influenza vaccines in adults with chronic liver disease: a systematic review and meta-analysis. BMJ Open 2019; 9:e031070. [PMID: 31494620 PMCID: PMC6731888 DOI: 10.1136/bmjopen-2019-031070] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 08/13/2019] [Accepted: 08/19/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Patients with liver disease frequently require hospitalisation with infection often the trigger. Influenza vaccination is an effective infection prevention strategy in healthy and elderly but is often perceived less beneficial in patients with liver disease. We investigated whether influenza vaccination triggered serological response and prevented hospitalisation and death in liver disease. DESIGN Systematic review and meta-analysis. DATA SOURCES MEDLINE, EMBASE, PubMed and CENTRAL up to January 2019. ELIGIBILITY CRITERIA Randomised or observational studies of the effects of influenza vaccine in adults with liver disease. DATA EXTRACTION AND SYNTHESIS Two reviewers screened studies, extracted data and assessed risk of bias and quality of evidence. Primary outcomes were all-cause hospitalisation and mortality. Secondary outcomes were cause-specific hospitalisation and mortality, and serological vaccine response. Random-effects meta-analysis was used to estimate pooled effects of vaccination. RESULTS We found 10 041 unique records, 286 were eligible for full-text review and 12 were included. Most patients had viral liver disease. All studies were of very low quality. Liver patients both with and without cirrhosis mounted an antibody response to influenza vaccination, and vaccination was associated with a reduction in risk of hospital admission from 205/1000 to 149/1000 (risk difference -0.06, 95% CI -0.07 to 0.04) in patients with viral liver disease. Vaccinated patients were 27% less likely to be admitted to hospital compared with unvaccinated patients (risk ratio 0.73, 95% CI 0.66 to 0.80). No effect against all-cause or cause-specific mortality or cause-specific hospitalisation was found. CONCLUSIONS The low quantity and quality of the evidence means that the protective vaccine effect may be uncertain. Considering the high risk of serious health outcomes from influenza infection in patients with liver disease and the safety and low cost of vaccination, overall, the potential benefits of seasonal vaccination both to patients and the healthcare systems are likely to outweigh the costs and risks associated with vaccination. PROSPERO REGISTRATION NUMBER CRD42017067277.
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Affiliation(s)
- Suvi Härmälä
- Institute of Health Informatics, University College London, London, UK
| | | | - Laura Shallcross
- Institute of Health Informatics, University College London, London, UK
| | | | - Andrew Hayward
- Institute of Epidemiology and Health Care, University College London, London, UK
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Moreau R, Périanin A, Arroyo V. Review of Defective NADPH Oxidase Activity and Myeloperoxidase Release in Neutrophils From Patients With Cirrhosis. Front Immunol 2019; 10:1044. [PMID: 31134093 PMCID: PMC6517494 DOI: 10.3389/fimmu.2019.01044] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 04/24/2019] [Indexed: 12/15/2022] Open
Abstract
Patients with decompensated cirrhosis are highly susceptible to develop bacterial infections and these can trigger multiorgan failure associated with high in-hospital mortality. Neutrophils from patients with decompensated cirrhosis exhibit marked alterations that may explain the susceptibility of these patients to develop bacterial infections. These neutrophil alterations include marked defects in intracellular signaling pathways involving serine/threonine kinases such as protein kinase B (AKT), p38-mitogen-activated protein kinase (MAPK), and the MAP kinases1/2; activation of the NADPH oxidase complex; myeloperoxidase (MPO) release; and bactericidal activity of neutrophils stimulated by the bacterial peptide formyl-Methionine-Leucine-Phenylalanine (fMLF). Impaired activity of the NADPH oxidase 2 (NOX2) complex is also related to reduced levels of expression of its major components through post-transcriptional mechanisms. In addition, the catalytic NOX2 component gp91 phox is subject to degradation by elastase highly present in patients' plasma. A defect in the protein kinase B (AKT) and p38 MAPK-mediated signaling pathways may explain the decrease in phosphorylation of p47 phox (an important component of the NADPH oxidase complex) and MPO release, in response to neutrophil stimulation by fMLF. Most of these alterations are reversible ex vivo with TLR7/8 agonists (CL097, R848), raising the possibility that these agonists might be used in the future to restore neutrophil antibacterial functions in patients with cirrhosis.
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Affiliation(s)
- Richard Moreau
- Inserm, U1149, Centre de Recherche sur l'Inflammation, Paris, France.,UMRS1149, Université Paris Diderot-Paris 7, Paris, France.,Département Hospitalo-Universitaire UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.,Centre National de la Recherche Scientifique (CNRS), Paris, France
| | - Axel Périanin
- Inserm, U1149, Centre de Recherche sur l'Inflammation, Paris, France.,UMRS1149, Université Paris Diderot-Paris 7, Paris, France.,Centre National de la Recherche Scientifique (CNRS), Paris, France
| | - Vicente Arroyo
- EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain
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Irvine KM, Ratnasekera I, Powell EE, Hume DA. Causes and Consequences of Innate Immune Dysfunction in Cirrhosis. Front Immunol 2019; 10:293. [PMID: 30873165 PMCID: PMC6401613 DOI: 10.3389/fimmu.2019.00293] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 02/05/2019] [Indexed: 12/15/2022] Open
Abstract
Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. At the two extremes of the CAID spectrum are systemic inflammation, which can exacerbate clinical manifestations of cirrhosis such as hemodynamic derangement and kidney injury; and immunodeficiency, which contributes to the high rate of infection in patients with decompensated cirrhosis. Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies.
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Affiliation(s)
- Katharine Margaret Irvine
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Isanka Ratnasekera
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Elizabeth E. Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - David Arthur Hume
- Mater Research Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia
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Immune Dysfunction and Albumin-Related Immunity in Liver Cirrhosis. Mediators Inflamm 2019; 2019:7537649. [PMID: 30930689 PMCID: PMC6410448 DOI: 10.1155/2019/7537649] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/15/2019] [Accepted: 01/26/2019] [Indexed: 02/07/2023] Open
Abstract
Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world's most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports—and is supported by—uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as “leaky gut.” Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation.
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40
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Gao B, Ahmad MF, Nagy LE, Tsukamoto H. Inflammatory pathways in alcoholic steatohepatitis. J Hepatol 2019; 70:249-259. [PMID: 30658726 PMCID: PMC6361545 DOI: 10.1016/j.jhep.2018.10.023] [Citation(s) in RCA: 264] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022]
Abstract
Inflammatory processes are primary contributors to the development and progression of alcoholic steatohepatitis (ASH), with severe alcoholic hepatitis characterised by non-resolving inflammation. Inflammation in the progression of ASH is a complex response to microbial dysbiosis, loss of barrier integrity in the intestine, hepatocellular stress and death, as well as inter-organ crosstalk. Herein, we review the roles of multiple cell types that are involved in inflammation in ASH, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system. In response to chronic, heavy alcohol exposure, hepatocytes themselves also contribute to the inflammatory process; hepatocytes express a large number of chemokines and inflammatory mediators and can also release damage-associated molecular patterns during injury and death. These cellular responses are mediated and accompanied by changes in the expression of pro- and anti-inflammatory cytokines and chemokines, as well as by signals which orchestrate the recruitment of immune cells and activation of the inflammatory process. Additional mechanisms for cell-cell and inter-organ communication in ASH are also reviewed, including the roles of extracellular vesicles and microRNAs, as well as inter-organ crosstalk. We highlight the concept that inflammation also plays an important role in promoting liver repair and controlling bacterial infection. Understanding the complex regulatory processes that are disrupted during the progression of ASH will likely lead to better targeted strategies for therapeutic interventions.
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, United States.
| | - Maleeha F Ahmad
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Laura E Nagy
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States; Northern Ohio Alcohol Center, Departments of Molecular Medicine, Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States.
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Greater Los Angeles VA Healthcare System, Los Angeles, CA, United States.
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Acharya C, Bajaj JS. Altered Microbiome in Patients With Cirrhosis and Complications. Clin Gastroenterol Hepatol 2019; 17:307-321. [PMID: 30099098 PMCID: PMC6314917 DOI: 10.1016/j.cgh.2018.08.008] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 07/06/2018] [Accepted: 08/03/2018] [Indexed: 02/07/2023]
Abstract
In patients with cirrhosis, the gut microbiome are affected by multiple gut and systemic alterations. These changes lead to dysbiosis in the microbiota of different parts of the body, resulting in inflammation. The constant immune stimulation resulting in part from dysbiosis is associated with morbidity in patients with cirrhosis. Dysbiosis as a dynamic event worsens with decompensation such as with hepatic encephalopathy, infections or acute-on-chronic liver failure (ACLF). These microbial patterns could be applied as diagnostic and prognostic measures in cirrhosis in the outpatient and inpatient setting. Current therapies for cirrhosis have differing impacts on gut microbial composition and functionality. Dietary modifications and the oral cavity have emerged as newer targetable factors to modulate the microbiome, which could affect inflammation and, potentially improve outcomes. Additionally, fecal microbial transplant is being increasingly studied to provide compositional and functional modulation of the microbiome. Ultimately, a combination of targeted therapies may be needed to provide an optimal gut milieu to improve outcomes in cirrhosis.
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Abstract
Liver transplantation has become an important treatment modality for patients with end-stage liver disease/cirrhosis, acute liver failure, and hepatocellular carcinoma. Although surgical techniques and immunosuppressive regimens for liver transplantation have improved significantly over the past 20 years, infectious complications continue to contribute to the morbidity and mortality in this patient population. The use of standardized screening protocols for both donors and recipients, coupled with targeted prophylaxis against specific pathogens, has helped to mitigate the risk of infection in liver transplant recipients. Patients with chronic liver disease and cirrhosis have immunological deficits that place them at increased risk for infection while awaiting liver transplantation. The patient undergoing liver transplantation is prone to develop healthcare-acquired infections due to multidrug-resistant organisms that could potentially affect patient outcomes after transplantation. The complex nature of liver transplant surgery that involves multiple vascular and hepatobiliary anastomoses further increases the risk of infection after liver transplantation. During the early post-transplantation period, healthcare-acquired bacterial and fungal infections are the most common types of infection encountered in liver transplant recipients. The period of maximal immunosuppression that occurs at 1–6 months after transplantation can be complicated by opportunistic infections due to both primary infection and reactivation of latent infection. Severe community-acquired infections can complicate the course of liver transplantation beyond 12 months after transplant surgery. This chapter provides an overview of liver transplantation including indications, donor-recipient selection criteria, surgical procedures, and immunosuppressive therapies. A focus on infections in patients with chronic liver disease/cirrhosis and an overview of the specific infectious complications in liver transplant recipients are presented.
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China L, Skene SS, Bennett K, Shabir Z, Hamilton R, Bevan S, Chandler T, Maini AA, Becares N, Gilroy D, Forrest EH, O’Brien A. ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for an interventional randomised controlled trial. BMJ Open 2018; 8:e023754. [PMID: 30344180 PMCID: PMC6196858 DOI: 10.1136/bmjopen-2018-023754] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds to and inactivates this immune-suppressive lipid mediator. Human albumin solution (HAS) could thus be repurposed as an immune-restorative drug in these patients.This is a phase III randomised controlled trial (RCT) to verify whether targeting a serum albumin level of ≥35 g/L in hospitalised patients with decompensated cirrhosis using repeated intravenous infusions of 20% HAS will reduce incidence of infection, renal dysfunction and mortality for the treatment period (maximum 14 days or discharge if <14 days) compared with standard medical care. METHODS AND ANALYSIS Albumin To prevenT Infection in chronic liveR failurE stage 2 is a multicentre, open-label, interventional RCT. Patients with decompensated cirrhosis admitted to the hospital with a serum albumin of <30 g/L are eligible, subject to exclusion criteria. Patients randomised to intravenous HAS will have this administered, according to serum albumin levels, for up to 14 days or discharge. The infusion protocol aims to increase serum albumin to near-normal levels.The composite primary endpoint is: new infection, renal dysfunction or mortality within the trial treatment period. Secondary endpoints include mortality at up to 6 months, incidence of other organ failures, cost-effectiveness and quality of life outcomes and time to liver transplant. The trial will recruit 866 patients at more than 30 sites across the UK. ETHICSANDDISSEMINATION Research ethics approval was given by the London-Brent research ethics committee (ref: 15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001-0001). The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the National Institute for Health Research (ISRCTN 14174793). This manuscript refers to version 6.0 of the protocol. Results will be disseminated through peer-reviewed journals and international conferences. Recruitment of the first participant occurred on 25 January 2016.
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Affiliation(s)
- Louise China
- Division of Medicine, University College London, London, UK
| | - Simon S Skene
- School of Biosciences and Medicine, University of Surrey, Guildford, UK
| | - Kate Bennett
- Comprehensive Clinical Trials Unit, UCL, London, UK
| | | | | | - Scott Bevan
- Comprehensive Clinical Trials Unit, UCL, London, UK
| | | | | | | | - Derek Gilroy
- Division of Medicine, University College London, London, UK
| | - Ewan H Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, UK
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Abstract
The syndrome of decreased immunity caused by cirrhosis is a combination of different immunological mechanisms and reactions which result from an advanced stage of the liver disease. The synthesis of proteins of the acute phase becomes impaired, there develop different deficiencies of the complement system, and there ensues a decrease of receptors that are meant to recognize antigens. The negative changes become apparent in the field of cell responses, e.g. there are changes in the amounts of generated monocytes and macrophages, and their phagocytic capabilities and chemotaxic reactions are impacted as well. The humoral response results in distorted synthesis of particular antigen categories. The risk of detrimental immunoresponses with the end result of endotoxemia is not rarely coupled with both local and global infections. The combination of the aforesaid immunodeficiencies worsens the healing chances of cirrhosis sufferers and more often than not it increases the mortality of the affected patients.
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45
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Rolas L, Boussif A, Weiss E, Lettéron P, Haddad O, El-Benna J, Rautou PE, Moreau R, Périanin A. NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation. Gut 2018; 67:1505-1516. [PMID: 28601846 DOI: 10.1136/gutjnl-2016-313443] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 04/27/2017] [Accepted: 05/01/2017] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Cirrhosis downregulates phagocyte oxidant production via their antibacterial superoxide-generating system, NADPH oxidase (NOX2) and increases patients' susceptibility to infection and mortality rate. To explore novel biochemical parameters that explain susceptibility to infections, we investigated the expression of NOX2 and partners in neutrophils of patients with severe alcoholic cirrhosis and have provided a novel approach to restore superoxide production capacity in patients' neutrophils and blood. DESIGN Neutrophils were isolated from patients with decompensated alcoholic cirrhosis. NOX2 activity was assessed after stimulation of purified neutrophils or whole blood with the bacterial-derived peptide fMet-Leu-Phe. The expression of NOX2 and partners was studied by western blot analysis, flow cytometry and reverse transcription-PCR. RESULTS The impaired superoxide production by patients' neutrophils was associated with a severe deficient expression of the NADPH oxidase catalytic core flavocytochrome-b558 (gp91 phox /NOX2 and p22 phox ), its cytosolic partner p47 phox but not p67 phox . NOX2 expression decreased rapidly by protein degradation involving elastase released during degranulation of healthy neutrophils stimulated with fMet-Leu-Phe, or highly present in patients' plasma. Interestingly, the deficient superoxide production was reversed by treatment of patients' neutrophils and whole blood with toll-like receptor 7/8 (TLR7/8) agonists. This treatment stimulated a rapid NOX2 transcription and translation through a process involving mammalian target of rapamycin (mTOR) whose expression was also deficient in patients' neutrophils. NOX2 expression was also increased by the TLR4 agonist lipopolysaccharide but with only a modest improvement of reactive oxygen species production. CONCLUSION Impairment of neutrophil oxidants production in alcoholic cirrhosis is associated with NOX2 degradation and deficient mTOR-dependent translational machinery. The NOX2 depletion can be reversed via TRL7/8 activation and might be used to restore antimicrobial responses of immunocompromised patients.
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Affiliation(s)
- Loïc Rolas
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
| | - Abdelali Boussif
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France.,Département de Biochimie, Université de Batna, Faculté de Biologie, Batna, Algérie
| | - Emmanuel Weiss
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France.,Département d'Anesthésie Réanimation, Hôpital Beaujon, APHP, Clichy, France
| | - Philippe Lettéron
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
| | - Oualid Haddad
- UFR SMBH, Université Paris 13, Sorbonne Paris Cité, Bobigny, France
| | - Jamel El-Benna
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
| | - Pierre-Emmanuel Rautou
- Département Hospitalo-Universitaire (DHU) Unity, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France.,INSERM U970, Paris Cardiovascular Research Center-PARCC, Paris, France
| | - Richard Moreau
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France.,Département Hospitalo-Universitaire (DHU) Unity, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France
| | - Axel Périanin
- INSERM UMRS-1149, Faculté de Médecine Xavier Bichat, Paris, France.,CNRS ERL-8252, Centre de Recherche sur l'Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence INFLAMEX, Paris, France
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China L, Skene SS, Shabir Z, Maini A, Sylvestre Y, Bennett K, Bevan S, O'Beirne J, Forrest E, Portal J, Ryder S, Wright G, Gilroy DW, O'Brien A. Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial. Clin Gastroenterol Hepatol 2018; 16:748-755.e6. [PMID: 28911947 PMCID: PMC6168936 DOI: 10.1016/j.cgh.2017.09.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/21/2017] [Accepted: 09/06/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial. METHODS We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels. RESULTS The patients' mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded. CONCLUSIONS In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793.
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Affiliation(s)
- Louise China
- Division of Medicine, University College London, United Kingdom.
| | - Simon S Skene
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - Zainib Shabir
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - Alexander Maini
- Division of Medicine, University College London, United Kingdom
| | - Yvonne Sylvestre
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - Kate Bennett
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - Scott Bevan
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - James O'Beirne
- Royal Free National Health Service Trust, London, United Kingdom
| | - Ewan Forrest
- Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Jim Portal
- Bristol Royal Infirmary, Bristol, United Kingdom
| | - Steve Ryder
- Nottingham University Hospital, Nottingham, United Kingdom
| | - Gavin Wright
- Basildon University Hospital, Essex, United Kingdom
| | - Derek W Gilroy
- Division of Medicine, University College London, United Kingdom
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47
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China L, Maini A, Skene SS, Shabir Z, Sylvestre Y, Colas RA, Ly L, Becares Salles N, Belloti V, Dalli J, Gilroy DW, O’Brien A. Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease. Clin Gastroenterol Hepatol 2018; 16:738-747.e7. [PMID: 28859868 PMCID: PMC6168974 DOI: 10.1016/j.cgh.2017.08.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 07/28/2017] [Accepted: 08/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids. METHODS We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients' samples, we investigated the effects of PGE2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration. RESULTS At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P < .0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 ± 4.8 ng/mL) compared with plasma collected before treatment (17.7 ± 4.5 ng/mL; P = .0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P = .0012). AD/ACLF plasma protein binding to PGE2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P < .0001). Circulating levels of PGE2, lipopolysaccharide, and inflammatory or anti-inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group. CONCLUSIONS Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE2. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793).
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Affiliation(s)
- Louise China
- Division of Medicine, University College London, London, United Kingdom.
| | - Alexander Maini
- Division of Medicine, University College London, London, United Kingdom
| | - Simon S. Skene
- University of London Comprehensive Clinical Trials Unit, London, United Kingdom
| | - Zainib Shabir
- University of London Comprehensive Clinical Trials Unit, London, United Kingdom
| | - Yvonne Sylvestre
- University of London Comprehensive Clinical Trials Unit, London, United Kingdom
| | - Romain A. Colas
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Lucy Ly
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | | | - Vittorio Belloti
- Division of Medicine, University College London, London, United Kingdom
| | - Jesmond Dalli
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Derek W. Gilroy
- Division of Medicine, University College London, London, United Kingdom
| | - Alastair O’Brien
- Division of Medicine, University College London, London, United Kingdom
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48
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The emergency medicine evaluation and management of the patient with cirrhosis. Am J Emerg Med 2018; 36:689-698. [PMID: 29290508 DOI: 10.1016/j.ajem.2017.12.047] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 12/21/2017] [Accepted: 12/22/2017] [Indexed: 12/12/2022] Open
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49
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Härmälä S, Parisinos C, Shallcross L, O'Brien A, Hayward A. Effectiveness of pneumococcal and influenza vaccines to prevent serious health complications in adults with chronic liver disease: a protocol for a systematic review. BMJ Open 2018; 8:e018223. [PMID: 29549199 PMCID: PMC5857657 DOI: 10.1136/bmjopen-2017-018223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 01/31/2018] [Accepted: 02/08/2018] [Indexed: 01/28/2023] Open
Abstract
INTRODUCTION In advanced chronic liver disease, diseases caused by common bacteria Streptococcus pneumoniae or influenza virus put people at an increased risk of serious health complications and death. The effectiveness of the available vaccines in reducing the risk of poor health outcomes, however, is less clear. METHODS AND ANALYSIS We will search Medline (Ovid), Embase (Ovid), PubMed and Cochrane Central Register of Controlled Trials for published reports on randomised controlled trials and observational studies on the effectiveness of pneumococcal and influenza vaccines in people with chronic liver disease. Two independent reviewers will screen the studies for eligibility, extract data and assess study quality and risk of bias. Random effects meta-analyses will be performed as appropriate. ETHICS AND DISSEMINATION Formal ethical approval is not required, as no primary data will be collected for this study. We will publish results of this study in relevant peer-reviewed medical journal or journals. Where possible, the study results will also be presented as posters or talks at relevant medical conferences and meetings. PROSPERO REGISTRATION NUMBER CRD42017067277.
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Affiliation(s)
- Suvi Härmälä
- Institute of Health Informatics, University College London, London, UK
| | | | - Laura Shallcross
- Institute of Health Informatics, University College London, London, UK
| | | | - Andrew Hayward
- Institute of Epidemiology and Health Care, University College London, London, UK
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50
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Bodro M, Sanclemente G, Crespo G, Linares L, Marcos MA, Marco F, Miquel R, Forns X, Navasa M, Moreno A. Severe Hepatitis C Recurrence as a Risk Factor for Opportunistic Infections in Liver Transplant Recipients. Transplant Proc 2018; 50:1437-1443. [PMID: 29880367 DOI: 10.1016/j.transproceed.2018.02.081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/13/2017] [Accepted: 02/17/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The aim of the study was to determine the clinical characteristics, frequency of opportunistic infections (OI), and the outcomes for liver transplant recipients with severe hepatitis C virus (HCV) recurrence. In addition, the objective was to evaluate HCV recurrence as a risk factor for developing an OI. METHODS We conducted a retrospective observational study recording all liver transplant recipients from July 1, 2003, to December 31, 2012. Patients with liver disease due to HCV were selected. Active surveillance of infections was conducted periodically, and patients were classified according to presence of severe HCV recurrence. RESULTS Three hundred seventy patients underwent liver transplantation because of chronic HCV. One hundred forty-seven patients presented severe recurrence (SR) (49%) and 50 (17%) of them had post-liver transplant cholestatic hepatitis C. Patients with SR presented OI, especially cytomegalovirus (CMV) infections and invasive fungal infections, more frequently than patients without SR (33% vs 13%; P < .001). From the diagnosis of SR to the presentation of OI, the median number of days was 169 (6-2083). Acute allograft rejection (OR 1.8 95% confidence interval [CI] 1.1-3.3) donor age ≥60 years (OR 2.9 95% CI 1.3-6.8), and SR (OR 2.8, 95% CI 1.6-5.1) were independently associated with the development of OI in liver transplant recipients. CONCLUSION A high index of suspicion of opportunistic infections must be maintained when faced with severe HCV recurrence in liver transplant recipients. Moreover, active surveillance against CMV infection and other prophylactic strategies against opportunistic infections should be considered.
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Affiliation(s)
- M Bodro
- Infectious Diseases Department, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain.
| | - G Sanclemente
- Infectious Diseases Department, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - G Crespo
- Liver Transplant Unit, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - L Linares
- Infectious Diseases Department, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - M A Marcos
- Microbiology Department, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - F Marco
- Microbiology Department, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - R Miquel
- Pathology Unit, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - X Forns
- Liver Transplant Unit, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - M Navasa
- Liver Transplant Unit, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
| | - A Moreno
- Infectious Diseases Department, Hospital Clínic-IDIBAPS-CIBERHED, University of Barcelona, Barcelona, Spain
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