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1
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Braga QM, Schacher FC, Mattos AA, Mattos ÂZ. Terlipressin for the treatment of hepatorenal syndrome: a meta-analysis of randomized controlled trials. Eur J Gastroenterol Hepatol 2025; 37:753-760. [PMID: 40207491 DOI: 10.1097/meg.0000000000002954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
OBJECTIVE This study aimed to evaluate the efficacy and safety of terlipressin and albumin in patients with hepatorenal syndrome. METHODS A systematic review with meta-analysis of randomized controlled trials comparing terlipressin and albumin versus albumin with or without placebo in patients with cirrhosis and hepatorenal syndrome was performed. The study protocol was registered at the PROSPERO platform (CRD42021246684). RESULTS Nine randomized controlled trials fulfilled the selection criteria and were included in this meta-analysis. There was no evidence of a significant difference between the groups regarding mortality in 15 days [risk ratio (RR) = 0.73, 95% confidence interval (CI) = 0.47-1.13, P = 0.16, I2 = 52%] or in 90 days (RR = 0.94, 95% CI = 0.80-1.09, P = 0.84, I2 = 29%). Regarding hepatorenal syndrome reversal failure, a significant benefit was demonstrated in the terlipressin and albumin group (RR = 0.64, 95% CI = 0.53-0.78, P < 0.00001, I2 = 72%). There was no evidence of a significant difference between the groups regarding adverse events (RR = 3.5, 95% CI = 0.94-13.09, P = 0.06, I2 = 89%). CONCLUSION Terlipressin associated with albumin led to a significantly lower rate of hepatorenal syndrome reversal failure, but there was no evidence of a significant effect of this treatment regarding mortality or adverse events.
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Affiliation(s)
- Quelen M Braga
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre
| | | | - Angelo A Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
| | - Ângelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
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Zampino R, Patauner F, Durante-Mangoni E. Clinical trajectories in liver cirrhosis: An evidence-based reappraisal for the internist. Eur J Intern Med 2025:S0953-6205(25)00169-4. [PMID: 40318914 DOI: 10.1016/j.ejim.2025.04.028] [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: 10/24/2024] [Revised: 04/19/2025] [Accepted: 04/20/2025] [Indexed: 05/07/2025]
Abstract
Over the last few years, the approach to clinical recognition and risk stratification of advanced liver disease has changed substantially, and liver cirrhosis has been increasingly conceptualized as a clinical rather than a histopathologic condition. In this Clinical Insight, we summarize the latest developments on recognition and management of 'clinically' advanced chronic liver disease.
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Affiliation(s)
- Rosa Zampino
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia 2, 80138 Napoli, Italy; Unit of Internal Medicine & Transplants, A.O.R.N. Ospedali dei Colli - Ospedale Monaldi, Piazzale Ettore Ruggieri, 80131 Napoli Italy
| | - Fabian Patauner
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", P.zza L. Miraglia 2, 80138 Napoli, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via de Crecchio 7, 80138 Napoli, Italy; Unit of Internal Medicine & Transplants, A.O.R.N. Ospedali dei Colli - Ospedale Monaldi, Piazzale Ettore Ruggieri, 80131 Napoli Italy.
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Ikeda Y, Nago H, Yamaguchi M, Om R, Terai Y, Kita Y, Sato S, Murata A, Sato S, Shimada Y, Nagahara A, Genda T. Serum pro-inflammatory cytokine interleukin-6 level is predictive of further decompensation and mortality in liver cirrhosis. Hepatol Res 2025; 55:696-706. [PMID: 40317675 DOI: 10.1111/hepr.14175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 01/27/2025] [Accepted: 02/02/2025] [Indexed: 05/07/2025]
Abstract
AIM Systemic inflammation drives the progression of portal hypertension in patients with liver cirrhosis. Interleukin-6 is a key mediator of the cytokine network in acute inflammation that stimulates the production of many acute phase reactants. In this study, we investigated the association between serum interleukin-6 and acute phase reactant levels and the disease stage and prognosis of patients with liver cirrhosis. METHODS A single-center retrospective cohort of 359 patients with liver cirrhosis was staged according to the symptomatic decompensation. Baseline serum C-reactive protein , interleukin-6, procalcitonin, and serum amyloid A protein levels were measured. The outcomes of further decompensation, hepatocellular carcinoma development, and mortality were identified during a 3.3-year median follow-up period. RESULTS Serum C-reactive protein , interleukin-6, and procalcitonin levels were significantly different across the stages. The multivariate Cox proportional hazards model identified serum interleukin-6 as an independent predictor of further decompensation in patients with compensated and the first single decompensated cirrhosis. Kaplan-Meier analyses showed that the probability of further decompensation was stratified by serum interleukin-6 level in a dose-dependent manner. In the entire cohort, serum interleukin-6 level also showed a significant association with liver-related and all-cause mortalities, but not with hepatocellular carcinoma development, independent of stage and liver disease severity indices. CONCLUSIONS Elevated levels of serum markers of systemic inflammation were associated with symptomatic decompensation, and serum interleukin-6 level is a predictor of further decompensation and mortality in patients with liver cirrhosis.
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Affiliation(s)
- Yuji Ikeda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Hiroki Nago
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Masahiro Yamaguchi
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Rihwa Om
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Yuichiro Terai
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Yuji Kita
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Sho Sato
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Ayato Murata
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Shunsuke Sato
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Yuji Shimada
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
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Song Y, Yang X, Yu C. Understanding and Treating Hepatorenal Syndrome: Insights from Recent Research. Semin Liver Dis 2025. [PMID: 40169136 DOI: 10.1055/a-2570-3330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/03/2025]
Abstract
Acute kidney injury (AKI) is a critical and often fatal complication in decompensated cirrhosis, significantly affecting inpatient survival rates. Hepatorenal syndrome (HRS), a distinct subtype of AKI, develops in individuals with advanced cirrhosis and portal hypertension. It is marked by progressive kidney dysfunction, poor prognosis, and frequently causes death before liver transplantation. The pathogenesis of HRS involves vasodilation of the splanchnic vessels, leading to overactivation of the endogenous vasoactive systems, circulatory dysfunction, and reduced renal perfusion, which ultimately impairs glomerular filtration. Recent studies have highlighted the role of systemic inflammation in exacerbating renal damage. Despite these changes, renal histology in HRS usually shows no significant abnormalities, and there is typically no hematuria, proteinuria, or abnormal findings on ultrasound. Common risk factors for HRS include spontaneous bacterial peritonitis, infections, and large-volume paracentesis without albumin infusion. Diagnosing HRS is challenging, particularly in distinguishing it from acute tubular necrosis, due to the absence of specific biomarkers. Treatment primarily involves vasoconstrictors such as terlipressin and albumin, with liver transplantation being the definitive therapeutic option. This review provides an updated understanding of HRS, addressing its pathophysiology, diagnosis, management, and future challenges, based on recent expert consensus.
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Affiliation(s)
- Yuli Song
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Xiaochen Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Chengbo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China
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Suksamai A, Khaoprasert S, Chaiprasert A, Chirapongsathorn S. Urine TIMP2.IGFBP7 Reflects Kidney Injury After Moderate Volume Paracentesis in Patients With Ascites: A Randomized Control Study. JGH Open 2025; 9:e70168. [PMID: 40264987 PMCID: PMC12012385 DOI: 10.1002/jgh3.70168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 04/01/2025] [Accepted: 04/12/2025] [Indexed: 04/24/2025]
Abstract
Background Urinary biomarkers may predict acute kidney injury (AKI) in cirrhosis with ascites in a moderate volume paracentesis setting. Objective The study aimed to assess the risk and consequence of AKI and its progression in patients with decompensated cirrhosis undergoing paracentesis using a urine test measuring tissue inhibitor of metalloproteinases-2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7). Methods A randomized, controlled trial was performed. All outpatients with decompensated cirrhosis with ascites and diuretic complications were enrolled and randomized into 3 and 5 L paracentesis groups. Serial urine samples were analyzed for TIMP2. IGFBP7 concentration before and after paracentesis. Results A total of 90 patients with decompensated cirrhosis were consecutively enrolled during the study period. After screening, 29 patients were enrolled in the 3-L paracentesis group, and 25 patients were enrolled in the 5-L paracentesis group. The mean of the MELD score was 8 ± 1.2. Urine TIMP2.IGFBP7 > 2, rising urine TIMP2, and rising urine TIMP2/urine Cr were shown in patients within the 5-L group for 48% (p = 0.015), 32% (p = 0.049), and 76% (p = 0.010) respectively, indicating a higher incidence of renal tubular injury markers in this group. Urine TIMP2.IGFBP7/1000 > 2 was statistically significant to predict a hemodynamic event (p = 0.002). Conclusion In cirrhotic patients with ascites undergoing paracentesis, a 5-L paracentesis volume was associated with a higher incidence of renal tubular injury markers. Trail Registration: The national clinical registration number was TCTR20191116003.
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Affiliation(s)
- Anuchit Suksamai
- Division of Gastroenterology and Hepatology, Department of MedicinePhramongkutklao Hospital and College of MedicineBangkokThailand
| | - Sanpolpai Khaoprasert
- Division of Gastroenterology and Hepatology, Department of MedicinePhramongkutklao Hospital and College of MedicineBangkokThailand
| | - Amnart Chaiprasert
- Division of Nephrology, Department of MedicinePhramongkutklao Hospital and College of MedicineBangkokThailand
| | - Sakkarin Chirapongsathorn
- Division of Gastroenterology and Hepatology, Department of MedicinePhramongkutklao Hospital and College of MedicineBangkokThailand
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Karbannek H, Reichert MC, Greinert R, Zipprich A, Lammert F, Ripoll C. Exploring the Relationship Between NOD2 Risk Variants and First Decompensation Events in Cirrhotic Patients With Varices. Liver Int 2025; 45:e16143. [PMID: 39469976 PMCID: PMC11891376 DOI: 10.1111/liv.16143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 10/05/2024] [Accepted: 10/09/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND AND AIMS NOD2 mutations are associated with impaired gut mucosal barrier function. According to the systemic inflammation hypothesis, bacterial translocation is central in the development of decompensation. The aim was to evaluate whether the presence of NOD2 variants is associated with the development of first decompensation. METHOD Secondary analysis of prospectively collected consecutive patients with compensated cirrhosis, who were screened between 2014 and 2018. Patients with and without NOD2 variants were compared and stratified analysis according to the presence of varices was performed. RESULTS 360 patients [239 (66%) men, median age 61 (53-69) years, 70 (19%) with NOD2 variants, 90 (25%) with varices] were followed for a median of 9 (4-16) months. Similar baseline characteristics were observed across NOD2 status groups, except for beta-blocker use (45% vs. 32% amongst variant carriers vs. non-carriers, p = 0.05). During follow-up, 34 patients (12%) developed their first decompensation, with no differences according to NOD2 status [HR 1.75 (95% CI 0.84-3.67)]. On multivariate analysis, only MELD remained an independent predictor of decompensation. Amongst patients with varices (n = 90), 18 (24.4%) carried a NOD2 variants, with a higher incidence of first decompensation [HR 3.00 (95% CI 1.08-8.32)], primarily due to ascites [HR 3.32 (95% CI 1.07-10.32)]. In this subgroup, MELD [HR 1.18 (95% CI 1.06-1.32)] and NOD2 variants [HR 2.91 (95% CI 0.95-8.89)] were determined to be independent predictors of decompensation. CONCLUSIONS The presence of NOD2 risk variants leads to a greater incidence of first decompensation only in compensated patients with varices.
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Affiliation(s)
- Henrik Karbannek
- Department of Internal Medicine IVJena University HospitalJenaGermany
| | - Matthias C. Reichert
- Department of Medicine II, Saarland University Medical CenterSaarland UniversityHomburgGermany
| | - Robin Greinert
- Department of Internal Medicine IMartin Luther University Halle‐WittenbergHalleGermany
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical CenterSaarland UniversityHomburgGermany
- Health Sciences, Hannover Medical School (MHH)HannoverGermany
| | - Cristina Ripoll
- Department of Internal Medicine IVJena University HospitalJenaGermany
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Hofer BS, Simbrunner B, Königshofer P, Brusilovskaya K, Petrenko O, Taru V, Sorz‐Nechay T, Zinober K, Regnat K, Semmler G, Lackner C, Trauner M, Mandorfer M, Schwabl P, Reiberger T. Inflammation remains a dynamic component of portal hypertension in regressive alcohol-related cirrhosis. United European Gastroenterol J 2025; 13:317-329. [PMID: 39708052 PMCID: PMC11999040 DOI: 10.1002/ueg2.12643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 06/28/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Portal hypertension (PH) resulting from static and dynamic intrahepatic changes drives liver-related complications even after removing the underlying aetiological factor. OBJECTIVE We investigated the impact of inflammation on the dynamic component of PH during disease regression in animal models of toxin-induced cirrhosis and patients with alcohol-related cirrhosis. METHODS In mice, cirrhosis was induced via toxin application for 12 weeks followed by toxin-withdrawal allowing for one or 2 weeks of regression. Furthermore, 128 patients with alcohol-related cirrhosis and alcohol abstinence undergoing same-day hepatic venous pressure gradient (HVPG) and liver stiffness measurement (LSM) were included. The influence of inflammation on the dynamic PH component was assessed using linear models. Specifically, we explored proinflammatory changes in mice/patients in whom the measured portal pressure (PP)/HVPG was significantly higher than the PP/HVPG expected from the static PH component (histological collagen proportionate area [CPA; %] in mice, LSM in patients). RESULTS In mice, toxin discontinuation induced a significant decrease in PP, CPA, histological hepatic inflammation and hepatic expression of proinflammatory genes (Tnfa, Il6, Cxcl1, Mcp1; all p < 0.05 for one/2 week regression vs. peak disease). Similarly, prolonged abstinence in alcohol-related cirrhosis was linked to lower HVPG/LSM and longer abstinence was correlated to lower C-reactive protein (CRP), IL-6, immunoglobulin A (IgA) and IgG levels (all p < 0.05). Nevertheless, the persistence of a low-grade proinflammatory state during regression was linked to a higher PP/HVPG than expected from static PH components. In regressive mice, higher hepatic proinflammatory gene expression (Tnfa, Il6, Il1b; all p < 0.05) was linked to higher-than-expected PP. Similarly, higher CRP, IL-6, IgA and IgG and lower complement factor C3c (all p < 0.05) were associated with higher-than-expected HVPG in abstinent patients with alcohol-related cirrhosis. CONCLUSIONS Although removing the underlying aetiological factor resulted in significant improvements, a persistent hepatic proinflammatory environment remained a key driver of the dynamic PH component in regressive liver disease. CLINICAL TRIAL NUMBER NCT03267615.
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Affiliation(s)
- Benedikt Silvester Hofer
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
- Center for Molecular Medicine (CeMM) of the Austrian Academy of SciencesViennaAustria
| | - Philipp Königshofer
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Ksenia Brusilovskaya
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Oleksandr Petrenko
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
- Center for Molecular Medicine (CeMM) of the Austrian Academy of SciencesViennaAustria
| | - Vlad Taru
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Thomas Sorz‐Nechay
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
- Center for Molecular Medicine (CeMM) of the Austrian Academy of SciencesViennaAustria
| | - Kerstin Zinober
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Katharina Regnat
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Georg Semmler
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | | | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Mattias Mandorfer
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
| | - Philipp Schwabl
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
- Center for Molecular Medicine (CeMM) of the Austrian Academy of SciencesViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Haemodynamic LabDivision of Gastroenterology and HepatologyDepartment of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
- Center for Molecular Medicine (CeMM) of the Austrian Academy of SciencesViennaAustria
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Verma N, Kaur P, Garg P, Ranjan V, Ralmilay S, Rathi S, De A, Premkumar M, Taneja S, Roy A, Goenka M, Duseja A, Jalan R. Clinical and pathophysiological characteristics of non-acute decompensation of cirrhosis. J Hepatol 2025:S0168-8278(25)00137-0. [PMID: 40056937 DOI: 10.1016/j.jhep.2025.02.028] [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: 10/28/2024] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND & AIMS The heterogenous presentation patterns in decompensated cirrhosis confer variable outcomes. While acute decompensation (AD) is well-characterized, the presentation patterns and outcomes of non-acute decompensation (NAD) remain unclear. The aim of this study was to characterize clinical and pathophysiological features of NAD and identify predictors of progression in NAD. METHODS In this prospective study, patients across the cirrhosis spectrum were enrolled from two centers in India between 2020-2023: compensated cirrhosis (CC; n = 29), NAD (n = 311), AD (n = 201), and healthy controls (n = 10). Clinical and laboratory parameters, cytokine levels (IL-6, TNF, IL-10, MCP-1) and cell death markers (M30, M65, Gasdermin-D, RIPK3, MLKL) were assessed at baseline. Twelve-month overall survival was assessed in all patients. The predictors of progression to AD and mortality were evaluated in patients with NAD. RESULTS Survival was lower in patients with NAD (81.7%) than in those with CC (100%), but higher than in those with AD (31.2%) (p <0.001). Despite no significant systemic inflammation, patients with NAD exhibited elevated levels of cell death markers, particularly Gasdermin-D and RIPK3, compared to healthy controls and patients with CC. Both inflammatory and cell death markers were most pronounced in AD. Over 12 months, the cumulative incidence of progression to AD among those with NAD was 55.1%, significantly reducing their survival (68.2% vs. 95.3%, p <0.001). Predictors of such progression to AD included severe ascites, lower IGF-1, albumin, BMI, and higher bilirubin, Gasdermin-D, and RIPK3 levels, as well as higher CTP and MELD scores. CONCLUSIONS NAD represents a clinically, prognostically and pathophysiologically distinct entity in cirrhosis. Patients with NAD express elevated cell death markers and remain at risk of progression to AD and mortality. Identifying such high-risk patients should prompt interventions to prevent progression. Modulation of cell death is a potentially disease-modifying target in cirrhosis. IMPACT AND IMPLICATIONS This study highlights non-acute decompensation as a clinically, prognostically and pathophysiologically distinct subset of cirrhosis, underscoring the importance of understanding its progression dynamics. Identifying key predictors of acute decompensation, including ascites severity, low IGF-1 levels, and elevated cell death markers, such as Gasdermin-D and RIPK3, potentially uncovers new therapeutic avenues. These findings are crucial for helping hepatologists and researchers to risk stratify patients and optimize transplant candidacy. Interventions targeting necroptosis and pyroptosis pathways may improve outcomes, providing a significant shift towards precision medicine in cirrhosis care.
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Affiliation(s)
- Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India.
| | - Parminder Kaur
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Pratibha Garg
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Vivek Ranjan
- Institute of Gastrosciences and Liver Transplantation, Apollo Multispecialty Hospitals, Kolkata, India
| | - Samonee Ralmilay
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Sahaj Rathi
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Akash Roy
- Institute of Gastrosciences and Liver Transplantation, Apollo Multispecialty Hospitals, Kolkata, India
| | - Mahesh Goenka
- Institute of Gastrosciences and Liver Transplantation, Apollo Multispecialty Hospitals, Kolkata, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.
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Pohl J, Aretakis D, Tacke F, Engelmann C, Sigal M. Role of Intestinal Barrier Disruption to Acute-on-Chronic Liver Failure. Semin Liver Dis 2025; 45:52-65. [PMID: 40081417 DOI: 10.1055/a-2516-2361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut-liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut-liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.
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Affiliation(s)
- Julian Pohl
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Dimitrios Aretakis
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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10
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Schulz MS, Angeli P, Trebicka J. Acute and non-acute decompensation of liver cirrhosis (47/130). Liver Int 2025; 45:e15861. [PMID: 38426268 PMCID: PMC11815624 DOI: 10.1111/liv.15861] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 12/18/2023] [Accepted: 01/19/2024] [Indexed: 03/02/2024]
Abstract
In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.
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Affiliation(s)
- Martin S. Schulz
- Department of Internal Medicine BUniversity of MünsterMünsterGermany
| | - Paolo Angeli
- European Foundation for Study of Chronic Liver FailureBarcelonaSpain
| | - Jonel Trebicka
- Department of Internal Medicine BUniversity of MünsterMünsterGermany
- European Foundation for Study of Chronic Liver FailureBarcelonaSpain
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11
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Piano S, Mahmud N, Caraceni P, Tonon M, Mookerjee RP. Mechanisms and treatment approaches for ACLF. Liver Int 2025; 45:e15733. [PMID: 37715608 PMCID: PMC12036731 DOI: 10.1111/liv.15733] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/03/2023] [Accepted: 09/02/2023] [Indexed: 09/17/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF.
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Affiliation(s)
- Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine –DIMED, University and Hospital of Padova, Padova, Italy
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Leonard Davis Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
- Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine –DIMED, University and Hospital of Padova, Padova, Italy
| | - Rajeshwar Prosad Mookerjee
- Institute for Liver and Digestive Health, University College London, London, UK
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark
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12
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Praktiknjo M, Shawcross D, Laleman W. The clinical relevance of acute-on-chronic liver failure in medical procedures: Endoscopy, interventions and surgery. Liver Int 2025; 45:e15749. [PMID: 37753553 PMCID: PMC11815627 DOI: 10.1111/liv.15749] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 08/30/2023] [Accepted: 09/13/2023] [Indexed: 09/28/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a specific, but complex and multifactorial form of acute decompensation (AD) of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure and high short-term mortality. In daily clinical practice, patients with liver cirrhosis and decompensation have indications for different medical procedures such as endoscopies, interventional treatments like transjugular intrahepatic portosystemic shunt (TIPS) or even surgical procedures. In these situations, clinicians often need to balance the expected benefits of such procedures with the risks of causing acute decompensation or ACLF. This review summarizes the evidence of medical procedures and their role in precipitating or preventing ACLF and highlights the aspects to consider during patient selection.
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Affiliation(s)
- Michael Praktiknjo
- Department of Medicine B, Gastroenterology, Hepatology, Endocrinology, Infectious DiseasesUniversitätsklinikum MünsterMünsterGermany
| | - Debbie Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College LondonLondonUK
| | - Wim Laleman
- Department of Medicine B, Gastroenterology, Hepatology, Endocrinology, Infectious DiseasesUniversitätsklinikum MünsterMünsterGermany
- Department of Gastroenterology & HepatologyUniversity Hospitals LeuvenLeuvenBelgium
- Department of Chronic Diseases, Metabolism and Aging (CHROMETA)Catholic University of LeuvenLeuvenBelgium
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13
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Lai JCT, Dai J, Liang LY, Wong GLH, Wong VWS, Yip TCF. Pharmacological Treatment of Ascites: Challenges and Controversies. Pharmaceuticals (Basel) 2025; 18:339. [PMID: 40143117 PMCID: PMC11945444 DOI: 10.3390/ph18030339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/28/2025] Open
Abstract
Ascites is the most common complication from cirrhosis related to portal hypertension and depicts the onset of hepatic decompensation. Ranging from uncomplicated to refractory ascites, the progression carries prognostic value by reflecting the deterioration of underlying cirrhosis and portal hypertension. Diuretics have been the mainstay of treatment to control ascites, but the side effects heighten when the dosage is escalated. Non-selective beta-blockers (NSBBs) are widely used nowadays to prevent hepatic decompensation and variceal hemorrhage. However, with worsening systemic vasodilation and inflammation when ascites progresses, patients on NSBBs are at risk of hemodynamic collapse leading to renal hypoperfusion and thus hepatorenal syndrome. Long-term albumin infusion was studied to prevent the progression of ascites. However, the results were conflicting. Sodium-glucose cotransporter-2 inhibitors are under investigation to control refractory ascites. With that, patients with refractory ascites may require regular large-volume paracentesis. With an aging population, more patients are put on anti-thrombotic agents and their risks in decompensated cirrhosis and invasive procedures have to be considered. In general, decompensated cirrhosis with ascites poses multiple issues to pharmacological treatment. In the present review, we discuss the challenges and controversies in the pharmacological treatment of ascites.
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Affiliation(s)
- Jimmy Che-To Lai
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Junlong Dai
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lilian Yan Liang
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Lai-Hung Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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14
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Jiang H, Zhao Z, Cui S, Kong X, Jiang X. Prognostic factors for mortality in patients with acute-on-chronic liver failure. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00497. [PMID: 40207511 DOI: 10.1097/meg.0000000000002958] [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] [Indexed: 04/11/2025]
Abstract
OBJECTIVE The aim is to explore significant prognostic factors for 90-day mortality in patients with acute-on-chronic liver failure (ACLF) and assist clinicians in the early identification of critically ill ACLF patients. METHODS A retrospective analysis was conducted on 288 ACLF patients, who were classified into survivors (n = 187) and nonsurvivors (n = 101) based on 90-day outcomes. Multivariate stepwise logistic regression analyses were employed to identify significant prognostic factors and construct a novel prognostic model, the AHUCTPI. The model's performance was assessed and the internal validation was performed. Additionally, the influence of dynamic changes in laboratory markers on 90-day mortality was examined. RESULTS Independent risk factors for 90-day mortality included age ≥45 years, presence of hepatic encephalopathy (HE), and upper gastrointestinal bleeding (UGB) during hospitalization, imaging-confirmed cirrhosis at admission, elevated baseline total bilirubin (TBIL), reduced baseline platelet-to-neutrophil ratio (PNR), and elevated baseline international normalized ratio (INR) (P < 0.05 for all). The AHUCTPI model's formula is as follows: Logit (p) = -10.019 + 1.808 × age (1 if ≥45 years, 0 if <45 years) + 1.048 × HE (1 if present, 0 if absent) + 1.721 × UGB (1 if present, 0 if absent) + 1.362 × cirrhosis (1 if present, 0 if absent) + 0.008 × TBIL (μmol/L) - 0.039 × PNR + 1.963 × INR. The AUHCTPI model demonstrated superior predictive accuracy compared with the MELD (Model for End-Stage Liver Disease) score, with the area under the receiver operating characteristic curve values of 0.914 and 0.739, respectively, and calibration curves closely approximating the ideal curve. CONCLUSION ACLF is a complex, dynamic syndrome. Age, HE, and UGB during hospitalization, imaging-diagnosed cirrhosis at admission, baseline TBIL, PNR, and INR were significant predictors for 90-day mortality in ACLF patients, and the AHUCTPI model provides excellent calibration and discrimination. Dynamic monitoring of laboratory trends enhances prognostic accuracy and supports timely clinical decision-making.
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Affiliation(s)
- Huijie Jiang
- Department of Liver Diseases, Public Health Clinical Center Affiliated to Shandong University, Jinan, China
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15
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Loyola-Vélez AJ, John BV. SGLT2 Inhibitors in Cirrhosis: A Promising Therapeutic Avenue with Potential Risks. Dig Dis Sci 2025; 70:456-458. [PMID: 39581899 DOI: 10.1007/s10620-024-08703-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Accepted: 10/19/2024] [Indexed: 11/26/2024]
Affiliation(s)
| | - Binu V John
- Division of Gastroenterology and Hepatology, Miami VA Medical System, Miami, USA
- Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, FL, USA
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16
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Singh V, De A, Aggrawal R, Singh A, Charak S, Bhagat N. Safety and Efficacy of Dapagliflozin in Recurrent Ascites: A Pilot Study. Dig Dis Sci 2025; 70:835-842. [PMID: 39384712 DOI: 10.1007/s10620-024-08667-4] [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: 07/14/2024] [Accepted: 09/24/2024] [Indexed: 10/11/2024]
Abstract
BACKGROUND In cirrhosis, activation of renin-angiotensin-aldosterone system leads to sodium and water retention causing ascites. Dapagliflozin, a sodium glucose linked transporter-2 inhibitor, induces natriuresis in patients with heart failure. A similar natriuretic effect may improve ascites in patients with cirrhosis. In this pilot study, we evaluated the safety and efficacy of dapagliflozin in patients with cirrhosis and recurrent ascites. METHODS Forty patients with recurrent ascites and cirrhosis were randomized to 1:1 in a double blinded fashion to receive either dapagliflozin (10 mg/day) with standard medical therapy (Group A) or placebo with standard medical therapy (Group B). The primary outcome was control of ascites at 6 months. Secondary outcomes were urine output, 24-h urinary sodium, Child Turcotte Pugh (CTP), model for end-stage liver disease (MELD) scores, survival at 6 months, incidence of acute kidney injury (AKI) and infections. RESULTS The 2 groups were comparable at baseline. Control of ascites at 6 months was significantly better in group A than that in Group B (p = 0.04). Change in urinary sodium was significantly higher in Group A (p < 0.001]. However, there was no difference in change in urine output, CTP or MELD scores and survival (65% vs 72.2%, p = 0.75) between the groups at 6 months. Incidence of AKI (50% vs 15%, p = 0.04) and infections (55% vs 20%, p = 0.04) were significantly higher in Group A. CONCLUSION Significantly better control of ascites and higher natriuresis are observed with dapagliflozin. However, it does not improve disease severity scores or survival, and is associated with increased AKI and infections (NCT05014594).
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Affiliation(s)
- Virendra Singh
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
- Punjab Institute of Liver and Biliary Sciences, Mohali, India.
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rishav Aggrawal
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Akash Singh
- Albert Einstein Healthcare Network, Philadelphia, USA
| | - Swati Charak
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Naveen Bhagat
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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17
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Porada M, Bułdak Ł. From Pathophysiology to Practice: Evolving Pharmacological Therapies, Clinical Complications, and Pharmacogenetic Considerations in Portal Hypertension. Metabolites 2025; 15:72. [PMID: 39997697 PMCID: PMC11857179 DOI: 10.3390/metabo15020072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/07/2025] [Accepted: 01/18/2025] [Indexed: 02/26/2025] Open
Abstract
Background: Portal hypertension is a major complication of chronic liver diseases, leading to serious issues such as esophageal variceal bleeding. The increase in portal vein pressure is driven by both an organic component and a functional component, including tonic contraction of hepatic stellate cells. These processes result in a pathological rise in intrahepatic vascular resistance, stemming from partial impairment of hepatic microcirculation, which is further exacerbated by abnormalities in extrahepatic vessels, including increased portal blood flow. Objectives: This review aims to provide a comprehensive overview of the evolving pharmacological therapies for portal hypertension, with consideration and discussion of pathophysiological mechanisms, clinical complications, and pharmacogenetic considerations, highlighting potential directions for future research. Methods: A review of recent literature was performed to evaluate current knowledge and potential therapeutic strategies in portal hypertension. Results: For over 35 years, non-selective beta-blockers have been the cornerstone therapy for portal hypertension by reducing portal vein inflow as an extrahepatic target, effectively preventing decompensation and variceal hemorrhages. However, since not all patients exhibit an adequate response to non-selective beta-blockers (NSBBs), and some may not tolerate NSBBs, alternative or adjunctive therapies that enhance the effects of NSBBs on portal pressure are being investigated in preclinical and early clinical studies. Conclusions: A better understanding of pharmacogenetic factors and pathophysiological mechanisms could lead to more individualized and effective treatments for portal hypertension. These insights highlight potential directions for future research.
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Affiliation(s)
- Michał Porada
- Students’ Scientific Society, Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland;
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
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18
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Geng A, Brenig RG, Roux J, Lütge M, Cheng HW, Flint EE, Lussier POG, Meier MA, Pop OT, Künzler-Heule P, Matter MS, Wendon J, McPhail MJW, Soysal S, Semela D, Heim M, Weston CJ, Ludewig B, Bernsmeier C. Circulating monocytes upregulate CD52 and sustain innate immune function in cirrhosis unless acute decompensation emerges. J Hepatol 2025:S0168-8278(24)02818-6. [PMID: 39818234 DOI: 10.1016/j.jhep.2024.12.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 12/09/2024] [Accepted: 12/11/2024] [Indexed: 01/18/2025]
Abstract
BACKGROUND & AIMS The susceptibility of patients with cirrhosis to infection, a major determinant of prognosis, relates to the development of immuneparesis, a complex interplay of different immunosuppressive cells and soluble factors. The mechanisms underlying the dynamics of immuneparesis of innate immunity remain unclear. We aimed to dissect the heterogeneity of circulating monocyte states in different stages of cirrhosis, and to determine the function of selected differentially expressed genes. METHODS We systematically investigated circulating monocytes in health and compensated/non-acutely decompensated cirrhosis using single-cell RNA sequencing. Selective genes were confirmed by flow cytometry and diverse functional assays on monocytes ex vivo. RESULTS We partitioned monocytes into seven clusters. Their abundances varied between cirrhosis stages, confirming previously reported changes, i.e. the reduction in CD14lowCD16++ and emergence of monocytic myeloid-derived suppressor cells in advanced stages. Differentially expressed genes between health and disease and among stages were detected, including CD52 for the first time. CD52 expression on monocytes significantly increased through compensated and non-acutely decompensated cirrhosis. In patients with cirrhosis, CD52highCD14+CD16highHLA-DRhigh monocytes had a functional phenotype of active phagocytes, with enhanced migratory potential and increased cytokine production capacity but limited ability to activate T cells. Following acute decompensation, CD52 was cleaved by elevated PLC, and soluble CD52 was detected in the circulation. Inhibition and cleavage of CD52 significantly suppressed monocyte functions ex vivo and in vitro, while the predominance of immunosuppressive CD52low circulating monocytes in patients with acute decompensation was associated with infection and low transplant-free survival. CONCLUSION CD52 may represent a biologically relevant target for future immunotherapy. Stabilising CD52 may enhance monocyte functions and infection control in the context of cirrhosis, guided by soluble CD52/PLC as biomarkers of immuneparesis. IMPACT AND IMPLICATIONS Monocyte dysfunction substantially contributes to infection susceptibility, which is a major determinant of the prognosis of patients with cirrhosis and represents a major unmet therapeutic need. Its underlying mechanisms remain poorly understood, although, among hepatologists, it is thought that the therapeutic reconstitution of monocyte function could enhance defence against infection and thus reduce morbidity and mortality of patients with cirrhosis. By systematically delineating the heterogeneity and function of circulating monocytes ex vivo, we identified that the absence of CD52 expression on monocytes represented a distinct biomarker of monocyte dysfunction in patients with cirrhosis, discriminating patients at substantial risk of infectious complications. Otherwise, given the beneficial antimicrobial functions of CD52-expressing monocytes, CD52 stablisation may also represent a therapeutic approach worth exploring.
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Affiliation(s)
- Anne Geng
- Department of Biomedicine, University of Basel, Switzerland; University Centre for Gastrointestinal and Liver Disease Basel, Switzerland
| | - Robert G Brenig
- Department of Biomedicine, University of Basel, Switzerland; University Centre for Gastrointestinal and Liver Disease Basel, Switzerland
| | - Julien Roux
- Bioinformatics Core Facility, Department of Biomedicine, University of Basel, Switzerland; Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Mechthild Lütge
- Institute of Immunobiology, Cantonal Hospital St. Gallen, Switzerland
| | - Hung-Wei Cheng
- Institute of Immunobiology, Cantonal Hospital St. Gallen, Switzerland
| | - Emilio E Flint
- Department of Biomedicine, University of Basel, Switzerland; University Centre for Gastrointestinal and Liver Disease Basel, Switzerland
| | - Paul O G Lussier
- Department of Biomedicine, University of Basel, Switzerland; University Centre for Gastrointestinal and Liver Disease Basel, Switzerland
| | | | - Oltin T Pop
- Institute of Immunobiology, Cantonal Hospital St. Gallen, Switzerland; Liver Biology Laboratory, Division of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, Switzerland
| | - Patrizia Künzler-Heule
- Liver Biology Laboratory, Division of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, Switzerland
| | - Matthias S Matter
- University Hospital, Basel, Institute of Pathology, Basel, Switzerland
| | - Julia Wendon
- Institute of Liver Studies, King's College Hospital, and School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Mark J W McPhail
- Institute of Liver Studies, King's College Hospital, and School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Savas Soysal
- University Centre for Gastrointestinal and Liver Disease Basel, Switzerland
| | - David Semela
- Liver Biology Laboratory, Division of Gastroenterology and Hepatology, Cantonal Hospital St. Gallen, Switzerland
| | - Markus Heim
- Department of Biomedicine, University of Basel, Switzerland; University Centre for Gastrointestinal and Liver Disease Basel, Switzerland
| | - Chris J Weston
- Institute of Immunology and Immunotherapy, NIHR Biomedical Research Unit and Centre for Liver Research, The Medical School, University of Birmingham, Birmingham, United Kingdom
| | - Burkhard Ludewig
- Institute of Immunobiology, Cantonal Hospital St. Gallen, Switzerland
| | - Christine Bernsmeier
- Department of Biomedicine, University of Basel, Switzerland; University Centre for Gastrointestinal and Liver Disease Basel, Switzerland.
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19
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Kronsten VT, Shawcross DL. Clinical Implications of Inflammation in Patients With Cirrhosis. Am J Gastroenterol 2025; 120:65-74. [PMID: 39194320 PMCID: PMC11676607 DOI: 10.14309/ajg.0000000000003056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.
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Affiliation(s)
- Victoria T. Kronsten
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
| | - Debbie L. Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
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20
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Davis BC, Lin KC, Shahub S, Ramasubramanya A, Fagan A, Muthukumar S, Prasad S, Bajaj JS. A novel sweat sensor detects inflammatory differential rhythmicity patterns in inpatients and outpatients with cirrhosis. NPJ Digit Med 2024; 7:382. [PMID: 39733165 DOI: 10.1038/s41746-024-01404-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/20/2024] [Indexed: 12/30/2024] Open
Abstract
Patients with cirrhosis have high systemic inflammation (TNFα, CRP, and IL-6) that is associated with poor outcomes. These biomarkers need continuous non-invasive monitoring, which is difficult with blood. We studied the AWARE sweat-sensor to measure these in passively expressed sweat in healthy people (N = 12) and cirrhosis (N = 32, 10 outpatients/22 inpatients) for 3 days. Blood CRP, TNFα, IL6, levels, and liver function and quality of life were measured. We found that CRP, TNFα, and IL6 were correlated in sweat and serum among both groups and were evaluated in inpatients versus outpatients/controls. IL6 is associated with lower transplant-free survival. Sweat monitoring nocturnal CRP/IL6 elevations in cirrhosis versus controls. Outpatients with cirrhosis had inflammation levels that elevated during the evening and peaked towards the early night periods. The levels start to fall much later at night and early morning. These data suggest that further investigation of continuous measurement of sweat biomarkers in cirrhosis is warranted.
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Affiliation(s)
- Brian C Davis
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA
| | - Kai-Chun Lin
- University of Texas at Dallas, Richardson, TX, USA
| | - Sarah Shahub
- University of Texas at Dallas, Richardson, TX, USA
| | | | - Andrew Fagan
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA
| | | | | | - Jasmohan S Bajaj
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA.
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21
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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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22
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Burra P, Zanetto A, Schnabl B, Reiberger T, Montano-Loza AJ, Asselta R, Karlsen TH, Tacke F. Hepatic immune regulation and sex disparities. Nat Rev Gastroenterol Hepatol 2024; 21:869-884. [PMID: 39237606 DOI: 10.1038/s41575-024-00974-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/07/2024]
Abstract
Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.
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Affiliation(s)
- Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy.
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Tom Hemming Karlsen
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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23
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Wang J, Niu D, Li X, Zhao Y, Ye E, Huang J, Yue S, Hou X, Wu J. Effects of 24-hour urine-output trajectories on the risk of acute kidney injury in critically ill patients with cirrhosis: a retrospective cohort analysis. Ren Fail 2024; 46:2298900. [PMID: 38178568 PMCID: PMC10773636 DOI: 10.1080/0886022x.2023.2298900] [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: 08/03/2023] [Accepted: 12/20/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is one of the most common complications for critically ill patients with cirrhosis, but it has remained unclear whether urine output fluctuations are associated with the risk of AKI in such patients. Thus, we explored the influence of 24-h urine-output trajectory on AKI in patients with cirrhosis through latent category trajectory modeling. MATERIALS AND METHODS This retrospective cohort study examined patients with cirrhosis using the MIMIC-IV database. Changes in the trajectories of urine output within 24 h after admission to the intensive care unit (ICU) were categorized using latent category trajectory modeling. The outcome examined was the occurrence of AKI during ICU hospitalization. The risk of AKI in patients with different trajectory classes was explored using the cumulative incidence function (CIF) and the Fine-Gray model with the sub-distribution hazard ratio (SHR) and the 95% confidence interval (CI) as size effects. RESULTS The study included 3,562 critically ill patients with cirrhosis, of which 2,467 (69.26%) developed AKI during ICU hospitalization. The 24-h urine-output trajectories were split into five classes (Classes 1-5). The CIF curves demonstrated that patients with continuously low urine output (Class 2), a rapid decline in urine output after initially high levels (Class 3), and urine output that decreased slowly and then stabilized at a lower level (Class 4) were at higher risk for AKI than those with consistently moderate urine output (Class 1). After fully adjusting for various confounders, Classes 2, 3, and 4 were associated with a higher risk of AKI compared with Class 1, and the respective SHRs (95% CIs) were 2.56 (1.87-3.51), 1.86 (1.34-2.59), and 1.83 1.29-2.59). CONCLUSIONS The 24-h urine-output trajectory is significantly associated with the risk of AKI in critically ill patients with cirrhosis. More attention should be paid to the dynamic nature of urine-output changes over time, which may help guide early intervention and improve patients' prognoses.
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Affiliation(s)
- Jia Wang
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Dongdong Niu
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xiaolin Li
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yumei Zhao
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Enlin Ye
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiasheng Huang
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Suru Yue
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Xuefei Hou
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiayuan Wu
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Guangdong Engineering Research Center of Collaborative Innovation of Clinical Medical Big Data Cloud Service in Western Guangdong Medical Union, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Nesci A, Ruggieri V, Manilla V, Spinelli I, Santoro L, Di Giorgio A, Santoliquido A, Ponziani FR. Endothelial Dysfunction and Liver Cirrhosis: Unraveling of a Complex Relationship. Int J Mol Sci 2024; 25:12859. [PMID: 39684569 DOI: 10.3390/ijms252312859] [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: 09/27/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Endothelial dysfunction (ED) is the in the background of multiple metabolic diseases and a key process in liver disease progression and cirrhosis decompensation. ED affects liver sinusoidal endothelial cells (LSECs) in response to different damaging agents, causing their progressive dedifferentiation, unavoidably associated with an increase in intrahepatic resistance that leads to portal hypertension and hyperdynamic circulation with increased cardiac output and low peripheral artery resistance. These changes are driven by a continuous interplay between different hepatic cell types, invariably leading to increased reactive oxygen species (ROS) formation, increased release of pro-inflammatory cytokines and chemokines, and reduced nitric oxide (NO) bioavailability, with a subsequent loss of proper vascular tone regulation and fibrosis development. ED evaluation is often accomplished by serum markers and the flow-mediated dilation (FMD) measurement of the brachial artery to assess its NO-dependent response to shear stress, which usually decreases in ED. In the context of liver cirrhosis, the ED assessment could help understand the complex hemodynamic changes occurring in the early and late stages of the disease. However, the instauration of a hyperdynamic state and the different NO bioavailability in intrahepatic and systemic circulation-often defined as the NO paradox-must be considered confounding factors during FMD analysis. The primary purpose of this review is to describe the main features of ED and highlight the key findings of the dynamic and intriguing relationship between ED and liver disease. We will also focus on the significance of FMD evaluation in this setting, pointing out its key role as a therapeutic target in the never-ending battle against liver cirrhosis progression.
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Affiliation(s)
- Antonio Nesci
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Vittorio Ruggieri
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Vittoria Manilla
- Liver Unit, CEMAD-Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Irene Spinelli
- Liver Unit, CEMAD-Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
| | - Luca Santoro
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Angela Di Giorgio
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Angelo Santoliquido
- Angiology and Noninvasive Vascular Diagnostics Unit, Department of Cardiovascular Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Liver Unit, CEMAD-Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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25
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Chen SY, Ng CJ, Huang YB, Lo HY. Analyzing prognosis and comparing predictive scoring systems for mortality of COVID-19 patients with liver cirrhosis: a multicenter retrospective study. BMC Infect Dis 2024; 24:1315. [PMID: 39558236 PMCID: PMC11572522 DOI: 10.1186/s12879-024-10223-4] [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: 03/24/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Limited research suggested that liver cirrhosis is an independent risk factor for severe COVID-19, leading to higher hospitalization and mortality rates. This study aimed to identify the prognostic factors and validate scoring systems for predicting mortality in COVID-19 patients with liver cirrhosis. METHODS This retrospective cohort study extracted electronic health records of patients with COVID-19 who visited the emergency department between April 2021 and September 2022. Adult COVID-19 patients with liver cirrhosis were included, excluding those aged < 18 years and who did not require hospitalization. The primary outcome was in-hospital mortality. The effectiveness of the scoring systems were analyzed for COVID-19 in-house mortality prediction. RESULTS A total of 1,368 adult COVID-19 patients with liver cirrhosis were included in this study. Compared with the survival group, the non-survival group had lower vital signs such as systolic blood pressure and blood oxygen saturation, higher levels of white blood cells, creatinine, bilirubin, and C-reactive protein, and longer prothrombin time. Higher rates of intubation, oxygen use, and dexamethasone use were observed in the non-survivor group. The WHO ordinal scale, MELD, and MELD-Na scores showed good predictive ability for in-hospital mortality. CONCLUSIONS The WHO ordinal scale showed the best performance in predicting mortality in patients with cirrhosis and COVID-19. MELD and MELD-Na scores were also found good performance for mortality prediction. Coagulation function, intubation, and dexamethasone administration were the most significant prognostic factors.
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Affiliation(s)
- Shou-Yen Chen
- Department of Emergency Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 5 Fushing St., Gueishan Shiang, Taoyuan, 333, Taiwan
- Graduate Institute of Management, College of Management, Chang Gung University, Taoyuan, 333, Taiwan
| | - Chip-Jin Ng
- Department of Emergency Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 5 Fushing St., Gueishan Shiang, Taoyuan, 333, Taiwan
| | - Yan-Bo Huang
- Department of Emergency Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 5 Fushing St., Gueishan Shiang, Taoyuan, 333, Taiwan
| | - Hsiang-Yun Lo
- Department of Emergency Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 5 Fushing St., Gueishan Shiang, Taoyuan, 333, Taiwan.
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26
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Alvarado-Tapias E, Brujats A, Puente A, Ardevol A, Rodriguez-Arias A, Fajardo J, Pavel O, Garcia-Guix M, Aracil C, Poca M, Cuyàs B, Cantó E, Montañés R, Garcia-Osuna A, Escorsell À, Torras X, Villanueva C. Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial. Hepatology 2024:01515467-990000000-01072. [PMID: 39509369 DOI: 10.1097/hep.0000000000001148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND AND AIMS Carvedilol is a nonselective β-blocker (NSBB) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal pressure hepatic venous pressure gradient (HVPG). However, 35%-45% of patients still have insufficient HVPG decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal hypertension and suboptimal response to traditional NSBBs. METHODS Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v. propranolol. Suboptimal responders (HVPG decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6 weeks, repeating HVPG measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. RESULTS Of 184 eligible patients, 82 were randomized to carvedilol + simvastatin (N = 41) or carvedilol + placebo (N = 41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol + simvastatin (18.6 ± 4 to 15.7 ± 4 mm Hg, p < 0.001) and carvedilol + placebo (18.9 ± 3 to 16.9 ± 3 mm Hg, p < 0.001). The decrease was greater with carvedilol + simvastatin (2.97 ± 2.5 vs. 2.05 ± 1.6 mm Hg, p = 0.031). An HVPG decrease ≥20% occurred in 37% versus 15% of patients, respectively (OR: 3.37, 95% CI = 1.15-9.85; p = 0.021). With test meal, HVPG increased in both groups ( p < 0.01), although carvedilol + simvastatin attenuated such increment (12 ± 8% vs. 23 ± 16%, p < 0.001). Cytokine levels (Interleukine-6, monocyte-chemoattractant protein-1, and malondialdehyde) decreased significantly more with carvedilol + simvastatin ( p < 0.01). The incidence of adverse events was similar. CONCLUSIONS In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal pressure reduction achieved with carvedilol monotherapy, improves endothelial dysfunction, and reduces proinflammatory cytokines.
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Affiliation(s)
- Edilmar Alvarado-Tapias
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Anna Brujats
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Angela Puente
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Alba Ardevol
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Javier Fajardo
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Oana Pavel
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Marta Garcia-Guix
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Carles Aracil
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Maria Poca
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Berta Cuyàs
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Elisabet Cantó
- Inflammatory Diseases Department, Institut Recerca Hospital Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Rosa Montañés
- Inflammatory Diseases Department, Institut Recerca Hospital Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Alvaro Garcia-Osuna
- Department of Biochemistry, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Àngels Escorsell
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Xavier Torras
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Càndid Villanueva
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
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27
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Schwarz M, Simbrunner B, Jachs M, Hartl L, Balcar L, Bauer DJM, Semmler G, Hofer BS, Scheiner B, Pinter M, Stättermayer AF, Trauner M, Reiberger T, Mandorfer M. High histamine levels are associated with acute-on-chronic liver failure and liver-related death in patients with advanced chronic liver disease. Liver Int 2024; 44:2904-2914. [PMID: 39136222 DOI: 10.1111/liv.16056] [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: 11/03/2023] [Revised: 06/20/2024] [Accepted: 07/22/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND AND AIMS The role of histamine in advanced chronic liver disease (ACLD) is poorly understood. We investigated plasma histamine levels across ACLD stages and their prognostic value. METHODS We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint. RESULTS Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001. CONCLUSION High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.
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Affiliation(s)
- Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - David J M Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt S Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Albert F Stättermayer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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28
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Zhai Y, Hai D, Zeng L, Lin C, Tan X, Mo Z, Tao Q, Li W, Xu X, Zhao Q, Shuai J, Pan J. Artificial intelligence-based evaluation of prognosis in cirrhosis. J Transl Med 2024; 22:933. [PMID: 39402630 PMCID: PMC11475999 DOI: 10.1186/s12967-024-05726-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 10/02/2024] [Indexed: 10/19/2024] Open
Abstract
Cirrhosis represents a significant global health challenge, characterized by high morbidity and mortality rates that severely impact human health. Timely and precise prognostic assessments of liver cirrhosis are crucial for improving patient outcomes and reducing mortality rates as they enable physicians to identify high-risk patients and implement early interventions. This paper features a thorough literature review on the prognostic assessment of liver cirrhosis, aiming to summarize and delineate the present status and constraints associated with the application of traditional prognostic tools in clinical settings. Among these tools, the Child-Pugh and Model for End-Stage Liver Disease (MELD) scoring systems are predominantly utilized. However, their accuracy varies significantly. These systems are generally suitable for broad assessments but lack condition-specific applicability and fail to capture the risks associated with dynamic changes in patient conditions. Future research in this field is poised for deep exploration into the integration of artificial intelligence (AI) with routine clinical and multi-omics data in patients with cirrhosis. The goal is to transition from static, unimodal assessment models to dynamic, multimodal frameworks. Such advancements will not only improve the precision of prognostic tools but also facilitate personalized medicine approaches, potentially revolutionizing clinical outcomes.
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Affiliation(s)
- Yinping Zhai
- Department of Gastroenterology Nursing Unit, Ward 192, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Darong Hai
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Li Zeng
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325000, China
| | - Chenyan Lin
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Xinru Tan
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, 325000, China
| | - Zefei Mo
- School of Biomedical Engineering, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Qijia Tao
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Wenhui Li
- The School of Nursing, Wenzhou Medical University, Wenzhou, 325000, China
| | - Xiaowei Xu
- Department of Gastroenterology Nursing Unit, Ward 192, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Qi Zhao
- School of Computer Science and Software Engineering, University of Science and Technology Liaoning, Anshan, 114051, China.
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China.
| | - Jianwei Shuai
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Wenzhou, 325000, China.
| | - Jingye Pan
- Department of Big Data in Health Science, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou, 325000, China.
- Zhejiang Engineering Research Center for Hospital Emergency and Process Digitization, Wenzhou, 325000, China.
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29
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Brujats A, Villanueva C. Examining the therapeutic landscape of beta-blockers in portal hypertension. Clin Mol Hepatol 2024; 30:1055-1059. [PMID: 38447532 PMCID: PMC11540378 DOI: 10.3350/cmh.2024.0144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 03/04/2024] [Accepted: 03/04/2024] [Indexed: 03/08/2024] Open
Affiliation(s)
- Anna Brujats
- Hospital Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
| | - Càndid Villanueva
- Hospital Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Barcelona, Spain
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30
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Verma N, Vinod AP, Singal AK. The pharmacological management of alcohol-related cirrhosis: what's new? Expert Opin Pharmacother 2024; 25:1923-1941. [PMID: 39360770 DOI: 10.1080/14656566.2024.2409941] [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: 06/28/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Alcohol use disorder (AUD) is present in the majority of patients with alcohol-associated liver disease (ALD), which leads to about 50% of cirrhosis-related hospitalizations and over 25% of deaths worldwide. Patients with ALD often present at an advanced stage, like cirrhosis with its complications and alcohol-associated hepatitis (AH), which has high short-term mortality. Current treatments are limited, with the limited benefit of glucocorticoids only in the short-term among patients with AH, highlighting an urgent need for novel therapies. AREAS COVERED This review applies the PIRO (Predisposition, Injury, Response, Organ dysfunction) concept to ALD, understanding an ongoing process of liver damage, and opportunities to address and halt the progression. We also highlight the significance of treating AUD to improve long-term outcomes in ALD. EXPERT OPINION Personalized therapies targeting specific genetic profiles and multiple pathogenic pathways are crucial in managing ALD. Emerging therapies like gut-liver-brain axis modulators like fecal microbiota transplant and probiotics, interleukin-22, granulocyte-colony stimulating factor (G-CSF) and stem cells, epigenetic regulators of inflammation and regeneration are encouraging with the potential of efficacy in patients with ALD. Liver transplantation (LT) is a definitive therapy for advanced cirrhosis with increasing impetus on early LT select patients with active alcohol use.
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Affiliation(s)
- Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwin P Vinod
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwani K Singal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Louisville School of Medicine, Louisville, KY, USA
- Department of Transplant Hepatology, Jewish Hospital and Trager Transplant Center, Louisville, Kentucky, USA
- Department of Research, Veteran Affairs Medical Center, Sioux Falls, SD, USA
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31
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Yang JX, Peng YM, Zeng HT, Lin XM, Xu ZL. Drainage of ascites in cirrhosis. World J Hepatol 2024; 16:1245-1257. [PMID: 39351514 PMCID: PMC11438587 DOI: 10.4254/wjh.v16.i9.1245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/20/2024] [Accepted: 07/29/2024] [Indexed: 09/23/2024] Open
Abstract
For cirrhotic refractory ascites, diuretics combined with albumin and vasoactive drugs are the first-line choice for ascites management. However, their therapeutic effects are limited, and most refractory ascites do not respond to medication treatment, necessitating consideration of drainage or surgical interventions. Consequently, numerous drainage methods for cirrhotic ascites have emerged, including large-volume paracentesis, transjugular intrahepatic portosystemic shunt, peritoneovenous shunt, automated low-flow ascites pump, cell-free and concentrated ascites reinfusion therapy, and peritoneal catheter drainage. This review introduces the advantages and disadvantages of these methods in different aspects, as well as indications and contraindications for this disease.
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Affiliation(s)
- Jia-Xing Yang
- Department of Gastroenterology, The Second Clinical Medical College, Jinan University, Shenzhen 518000, Guangdong Province, China
| | - Yue-Ming Peng
- Department of Nursing, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen 518000, Guangdong Province, China
| | - Hao-Tian Zeng
- Department of Gastroenterology, The Second Clinical Medical College, Jinan University, Shenzhen 518000, Guangdong Province, China
| | - Xi-Min Lin
- Department of Gastroenterology, The Second Clinical Medical College, Jinan University, Shenzhen 518000, Guangdong Province, China
| | - Zheng-Lei Xu
- Department of Gastroenterology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen 518000, Guangdong Province, China.
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Rodríguez-Negrete EV, Gálvez-Martínez M, Sánchez-Reyes K, Fajardo-Felix CF, Pérez-Reséndiz KE, Madrigal-Santillán EO, Morales-González Á, Morales-González JA. Liver Cirrhosis: The Immunocompromised State. J Clin Med 2024; 13:5582. [PMID: 39337069 PMCID: PMC11432654 DOI: 10.3390/jcm13185582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Systemic inflammation and immunodeficiency are important components of cirrhosis-associated immune dysfunction (CAID), the severity of which is dynamic, progressive, and associated with the greater deterioration of liver function. Two inflammation phenotypes have been described: low-grade and high-grade systemic inflammation. Both of these phenotypes are related to liver cirrhosis function; thus, high-grade inflammation is correlated with the severity of hepatic insufficiency, bacterial translocation, and organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation (BT) plays a relevant role in persistent systemic inflammation in patients with cirrhosis, and the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.
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Affiliation(s)
- Elda Victoria Rodríguez-Negrete
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Marisol Gálvez-Martínez
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karina Sánchez-Reyes
- Servicio de Cirugía General, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico;
| | - Carlos Fernando Fajardo-Felix
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karla Erika Pérez-Reséndiz
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | | | - Ángel Morales-González
- Escuela Superior de Cómputo, Instituto Politécnico Nacional, Unidad Profesional “A. López Mateos”, Ciudad de México 07738, Mexico
| | - José Antonio Morales-González
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
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Wang B, Zhou A, Wu Y, Pan Q, Wei X, Gao Y, Xiao W, Jin J, Zhou T, Luo Y, Zhan Z, Liu Y, Gao W, Liu Y, Xia Q. Establishment and validation of a predictive model of immune tolerance after pediatric liver transplantation: a multicenter cohort study. Int J Surg 2024; 110:5615-5626. [PMID: 38833360 PMCID: PMC11392161 DOI: 10.1097/js9.0000000000001671] [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: 01/25/2024] [Accepted: 05/09/2024] [Indexed: 06/06/2024]
Abstract
Background: Side-effect of life-long immunosuppressants (IS) administration is a major obstacle for the long-term survival of pediatric liver transplantation (LT) recipients. Immunotolerance is the status that recipients discontinued IS with normal liver function and intrahepatic histology. So far, only a few clinical parameters were identified related with tolerance but failed to accurately discriminate tolerant recipients in clinical practice. Here, the authors aimed to provide a comprehensive view of pre-LT and post-LT risk factors associated with the achievement of tolerance after pediatric LT and established a tolerance predictive nomogram (ITPLT) with high accuracy and specificity. Methods: The authors enrolled 2228 pediatric recipients who received LT in Renji Hospital between October 2006 and December 2020. All participants survived over 3 years after transplantation with comprehensive and intact medical history and follow-up data. They were randomly assigned to training and validation cohorts in accordance with a ratio of 1:1. Univariate and multivariable Logistic regression were used to identify clinical factors associated with post-LT immune tolerance and establish a predictive model. The model was further validated in an independent external validation cohort from Tianjin First Central Hospital. Results: Among all participants, 6% recipients successfully tapered IS with intact allograft function. The most common reason for IS discontinuity was pneumonia. Univariate analysis identified 15 clinical factors associated with tolerance achievement, including age at LT, follow-up time, preoperative total bilirubin, creatinine, INR, CYP polymorphism, types of transplantation, massive postoperative ascites, episodes of acute rejection, and the severity of EBV and CMV infection. Using multivariable Logistic regression, the authors established the predictive ITPLT model for post-LT tolerance, which included seven easily accessible clinical factors (age at LT, CYP3A5 genotype, types of transplantation, post-LT massive ascites, preoperative INR, creatinine, and total bilirubin levels). Then, the authors visualized the model using nomogram. The c -statistics for predicting tolerance achievement in the training, internal validation, and external validation cohorts were 0.854, 0.787, and 0.746, respectively. Conclusion: Multiple pre-LT and post-LT clinical factors affected the process of immune remodeling after pediatric LT. The predictive ITPLT model, composed of seven easily accessible clinical factors, could comprehensively reveal the effect of these clinical parameters on immune remodeling and accurately identify tolerant recipients after pediatric LT. The application of ITPLT could facilitate the individualized IS strategy in the future.
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Affiliation(s)
- Bingran Wang
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Aiwei Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Yichi Wu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Qi Pan
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Xinzhe Wei
- Department of Pediatric Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin
| | - Yunmu Gao
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Wanglong Xiao
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Jing Jin
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Tao Zhou
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
| | | | - Yongbo Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Institute of Transplantation
| | - Wei Gao
- Department of Pediatric Transplantation, Organ Transplantation Center, Tianjin First Central Hospital, Tianjin
| | - Yuan Liu
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Immune Therapy Institute
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
- Shanghai Institute of Transplantation
- Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, People’s Republic of China
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Kalo E, Read S, Baig A, Marshall K, Ma WS, Crowther H, Gofton C, Lynch KD, Sood S, Holmes J, Lubel J, Wigg A, McCaughan G, Roberts SK, Caraceni P, Ahlenstiel G, Majumdar A. Efficacy of albumin use in decompensated cirrhosis and real-world adoption in Australia. JGH Open 2024; 8:e70029. [PMID: 39301299 PMCID: PMC11410680 DOI: 10.1002/jgh3.70029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 08/26/2024] [Accepted: 09/03/2024] [Indexed: 09/22/2024]
Abstract
The current treatment approach to patients with liver cirrhosis relies on the individual management of complications. Consequently, there is an unmet need for an overall therapeutic strategy for primary and secondary prevention of complications. The clinical potential of long-term albumin infusions supported by recent clinical trials has expanded its indications and holds promise to transform the management and secondary prevention of cirrhosis-related complications. This renewed interest in albumin comes with inherent controversies, compounding challenges and pressing need for rigorous evaluation of its clinical potential to capitalize on its therapeutic breakthroughs. Australia is among a few countries worldwide to adopt outpatient human albumin infusion. Here, we summarize currently available evidence of the potential benefits of human albumin for the management of multiple liver cirrhosis-related complications and discuss key challenges for wide application of long-term albumin administration strategy in Australian clinical practice. Australian Gastroenterological week (AGW), organised by the Gastroenterological Society of Australia (GESA), was held between 9-11 September 2022. A panel of hepatologists, advanced liver nurses and one haematologist, were invited to a roundtable meeting to discuss the use of long-term albumin infusions for liver cirrhosis. management in Australia. In this review, we summarise the proceedings of this meeting in context of the current literature.
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Affiliation(s)
- Eric Kalo
- Blacktown Clinical School and Research Centre, School of Medicine Western Sydney University Blacktown New South Wales Australia
- Blacktown Hospital, Western Sydney Local Health District Blacktown New South Wales Australia
| | - Scott Read
- Blacktown Clinical School and Research Centre, School of Medicine Western Sydney University Blacktown New South Wales Australia
- Blacktown Hospital, Western Sydney Local Health District Blacktown New South Wales Australia
- Storr Liver Centre, The Westmead Institute for Medical Research University of Sydney Westmead New South Wales Australia
| | - Asma Baig
- Blacktown Hospital, Western Sydney Local Health District Blacktown New South Wales Australia
| | - Kate Marshall
- Royal Prince Alfred Hospital Sydney New South Wales Australia
| | - Wai-See Ma
- Blacktown Hospital, Western Sydney Local Health District Blacktown New South Wales Australia
| | - Helen Crowther
- Blacktown Hospital, Western Sydney Local Health District Blacktown New South Wales Australia
| | - Cameron Gofton
- Storr Liver Centre, The Westmead Institute for Medical Research University of Sydney Westmead New South Wales Australia
- Department of Gastroenterology and Hepatology Royal North Shore Hospital St Leonards New South Wales Australia
| | - Kate D Lynch
- Department of Gastroenterology and Hepatology Royal Adelaide Hospital, Central Adelaide Local Health Network Adelaide South Australia Australia
- Faculty of Health and Medical Sciences University of Adelaide Adelaide South Australia Australia
| | - Siddharth Sood
- Department of Gastroenterology Northern Health Melbourne Victoria Australia
- Department of Medicine The University of Melbourne Parkville Victoria Australia
| | - Jacinta Holmes
- Department of Medicine The University of Melbourne Parkville Victoria Australia
- Department of Gastroenterology St Vincent's Hospital Fitzroy Victoria Australia
| | - John Lubel
- Department of Gastroenterology Alfred Health Melbourne Victoria Australia
- Central Clinical School Monash University Melbourne Victoria Australia
| | - Alan Wigg
- Hepatology and Liver Transplant Medicine Unit Southern Adelaide Local Health Network Adelaide South Australia Australia
- Flinders University of South Australia Adelaide South Australia Australia
| | - Geoff McCaughan
- A.W. Morrow Gastroenterology and Liver Centre Centenary Research Institute for Cancer Research and Cell Biology Camperdown New South Wales Australia
- Australian National Liver Transplant Unit Royal Prince Alfred Hospital Sydney New South Wales Australia
- Faculty of Medicine and Health University of Sydney Sydney New South Wales Australia
| | - Stuart K Roberts
- Department of Gastroenterology Alfred Health Melbourne Victoria Australia
- Central Clinical School Monash University Melbourne Victoria Australia
| | - Paolo Caraceni
- Unit of Semeiotics, Liver and Alcohol-Related Diseases IRCCS Azienda-Ospedaliera Universitaria di Bologna, EMR Bologna Italy
- Department of Medical and Surgical Sciences University of Bologna, EMR Bologna Italy
| | - Golo Ahlenstiel
- Blacktown Clinical School and Research Centre, School of Medicine Western Sydney University Blacktown New South Wales Australia
- Blacktown Hospital, Western Sydney Local Health District Blacktown New South Wales Australia
- Storr Liver Centre, The Westmead Institute for Medical Research University of Sydney Westmead New South Wales Australia
| | - Avik Majumdar
- Department of Medicine The University of Melbourne Parkville Victoria Australia
- Victorian Liver transplant Unit Austin Health Heidelberg Victoria Australia
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Anis MA, Majeed AA, Abid S. Road to recompensation: Baveno VII criteria and transjugular intrahepatic portosystemic shunt in liver cirrhosis. World J Gastroenterol 2024; 30:3743-3747. [PMID: 39221069 PMCID: PMC11362878 DOI: 10.3748/wjg.v30.i32.3743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 07/15/2024] [Accepted: 07/29/2024] [Indexed: 08/26/2024] Open
Abstract
Liver cirrhosis has long been considered a point of no return, with limited hope for recovery. However, recent advancements, particularly the Baveno VII criteria and the utilization of transjugular intrahepatic portosystemic shunt (TIPS), have illuminated the concept of hepatic recompensation. In this editorial we comment on the article by Gao et al published in the recent issue. This editorial provides a comprehensive overview of the evolution of understanding cirrhosis, the criteria for recompensation, and the efficacy of TIPS in achieving recompensation. We discuss key findings from recent studies, including the promising outcomes observed in patients who achieved recompensation post-TIPS insertion. While further research is needed to validate these findings and elucidate the mech-anisms underlying recompensation, the insights presented here offer renewed hope for patients with decompensated cirrhosis and highlight the potential of TIPS as a therapeutic option in their management.
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Affiliation(s)
- Muhammad Aarish Anis
- Department of Medicine, Section of Gastroenterology, Aga Khan University Hospital, Sindh, Karachi 74800, Pakistan
| | - Ammara Abdul Majeed
- Department of Medicine, Section of Gastroenterology, Aga Khan University Hospital, Sindh, Karachi 74800, Pakistan
| | - Shahab Abid
- Department of Medicine, Section of Gastroenterology, Aga Khan University Hospital, Sindh, Karachi 74800, Pakistan
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Efremova I, Maslennikov R, Kudryavtseva A, Avdeeva A, Krasnov G, Diatroptov M, Bakhitov V, Aliev S, Sedova N, Fedorova M, Poluektova E, Zolnikova O, Aliev N, Levshina A, Ivashkin V. Gut Microbiota and Cytokine Profile in Cirrhosis. J Clin Transl Hepatol 2024; 12:689-700. [PMID: 39130620 PMCID: PMC11310756 DOI: 10.14218/jcth.2024.00090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 08/13/2024] Open
Abstract
BACKGROUND AND AIMS Gut dysbiosis and abnormal cytokine profiles are common in cirrhosis. This study aimed to evaluate the correlations between them. METHODS In the blood plasma of cirrhosis patients and controls, 27 cytokines were examined using a multiplex assay. The plasma levels of nitrites (stable metabolites of the endothelial dysfunction biomarker nitric oxide) and lipopolysaccharide (LPS) were examined. The fecal microbiota was assessed by 16S rRNA gene sequencing. RESULTS Levels of IL-1b, IL-2, IL-6, IL-13, IP-10, IFN-g, TNF-a, LPS, and nitrites were higher in cirrhosis patients than in controls, while levels of IL-4, IL-7, and PDGF-BB were lower. The LPS level was directly correlated with the levels of IL-1b, IL1-Ra, IL-9, IL-17, PDGF-BB, IL-6, TNF-a, and nitrites. The nitrite level was significantly directly correlated with the levels of TNF-a, GM-CSF, IL-17, and IL-12, and inversely correlated with the IL-7 level. TNF-a levels were directly correlated with ascites severity and the abundance of Negativicutes, Enterobacteriaceae, Veillonellaceae, and Klebsiella, while inversely correlated with the abundance of Firmicutes, Clostridia, and Subdoligranulum. IFN-g levels were directly correlated with the abundance of Bacteroidaceae, Lactobacillaceae, Bacteroides, and Megasphaera, and inversely correlated with the abundance of Verrucomicrobiota, Akkermansiaceae, Coriobacteriaceae, Akkermansia, Collinsella, and Gemella. IL-1b levels were directly correlated with the abundance of Comamonadaceae and Enterobacteriaceae and inversely correlated with the abundance of Marinifilaceae and Dialister. IL-6 levels were directly correlated with the abundance of Enterobacteriaceae, hepatic encephalopathy, and ascites severity, and inversely correlated with the abundance of Peptostreptococcaceae, Streptococcaceae, and Streptococcus. CONCLUSIONS The abundance of harmful gut microbiota taxa and endotoxinemia directly correlates with the levels of proinflammatory cytokines.
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Affiliation(s)
- Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow, Russia
| | - Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow, Russia
| | - Anna Kudryavtseva
- Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | | | - George Krasnov
- Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | | | - Vyacheslav Bakhitov
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Moscow, Russia
| | - Salekh Aliev
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Moscow, Russia
- First Hospital Surgery Department, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Natalia Sedova
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Moscow, Russia
- Department of Clinical Laboratory Diagnostics, FGBOU DPO “Russian Medical Academy of Continuing Professional Education of the Ministry of Health of the Russian Federation”, Moscow, Russia
| | - Maria Fedorova
- Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow, Russia
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study”, Moscow, Russia
| | - Oxana Zolnikova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow, Russia
| | - Nariman Aliev
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Moscow, Russia
- First Hospital Surgery Department, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Anna Levshina
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow, Russia
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Li Y, Quan X, Tai Y, Wu YT, Wei B, Wu H. Causal association between 731 immunocyte phenotypes and liver cirrhosis: A bidirectional two-sample mendelian randomization analysis. World J Hepatol 2024; 16:1156-1166. [PMID: 39221101 PMCID: PMC11362904 DOI: 10.4254/wjh.v16.i8.1156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 07/24/2024] [Accepted: 08/02/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Liver cirrhosis is a progressive hepatic disease whose immunological basis has attracted increasing attention. However, it remains unclear whether a concrete causal association exists between immunocyte phenotypes and liver cirrhosis. AIM To explore the concrete causal relationships between immunocyte phenotypes and liver cirrhosis through a mendelian randomization (MR) study. METHODS Data on 731 immunocyte phenotypes were obtained from genome-wide association studies. Liver cirrhosis data were derived from the Finn Gen dataset, which included 214403 individuals of European ancestry. We used inverse variable weighting as the primary analysis method to assess the causal relationship. Sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. RESULTS The MR analysis demonstrated that 11 immune cell phenotypes have a positive association with liver cirrhosis [P < 0.05, odds ratio (OR) > 1] and that 9 immunocyte phenotypes were negatively correlated with liver cirrhosis (P < 0.05, OR < 1). Liver cirrhosis was positively linked to 9 immune cell phenotypes (P < 0.05, OR > 1) and negatively linked to 10 immune cell phenotypes (P < 0.05; OR < 1). None of these associations showed heterogeneity or horizontally pleiotropy (P > 0.05). CONCLUSION This bidirectional two-sample MR study demonstrated a concrete causal association between immunocyte phenotypes and liver cirrhosis. These findings offer new directions for the treatment of liver cirrhosis.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Quan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yang Tai
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Tong Wu
- Department of Clinical Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Bo Wei
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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Nautiyal N, Maheshwari D, Kumar D, Rao EP, Tripathi DM, Kumar S, Diwakar S, Bhardwaj M, Mohanty S, Baligar P, Kumari A, Bihari C, Biswas S, Sarin SK, Kumar A. Rejuvenating bone marrow hematopoietic reserve prevents regeneration failure and hepatic decompensation in animal model of cirrhosis. Front Immunol 2024; 15:1439510. [PMID: 39188716 PMCID: PMC11345600 DOI: 10.3389/fimmu.2024.1439510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/24/2024] [Indexed: 08/28/2024] Open
Abstract
Background and aim Bone marrow stem cells (BM-SCs) and their progeny play a central role in tissue repair and regeneration. In patients with chronic liver failure, bone marrow (BM) reserve is severally compromised and they showed marked defects in the resolution of injury and infection, leading to liver failure and the onset of decompensation. Whether BM failure is the cause or consequence of liver failure during cirrhosis is not known. In this study, we aimed to determine the underlying relationship between BM failure and regeneration failure in cirrhosis. Methodology C57Bl/6(J) mice were used to develop chronic liver injury through intra-peritoneal administration of carbon tetrachloride (CCl4) for 15 weeks (0.1-0.5 ml/kg). Animals were sacrificed to study the transition of cirrhosis and BM defects. To restore the BM-SC reserve; healthy BM cells were infused via intra-BM infusion and assessed for changes in liver injury, regeneration, and BM-SC reserve. Results Using a CCl4-induced animal - model of cirrhosis, we showed the loss of BM-SCs reserve occurred before regeneration failure and the onset of non-acute decompensation. Intra-BM infusion of healthy BM cells induced the repopulation of native hematopoietic stem cells (HSCs) in cirrhotic BM. Restoring BM-HSCs reserve augments liver macrophage-mediated clearance of infection and inflammation dampens neutrophil-mediated inflammation, accelerates fibrosis regression, enhances hepatocyte proliferation, and delays the onset of non-acute decompensation. Conclusion These findings suggest that loss of BM-HSCs reserve underlies the compromised innate immune function of the liver, drives regeneration failure, and the onset of non-acute decompensation. We further provide the proof-of-concept that rejuvenating BM-HSC reserve can serve as a potential therapeutic approach for preventing regeneration failure and transition to decompensated cirrhosis.
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Affiliation(s)
- Nidhi Nautiyal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India
| | - Deepanshu Maheshwari
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dhananjay Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - E. Pranshu Rao
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Dinesh Mani Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sandeep Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sunidhi Diwakar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manisha Bhardwaj
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sujata Mohanty
- Stem Cell Facility, All India Institute of Medical Sciences, New Delhi, India
| | - Prakash Baligar
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India
| | - Anupama Kumari
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Subhrajit Biswas
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India
| | - S. K. Sarin
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Anupam Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Wei N, Liu C, Zhu H, Wang C, Zhou Y, Xiao Z, Du L, Song Y. Hypoalbuminemia contributes to ascites formation via sodium and water retention: Evidence from clinical date and albumin deficient mice. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167275. [PMID: 38844112 DOI: 10.1016/j.bbadis.2024.167275] [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: 01/15/2024] [Revised: 05/10/2024] [Accepted: 05/28/2024] [Indexed: 06/10/2024]
Abstract
Albumin infusions improve circulatory and renal function in patients with decompensated cirrhosis. However, there is no convincing evidence that hypoalbuminemia contributes to ascites formation in liver cirrhosis. The aim of our study is to determine the exact role of hypoalbuminemia in the formation of ascites caused by liver cirrhosis and its underlying mechanism. Clinical profiles of patients with liver cirrhosis retrospectively analyzed. The details of albumin involved in ascites formation were investigated in rat model and murine model. Statistical analysis demonstrated hypoalbuminemia was an independent risk factor for ascites formation in patients with liver cirrhosis (OR = 0.722, P < 0.001). In carbon tetrachloride (CCl4)-induced rat model of liver cirrhosis, a significant reduction in serum albumin was observed in rats with ascites (13.37 g/L) compared with rats without ascites (21.43 g/L, P < 0.001). In thioacetamide (TAA)-treated mice, ascites amount of heterozygous albumin (Alb+/-) mice (112.0 mg) was larger than that of wild-type (Alb+/+) mice (58.46 mg, P < 0.001). In CCl4-induced chronic liver injury, ascites amounts of Alb+/- or Alb+/+ mice were 80.00 mg or 48.46 mg (P = 0.001). Further study demonstrated 24-h urinary sodium excretion in Alb+/- mice was lower than that of Alb+/+ mice in TAA/CCl4-induce murine models of liver cirrhosis. Additionally, serum sodium concentration of Alb+/- mice was lower than that of Alb+/+ mice. In cirrhotic mice, higher level of antidiuretic hormone was observed in Alb+/- mice compared with the control; and renal aquaporin (AQP2) expression in Alb+/- mice was significantly higher than that of WT mice. These revealed hypoalbuminemia contributed to the occurrence of ascites in liver cirrhosis through sodium and water retention.
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Affiliation(s)
- Ning Wei
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chang Liu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huifang Zhu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chengbo Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yangyang Zhou
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhuanglong Xiao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Du
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuhu Song
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Garcia-Guix M, Ardevol A, Sapena V, Alvarado-Tápias E, Huertas A, Brujats A, Fajardo J, Cuyas B, Poca M, Guarner C, Torras X, Escorsell À, Villanueva C. Influence of further decompensation on survival across clinical stages of decompensated cirrhosis: The role of portal hypertension and HVPG changes. Liver Int 2024; 44:1971-1989. [PMID: 38634685 DOI: 10.1111/liv.15937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/13/2024] [Accepted: 04/02/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND AND AIMS Decompensated-cirrhosis encompasses several stages with different prognosis, such as bleeding, ascites and bleeding-plus-ascites. Development of further-decompensation worsens survival, while non-selective β-blockers (NSBBs) can modify the risk. However, how this applies to each stage is uncertain. We aimed to investigate, in each stage of decompensated-cirrhosis, the influence of further-decompensation on mortality and whether changes in portal-pressure (HVPG) under NSBBs influence these outcomes. METHODS Patients with variceal bleeding were consecutively included differentiating those with bleeding-alone from those who also had ascites. Patients with ascites and high-risk varices referred for primary-prophylaxis were also investigated. A baseline haemodynamic study was performed and was repeated after 1-3-months under NSBBs. Outcomes were investigated by competing-risk. RESULTS Totally 103 patients had bleeding-alone, 186 bleeding-plus-ascites and 187 ascites-alone. Mean follow-up was 32-months (IQR, 12-60). Patients with bleeding-plus-ascites had higher HVPG and were more hyperdynamic than patients with ascites-alone and these than those with bleeding-alone. At each stage, the mortality risk was more than twice in patients developing further-decompensation vs. those without (p < .001). In each stage, HVPG-decrease under NSBBs showed better discrimination to predict further-decompensation than the baseline MELD, Child-Pugh or HVPG, by time-dependent ROC-curves (c-statistic >70%). At each stage, patients without HVPG-decreases, either ≥10% or ≥20% from the baseline, had higher risk of further-decompensation (sHR from 2.43 to 6.73, p < .01) and worse survival. CONCLUSIONS In each stage of decompensated cirrhosis, mortality risk significantly and very markedly increase with further-decompensation. HVPG-non-response to NSBBs may adequately stratify the risk of further decompensation and death, in each stage. This suggests potential benefit with pre-emptive therapies in HVPG-non-responders at each-stage.
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Affiliation(s)
- Marta Garcia-Guix
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Alba Ardevol
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Victor Sapena
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
- Medical Statistics Core Faculty, IDIBAPS, Hospital Clinic, Barcelona, Spain
| | - Edilmar Alvarado-Tápias
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Anna Huertas
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Anna Brujats
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Javier Fajardo
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Berta Cuyas
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - María Poca
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Carlos Guarner
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Xavier Torras
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Àngels Escorsell
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Càndid Villanueva
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Gananandan K, Wiese S, Møller S, Mookerjee RP. Cardiac dysfunction in patients with cirrhosis and acute decompensation. Liver Int 2024; 44:1832-1841. [PMID: 38712826 DOI: 10.1111/liv.15896] [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: 01/22/2024] [Revised: 02/25/2024] [Accepted: 03/04/2024] [Indexed: 05/08/2024]
Abstract
The prevalence of cirrhotic cardiomyopathy (CCM) has been reported as high as 60%-70% in patients with liver cirrhosis and is associated with various negative outcomes. There has been a growing understanding of CCM over recent years. Indeed, the development of imaging techniques has enabled new diagnostic criteria to be proposed by the Cirrhotic Cardiomyopathy Consortium. However, important unanswered questions remain over pathophysiological mechanisms, optimal diagnostic modalities and potential treatment options. While there has been an increasing volume of literature evaluating CCM, there is a lack of clarity on its implications in acute decompensation, acute-on-chronic liver failure and following interventions such as transjugular intrahepatic portosystemic shunt insertion and liver transplantation. This review aims to summarise the literature in these challenging domains and suggest where future research should focus. We conclude that systemic inflammation and structural myocardial changes are likely to be crucial in the pathophysiology of the disease, but the relative contribution of different components remains elusive. Furthermore, future studies need to use standardised diagnostic criteria for CCM as well as incorporate newer imaging techniques assessing both myocardial structure and function. Finally, while specific treatments are currently lacking, therapeutics targeting systemic inflammation, microbial dysbiosis and bacterial translocation are promising targets and warrant further research.
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Affiliation(s)
- Kohilan Gananandan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
| | - Signe Wiese
- Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, University of Copenhagen, Copenhagen, Denmark
- Gastroenterology Unit, Medical Division, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Søren Møller
- Centre of Functional Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Rajeshwar P Mookerjee
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Incicco S, Angeli P, Piano S. Infectious Complications of Portal Hypertension. Clin Liver Dis 2024; 28:525-539. [PMID: 38945641 DOI: 10.1016/j.cld.2024.03.007] [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] [Indexed: 07/02/2024]
Abstract
Patients with cirrhosis and clinically significant portal hypertension are at high risk of developing bacterial infections (BIs) that are the most common trigger of acute decompensation and acute-on-chronic liver failure. Furthermore, after decompensation, the risk of developing BIs further increases in an ominous vicious circle. BIs may be subtle, and they should be ruled out in all patients at admission and in case of deterioration. Timely administration of adequate empirical antibiotics is the cornerstone of treatment. Herein, we reviewed current evidences about pathogenesis, clinical implications and management of BIs in patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Simone Incicco
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University and Hospital of Padova, via Giustiniani 2, Padova 35100, Italy.
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Oyelade T, Moore KP, Mani AR. Physiological network approach to prognosis in cirrhosis: A shifting paradigm. Physiol Rep 2024; 12:e16133. [PMID: 38961593 PMCID: PMC11222171 DOI: 10.14814/phy2.16133] [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: 04/30/2024] [Revised: 06/12/2024] [Accepted: 06/24/2024] [Indexed: 07/05/2024] Open
Abstract
Decompensated liver disease is complicated by multi-organ failure and poor prognosis. The prognosis of patients with liver failure often dictates clinical management. Current prognostic models have focused on biomarkers considered as individual isolated units. Network physiology assesses the interactions among multiple physiological systems in health and disease irrespective of anatomical connectivity and defines the influence or dependence of one organ system on another. Indeed, recent applications of network mapping methods to patient data have shown improved prediction of response to therapy or prognosis in cirrhosis. Initially, different physical markers have been used to assess physiological coupling in cirrhosis including heart rate variability, heart rate turbulence, and skin temperature variability measures. Further, the parenclitic network analysis was recently applied showing that organ systems connectivity is impaired in patients with decompensated cirrhosis and can predict mortality in cirrhosis independent of current prognostic models while also providing valuable insights into the associated pathological pathways. Moreover, network mapping also predicts response to intravenous albumin in patients hospitalized with decompensated cirrhosis. Thus, this review highlights the importance of evaluating decompensated cirrhosis through the network physiologic prism. It emphasizes the limitations of current prognostic models and the values of network physiologic techniques in cirrhosis.
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Affiliation(s)
- Tope Oyelade
- Institute for Liver and Digestive Health, Division of MedicineUCLLondonUK
- Network Physiology Laboratory, Division of MedicineUCLLondonUK
| | - Kevin P. Moore
- Institute for Liver and Digestive Health, Division of MedicineUCLLondonUK
| | - Ali R. Mani
- Institute for Liver and Digestive Health, Division of MedicineUCLLondonUK
- Network Physiology Laboratory, Division of MedicineUCLLondonUK
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Velarde-Ruiz Velasco JA, Crespo J, Montaño-Loza A, Aldana-Ledesma JM, Cano-Contreras AD, Cerda-Reyes E, Fernández Pérez NJ, Castro-Narro GE, García-Jiménez ES, Lira-Vera JE, López-Méndez YI, Meza-Cardona J, Moreno-Alcántar R, Pérez-Escobar J, Pérez-Hernández JL, Tapia-Calderón DK, Higuera-de-la-Tijera F. Position paper on perioperative management and surgical risk in the patient with cirrhosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:418-441. [PMID: 39003101 DOI: 10.1016/j.rgmxen.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/02/2024] [Indexed: 07/15/2024]
Abstract
INTRODUCTION Management of the patient with cirrhosis of the liver that requires surgical treatment has been relatively unexplored. In Mexico, there is currently no formal stance or expert recommendations to guide clinical decision-making in this context. AIMS The present position paper reviews the existing evidence on risks, prognoses, precautions, special care, and specific management or procedures for patients with cirrhosis that require surgical interventions or invasive procedures. Our aim is to provide recommendations by an expert panel, based on the best published evidence, and consequently ensure timely, quality, efficient, and low-risk care for this specific group of patients. RESULTS Twenty-seven recommendations were developed that address preoperative considerations, intraoperative settings, and postoperative follow-up and care. CONCLUSIONS The assessment and care of patients with cirrhosis that require major surgical or invasive procedures should be overseen by a multidisciplinary team that includes the anesthesiologist, hepatologist, gastroenterologist, and clinical nutritionist. With respect to decompensated patients, a nephrology specialist may be required, given that kidney function is also a parameter involved in the prognosis of these patients.
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Affiliation(s)
- J A Velarde-Ruiz Velasco
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - J Crespo
- Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - A Montaño-Loza
- División de Gastroenterología y Hepatología, Hospital de la Universidad de Alberta, Alberta, Canada
| | - J M Aldana-Ledesma
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - A D Cano-Contreras
- Instituto de Investigaciones Médico Biológicas, Universidad Veracruzana, Veracruz, Veracruz, Mexico
| | | | | | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - E S García-Jiménez
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - J E Lira-Vera
- Servicio de Gastroenterología y Hepatología, Hospital Central «Dr. Ignacio Morones Prieto», San Luis Potosí, San Luis Potosí, Mexico
| | - Y I López-Méndez
- Departamento de Gastroenterología, Medica Sur, Mexico City, Mexico
| | - J Meza-Cardona
- Departamento de Gastroenterología, Hospital Español, Mexico City, Mexico
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades «Dr. Bernando Sepúlveda», UMAE Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - J Pérez-Escobar
- Servicio de Gastroenterología y Unidad de Trasplante Hepático, Hospital Juárez de México, Mexico City, Mexico
| | - J L Pérez-Hernández
- Servicio de Gastroenterología y Hepatología, Hospital General de México «Dr. Eduardo Liceaga», Mexico City, Mexico
| | - D K Tapia-Calderón
- Servicio de Gastroenterología, Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, Jalisco, Mexico
| | - F Higuera-de-la-Tijera
- Servicio de Gastroenterología y Hepatología, Hospital General de México «Dr. Eduardo Liceaga», Mexico City, Mexico.
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Velarde-Ruiz Velasco J, Crespo J, Montaño-Loza A, Aldana-Ledesma J, Cano-Contreras A, Cerda-Reyes E, Fernández Pérez N, Castro-Narro G, García-Jiménez E, Lira-Vera J, López-Méndez Y, Meza-Cardona J, Moreno-Alcántar R, Pérez-Escobar J, Pérez-Hernández J, Tapia-Calderón D, Higuera-de-la-Tijera F. Posicionamiento sobre manejo perioperatorio y riesgo quirúrgico en el paciente con cirrosis. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2024; 89:418-441. [DOI: 10.1016/j.rgmx.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/21/2025]
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Yue B, Gao Y, Hu Y, Zhan M, Wu Y, Lu L. Harnessing CD8 + T cell dynamics in hepatitis B virus-associated liver diseases: Insights, therapies and future directions. Clin Transl Med 2024; 14:e1731. [PMID: 38935536 PMCID: PMC11210506 DOI: 10.1002/ctm2.1731] [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: 02/05/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/29/2024] Open
Abstract
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8+ T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8+ T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8+ T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8+ T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8+ T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8+ T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8+ T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
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Affiliation(s)
- Bing Yue
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yuxia Gao
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yi Hu
- Microbiology and Immunology DepartmentSchool of MedicineFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Yangzhe Wu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumour Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Jinan UniversityZhuhaiGuangdongChina
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Du L, Wei N, Maiwall R, Song Y. Differential diagnosis of ascites: etiologies, ascitic fluid analysis, diagnostic algorithm. Clin Chem Lab Med 2024; 62:1266-1276. [PMID: 38112289 DOI: 10.1515/cclm-2023-1112] [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: 10/06/2023] [Accepted: 12/07/2023] [Indexed: 12/21/2023]
Abstract
Ascites is the pathological accumulation of fluid within the peritoneal cavity. It often occurs as results of liver cirrhosis, malignant neoplasia, tuberculous infection, cardiac insufficiency, renal diseases, etc. Determining the etiology is an essential step in the management of patients with new-onset ascites. Abdominal paracentesis with appropriate ascitic fluid analysis is probably the most cost-effective method of determining the cause of ascites. We performed a literature search of PubMed and identified articles published in the field of ascites, to evaluate diagnostic values of various parameters in defining the etiologies of ascites and then provides diagnostic algorithm for patients with new-onset ascites. In patients with ascites, the constituent ratio of underlying etiology varies between developed and developing countries. It is a challenge to define the etiologies of ascites in developing countries. Routine ascitic fluid analysis should include the serum ascites albumin gradient (SAAG), total protein concentration, cell count and differential. Optional ascitic fluid analysis includes cholesterol, fluid culture, cytology, tumor markers, lactate dehydrogenase, adenosine deaminase (ADA), triglyceride, amylase, glucose, brain natriuretic peptide (BNP), etc. Our review evaluated diagnostic values of the above parameters in defining the etiologies of ascites. Diagnostic algorithm established in this review would provide a practical and convenient diagnostic strategy for clinicians in diagnosing patients with new-onset ascites.
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Affiliation(s)
- Li Du
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Ning Wei
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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48
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Chinese consensus on the management of liver cirrhosis. J Dig Dis 2024; 25:332-352. [PMID: 39044465 DOI: 10.1111/1751-2980.13294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/19/2024] [Accepted: 06/11/2024] [Indexed: 07/25/2024]
Abstract
Liver cirrhosis, characterized by diffuse necrosis, insufficient regeneration of hepatocytes, angiogenesis, severe fibrosis, and the formation of pseudolobules, is a progressive, chronic liver disease induced by a variety of causes. It is clinically characterized by liver function damage and portal hypertension, and many complications may occur in its late stage. Based on the updated practice guidelines, expert consensuses, and research advances on the diagnosis and treatment of cirrhosis, the Chinese Society of Gastroenterology of Chinese Medical Association established the current consensus to standardize the clinical diagnosis and management of liver cirrhosis and guide clinical practice. This consensus contains 43 statements on the etiology, pathology and pathogenesis, clinical manifestations, major complications, diagnosis, treatment, prognosis, and chronic disease control of liver cirrhosis. Since several practice guidelines and expert consensuses on the complications of liver cirrhosis have been published, this consensus emphasizes the research progress of liver cirrhosis itself.
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Batra N, Gaidhane SA, Kumar S, Acharya S. Outcome Predictors of Acute-on-Chronic Liver Failure: A Narrative Review. Cureus 2024; 16:e61655. [PMID: 38966452 PMCID: PMC11223737 DOI: 10.7759/cureus.61655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 06/04/2024] [Indexed: 07/06/2024] Open
Abstract
Complications of acute-on-chronic liver failure (ACLF) include increased short-term mortality. Extrahepatic organ failures result from chronic liver disease and acute hepatic injury. This combination characterizes end-stage liver disease. Its rapid progression makes it challenging for hepatologists and intensivists to treat. The varied definitions of this condition lead to varied clinical presentations. Hepatic or extrahepatic failures are more prevalent in chronic hepatitis B or cirrhosis patients who receive an additional injury. Numerous intensity parameters and prognosis ratings, including those for hepatitis B virus (HBV), have been developed and verified for various patients and causes of the disease. Liver regeneration, liver transplantation (LT), or antiviral therapy for HBV-related ACLF are the main treatment aims for various organ failures. LT is the best treatment for HBV-ACLF. In some HBV-related ACLF patients, nucleos(t)ide analogs and artificial liver assistance may enhance survival. Combining epidemiological and clinical studies, this review updates our understanding of HBV-ACLF's definition, diagnosis, epidemiology, etiology, therapy, and prognosis.
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Affiliation(s)
- Nitish Batra
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Shilpa A Gaidhane
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sunil Kumar
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sourya Acharya
- Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Kalambokis G, Christaki M, Tsiakas I, Despotis G, Lakkas L, Tsiouris S, Xourgia X, Markopoulos GS, Dova L, Milionis H. Association of left ventricular diastolic dysfunction with inflammatory activity, renal dysfunction, and liver-related mortality in patients with cirrhosis and ascites. Eur J Gastroenterol Hepatol 2024; 36:775-783. [PMID: 38526935 DOI: 10.1097/meg.0000000000002762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Left ventricular diastolic dysfunction (LVDD) is the predominant cardiac abnormality in cirrhosis. We investigated the association of LVDD with systemic inflammation and its impact on renal function, occurrence of hepatorenal syndrome (HRS) and survival in patients with cirrhosis and ascites. We prospectively enrolled 215 patients with cirrhosis and ascites. We evaluated the diagnosis and grading of LVDD by Doppler echocardiography, inflammatory markers, systemic hemodynamics, vasoactive factors, radioisotope-assessed renal function and blood flow, HRS development and liver-related mortality. LVDD was diagnosed in 142 (66%) patients [grade 2/3: n = 61 (43%)]. Serum lipopolysaccharide-binding protein (LBP), plasma renin activity (PRA) and glomerular filtration rate (GFR) were independently associated with the presence of grade 2/3 LVDD and the severity of diastolic dysfunction. Serum tumor necrosis factor-α, cardiac output and plasma noradrenaline were also independently associated with the presence of grade 2/3 LVDD. The diastolic function marker E / e ' was strongly correlated with serum LBP ( r = 0.731; P < 0.001), PRA ( r = 0.714; P < 0.001) and GFR ( r = -0.609; P < 0.001) among patients with LVDD. The 5-year risk of HRS development and death was significantly higher in patients with grade 2/3 LVDD compared to those with grade 1 (35.5 vs. 14.4%; P = 0.01 and 53.3 vs. 28.2%; P = 0.03, respectively). The occurrence and severity of LVDD in patients with cirrhosis and ascites is closely related to inflammatory activity. Advanced LVDD is associated with baseline circulatory and renal dysfunction, favoring HRS development, and increased mortality.
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Affiliation(s)
| | | | | | | | | | | | | | - Georgios S Markopoulos
- Hematology Laboratory, Unit of Molecular Biology and Translational Flow Cytometry, Medical School, University of Ioannina, Ioannina, Greece
| | - Lefkothea Dova
- Hematology Laboratory, Unit of Molecular Biology and Translational Flow Cytometry, Medical School, University of Ioannina, Ioannina, Greece
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