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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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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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Airola C, Varca S, Del Gaudio A, Pizzolante F. The Covert Side of Ascites in Cirrhosis: Cellular and Molecular Aspects. Biomedicines 2025; 13:680. [PMID: 40149656 PMCID: PMC11940454 DOI: 10.3390/biomedicines13030680] [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: 12/21/2024] [Revised: 02/25/2025] [Accepted: 03/07/2025] [Indexed: 03/29/2025] Open
Abstract
Ascites, a common complication of portal hypertension in cirrhosis, is characterized by the accumulation of fluid within the peritoneal cavity. While traditional theories focus on hemodynamic alterations and renin-angiotensin-aldosterone system (RAAS) activation, recent research highlights the intricate interplay of molecular and cellular mechanisms. Inflammation, mediated by cytokines (interleukin-1, interleukin-4, interleukin-6, tumor necrosis factor-α), chemokines (chemokine ligand 21, C-X-C motif chemokine ligand 12), and reactive oxygen species (ROS), plays a pivotal role. Besides pro-inflammatory cytokines, hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and smooth muscle cells (SMCs) contribute to the process through their activation and altered functions. Once activated, these cell types can worsen ascites accumulationthrough extracellular matrix (ECM) deposition and paracrine signals. Besides this, macrophages, both resident and infiltrating, through their plasticity, participate in this complex crosstalk by promoting inflammation and dysregulating lymphatic system reabsorption. Indeed, the lymphatic system and lymphangiogenesis, essential for fluid reabsorption, is dysregulated in cirrhosis, exacerbating ascites. The gut microbiota and intestinal barrier alterations which occur in cirrhosis and portal hypertension also play a role by inducing inflammation, creating a vicious circle which worsens portal hypertension and fluid accumulation. This review aims to gather these aspects of ascites pathophysiology which are usually less considered and to date have not been addressed using specific therapy. Nonetheless, it emphasizes the need for further research to understand the complex interactions among these mechanisms, ultimately leading to targeted interventions in specific molecular pathways, aiming towards the development of new therapeutic strategies.
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Affiliation(s)
- Carlo Airola
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
- Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy
| | - Simone Varca
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
- Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy
| | - Angelo Del Gaudio
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
- Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy
| | - Fabrizio Pizzolante
- CEMAD Centro Malattie dell’Apparato Digerente, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (S.V.); (A.D.G.)
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Li Y, Lyu L, Ding H. The potential roles of gut microbiome in porto-sinusoidal vascular disease: an under-researched crossroad. Front Microbiol 2025; 16:1556667. [PMID: 40099185 PMCID: PMC11911366 DOI: 10.3389/fmicb.2025.1556667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 02/14/2025] [Indexed: 03/19/2025] Open
Abstract
Accumulating evidence indicates that patients with liver diseases exhibit distinct microbiological profiles, which can be attributed to the bidirectional relationship of the gut-liver axis. Porto-sinusoidal vascular disease (PSVD) has recently been introduced to describe a group of vascular diseases of the liver, involving the portal venules and sinusoids. Although the pathophysiology of PSVD is not yet fully understood, several predisposing conditions, including immunodeficiency, inflammatory bowel disease, abdominal bacterial infections are associated with the increasing in intestinal permeability and microbial translocation, supporting the role of altered gut microbiota and gut-derived endotoxins in PSVD etiopathogenesis. Recent studies have proposed that the gut microbiome may play a crucial role in the pathophysiology of intrahepatic vascular lesions, potentially influencing the onset and progression of PSVD in this context. This review aims to summarize the current understanding of the gut microbiome's potential role in the pathogenesis of hepatic microvascular abnormalities and thrombosis, and to briefly describe their interactions with PSVD. The insights into gut microbiota and their potential influence on the onset and progression of PSVD may pave the way for new diagnostic, prognostic, and therapeutic strategies.
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Affiliation(s)
| | | | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing Youan Hospital Affiliated with Capital Medical University, Beijing, China
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Vairappan B, Ts R, Ram AK, Mohan P, Pottakkat B. NOSTRIN is an emerging positive regulator of decompensated cirrhotic patients with portal hypertension. Dig Liver Dis 2025; 57:427-435. [PMID: 39294044 DOI: 10.1016/j.dld.2024.08.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND AND AIMS Decreased nitric oxide (NO) bioavailability in a cirrhotic liver contributes to high intrahepatic vascular resistance (IHVR) and portal hypertension (PHT). Nostrin is an inhibitory protein of NO synthesising enzyme endothelial NO synthase (eNOS), shown to increase in cirrhosis with PHT, however, the precise molecular mechanism is poorly documented. This study aimed to elucidate the role of Nostrin and associated derangement in hepatic NO generation in cirrhotic liver. Further, we investigate whether Nostrin could be a biomarker in the progression of cirrhosis. METHODS This study was conducted on sixty healthy subjects and 120 cirrhotic patients. In addition, liver tissue samples were collected from cirrhotic patients for the analysis of Nostrin, eNOS and inflammatory markers. RESULTS When compared to healthy controls, systemic levels of Nostrin and cGMP were elevated in compensated cirrhosis. In decompensated cirrhosis, further robust increases in Nostrin and cGMP were noted. Furthermore, Nostrin expression was considerably higher whilst reduced eNOS activity and hepatic cGMP levels in cirrhotic liver compared to control liver. CONCLUSIONS In cirrhotic patients, a robust increase in hepatic Nostrin expression may reduce eNOS activity and associated local NO generation. Furthermore, Blood Nostrin concentration was higher and parallel to disease severity and could be a key diagnostic and prognostic biomarker in cirrhotic patients with PHT.
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Affiliation(s)
- Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India.
| | | | - Amit Kumar Ram
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry 605006, India
| | - Pazhanivel Mohan
- Department of Medical Gastroenterology, JIPMER, Pondicherry 605006, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, JIPMER, Pondicherry 605006, India
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Hofer BS, Simbrunner B, Königshofer P, Brusilovskaya K, Petrenko O, Taru V, Sorz T, Zinober K, Semmler G, Kauschke SG, Pfisterer L, Trauner M, Mandorfer M, Schwabl P, Reiberger T. Aetiology-specific inflammation patterns in patients and rat models of compensated cirrhosis. Dig Liver Dis 2025; 57:450-458. [PMID: 39343656 DOI: 10.1016/j.dld.2024.09.006] [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: 07/18/2024] [Revised: 08/20/2024] [Accepted: 09/05/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Cirrhosis is associated with a proinflammatory environment. AIMS To analyse aetiology-specific inflammation patterns in compensated cirrhosis in animal models and patients. METHODS Portal pressure (PP), fibrosis (collagen proportionate area [CPA]) and hepatic inflammation were measured in cirrhotic rat models (thioacetamide [TAA;n = 12]; choline-deficient high-fat diet [CDHFD;n = 12]; bile duct ligation [BDL;n = 16]). Compensated cirrhotic patients (alcohol-related liver disease [ALD;n = 67]; metabolic dysfunction-associated steatohepatitis [MASH;n = 50]; cholestatic liver disease [primary biliary cholangitis [PBC]/primary sclerosing cholangitis [PSC];n = 22]) undergoing hepatic venous pressure gradient (HVPG) measurement were included. RESULTS In rats, hepatic proinflammatory gene expression was highest in CDHFD and lowest in TAA, despite comparable PP levels. Across all animal models, Tnfa/Il6 correlated positively with CPA, and Mcp1 with elevated PP. Mcp1 was also associated with increased CPA in TAA/CDHFD. Mcp1/Cxcl1 showed a model-independent positive correlation to transaminases. Il1b correlated positively with CPA/PP in BDL and with transaminases in CDHFD. In patients, CRP/IL-6 were lower in MASH compared to ALD or PBC/PSC, regardless of hepatic function. IgA/IgG were highest and complement factors lowest in ALD. More pronounced systemic inflammation was linked to higher HVPG primarily in ALD/MASH. CONCLUSION Proinflammatory pathways are upregulated across all liver disease aetiologies, yet their association with fibrosis and portal hypertension can vary.
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Affiliation(s)
- Benedikt Silvester 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; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, 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; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria
| | - Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Ksenia Brusilovskaya
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Oleksandr Petrenko
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria
| | - Vlad Taru
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Thomas Sorz
- 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; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria
| | - Kerstin Zinober
- 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
| | - Stefan G Kauschke
- Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach an der Riss, Germany
| | - Larissa Pfisterer
- Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach an der Riss, Germany
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, 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
| | - Philipp Schwabl
- 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; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, 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; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
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Tiede A, Stockhoff L, Liu Z, Rieland H, Mauz JB, Ohlendorf V, Bremer B, Witt J, Kraft A, Cornberg M, Hinrichs JB, Meyer BC, Wedemeyer H, Xu CJ, Falk CS, Maasoumy B. Insertion of a transjugular intrahepatic portosystemic shunt leads to sustained reversal of systemic inflammation in patients with decompensated liver cirrhosis. Clin Mol Hepatol 2025; 31:240-255. [PMID: 39568127 PMCID: PMC11791575 DOI: 10.3350/cmh.2024.0587] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 11/04/2024] [Accepted: 11/18/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND/AIMS Systemic Inflammation (SI) is considered a key mechanism in disease progression and development of complications in decompensated liver cirrhosis. SI is mainly driven by portal hypertension and bacterial translocation. Transjugular intrahepatic portosystemic shunt (TIPS) insertion represents an effective treatment for portal hypertension. This study aims to investigate the impact of TIPS insertion on SI and bacterial translocation. METHODS We prospectively included 59 cirrhotic patients undergoing TIPS insertion. Blood samples were collected at TIPS insertion and follow-up (FU) 1, 3, 6, and 12 months thereafter. At all time points, we performed a comprehensive analysis of SI including 43 soluble inflammatory markers (SIMs), and surrogates of bacterial translocation (sCD14, sCD163). To investigate long-term kinetics of SI, C-reactive protein (CRP) and white blood cells (WBC) were retrospectively analyzed in a cohort of 177 patients up to 3 years after TIPS insertion. RESULTS At TIPS insertion, 30/43 SIMs, sCD14, and sCD163 measured significantly higher in cirrhotic patients compared to healthy controls. By FU6 25 SIMs and sCD14 measured at significantly lower levels compared to baseline. Interestingly, in patients with TIPS indication of refractory ascites, IL-6 decreased to levels documented in earlier stages of cirrhosis. In long-term follow-up, CRP levels significantly decreased after TIPS insertion, which translated into lower mortality in Cox regression analysis (HR 0.968, p=0.042). Notably, patients with residual ascites post-TIPS showed significantly higher CRP and IL-6 levels across all follow-ups compared to patients with resolved ascites. CONCLUSION Decreasing portal hypertension via TIPS insertion leads to a significant attenuation of SI and bacterial translocation over time.
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Affiliation(s)
- Anja Tiede
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Lena Stockhoff
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Niels-Stensen-Kliniken Marienhospital, Osnabrück, Germany
| | - Zhaoli Liu
- Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Hannah Rieland
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jim B. Mauz
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Valerie Ohlendorf
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jennifer Witt
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anke Kraft
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
- Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
- Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
- Cluster of Excellence RESIST (EXC2155), Hannover Medical School, Hannover, Germany
| | - Jan B. Hinrichs
- St. Bernward Hospital, Radiology, Hildesheim, Germany
- Hannover Medical School, Department of Diagnostic and Interventional Radiology, Hannover, Germany
| | - Bernhard C. Meyer
- Hannover Medical School, Department of Diagnostic and Interventional Radiology, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
- Cluster of Excellence RESIST (EXC2155), Hannover Medical School, Hannover, Germany
| | - Cheng-Jian Xu
- Center for Individualized Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Christine S. Falk
- Cluster of Excellence RESIST (EXC2155), Hannover Medical School, Hannover, Germany
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
- Cluster of Excellence RESIST (EXC2155), Hannover Medical School, Hannover, Germany
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8
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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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9
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Ye Y, Xia C, Hu H, Tang S, Huan H. Metabolomics reveals altered metabolites in cirrhotic patients with severe portal hypertension in Tibetan population. Front Med (Lausanne) 2024; 11:1404442. [PMID: 39015788 PMCID: PMC11250582 DOI: 10.3389/fmed.2024.1404442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 06/17/2024] [Indexed: 07/18/2024] Open
Abstract
Background Portal hypertension (PHT) presents a challenging issue of liver cirrhosis. This study aims to identify novel biomarkers for severe PHT (SPHT) and explore the pathophysiological mechanisms underlying PHT progression. Methods Twenty-three Tibetan cirrhotic patients who underwent hepatic venous pressure gradient (HVPG) measurement were included. Eleven patients had an HVPG between 5 mmHg and 15 mmHg (MPHT), while 12 had an HVPG ≥16 mmHg (SPHT). Peripheral sera were analyzed using liquid chromatograph-mass spectrometer for metabolomic assessment. An additional 14 patients were recruited for validation of metabolites. Results Seven hundred forty-five metabolites were detected and significant differences in metabolomics between MPHT and SPHT patients were observed. Employing a threshold of p < 0.05 and a variable importance in projection score >1, 153 differential metabolites were identified. A significant number of these metabolites were lipids and lipid-like molecules. Pisumionoside and N-decanoylglycine (N-DG) exhibited the highest area under the curve (AUC) values (0.947 and 0.9091, respectively). Additional differential metabolites with AUC >0.8 included 6-(4-ethyl-2-methoxyphenoxy)-3,4,5-trihydroxyoxane-2-carboxylic acid, sphinganine 1-phosphate, 4-hydroxytriazolam, 4,5-dihydroorotic acid, 6-hydroxy-1H-indole-3-acetamide, 7alpha-(thiomethyl)spironolactone, 6-deoxohomodolichosterone, glutaminylisoleucine, taurocholic acid 3-sulfate, and Phe Ser. Enzyme-linked immunosorbent assay further confirmed elevated levels of sphinganine 1-phosphate, N-DG, and serotonin in SPHT patients. Significant disruptions in linoleic acid, amino acid, sphingolipid metabolisms, and the citrate cycle were observed in SPHT patients. Conclusion Pisumionoside and N-DG are identified as promising biomarkers for SPHT. The progression of PHT may be associated with disturbances in lipid, linoleic acid, and amino acid metabolisms, as well as alterations in the citrate cycle.
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Affiliation(s)
- Yanting Ye
- Lab of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Chao Xia
- Department of Radiology, and Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
- Huaxi MR Research Center (HMRRC), West China Hospital, Sichuan University, Chengdu, China
| | - Hong Hu
- Department of Gastroenterology, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region, Chengdu, China
| | - Shihang Tang
- Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China
| | - Hui Huan
- Department of Gastroenterology, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region, Chengdu, China
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10
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Yagoda AV, Koroy PV, Baisaeva LS, Dudov TR. Portal Vein Thrombosis in Liver Cirrhosis. Part 1: Epidemiology, Pathogenesis, Clinic, Diag-nosis, Impact on Prognosis. THE RUSSIAN ARCHIVES OF INTERNAL MEDICINE 2024; 14:165-172. [DOI: 10.20514/2226-6704-2024-14-3-165-172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Portal vein thrombosis is the most common thrombotic complication in patients with liver cirrhosis, especially in cases of severe forms. The pathogenesis is multifactorial in nature, it determined by a change in the balance between the coagulation and anticoagulation systems. Thrombosis is often asymptomatic and is accidentally detected, although it can be complicated by varicose bleeding, intestinal ischemia, and portal biliopathy. Ultrasound Doppler examination is a screening method, as an alternative, computed tomography and magnetic resonance imaging are used. The review highlights data on epidemiology, risk factors, clinical features, and diagnosis of portal vein thrombosis in patients with liver cirrhosis. The data on the effect of portal vein thrombosis on the progression of liver cirrhosis and the survival of patients, including after liver transplantation, are presented.
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11
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Baffy G, Portincasa P. Gut Microbiota and Sinusoidal Vasoregulation in MASLD: A Portal Perspective. Metabolites 2024; 14:324. [PMID: 38921459 PMCID: PMC11205793 DOI: 10.3390/metabo14060324] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 05/30/2024] [Accepted: 06/06/2024] [Indexed: 06/27/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition with heterogeneous outcomes difficult to predict at the individual level. Feared complications of advanced MASLD are linked to clinically significant portal hypertension and are initiated by functional and mechanical changes in the unique sinusoidal capillary network of the liver. Early sinusoidal vasoregulatory changes in MASLD lead to increased intrahepatic vascular resistance and represent the beginning of portal hypertension. In addition, the composition and function of gut microbiota in MASLD are distinctly different from the healthy state, and multiple lines of evidence demonstrate the association of dysbiosis with these vasoregulatory changes. The gut microbiota is involved in the biotransformation of nutrients, production of de novo metabolites, release of microbial structural components, and impairment of the intestinal barrier with impact on innate immune responses, metabolism, inflammation, fibrosis, and vasoregulation in the liver and beyond. The gut-liver axis is a conceptual framework in which portal circulation is the primary connection between gut microbiota and the liver. Accordingly, biochemical and hemodynamic attributes of portal circulation may hold the key to better understanding and predicting disease progression in MASLD. However, many specific details remain hidden due to limited access to the portal circulation, indicating a major unmet need for the development of innovative diagnostic tools to analyze portal metabolites and explore their effect on health and disease. We also need to safely and reliably monitor portal hemodynamics with the goal of providing preventive and curative interventions in all stages of MASLD. Here, we review recent advances that link portal metabolomics to altered sinusoidal vasoregulation and may allow for new insights into the development of portal hypertension in MASLD.
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Affiliation(s)
- Gyorgy Baffy
- Section of Gastroenterology, Department of Medicine, VA Boston Healthcare System, Boston, MA 02130, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Piero Portincasa
- Division of Internal Medicine, Department of Precision and Regenerative Medicine, University ‘Aldo Moro’ Medical School, 70121 Bari, Italy;
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12
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Liu J, MacNaughtan J, Kerbert AJC, Portlock T, Martínez Gonzalez J, Jin Y, Clasen F, Habtesion A, Ji H, Jin Q, Phillips A, De Chiara F, Ingavle G, Jimenez C, Zaccherini G, Husi K, Rodriguez Gandia MA, Cordero P, Soeda J, McConaghy L, Oben J, Church K, Li JV, Wu H, Jalan A, Gines P, Solà E, Eaton S, Morgan C, Kowalski M, Green D, Gander A, Edwards LA, Cox IJ, Cortez-Pinto H, Avery T, Wiest R, Durand F, Caraceni P, Elosua R, Vila J, Pavesi M, Arroyo V, Davies N, Mookerjee RP, Vargas V, Sandeman S, Mehta G, Shoaie S, Marchesi J, Albillos A, Andreola F, Jalan R. Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis. Gut 2024; 73:1183-1198. [PMID: 38621924 DOI: 10.1136/gutjnl-2023-330699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 03/17/2024] [Indexed: 04/17/2024]
Abstract
OBJECTIVE Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER NCT03202498.
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Affiliation(s)
- Jinxia Liu
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jane MacNaughtan
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Annarein J C Kerbert
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Theo Portlock
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Javier Martínez Gonzalez
- Hospital Ramón y Cajal, IRYCIS, CIBEREHD, Universidad de Alcalá, Madrid, Spain
- Liver Unit, Hospital Vall d'Hebron, Universitat Autónoma, CIBERehd, Barcelona, Spain
| | - Yi Jin
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Frederick Clasen
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Abeba Habtesion
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Huoyan Ji
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Qin Jin
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Alexandra Phillips
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Francesco De Chiara
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Ganesh Ingavle
- Centre for Regenerative Medicine and Devices, School of Applied Sciences, University of Brighton, Brighton, UK
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune, India
| | - Cesar Jimenez
- Liver Unit, Hospital Vall d'Hebron, Universitat Autónoma, CIBERehd, Barcelona, Spain
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-related Diseases, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
| | - Katherine Husi
- Department of Gastroenterology, Inselspital University Hospital Bern, Bern, Switzerland
| | | | - Paul Cordero
- Symbiosis Centre for Stem Cell Research (SCSCR), Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University), Pune, India
| | - Junpei Soeda
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Lynda McConaghy
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Jude Oben
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Karen Church
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Jia V Li
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Haifeng Wu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | | | - Pere Gines
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Faculty of Medicine and Health sciences, University of Barcelona, Barcelona, Spain
| | - Elsa Solà
- Liver Unit, Hospital Clinic of Barcelona, IDIBAPS, Faculty of Medicine and Health sciences, University of Barcelona, Barcelona, Spain
| | - Simon Eaton
- Institute of Child Health, University College London, London, UK
| | - Carrie Morgan
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Michal Kowalski
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Daniel Green
- Yaqrit Discovery Limited. The Elms Courtyard, Bromesberrow, Ledbury, UK
| | - Amir Gander
- Tissue Access for Patient Benefit, University College London, London, UK
| | - Lindsey A Edwards
- Centre for Host Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, Guy's Tower, Guy's Hospital, King's College London, London, UK
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - I Jane Cox
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | | | - Reiner Wiest
- UVCM Gastroenterology, University Bern, Bern, Switzerland
| | - Francois Durand
- Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, University paris Cité, Paris, France
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | | | | | - Marco Pavesi
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Nathan Davies
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Rajeshwar P Mookerjee
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Victor Vargas
- Liver Unit, Hospital Vall d'Hebron, Universitat Autónoma, CIBERehd, Barcelona, Spain
| | - Susan Sandeman
- Centre for Regenerative Medicine and Devices, School of Applied Sciences, University of Brighton, Brighton, UK
| | - Gautam Mehta
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Julian Marchesi
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, St Mary's Hospital, Imperial College London, London, UK
| | - Agustín Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramon y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Fausto Andreola
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver & Digestive Health, Division of Medicine, London, UK
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
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13
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Gan C, Yaqoob U, Lu J, Xie M, Anwar A, Jalan-Sakrikar N, Jerez S, Sehrawat TS, Navarro-Corcuera A, Kostallari E, Habash NW, Cao S, Shah VH. Liver sinusoidal endothelial cells contribute to portal hypertension through collagen type IV-driven sinusoidal remodeling. JCI Insight 2024; 9:e174775. [PMID: 38713515 PMCID: PMC11382879 DOI: 10.1172/jci.insight.174775] [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: 08/18/2023] [Accepted: 04/25/2024] [Indexed: 05/09/2024] Open
Abstract
Portal hypertension (PHTN) is a severe complication of liver cirrhosis and is associated with intrahepatic sinusoidal remodeling induced by sinusoidal resistance and angiogenesis. Collagen type IV (COL4), a major component of basement membrane, forms in liver sinusoids upon chronic liver injury. However, the role, cellular source, and expression regulation of COL4 in liver diseases are unknown. Here, we examined how COL4 is produced and how it regulates sinusoidal remodeling in fibrosis and PHTN. Human cirrhotic liver sample RNA sequencing showed increased COL4 expression, which was further verified via immunofluorescence staining. Single-cell RNA sequencing identified liver sinusoidal endothelial cells (LSECs) as the predominant source of COL4 upregulation in mouse fibrotic liver. In addition, COL4 was upregulated in a TNF-α/NF-κB-dependent manner through an epigenetic mechanism in LSECs in vitro. Indeed, by utilizing a CRISPRi-dCas9-KRAB epigenome-editing approach, epigenetic repression of the enhancer-promoter interaction showed silencing of COL4 gene expression. LSEC-specific COL4 gene mutation or repression in vivo abrogated sinusoidal resistance and angiogenesis, which thereby alleviated sinusoidal remodeling and PHTN. Our findings reveal that LSECs promote sinusoidal remodeling and PHTN during liver fibrosis through COL4 deposition.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Usman Yaqoob
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Jianwen Lu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Man Xie
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Affiliated Hospital of Qingdao University, Qingdao, China
| | - Abid Anwar
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nidhi Jalan-Sakrikar
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sofia Jerez
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Tejasav S Sehrawat
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nawras W Habash
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sheng Cao
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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14
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Pastrovic F, Novak R, Grgurevic I, Hrkac S, Salai G, Zarak M, Grgurevic L. Serum proteomic profiling of patients with compensated advanced chronic liver disease with and without clinically significant portal hypertension. PLoS One 2024; 19:e0301416. [PMID: 38603681 PMCID: PMC11008873 DOI: 10.1371/journal.pone.0301416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 03/16/2024] [Indexed: 04/13/2024] Open
Abstract
INTRODUCTION Portal hypertension (PH) drives the progression of liver cirrhosis to decompensation and death. Hepatic venous pressure gradient (HVPG) measurement is the standard of PH quantification, and HVPG≥10 mmHg defines clinically significant PH (CSPH). We performed proteomics-based serum profiling to search for a proteomic signature of CSPH in patients with compensated advanced chronic liver disease (cACLD). MATERIALS AND METHODS Consecutive patients with histologically confirmed cACLD and results of HVPG measurements were prospectively included. Serum samples were pooled according to the presence/absence of CSPH and analysed by liquid chromatography-mass spectrometry. Gene set enrichment analysis was performed, followed by comprehensive literature review for proteins identified with the most striking difference between the groups. RESULTS We included 48 patients (30 with, and 18 without CSPH). Protein CD44, involved in the inflammatory response, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), both involved in lymphangiogenesis were found solely in the CSPH group. Although identified in both groups, proteins involved in neutrophil extracellular traps (NET) formation, as well as tenascin C, autotaxin and nephronectin which mediate vascular contractility and lymphangiogenesis were more abundant in CSPH. DISCUSSION AND CONCLUSION We propose that altered inflammatory response, including NET formation, vascular contractility and formation of new lymph vessels are key steps in PH development. Proteins such as CD44, VEGF-C, LYVE-1, tenascin C, Plasminogen activator inhibitor 1, Nephronectin, Bactericidal permeability-increasing protein, Autotaxin, Myeloperoxidase and a disintegrin and metalloproteinase with thrombospondin motifs-like protein 4 might be considered for further validation as potential therapeutic targets and candidate biomarkers of CSPH in cACLD.
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Affiliation(s)
- Frane Pastrovic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, Laboratory for Liver Diseases and Portal Hypertension, University Hospital Dubrava, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Rudjer Novak
- Department of Proteomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia
- University of Zagreb, School of Medicine, Zagreb, Croatia
- Biomedical Research Center Salata, University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, Laboratory for Liver Diseases and Portal Hypertension, University Hospital Dubrava, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
- University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Stela Hrkac
- Department of Clinical Immunology, Allergology and Rheumatology, University Hospital Dubrava, Zagreb, Croatia
| | - Grgur Salai
- Department of Pulmonology, University Hospital Dubrava, Zagreb, Croatia
| | - Marko Zarak
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
- Clinical Department of Laboratory Diagnostics, University Hospital Dubrava, Zagreb, Croatia
| | - Lovorka Grgurevic
- Department of Proteomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Biomedical Research Center Salata, University of Zagreb, School of Medicine, Zagreb, Croatia
- Department of Anatomy, ˝Drago Perovic˝, School of Medicine, University of Zagreb, Zagreb, Croatia
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15
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De Gaetano V, Pallozzi M, Cerrito L, Santopaolo F, Stella L, Gasbarrini A, Ponziani FR. Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives. Cancers (Basel) 2024; 16:1388. [PMID: 38611066 PMCID: PMC11011056 DOI: 10.3390/cancers16071388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.
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Affiliation(s)
- Valeria De Gaetano
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Maria Pallozzi
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Lucia Cerrito
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Francesco Santopaolo
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Leonardo Stella
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
| | - Antonio Gasbarrini
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Liver Unit, Centro Malattie dell’Apparato Digerente (CEMAD), Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario GemelliIstituto di Ricovero e Cura a Carattere Scientifico, IRCCS, 00168 Rome, Italy; (V.D.G.); (M.P.); (L.C.); (F.S.); (L.S.); (F.R.P.)
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16
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Mostafa DK, Eissa MM, Ghareeb DA, Abdulmalek S, Hewedy WA. Resveratrol protects against Schistosoma mansoni-induced liver fibrosis by targeting the Sirt-1/NF-κB axis. Inflammopharmacology 2024; 32:763-775. [PMID: 38041753 PMCID: PMC10907480 DOI: 10.1007/s10787-023-01382-y] [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: 08/10/2023] [Accepted: 10/19/2023] [Indexed: 12/03/2023]
Abstract
Hepatic schistosomiasis is a prevalent form of chronic liver disease that drastically affects human health. Nevertheless, an antifibrotic drug that could suppress the development of hepatic fibrosis does not exist yet. The current study aimed to evaluate the effect of resveratrol, a natural polyphenol with multiple biological activities, on Schistosoma mansoni (S. mansoni)-induced hepatic fibrosis and delineate the underlying molecular mechanism. Swiss male albino mice were randomly assigned into infected and non-infected groups. Hepatic schistosomiasis infection was induced via exposure to S. mansoni cercariae. 6 weeks later, resveratrol was administrated either as 20 mg/kg/day or 100 mg/kg/day for 4 weeks to two infected groups. Another group received vehicle and served as infected control group. At the end of the study, portal hemodynamic, biochemical, and histopathological evaluation of liver tissues were conducted. Remarkably, resveratrol significantly reduced portal pressure, portal and mesenteric flow in a dose-dependent manner. It improved several key features of hepatic injury as evidenced biochemically by a significant reduction of bilirubin and liver enzymes, and histologically by amelioration of the granulomatous and inflammatory reactions. In line, resveratrol reduced the expression of pro-inflammatory markers; TNF-α, IL-1β and MCP-1 mRNA, together with fibrotic markers; collagen-1, TGF-β1 and α-SMA. Moreover, resveratrol restored SIRT1/NF-κB balance in hepatic tissues which is the main switch-off control for all the fibrotic and inflammatory mechanisms. Taken together, it can be inferred that resveratrol possesses a possible anti-fibrotic effect that can halt the progression of hepatic schistosomiasis via targeting SIRT1/ NF-κB signaling.
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Affiliation(s)
- Dalia Kamal Mostafa
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt
| | - Maha M Eissa
- Medical Parasitology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Doaa A Ghareeb
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Shaymaa Abdulmalek
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Wafaa A Hewedy
- Clinical Pharmacology Department, Faculty of Medicine, Alexandria University, Al-Moassat Medical Campus, Elhadara, Alexandria, 21561, Egypt.
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17
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Badura K, Frąk W, Hajdys J, Majchrowicz G, Młynarska E, Rysz J, Franczyk B. Hepatorenal Syndrome-Novel Insights into Diagnostics and Treatment. Int J Mol Sci 2023; 24:17469. [PMID: 38139297 PMCID: PMC10744165 DOI: 10.3390/ijms242417469] [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: 10/30/2023] [Revised: 12/09/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatorenal syndrome (HRS) is a disorder associated with cirrhosis and renal impairment, with portal hypertension as its major underlying cause. Moreover, HRS is the third most common cause of acute kidney injury, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of HRS. We discuss pathogenesis associated with HRS. Mechanisms such as dysfunction of the circulatory system, bacterial infection, inflammation, impaired renal autoregulation, circulatory, and others, which have been identified as critical pathways for development of HRS, have become easier to diagnose in recent years. Additionally, relatively recently, renal dysfunction biomarkers have been found indicating renal injury, which are involved in the pathophysiology of HRS. This review also summarizes the available information on the management of HRS, focusing on vasoconstrictive drugs, renal replacement therapy, and liver transplant together with currently being investigated novel therapies. Analyzing new discoveries for the underlying causes of this condition assists the general research to improve understanding of the mechanism of pathophysiology and thus prevention of HRS.
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Affiliation(s)
- Krzysztof Badura
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Weronika Frąk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Joanna Hajdys
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Gabriela Majchrowicz
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Ewelina Młynarska
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
| | - Beata Franczyk
- Department of Nephrocardiology, Medical University of Lodz, Ul. Zeromskiego 113, 90-549 Lodz, Poland
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18
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Bai J, Qian B, Cai T, Chen Y, Li T, Cheng Y, Wu Z, Liu C, Ye M, Du Y, Fu W. Aloin Attenuates Oxidative Stress, Inflammation, and CCl 4-Induced Liver Fibrosis in Mice: Possible Role of TGF-β/Smad Signaling. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:19475-19487. [PMID: 38038700 PMCID: PMC10723061 DOI: 10.1021/acs.jafc.3c01721] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 11/03/2023] [Accepted: 11/15/2023] [Indexed: 12/02/2023]
Abstract
Liver fibrosis refers to the excessive buildup of extracellular matrix (ECM) components in liver tissue. It is considered a pathological response to liver damage for which there is no effective treatment. Aloin, an anthraquinone compound isolated from the aloe plant, has shown good pharmacological effects in the treatment of gastric cancer, ulcerative colitis, myocardial hypertrophy, traumatic brain injury, and other diseases; however, its specific impact on liver fibrosis remains unclear. To address this gap, we conducted a study to explore the mechanisms underlying the potential antifibrotic effect of aloin. We constructed a mouse liver fibrosis model using carbon tetrachloride (CCl4) dissolved in olive oil as a modeling drug. Additionally, a cellular model was developed by using transforming growth factor β1 (TGF-β1) as a stimulus applied to hepatic stellate cells. After aloin intervention, serum alanine aminotransferase, hepatic hydroxyproline, and serum aspartate aminotransferase were reduced in mice after aloin intervention compared to CCl4-mediated liver injury without aloin intervention. Aloin relieved the oxidative stress caused by CCl4 via reducing hepatic malondialdehyde in liver tissue and increasing the level of superoxide dismutase. Aloin treatment decreased interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and increased the expression of IL-10, which inhibited the inflammatory response in liver injury. In addition, aloin inhibited the activation of hepatic stellate cells and reduced the level of α-smooth muscle actin (α-SMA) and collagen type I. In cell and animal experiments, aloin attenuated liver fibrosis, acting through the TGF-β/Smad2/3 signaling pathway, and mitigated CCl4- and TGF-β1-induced inflammation. Thus, the findings of this study provided theoretical data support and a new possible treatment strategy for liver fibrosis.
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Affiliation(s)
- Junjie Bai
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Baolin Qian
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
- Key
Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, 150076 Harbin, Heilongjiang, China
| | - Tianying Cai
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Yifan Chen
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Tongxi Li
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Yonglang Cheng
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Ziming Wu
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Chen Liu
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Mingxin Ye
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Yichao Du
- Academician
(Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary
and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
| | - Wenguang Fu
- Department
of General Surgery (Hepatopancreatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
- Academician
(Expert) Workstation of Sichuan Province, Metabolic Hepatobiliary
and Pancreatic Diseases Key Laboratory of Luzhou City, The Affiliated Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China
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19
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Tyson LD, Atkinson S, Hunter RW, Allison M, Austin A, Dear JW, Forrest E, Liu T, Lord E, Masson S, Nunes J, Richardson P, Ryder SD, Wright M, Thursz M, Vergis N. In severe alcohol-related hepatitis, acute kidney injury is prevalent, associated with mortality independent of liver disease severity, and can be predicted using IL-8 and micro-RNAs. Aliment Pharmacol Ther 2023; 58:1217-1229. [PMID: 37781965 PMCID: PMC10946848 DOI: 10.1111/apt.17733] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/01/2023] [Accepted: 09/18/2023] [Indexed: 10/03/2023]
Abstract
BACKGROUND The prevalence, prediction and impact of acute kidney injury (AKI) in alcohol-related hepatitis (AH) is uncertain. AIMS We aimed to determine AKI incidence; association with mortality; evaluate serum biomarkers and the modifying effects of prednisolone and pentoxifylline in the largest AH cohort to date. METHODS Participants in the Steroids or Pentoxifylline for Alcoholic Hepatitis trial with day zero (D0) creatinine available were included. AKI was defined by modified International Club of Ascites criteria; incident AKI as day 7 (D7) AKI without D0-AKI. Survival was compared by Kaplan-Meier; mortality associations by Cox regression; associations with AKI by binary logistic regression; biomarkers by AUROC analyses. RESULTS D0-AKI was present in 198/1051 (19%) participants; incident AKI developed in a further 119/571 (21%) with available data. Participants with D0-AKI had higher 90-day mortality than those without (32% vs. 25%, p = 0.008), as did participants with incident AKI compared to those without D0-AKI or incident AKI (47% vs. 25%, p < 0.001). Incident AKI was associated with D90 mortality adjusted for age and discriminant function (AHR 2.15, 1.56-2.97, p < 0.001); D0-AKI was not. Prednisolone therapy reduced incident AKI (AOR 0.55, 0.36-0.85, p = 0.007) but not mortality. D0 bilirubin and IL-8 combined, miR-6826-5p, and miR-6811-3p predicted incident AKI (AUROCs 0.726, 0.821, 0.770, p < 0.01). CONCLUSIONS Incident AKI is associated with 90-day mortality independent of liver function. Prednisolone therapy was associated with reduced incident AKI. IL-8 and several miRNAs are potential biomarkers to predict AKI. Novel therapies to prevent incident AKI should be evaluated in AH to reduce mortality.
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Affiliation(s)
- Luke D. Tyson
- Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
- The Liver UnitSt Mary's HospitalLondonUK
| | - Stephen Atkinson
- Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
- The Liver UnitSt Mary's HospitalLondonUK
| | - Robert W. Hunter
- Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Michael Allison
- Cambridge NIHR Biomedical Research CentreAddenbrooke's HospitalCambridgeUK
| | | | - James W. Dear
- Centre for Cardiovascular ScienceUniversity of EdinburghEdinburghUK
| | - Ewan Forrest
- Department of HepatologyGlasgow Royal InfirmaryGlasgowUK
- University of GlasgowGlasgowUK
| | - Tong Liu
- Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Emma Lord
- Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Steven Masson
- Department of HepatologyNewcastle Freeman HospitalNewcastle upon TyneUK
| | | | - Paul Richardson
- Department of HepatologyThe Royal Liverpool University HospitalLiverpoolUK
| | - Stephen D. Ryder
- NIHR Nottingham Biomedical Research Centre at Nottingham University Hospitals NHS Trust and the University of NottinghamQueens Medical CentreNottinghamUK
| | - Mark Wright
- Department of HepatologyUniversity Hospital Southampton NHS Foundation TrustSouthamptonUK
| | - Mark Thursz
- Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
- The Liver UnitSt Mary's HospitalLondonUK
| | - Nikhil Vergis
- Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
- The Liver UnitSt Mary's HospitalLondonUK
- GSKBrentfordUK
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20
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Luo S, Luo R, Lu H, Zhang R, Deng G, Luo H, Yu X, Wang C, Zhang H, Zhang Y, Huang W, Sun J, Liu Y, Huang F, Lei Z. Activation of cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis. Int Immunopharmacol 2023; 125:111132. [PMID: 37951190 DOI: 10.1016/j.intimp.2023.111132] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 10/15/2023] [Accepted: 10/23/2023] [Indexed: 11/13/2023]
Abstract
Inflammation plays an essential role in the development liver fibrosis.The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is a central cytoplasmic DNA sensor which can recognize cytoplasmic DNA, known to trigger stimulator of interferon genes (STING) and downstream proinflammatory factors. Here, we investigated the role of cGAS-STING signaling pathway in the pathogenesis of liver fibrosis.Differentially expressed genes (DEGs) in human liver tissue were identified using RNA-Seq analysis. As models of liver fibrosis, chronic Carbon tetrachloride (CCl4) exposure were applied in cGAS-knockout mice. LX-2 cells were co-cultured with human liver sinusoidal endothelial cells (LSECs) to explore the underlying mechanisms of hepatic sinusoidal microthrombosis in an inflammatory microenvironment. The endoscopic ultrasound-guided portal vein pressure gradient (EUS-PPG) method was used to analyze the associations between hepatic sinusoidal microthrombosis and PPG in patients with liver fibrosis and portal hypertension (PTH). The RNA-seq analysis results showed that DEGs were enriched in inflammation and endothelial cell activation. The upregulation of the cGAS-STING signaling exacerbated liver fibrosis and intrahepatic inflammation. It also exacerbated LSECs impairment and increased the contribution of hepatic sinusoidal microthrombosis to liver fibrosis in vivo and in vitro. Prothrombotic mediators and proinflammatory factors were associated with PPG in patients with liver fibrosis and portal hypertension. Therefore, activating cGAS-STING signaling pathway promotes liver fibrosis and hepatic sinusoidal microthrombosis, which may lead to increased portal vein pressure.
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Affiliation(s)
- Shaobin Luo
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Rongkun Luo
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Huanyuan Lu
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Rui Zhang
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Gang Deng
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Hongwu Luo
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Xiao Yu
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Changfa Wang
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Hui Zhang
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Yuping Zhang
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Wei Huang
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Jichun Sun
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Yinghong Liu
- The Third Xiangya Hospital of Central South University, Surgery Center, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Feizhou Huang
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China
| | - Zhao Lei
- The Third Xiangya Hospital of Central South University, Department of Hepatopancreatobiliary Surgery, 138 Tongzipo Road, Changsha City, Hunan Province, China.
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21
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Butt MF, Jalan R. Review article: Emerging and current management of acute-on-chronic liver failure. Aliment Pharmacol Ther 2023; 58:774-794. [PMID: 37589507 DOI: 10.1111/apt.17659] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/02/2023] [Accepted: 07/24/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) is a clinically and pathophysiologically distinct condition from acutely decompensated cirrhosis and is characterised by systemic inflammation, extrahepatic organ failure, and high short-term mortality. AIMS To provide a narrative review of the diagnostic criteria, prognosis, epidemiology, and general management principles of ACLF. Four specific interventions that are explored in detail are intravenous albumin, extracorporeal liver assist devices, granulocyte-colony stimulating factor, and liver transplantation. METHODS We searched PubMed and Cochrane databases for articles published up to July 2023. RESULTS Approximately 35% of hospital inpatients with decompensated cirrhosis have ACLF. There is significant heterogeneity in the criteria used to diagnose ACLF; different definitions identify different phenotypes with varying mortality. Criteria established by the European Association for the Study of the Liver were developed in prospective patient cohorts and are, to-date, the most well validated internationally. Systemic haemodynamic instability, renal dysfunction, coagulopathy, neurological dysfunction, and respiratory failure are key considerations when managing ACLF in the intensive care unit. Apart from liver transplantation, there are no accepted evidence-based treatments for ACLF, but several different approaches are under investigation. CONCLUSION The recognition of ACLF as a distinct entity from acutely decompensated cirrhosis has allowed for better patient stratification in clinical settings, facilitating earlier engagement with the intensive care unit and liver transplantation teams. Research priorities over the next decade should focus on exploring novel treatment strategies with a particular focus on which, when, and how patients with ACLF should be treated.
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Affiliation(s)
- Mohsin F Butt
- Centre for Neuroscience, Trauma and Surgery, Wingate Institute of Neurogastroenterology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottinghamshire, UK
| | - Rajiv Jalan
- Liver Failure Group, University College London Medical School, Royal Free Hospital Campus, London, UK
- European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium, Barcelona, Spain
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22
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Ristovska EC, Genadieva-Dimitrova M, Todorovska B, Milivojevic V, Rankovic I, Samardziski I, Bojadzioska M. The Role of Endothelial Dysfunction in the Pathogenesis of Pregnancy-Related Pathological Conditions: A Review. Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2023; 44:113-137. [PMID: 37453122 DOI: 10.2478/prilozi-2023-0032] [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: 07/18/2023]
Abstract
In the recent decades, endothelial dysfunction (ED) has been recognized as a significant contributing factor in the pathogenesis of many pathological conditions. In interaction with atherosclerosis, hypercholesterolemia, and hypertension, ED plays a crucial role in the pathogenesis of coronary artery disease, chronic renal disease, and microvascular complications in diabetes mellitus. Although ED plays a significant role in the pathogenesis of several pregnancy-related disorders such as preeclampsia, HELLP syndrome, fetal growth restriction, and gestational diabetes mellitus, the exact pathogenetic mechanisms are still a matter of debate. The increased prevalence of these entities in patients with preexisting vascular diseases highlights the essential pathological role of the preexisting ED in these patients. The abnormal uteroplacental circulation and the release of soluble factors from the ischemic placenta into the maternal bloodstream are the main causes of the maternal ED underlying the characteristic preeclamptic phenotype. Besides the increased risk for maternal and fetal poor outcomes, the preexisting ED also increases the risk of development of future cardiovascular diseases in these patients. This study aimed to look deeper into the role of ED in the pathogenesis of several pregnancy-related hypertensive and liver diseases. Hopefully, it could contribute to improvement of the awareness, knowledge, and management of these conditions and also to the reduction of the adverse outcomes and additional long-term cardiovascular complications.
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Affiliation(s)
- Elena Curakova Ristovska
- 1University Clinic for Gastroenterohepatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Magdalena Genadieva-Dimitrova
- 1University Clinic for Gastroenterohepatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Beti Todorovska
- 1University Clinic for Gastroenterohepatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Vladimir Milivojevic
- 2Section for Internal Medicine, Medcompass Alliance, School of Medicine, Belgrade University, Belgrade, Serbia
| | - Ivan Rankovic
- 3Section for Internal Medicine, Medcompass Alliance, Belgrade, Serbia
| | - Igor Samardziski
- 4University Clinic for Gynecology and Obstetrics, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Maja Bojadzioska
- 5University Clinic for Rheumatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
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23
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Chen YL, Zhao ZW, Li SM, Guo YZ. Value of red blood cell distribution width in prediction of diastolic dysfunction in cirrhotic cardiomyopathy. World J Gastroenterol 2023; 29:2322-2335. [PMID: 37124890 PMCID: PMC10134422 DOI: 10.3748/wjg.v29.i15.2322] [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: 10/14/2022] [Revised: 01/27/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND Clinical diagnosis of cirrhotic cardiomyopathy (CCM) often encounters challenges of lack of timeliness and disease severity, with the commonly positive indicator usually associated with advanced heart failure.
AIM To explore suitable biomarkers for early CCM prediction.
METHODS A total of 505 eligible patients were enrolled in this study and divided into four groups according to Child-Pugh classification: Group I, Class A without CCM (105 cases); Group II, Class A with CCM (175 cases); Group III, Class B with CCM (139 cases); and Group IV, Class C with CCM (86 cases). Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to determine whether red blood cell distribution width (RDW) was an independent risk factor for CCM risk. The relationships between RDW and Child-Pugh scores, Model for End-Stage Liver Disease (MELD) scores, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were analyzed by Pearson correlation analysis.
RESULTS A constant RDW increase was evident from Group I to Group IV (12.54 ± 0.85, 13.29 ± 1.19, 14.30 ± 1.96, and 16.25 ± 2.13, respectively). Pearson correlation analysis showed that RDW was positively correlated with Child-Pugh scores (r = 0.642, P < 0.001), MELD scores (r = 0.592, P < 0.001), and NT-proBNP (r = 0.715, P < 0.001). Furthermore, between Group I and Group II, RDW was the only significant index (odds ratio: 2.175, 95% confidence interval [CI]: 1.549-3.054, P < 0.001), and it reached statistical significance when examined by ROC curve analysis (area under the curve: 0.686, 95%CI: 0.624-0.748, P < 0.001).
CONCLUSION RDW can serve as an effective and accessible clinical indicator for the prediction of diastolic dysfunction in CCM, in which a numerical value of more than 13.05% may indicate an increasing CCM risk.
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Affiliation(s)
- Yan-Ling Chen
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Zi-Wen Zhao
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Shu-Mei Li
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
| | - Yong-Zhe Guo
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian Province, China
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24
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Morris SM, Abbas N, Osei-Bordom DC, Bach SP, Tripathi D, Rajoriya N. Cirrhosis and non-hepatic surgery in 2023 - a precision medicine approach. Expert Rev Gastroenterol Hepatol 2023; 17:155-173. [PMID: 36594658 DOI: 10.1080/17474124.2023.2163627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/26/2022] [Indexed: 01/04/2023]
Abstract
INTRODUCTION Patients with liver disease and portal hypertension frequently require surgery carrying high morbidity and mortality. Accurately estimating surgical risk remains challenging despite improved medical and surgical management. AREAS COVERED This review aims to outline a comprehensive approach to preoperative assessment, appraise methods used to predict surgical risk, and provide an up-to-date overview of outcomes for patients with cirrhosis undergoing non-hepatic surgery. EXPERT OPINION Robust preoperative, individually tailored, and precise risk assessment can reduce peri- and postoperative complications in patients with cirrhosis. Established prognostic scores aid stratification, providing an estimation of postoperative mortality, albeit with limitations. VOCAL-Penn Risk Score may provide greater precision than established liver severity scores. Amelioration of portal hypertension in advance of surgery may be considered, with prospective data demonstrating hepatic venous pressure gradient as a promising surrogate marker of postoperative outcomes. Morbidity and mortality vary between types of surgery with further studies required in patients with more advanced liver disease. Patient-specific considerations and practicing precision medicine may allow for improved postoperative outcomes.
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Affiliation(s)
- Sean M Morris
- The Liver Unit, University Hospitals Birmingham, Birmingham, UK
| | - Nadir Abbas
- The Liver Unit, University Hospitals Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Daniel-Clement Osei-Bordom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Surgery, University Hospitals Birmingham, Birmingham, UK
| | - Simon P Bach
- Department of Surgery, University Hospitals Birmingham, Birmingham, UK
| | - Dhiraj Tripathi
- The Liver Unit, University Hospitals Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Neil Rajoriya
- The Liver Unit, University Hospitals Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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25
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Zhong X, Li S, Hu J, Lu J, Wang W, Hu M, Sun Q, Zhang S, Yang X, Yang C, Zhong L. Development and external validation of prognostic scoring models for portal vein thrombosis: a multicenter retrospective study. Thromb J 2023; 21:9. [PMID: 36691024 PMCID: PMC9869608 DOI: 10.1186/s12959-023-00455-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 01/18/2023] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Portal vein thrombosis is a common complication of liver cirrhosis and hepatocellular carcinoma; however, few studies have reported its long-term clinical prognosis. This study aimed to establish and validate easy-to-use nomograms for predicting gastrointestinal bleeding, portal vein thrombosis resolution, and mortality of patients with portal vein thrombosis. METHODS This multicenter retrospective cohort study included 425 patients with portal vein thrombosis who were divided into training (n = 334) and validation (n = 91) sets. Prediction models were developed using multivariate Cox regression analysis and evaluated using the consistency index and calibration plots. RESULTS Predictors of gastrointestinal bleeding included a history of gastrointestinal bleeding, superior mesenteric vein thrombosis, red color sign observed during endoscopy, and hepatic encephalopathy. Meanwhile, predictors of resolution of portal vein thrombosis included a history of abdominal infection, C-reactive protein and hemoglobin levels, and intake of thrombolytics. Predictors of death included abdominal infection, abdominal surgery, aspartate aminotransferase level, hepatic encephalopathy, and ascites. All models had good discriminatory power and consistency. Anticoagulation therapy significantly increased the probability of thrombotic resolution without increasing the risk of bleeding or death. CONCLUSIONS We successfully developed and validated three prediction models that can aid in the early evaluation and treatment of portal vein thrombosis.
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Affiliation(s)
- Xuan Zhong
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Shan Li
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Jiali Hu
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Jinlai Lu
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Wei Wang
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Miao Hu
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Qinjuan Sun
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Shuo Zhang
- Present Address: Department of Gastroenterology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoqing Yang
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
| | - Changqing Yang
- Present Address: Department of Gastroenterology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lan Zhong
- Present Address: Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150, Jimo Road, Pudong New Area, Shanghai, 200120 China
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26
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Di Tommaso N, Santopaolo F, Gasbarrini A, Ponziani FR. The Gut-Vascular Barrier as a New Protagonist in Intestinal and Extraintestinal Diseases. Int J Mol Sci 2023; 24:ijms24021470. [PMID: 36674986 PMCID: PMC9864173 DOI: 10.3390/ijms24021470] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
The intestinal barrier, with its multiple layers, is the first line of defense between the outside world and the intestine. Its disruption, resulting in increased intestinal permeability, is a recognized pathogenic factor of intestinal and extra-intestinal diseases. The identification of a gut-vascular barrier (GVB), consisting of a structured endothelium below the epithelial layer, has led to new evidence on the etiology and management of diseases of the gut-liver axis and the gut-brain axis, with recent implications in oncology as well. The gut-brain axis is involved in several neuroinflammatory processes. In particular, the recent description of a choroid plexus vascular barrier regulating brain permeability under conditions of gut inflammation identifies the endothelium as a key regulator in maintaining tissue homeostasis and health.
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Affiliation(s)
- Natalia Di Tommaso
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Translational Medicine and Surgery Department, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence:
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27
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Lee KC, Wu PS, Lin HC. Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis. Clin Mol Hepatol 2023; 29:77-98. [PMID: 36226471 PMCID: PMC9845678 DOI: 10.3350/cmh.2022.0237] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/11/2022] [Indexed: 02/02/2023] Open
Abstract
The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.
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Affiliation(s)
- Kuei-Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan,Corresponding author : Kuei-Chuan Lee Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan Tel: +886 2 2871 2121, Fax: +886 2 2873 9318, E-mail:
| | - Pei-Shan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan,Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan,Department of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan,Corresponding author : Kuei-Chuan Lee Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan Tel: +886 2 2871 2121, Fax: +886 2 2873 9318, E-mail:
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28
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Qi T, Zhu C, Wang J, Li B, Huang Z, Zhu Z, Tu M, Deng G, Zheng X, Huang Y, Meng Z, Wang X, Qian Z, Li H, Gao Y, Liu F, Shang J, Shi Y, Lu X, Wang S, Li H, Chen J. MELD score < 18 rule out 28-day ACLF development among inpatients with hepatitis B-related previous compensated liver disease. J Viral Hepat 2022; 29:1089-1098. [PMID: 36081337 DOI: 10.1111/jvh.13747] [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: 05/01/2022] [Revised: 08/03/2022] [Accepted: 08/24/2022] [Indexed: 12/29/2022]
Abstract
The acute-on-chronic liver failure (ACLF) development is highly dynamic. Currently, no satisfactory algorithm identifies patients with HBV at risk of this complication. The aim of the study was to characterize ACLF development in hospitalized HBV-related patients without previous decompensation and to test the performance of traditional prognostic models in ruling out ACLF development within 28 days on admission we conducted a cohort study. Two multi-center cohorts with hospitalized HBV-related previous compensated patients were analyzed. Performances of MELD, MELD-Na, CLIF-C AD, and CLIF-C ACLF-D in ruling out ACLF development within 28 days were compared and further validated by ROC analyses. In the derivation cohort (n = 892), there were 102 patients developed ACLF within 28 days, with profound systemic inflammatory levels and higher 28-day mortality rate (31.4% vs. 1.0%) than those without ACLF development. The MELD score (cut-off = 18) achieved acceptable missing rate (missed/total ACLF development) at 2.9%. In the validation cohort (n = 1656), the MELD score (<18) was able to rule out ACLF development within 28 days with missing rate at 3.0%. ACLF development within 28 days were both lower than 1% (0.6%, derivation cohort; 0.5%, validation cohort) in patients with MELD < 18. While in patients with MELD ≥ 18, 26.6% (99/372, derivation cohort) and 17.8% (130/732, validation cohort) developed into ACLF within 28 days, respectively. While MELD-Na score cut-off at 20 and CLIF-AD score cut-off at 42 did not have consistent performance in our two cohorts. MELD < 18 was able to safely rule out patients with ACLF development within 28 days in HBV-related patients without previous decompensation, which had a high 28-day mortality.
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Affiliation(s)
- Tingting Qi
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Congyan Zhu
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Hepatology Unit and Department of Infectious Disease, Zhuhai People's Hospital, Zhuhai, China
| | - Jiapeng Wang
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases, Tianjin First Central Hospital, Tianjin, China
| | - Beiling Li
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
- Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, China
| | - Zhibin Zhu
- The Forth Department of Hepatology, The Third People's Hospital of Shenzhen, Affiliated with Guangdong Medical College, Shenzhen, China
| | - Minghan Tu
- Department of Hepatology, The Ninth Hospital of Nanchang, Nanchang, China
- Hepatology Unit, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xin Zheng
- Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Huang
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China
| | - Zhongji Meng
- Department of Infectious Diseases, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Zhiping Qian
- Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China
| | - Hai Li
- Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health (Shanghai Jiao Tong University), Shanghai, China
| | - Yanhang Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Feng Liu
- Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan, China
| | - Jia Shang
- Department of Infectious Diseases, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yu Shi
- The State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Hangzhou, China
- National Clinical Research Center of Infectious Disease, Hangzhou, China
| | - Xiaobo Lu
- Infectious Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Shaoyang Wang
- Department of Infectious Diseases, Fuzhou General Hospital of Nanjing Military Command, Fujian, China
| | - Hai Li
- Department of Infectious Diseases, Affiliated Hospital of Logistics University of People's Armed Police Force, Tianjin, China
| | - Jinjun Chen
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Hepatology Unit, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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29
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de Assis Gadelha DD, de Brito Alves JL, da Costa PCT, da Luz MS, de Oliveira Cavalcanti C, Bezerril FF, Almeida JF, de Campos Cruz J, Magnani M, Balarini CM, Rodrigues Mascarenhas S, de Andrade Braga V, de França-Falcão MDS. Lactobacillus group and arterial hypertension: A broad review on effects and proposed mechanisms. Crit Rev Food Sci Nutr 2022; 64:3839-3860. [PMID: 36269014 DOI: 10.1080/10408398.2022.2136618] [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: 11/03/2022]
Abstract
Hypertension is the leading risk factor for cardiovascular diseases and is associated with intestinal dysbiosis with a decrease in beneficial microbiota. Probiotics can positively modulate the impaired microbiota and impart benefits to the cardiovascular system. Among them, the emended Lactobacillus has stood out as a microorganism capable of reducing blood pressure, being the target of several studies focused on managing hypertension. This review aimed to present the potential of Lactobacillus as an antihypertensive non-pharmacological strategy. We will address preclinical and clinical studies that support this proposal and the mechanisms of action by which these microorganisms reduce blood pressure or prevent its elevation.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Marciane Magnani
- Technology Center, Federal University of Paraíba, João Pessoa, PB, Brazil
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30
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Jiang SY, Huang XQ, Ni LY, Wu L, Ai YJ, Chen SY. Prognostic importance of interleukin 2 receptor for patients with a history of cirrhotic variceal bleeding. J Dig Dis 2022; 23:577-586. [PMID: 36300713 DOI: 10.1111/1751-2980.13141] [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: 02/09/2022] [Revised: 10/07/2022] [Accepted: 10/23/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Variceal hemorrhage is a fatal complication of cirrhosis. In this study, we aimed to investigate the role of serum interleukin 2 receptor (sIL-2R) as a predictive indicator in patients with a previous history of cirrhosis-related variceal bleeding. METHODS A total of 340 cirrhotic patients who had experienced variceal bleeding from December 2016 to December 2018 were enrolled, and were randomly assigned to the modeling group and the validation group. The 3-year variceal rebleeding rate and other outcomes including adverse events were analyzed between patients with different sIL-2R levels. RESULTS A time-dependent receiver operating characteristic (ROC) curve of variceal rebleeding indicated that sIL-2R had an area under the ROC curve (AUROC] of 0.731 and 0.837 for the modeling and validation groups, respectively, with a cut-off value of 426 U/mL. Kaplan-Meier analysis showed that higher sIL-2R level was related to an increased risk of variceal rebleeding rate (55.33% vs 24.34%, P = 0.024 and 51.28% vs 15.32%, P = 0.049) and decreased 3-year survival rate (91.16% vs 98.92%, P = 0.013 and 90.52% vs 97.50%, P = 0.180) in the modeling and validation groups. Elevated sIL-2R levels were associated with an increased risk of portal vein thrombosis and severe ascites as well as inferior liver function, hypercoagulable state, and increased portal pressure. CONCLUSION High sIL-2R levels were associated with poor prognosis in cirrhotic patients with previous variceal bleeding.
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Affiliation(s)
- Si Yu Jiang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao Quan Huang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Yuan Ni
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ling Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Jie Ai
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shi Yao Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.,Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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31
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Kim TE, Kang JS, An W, Sohn JH. Systemic exposure to propranolol in patients with chronic liver disease and its correlation with portal blood flow. Front Med (Lausanne) 2022; 9:973606. [PMID: 36213672 PMCID: PMC9533297 DOI: 10.3389/fmed.2022.973606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Propranolol is a beta-blocker used for the prevention of variceal bleeding in cirrhotic patients. We investigated the pharmacokinetics of propranolol in patients with chronic liver disease compared to that in healthy individuals. The relative amount of portal blood flow was measured to investigate the correlation of portal blood flow and the systemic exposure of propranolol. Thirty healthy subjects, 18 patients with chronic active hepatitis (CAH), and 54 patients with cirrhosis were included in this prospective study. Blood samples for pharmacokinetic analysis were taken up to 8 h post-dose. The portal blood flow was estimated by H/L ratio using thallium-201 (201TI) per rectal scintigraphy. A total of 78 subjects completed the study. The area under the concentration-time curve (AUC) to the last measurable time (AUClast, ng⋅h/mL) were 150.2 ± 154.1, 112.2 ± 84.7, and 204.0 ± 137.3 in healthy subjects, CAH patients, and cirrhosis patients, respectively. AUCrmlast showed positive correlation with the H/L ratio in patients with chronic liver disease (r = 0.5817, p < 0.0001). In conclusion, the patients with cirrhosis showed higher systemic exposure to propranolol than healthy subjects or patients with CAH. The increase in systemic exposure to propranolol was correlated with the decrease in portal blood flow.
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Affiliation(s)
- Tae-Eun Kim
- Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, South Korea
| | - Ju-Seop Kang
- Department of Pharmacology and Clinical Pharmacology, College of Medicine, Hanyang University, Seoul, South Korea
- *Correspondence: Ju-Seop Kang,
| | - Wen An
- Department of Pharmacology and Clinical Pharmacology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine (Gastroenterology), Hanyang University College of Medicine, Seoul, South Korea
- Hanyang University Guri Hospital, Guri-si, South Korea
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32
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Khayat AM, Thornburg B. Portal Vein Recanalization and Transjugular Intrahepatic Portosystemic Shunt Creation and the Management of Portal Vein Thrombosis. ADVANCES IN CLINICAL RADIOLOGY 2022; 4:147-156. [DOI: 10.1016/j.yacr.2022.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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33
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Santopaolo F, Coppola G, Giuli L, Gasbarrini A, Ponziani FR. Influence of Gut–Liver Axis on Portal Hypertension in Advanced Chronic Liver Disease: The Gut Microbiome as a New Protagonist in Therapeutic Management. MICROBIOLOGY RESEARCH 2022; 13:539-555. [DOI: 10.3390/microbiolres13030038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Clinically significant portal hypertension is associated with most complications of advanced chronic liver disease (ACLD), including variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. Gut dysbiosis is a hallmark of ACLD with portal hypertension and consists of the overgrowth of potentially pathogenic bacteria and a decrease in autochthonous bacteria; additionally, congestion makes the intestinal barrier more permeable to bacteria and their products, which contributes to the development of complications through inflammatory mechanisms. This review summarizes current knowledge on the role of the gut–liver axis in the pathogenesis of portal hypertension, with a focus on therapies targeting portal hypertension and the gut microbiota. The modulation of the gut microbiota on several levels represents a major challenge in the upcoming years; in-depth characterization of the molecular and microbiological mechanisms linking the gut–liver axis to portal hypertension in a bidirectional relationship could pave the way to the identification of new therapeutic targets for innovative therapies in the management of ACLD.
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Affiliation(s)
- Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Lucia Giuli
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Su SB, Tao L, Liang XL, Chen W. Long noncoding RNA GAS5 inhibits LX-2 cells activation by suppressing NF-κB signalling through regulation of the miR-433-3p/TLR10 axis. Dig Liver Dis 2022; 54:1066-1075. [PMID: 34903500 DOI: 10.1016/j.dld.2021.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/31/2021] [Accepted: 11/02/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Liver fibrosis is a common disease that can lead to hepatic failure. AIMS Our aims were to reveal the role of GAS5 in the regulation of liver fibrosis. METHODS LX-2 human hepatic satellite cells (HSCs) were cultured and activated using TGF-β1 treatment. A CCK-8 assay was performed to assess cell viability. A luciferase assay was employed to monitor the interactions between miR-433-3p and GAS5 or toll-like receptor 10 (TLR10). Western blotting and real-time quantitative PCR (RT-qPCR) were applied to detect the expression levels of α-SMA, Col. I, PCNA-, MMP2-, MMP9-, TLR10-, and NF-κB-related molecules at the protein and RNA levels. RESULTS GAS5 and TLR10 were decreased while miR-433-3p was upregulated in TGF-β1-activated LX-2 cells. Upregulation of GAS5 or downregulation of miR-433-3p suppressed HSC activation, and luciferase assays indicated that miR-433-3p binds with GAS5 and the 3'-UTR of TLR10. MiR-433-3p upregulation and TLR10 downregulation rescued the impacts of GAS5 overexpression or miR-433-3p knockdown on LX-2 cells. Upregulation of GAS5 also suppressed the phosphorylation of NF-κB through the miR-433-3p/TLR10 axis. CONCLUSION LncRNA GAS5 exerts an inhibitory effect on HSC activation by suppressing NF-κB signalling through regulation of the miR-433-3p/TLR10 axis.
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Affiliation(s)
- Si-Biao Su
- Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, P.R. China.
| | - Lin Tao
- Department of Gastroenterology, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, P.R. China
| | - Xiao-Le Liang
- Basic Medical College, Guangxi Medical University, Nanning, 530021, Guangxi Province, P.R. China
| | - Wen Chen
- Department of Teaching Affairs, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, P.R. China
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Osborn J, Mourya R, Thanekar U, Su W, Fei L, Shivakumar P, Bezerra JA. Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia. Hepatol Commun 2022; 6:995-1004. [PMID: 34962102 PMCID: PMC9035582 DOI: 10.1002/hep4.1878] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 11/21/2021] [Indexed: 11/17/2022] Open
Abstract
Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large-scale proteomics. We applied the slow off-rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) ≥ 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs ≥ 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs ≥ 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT.
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Affiliation(s)
- Julie Osborn
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Reena Mourya
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Unmesha Thanekar
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Weizhe Su
- Division of Biostatistics and EpidemiologyCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Lin Fei
- Division of Biostatistics and EpidemiologyCincinnati Children's Hospital Medical CenterCincinnatiOHUSA.,Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Pranavkumar Shivakumar
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA.,Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Jorge A Bezerra
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA.,Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
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Gupta T, Ranga N, Goyal SK. Predictors of mortality at 28-days in infection associated acute kidney injury in cirrhosis. World J Hepatol 2022; 14:592-601. [PMID: 35582297 PMCID: PMC9055202 DOI: 10.4254/wjh.v14.i3.592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/04/2021] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute kidney injury (AKI) in cirrhosis is important complication with poor outcomes. And infections are common cause for acute decompensation. Infections in cirrhosis lead to acute deterioration of hemodynamics leading to precipitation of AKI. AIM To study predictors of mortality in patients with infection-associated AKI in cirrhosis. METHODS This was a prospective, observational study conducted at tertiary care centre from January 2018 till April 2019. Total 119 participants with cirrhosis of liver presenting with AKI were included into the study. AKI was defined as per international club of Ascites-AKI criteria 2015. Patients were grouped into infection AKI and non-infection AKI. Non-infection AKI included patients with diuretic induced AKI and pre-renal AKI. Logistic regression analysis was used to determine predictors of mortality at 28-d. RESULTS Out of 119 patients, alcohol (n = 104) was most common etiology of cirrhosis. The infection AKI included 67 (56%) patients and non-infection AKI (n = 52) included pre-renal AKI in 36 (30%) and diuretic-induced AKI in 16 (14%) patients. Infection AKI had significantly higher bilirubin, higher international normalized ratio (INR), low serum sodium, higher total leukocyte count (TLC) and higher prevalence of hepatic encephalopathy (HE) as compared to non-infection AKI. Infection AKI had higher progression of AKI (19/67 vs 2/52; P = 0.01) and 28-d mortality (38/67 vs 4/5; P ≤ 0.01) as compared to non-infection AKI. At 28-d, non-survivors (n = 42) had significantly higher bilirubin, higher INR, low serum sodium, higher TLC and higher prevalence of HE as compared to survivors (n = 77). On subgroup analysis of Infection AKI group, on multivariate analysis, serum bilirubin as well as presence of HE were independent predictors of 28-d mortality. There was no significant difference of mortality at 90-d between two groups. CONCLUSION Infection AKI in cirrhosis has a dismal prognosis with higher 28-d mortality as compared to non-infection AKI. Serum bilirubin and presence of HE predict 28-d mortality in infection AKI.
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Affiliation(s)
- Tarana Gupta
- Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India.
| | - Naveen Ranga
- Department of Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
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Triantos C, Kalafateli M, Assimakopoulos SF, Karaivazoglou K, Mantaka A, Aggeletopoulou I, Spantidea PI, Tsiaoussis G, Rodi M, Kranidioti H, Goukos D, Manolakopoulos S, Gogos C, Samonakis DN, Daikos GL, Mouzaki A, Thomopoulos K. Endotoxin Translocation and Gut Barrier Dysfunction Are Related to Variceal Bleeding in Patients With Liver Cirrhosis. Front Med (Lausanne) 2022; 9:836306. [PMID: 35308545 PMCID: PMC8929724 DOI: 10.3389/fmed.2022.836306] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/10/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Bacterial infections are associated with the risk of variceal bleeding through complex pathophysiologic pathways. OBJECTIVES The primary objective of the present case-control study was to investigate the role of bacterial translocation and intestinal barrier dysfunction in the pathogenesis of variceal bleeding. A secondary objective was to determine independent predictors of key outcomes in variceal bleeding, including bleeding-related mortality. METHODS Eighty-four (n = 84) consecutive patients participated in the study, 41 patients with acute variceal bleeding and 43 patients with stable cirrhosis, and were followed up for 6 weeks. Peripheral blood samples were collected at patient admission and before any therapeutic intervention. RESULTS Child-Pugh (CP) score (OR: 1.868; p = 0.044), IgM anti-endotoxin antibody levels (OR: 0.954; p = 0.016) and TGF-β levels (OR: 0.377; p = 0.026) were found to be significant predictors of variceal bleeding. Regression analysis revealed that albumin (OR: 0.0311; p = 0.023), CRP (OR: 3.234; p = 0.034) and FABP2 levels (OR:1.000, p = 0.040), CP score (OR: 2.504; p = 0.016), CP creatinine score (OR: 2.366; p = 0.008), end-stage liver disease model (MELD), Na (OR: 1.283; p = 0.033), portal vein thrombosis (OR: 0.075; p = 0.008), hepatocellular carcinoma (OR: 0.060; p = 0.003) and encephalopathy (OR: 0.179; p = 0.045) were significantly associated with 6-week mortality. CONCLUSIONS Bacterial translocation and gut barrier impairment are directly related to the risk of variceal bleeding. Microbiota-modulating interventions and anti-endotoxin agents may be promising strategies to prevent variceal bleeding.
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Affiliation(s)
- Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Maria Kalafateli
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Katerina Karaivazoglou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Aikaterini Mantaka
- Department of Gastroenterology, University Hospital of Heraklion, Heraklion, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Panagiota I. Spantidea
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Georgios Tsiaoussis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Maria Rodi
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Hariklia Kranidioti
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | - Dimitrios Goukos
- Department of Propedeutic Medicine, Laiko General Hospital, Athens, Greece
| | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece
| | - Charalambos Gogos
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | | | - Georgios L. Daikos
- Department of Propedeutic Medicine, Laiko General Hospital, Athens, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Konstantinos Thomopoulos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece
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Liu G, Wang X, Yang T, Yan Y, Xiang T, Yang L, Luo X. High Interleukin-8 Levels Associated With Decreased Survival in Patients With Cirrhosis Following Transjugular Intrahepatic Portosystemic Shunt. Front Med (Lausanne) 2022; 9:829245. [PMID: 35295601 PMCID: PMC8918632 DOI: 10.3389/fmed.2022.829245] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 01/26/2022] [Indexed: 11/30/2022] Open
Abstract
Background Serum cytokines—reflecting systemic inflammation has been associated with the risk of decompensation and mortality in patients with cirrhosis. However, the role of systemic inflammation in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt procedure remains unknown. Patients and Methods Patients with cirrhosis who received transjugular intrahepatic portosystemic shunt between June 2015 and September 2017 were included. Portal and hepatic venous blood samples were obtained intraoperatively; serum cytokine levels (IL-10, IL-17A, IL-1RA, IL-8, and CXCL10) were measured in 105 patients. Associations with survival and other outcomes during long-term follow-up (median: 1,564 days) were assessed using logistic regression. Results IL-17A and CXCL10 levels were higher in the portal than in the hepatic veins, whereas IL-1RA levels were higher in the hepatic than in the portal veins. However, IL-8 or IL-10 levels between hepatic and portal veins showed no differences. Multivariate analysis demonstrated that Child–Pugh scores (P = 0.017, HR: 1.484, 95% CI: 1.072–2.055) and IL-8 level in hepatic veins (P < 0.001, HR: 1.043, 95% CI: 1.019–1.068) were independent predictors for mortality during long-term follow-up, with an optimal cut-off of 5.87 pg/ml for IL-8 in hepatic veins. Patients with hepatic IL-8 levels < 5.87 pg/ml had significantly higher cumulative survival rates (98.4 vs. 72.9% at 1 year, 98.4 vs. 65.3% at 2 years, 96.7 vs. 60.3% at 3 years, 94.2 vs. 60.3% at 4 years; P < 0.0001). Conclusions IL-8 levels in hepatic veins may reflect liver cirrhosis severity. Elevated IL-8 levels suggest shorter survival in patients receiving TIPS.
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Affiliation(s)
- Guofeng Liu
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoze Wang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Tingting Yang
- Department of Andrology/Sichuan Human Sperm Bank, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yuling Yan
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Tong Xiang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Li Yang
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xuefeng Luo
- Department of Gastroenterology and Hepatology, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xuefeng Luo
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Le Boutillier C, Snowdon C, Patel V, McPhail M, Ward C, Carter B, Uddin R, Zamalloa A, Lawrence V. Using a theory-informed approach to explore patient and staff perspectives on factors that influence clinical trial recruitment for patients with cirrhosis and small oesophageal varices. PLoS One 2022; 17:e0263288. [PMID: 35113923 PMCID: PMC8812916 DOI: 10.1371/journal.pone.0263288] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 01/17/2022] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVE The success of pharmacological randomised controlled trials (RCTs) depends on the recruitment of the required number of participants. Recruitment to RCTs for patients with cirrhosis and small oesophageal varices raises specific additional challenges. The objectives of the study were 1) to explore patient perspectives on factors that influence RCT recruitment, 2) to understand factors that influence the success of recruitment from a staff perspective, and 3) to identify opportunities for tailored interventions to improve trial recruitment in this context. METHODS The qualitative study was embedded in a multi-centre blinded RCT (BOPPP trial) and was conducted alongside site opening. Semi-structured interviews were conducted with patients who enrolled to participate in the trial (n = 13), patients who declined to take part (n = 5), and staff who were responsible for recruiting participants to the trial (n = 18). An open approach to data collection and analysis was adopted and the Theoretical Domains Framework (TDF) was used to provide a theoretical lens through which to view influences on behaviour. Data was analysed using thematic analysis. RESULTS The findings consist of 5 overarching themes that outline trial recruitment influences at the patient, staff, team, organisational and trial levels: i) patient risks and benefits ii) staff attitudes, knowledge and capacity, iii) team-based approach, iv) organisational context and v) Trial collective. Patient-generated themes map onto thirteen of the fourteen TDF domains and staff-generated themes map onto all TDF domains. The overarching themes are not mutually exclusive; with evidence of direct interactions between patient and staff-level themes that influence recruitment behaviours. CONCLUSIONS This study uses a theory-informed approach to gain new insights into improving clinical trial recruitment for patients with cirrhosis and small oesophageal varices. Although people with cirrhosis often display decreased healthcare-seeking behaviours, we found that patients used research to empower themselves to improve their health. Pragmatic trials involving unpredictable populations require staff expertise in building trust, and a deep knowledge of the patient group and their vulnerabilities. RCT recruitment is also more successful when research visits align with what staff identified as the natural rhythm of care. TRIAL REGISTRATION ISRCTN10324656; https://clinicaltrials.gov/.
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Affiliation(s)
- Clair Le Boutillier
- Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
| | - Claire Snowdon
- London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Vishal Patel
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom
- Faculty of Life Sciences and Medicine, School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, United Kingdom
| | - Mark McPhail
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom
- Faculty of Life Sciences and Medicine, School of Immunology and Microbial Sciences, King’s College London, London, United Kingdom
| | - Christopher Ward
- NIHR Clinical Research Network South London, London, United Kingdom
| | - Ben Carter
- Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
| | - Ruhama Uddin
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ane Zamalloa
- Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, London, United Kingdom
| | - Vanessa Lawrence
- Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
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Red cell distribution width as a predictor of outcome in hospitalized cirrhotic patients. Eur J Gastroenterol Hepatol 2021; 33:e978-e985. [PMID: 35048659 DOI: 10.1097/meg.0000000000002337] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND A systemic inflammatory response syndrome (SIRS) is linked to red cell distribution width (RCDW), which produces pro-inflammatory signals that act directly on hematopoietic stem cells in the bone marrow. This stimulation may cause alterations in the membrane of red blood cells (RBCs), as assessed by RCDW, which have been linked to increased morbidity and death in a number of systemic disorders. AIM This study aims to evaluate RCDW as a predictor of outcome in hospitalized cirrhotic patients. METHODS This prospective cross-sectional study was conducted on 1000 patients. The outcome was assessed by days of hospitalization; mortality in hospitalized patients or during short-term follow-up (3 months) and rehospitalization during follow-up of 6 months. RESULTS Male represented 69.6%. Mean age was 57.67 ± 13.07 years old. Baseline co-morbidities were recorded as the presence of diabetes mellitus (200 patients) and hypertension (400 patients). Hepatitis C virus was the commonest etiology of the diseased liver (90%). Child-Pugh classes A, B and C of studied patients represented (21.2%, 38.8% and 40%). The survived patients during follow-up represented 63.3%. Area under the curve for RCDW was 0.923 (95% CI, 0.904-0.943), 0.910 for C-reactive protein (95% CI, 0.890-0.930), 0.904 for Hb (95% CI, 0.883-0.925) and 0.903 for platelets (95% CI, 0.882-0.924). RCDW cutoff point at 21.35 for predicting survival had sensitivity 93%, specificity 91%, accuracy 92%, positive predictive value 85 and negative predictive value 96. Regression analysis revealed a significant positive association between both RCDW and white blood cells with mortality. CONCLUSION RCDW could provide useful information for predicting the length of hospitalization and survival in hospitalized cirrhotic patients.
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Abstract
Antifibrotic therapies for the treatment of liver fibrosis represent an unconquered area of drug development. The significant involvement of the gut microbiota as a driving force in a multitude of liver disease, be it pathogenesis or fibrotic progression, suggest that targeting the gut–liver axis, relevant signaling pathways, and/or manipulation of the gut’s commensal microbial composition and its metabolites may offer opportunities for biomarker discovery, novel therapies and personalized medicine development. Here, we review potential links between bacterial translocation and deficits of host-microbiome compartmentalization and liver fibrosis that occur in settings of advanced chronic liver disease. We discuss established and emerging therapeutic strategies, translated from our current knowledge of the gut–liver axis, targeted at restoring intestinal eubiosis, ameliorating hepatic fibrosis and rising portal hypertension that characterize and define the course of decompensated cirrhosis.
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Rittig N, Aagaard NK, Villadsen GE, Sandahl TD, Jessen N, Grønbaek H, George J. Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2021; 54:320-328. [PMID: 34165199 DOI: 10.1111/apt.16460] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/17/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect. AIMS To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion. METHODS In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90 minutes after ingestion of 1000-mg metformin (n = 16) or placebo (n = 16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow. RESULTS The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time × group interaction, P = 0.008). In patients with baseline HVPG ≥12 mm Hg clinically significant improvements in HVPG (HVPG <12 mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P = 0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O2 uptake or inflammation markers between groups. CONCLUSIONS A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Nikolaj Rittig
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.,Department and Laboratories of Diabetes and Hormone diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Kristian Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.,Research laboratories for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia
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Allaire M, Rudler M, Thabut D. Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…. Liver Int 2021; 41:1734-1743. [PMID: 34051060 DOI: 10.1111/liv.14977] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complication of cirrhosis which significantly contribute to morbidity and mortality. In this review, we aim to describe the consequences of both angiogenesis and inflammation in the pathogenesis of PHT and HCC, but also the difficulty to propose adapted treatment when PHT and HCC coexist in the same patients. METHODS Studies for review in this article were retrieved from the PubMed database using literature published in English until March 2021. RESULTS Portal hypertension occurs secondary to an increase of intrahepatic vascular resistances, the opening of portosystemic collateral vessels and the formation of neovessels, related to vascular endothelial growth factor (VEGF). Recently, bacterial translocation-mediated inflammation was also identified as a major contributor to PHT. Interestingly, VEGF and chronic inflammation also contribute to HCC occurrence. As PHT and HCC often coexist in the same patient, management of PHT and its related complications as well as HCC treatment appear more complex. Indeed, PHT-related complications such as significant ascites may hamper the access to HCC treatment and the presence of HCC is also independently associated with poor prognosis in patients with acute variceal bleeding related to PHT. Due to their respective mechanism of action, the combination of Atezolizumab and Bevacizumab for advanced HCC may impact the level of PHT and its related complications and to date, no real-life data are available. CONSLUSIONS Appropriate evaluation and treatment of PHT remains a major issue in order to improve the outcome of HCC patients.
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Affiliation(s)
- Manon Allaire
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,Inserm U1149, Centre de Recherche sur l'Inflammation, France Faculté de Médecine Xavier Bichat, Université Paris Diderot, Paris, France
| | - Marika Rudler
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
| | - Dominique Thabut
- Service d'Hépatolo-gastroentérologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Sorbonne Université, Paris, France.,INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France
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Gao Z, Zhao J, Liu X, Li S, Wang M, Gao Y. Portal vein thrombosis associated with high 14-day and 6-week rebleeding in patients after oesophageal variceal band ligation: a retrospective, multicentre, nested case-control study. Hepatol Int 2021; 15:1183-1195. [PMID: 34292507 DOI: 10.1007/s12072-021-10224-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The association between prognosis of variceal bleeding and portal vein thrombosis (PVT) is unclear. In this multicentre study, we determined the effect of PVT on rebleeding and mortality in patients with acute variceal bleeding (AVB) after oesophageal variceal band ligation (EVL). METHODS Cirrhotic patients with AVB who had undergone EVL were included. The patients were allocated to either the PVT group or the control cirrhotic group (CCG) based on the presence or absence of PVT. One-year rebleeding episodes and mortality after EVL were recorded. RESULTS A total of 218 cirrhotic patients with AVB from 3 centres were included. Patients with PVT had a higher rate of 14-day and 6-week rebleeding than those without PVT (14-day: 8.26% vs. 1.83%, p = 0.03; 6-week: 11.92% vs. 1.83%, p = 0.003). The rates of 5-day failure (3.67% vs. 0.92%, p = 0.175), 1-year rebleeding (21.10% vs. 20.18%, p = 0.867), and 14-day, 6-week, and 1-year mortality were similar between the groups (14-day: 3.67% vs. 0.92%, p = 0.175; 6-week: 3.67% vs. 0.92%, p = 0.175; 1-year: 3.67% vs. 1.83%, p = 0.408). The Child-Pugh class [p = 0.022, hazard ratio (HR): 1.453; 95% confidence interval (CI) 1.056-1.998], PVT (p = 0.050, HR: 4.622, 95% CI 0.999-21.395), albumin < 30 g/L (p = 0.023, HR: 5.886, 95% CI 1.272-27.245), and number of bands (p = 0.010, HR: 1.207, 95% CI 1.046-1.393) were identified as the predictors for 14-day rebleeding; the multivariate analysis revealed only the number of bands (p = 0.009, HR: 1.247, 95% CI 1.056-1.473) as the independent factor. PVT (p = 0.012, HR: 6.732, 95% CI 1.519-29.835) and albumin < 30 g/L (p = 0.027, HR: 3.643, 95% CI 1.160-11.441) were identified as predictors for 6-week rebleeding; however, only PVT (p = 0.015, HR: 6.380, 95% CI 1.427-28.515) was found to be the independent factor in the multivariate analysis. Further analysis showed that superior mesenteric vein (SMV) thrombosis is the only risk factor predicting 6-week rebleeding in patients with PVT (p = 0.032, HR: 3.405, 95% CI 1.112-10.429). CONCLUSIONS PVT was associated with high 14-day and 6-week rebleeding in patients after EVL. SMV thrombosis was the only risk factor for 6-week rebleeding in patients with PVT. High albumin levels may serve as a protective factor for the 14-day and 6-week rebleeding risk. PVT was not responsible for mortality after EVL during 1-year follow-up.
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Affiliation(s)
- Zhanjuan Gao
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province, People's Republic of China
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, Shandong Province, People's Republic of China
| | - Jingrun Zhao
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, Shandong Province, People's Republic of China
| | - Xiaofeng Liu
- Department of Gastroenterology, Chinese People's Liberation Army No.960 Hospital, Jinan, Shandong Province, People's Republic of China
| | - Senlin Li
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, Shandong Province, People's Republic of China
| | - Minghui Wang
- Department of Gastroenterology, Chinese People's Liberation Army No.960 Hospital, Jinan, Shandong Province, People's Republic of China
| | - Yanjing Gao
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province, People's Republic of China.
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Jalan R, D'Amico G, Trebicka J, Moreau R, Angeli P, Arroyo V. New clinical and pathophysiological perspectives defining the trajectory of cirrhosis. J Hepatol 2021; 75 Suppl 1:S14-S26. [PMID: 34039485 DOI: 10.1016/j.jhep.2021.01.018] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023]
Abstract
Traditionally, the complications of cirrhosis, namely variceal bleeding, ascites and hepatic encephalopathy, were thought to result predominantly from circulatory dysfunction and altered organ perfusion arising as a result of portal hypertension. Over the past 20 years, large, international prospective studies have indicated the importance of systemic inflammation and organ immunopathology as additional determinants of organ dysfunction in cirrhosis, which not only manifests in the liver, brain, circulation and the kidneys, but also the immune system, gut, muscles, adrenal glands, reproductive organs, heart and lungs. This review provides an overview of the traditional and emerging concepts around the initiation and maintenance of organ dysfunction in cirrhosis and proposes a new paradigm based upon a better understanding of acute decompensation of cirrhosis. The interaction between the traditional concepts and the emerging perspectives remains a matter of great interest and the basis for future research.
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Affiliation(s)
- Rajiv Jalan
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, United Kingdom.
| | - Gennaro D'Amico
- Gastroenterology Unit, Ospedale Cervello and University of Palermo, Italy
| | - Jonel Trebicka
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; JW Goethe University Hospital, Frankfurt, Germany
| | - Richard Moreau
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; APHP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France; Inserm, Université de Paris, Centre de Recherche sur L'Inflammation, Paris, France
| | - Paolo Angeli
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain; University of Padova, Padova, Italy
| | - Vicente Arroyo
- European Foundation for Study of Chronic Liver Failure, EF-Clif, Barcelona, Spain
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Hsu CC, Chen YH, Huang KH, Chen J, Chung CH, Liang CM, Chien WC, Chen CL. Evaluation of the relationship between central serous chorioretinopathy and liver cirrhosis: A nationwide, population-based study. J Chin Med Assoc 2021; 84:655-663. [PMID: 33871388 DOI: 10.1097/jcma.0000000000000533] [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: 11/27/2022] Open
Abstract
BACKGROUND Central serous chorioretinopathy (CSCR) and liver cirrhosis share numerous risk factors and may have possible connections. We aimed to investigate whether patients with liver cirrhosis and the severity of cirrhosis have an increased incidence of CSCR. METHODS This population-based retrospective cohort study was conducted by collecting data from the Taiwan National Health Insurance Research Database from January 1, 2000, to December 31, 2015. We included patients who were newly diagnosed with cirrhosis and selected an equal number of sex- and age-matched control subjects. The effect of cirrhosis on the risk of CSCR was examined via a Cox proportional hazard regression analysis. The cumulative incidence of CSCR was assessed with the Kaplan-Meier method and the log-rank test. RESULTS Both groups in this study comprised a total of 25 925 individuals. The cirrhotic patients had a significantly higher cumulative risk of developing CSCR in following years than patients without cirrhosis (log-rank test < 0.001). Furthermore, compared with noncirrhotic patients, the risk of CSCR was increased 3.59-fold (95% confidence interval [CI], 2.31-5.28) in cirrhotic patients with complications, and 2.34-fold (95% CI, 1.27-3.24) in cirrhotic patients without complications. Additionally, male sex, springtime, diabetes mellitus, hepatitis B virus, and hepatitis C virus statistical significantly increased the incidence of CSCR. CONCLUSION Cirrhosis is an independent indicator of CSCR. Among the cirrhotic population, patients with ascites and other complications have a higher incidence of CSCR than those with uncomplicated cirrhosis. Physicians should be observant when managing cirrhotic patients with visual disturbances.
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Affiliation(s)
- Chia-Chen Hsu
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Yi-Hao Chen
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Ke-Hao Huang
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
- Department of Ophthalmology, Song-Shan Branch of Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - JiannTorng Chen
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Chi-Hsiang Chung
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC
| | - Chang-Min Liang
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Ching-Long Chen
- Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
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Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality. J Hepatol 2021; 74:819-828. [PMID: 33075344 DOI: 10.1016/j.jhep.2020.10.004] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/18/2020] [Accepted: 10/07/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Distinct prognostic stages of advanced chronic liver disease (ACLD) are defined by severity of portal hypertension (PH) and the presence/absence of clinical complications. We characterised the degree of liver dysfunction, PH, and systemic inflammation across the distinct prognostic stages and assessed their relative impact on decompensation and mortality. METHODS A single-centre, prospective cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement between 01/2017 and 08/2019 were classified into 6 prognostic stages: mild PH (HVPG 6-9 mmHg, S0), clinically significant PH (HVPG ≥10 mmHg without varices, S1), presence of varices (S2), history of variceal bleeding (S3), first non-bleeding decompensation (S4), and further decompensation (S5). The model for end-stage liver disease (MELD), C-reactive protein (CRP), and IL-6 levels were assessed in relation to their predictive value for decompensation and death. RESULTS Among 168 ACLD patients 78 had compensated (cACLD, S0 = 13; S1 = 21; S2 = 44) and 90 had decompensated (dACLD, S3 = 10; S4 = 58; S5 = 22) disease. MELD increased across all stages (p <0.001), whereas HVPG mostly increased within cACLD substages. Significant increases in CRP and IL-6 levels were only noted across dACLD substages. IL-6 was an independent predictor of decompensation at 1-year follow-up in cACLD (hazard ratio [HR] 1.06, 95% CI 1.01-1.10; p = 0.013). In dACLD patients, IL-6 levels predicted death/transplantation after 1-year of follow-up (HR 1.02, 95% CI 1.01-1.03; p = 0.004). CONCLUSION HVPG progression occurs mostly in cACLD patients, whereas systemic inflammation, as reflected by IL-6 levels, only increases substantially across dACLD stages. IL-6 levels correlate with the risk of first decompensation in cACLD and of death/transplantation in dACLD patients. LAY SUMMARY Patients with advanced chronic liver disease (ACLD; i.e. liver cirrhosis) have a certain risk of mortality according to their stage of disease. Progression of disease is greatly influenced by increased pressure in the portal venous system (i.e. portal hypertension) and occurrence of clinical complications (i.e. decompensation). Our study demonstrates that systemic inflammation markedly increases across highest disease stages, and the inflammation biomarker IL-6 in blood may specifically indicate risk of disease progression in patients with ACLD. CLINICAL TRIALS REGISTRATION The study is registered at ClinicalTrials.gov (NCT03267615).
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Maruyama S, Koda M, Matono T, Isomoto H. Association of tumor size and internal echo pattern with coagulopathy associated with hepatic hemangioma. Mol Clin Oncol 2021; 14:83. [PMID: 33758664 PMCID: PMC7947948 DOI: 10.3892/mco.2021.2245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 02/05/2021] [Indexed: 01/18/2023] Open
Abstract
Little is known concerning causal factors associated with the size and echogenicity of hepatic hemangiomas. The aim of the present study was to investigate the associations between tumor size and echo pattern and coagulation factors, and to elucidate the growth pattern of hemangiomas. In 214 consecutive patients with hepatic hemangiomas, ultrasonography was performed to determine total tumor number, size, echogenicity and location, and serum laboratory tests for liver function and coagulation factors were carried out. The ultrasonographic appearance of hemangiomas was homogeneous in 75.7% of cases and mixed in 24.3% of cases. A mixed echo pattern was seen in 1 out of 145 masses (0.7%) with a diameter <20 mm, in 30 out of 48 (62.5%) with a diameter of 20-40 mm, and in all of the 21 (100%) with a diameter >40 mm. Platelet counts (P<0.0001) and fibrinogen levels (P<0.01) were lower in patients with larger and mixed tumors. Levels of thrombin-antithrombin III complex (TAT), D-dimer, and fibrin and fibrinogen degradation products (FDP) were significantly elevated along with an increase in tumor size (all P<0.0001), and the number of patients with the abnormal values of TAT, D-dimer, and FDP was significantly higher in the mixed group than in the homogeneous group (all P<0.0001). Fibrinogen (P<0.01), platelet count (P<0.001), portal vein diameter (P<0.0001), splenic index (P<0.01), and levels of TAT, D-dimer and FDP (all P<0.0001) were significantly associated with tumor size. Multivariate analysis revealed TAT, D-dimer and FDP as independent predictors of tumor size. The internal echo pattern became mixed as size increased. The size and echogenicity of hemangiomas were closely associated with coagulation factors. Therefore, it was speculated that differences in size and echogenicity were caused by intratumoral thrombosis and subsequent hemorrhage.
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Affiliation(s)
- Shigeo Maruyama
- Department of Internal Medicine, Maruyama Medical Clinic, Hamada, Shimane 697-0034, Japan
| | - Masahiko Koda
- Department of Internal Medicine, Hino Hospital, Hino, Tottori 689-4504, Japan
| | - Tomomitsu Matono
- Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Hajime Isomoto
- Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
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The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol 2021; 74:670-685. [PMID: 33301825 DOI: 10.1016/j.jhep.2020.11.048] [Citation(s) in RCA: 277] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022]
Abstract
Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequently impaired organ function.
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Association between effective hepatic blood flow and the severity and prognosis of hepatitis B virus-related acute on chronic liver failure. Eur J Gastroenterol Hepatol 2021; 32:246-254. [PMID: 32282547 DOI: 10.1097/meg.0000000000001721] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatic inflammation resulted in hepatocyte necrosis and microcirculatory dysfunction in acute on chronic liver failure (ACLF) with cirrhosis or not. The influence of effective hepatic blood flow (EHBF) on the severity of liver failure has not been fully elucidated. AIM The aim of this study was to assess the correlation between the EHBF and the severity and the prediction of 90-day mortality rate of hepatitis B virus-related ACLF (HBV-ACLF). METHODS In this retrospective study, patients hospitalized for HBV-ACLF or decompensated cirrhosis and who underwent an indocyanine green (ICG) clearance test between June 2016 and July 2018 were enrolled. EHBF was measured by the ICG clearance test and patients were categorized into the ACLF without cirrhosis (HBV-ACLF-no-Cir), ACLF with cirrhosis (HBV-ACLF-Cir) and decompensated cirrhosis (HBV-De-Cir). RESULTS A total of 522 patients (HBV-ACLF-no-Cir: 84, HBV-ACLF-Cir: 111 and HBV-De-Cir: 327) were enrolled. The mean EHBF in the HBV-De-Cir was significantly higher than that in the HBV-ACLF-no-Cir and HBV-ACLF-Cir (0.36 vs. 0.21 vs. 0.20 L/min, P < 0.001). EHBF was significantly correlated with the total bilirubin, prothrombin activity and model for end-stage liver disease (MELD) in the HBV-ACLF-no-Cir. The predicted 90-day mortality rate using the MELD, EHBF, ICG-retention rate at 15 min (R15%) and EHBF-R15% scores were similar. The sensitivity and specificity of the EHBF varied between 68.5-80.2% and 45.8-73.7%, respectively. The EHBF-MELD score had the highest specificity. CONCLUSION EHBF was significantly lower in the patients with ACLF compared to decompensated cirrhosis. The EHBF were closely related to the severity of HBV-ACLF and can be used for predicting the 90-day mortality rate of HBV-ACLF.
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