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1
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Myers S, Gupta DK, Izzy M. The clinical relevance of the new criteria for cirrhotic cardiomyopathy and future directions. Liver Transpl 2025; 31:521-530. [PMID: 39185907 DOI: 10.1097/lvt.0000000000000458] [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] [Received: 04/23/2024] [Accepted: 08/05/2024] [Indexed: 08/27/2024]
Abstract
Cardiac dysfunction in patients with liver disease has been recognized since the 1950s. Initially attributed to shared risk factors, it is now evident that cardiac dysfunction in patients with cirrhosis can occur in the absence of known cardiac, that is, coronary artery and valvular heart disease, and across all etiologies for cirrhosis. In 1996, this myocardial dysfunction was termed cirrhotic cardiomyopathy (CCM). The pathophysiologic mechanisms underlying CCM include impaired beta-adrenergic membrane function and circulating proinflammatory and cardiotoxic substances. In 2005, the first diagnostic criteria for CCM were introduced enabling greater sensitivity and accuracy of diagnosis. Since 2005, advancements in echocardiographic methods and a better understanding of the pathophysiology of cardiac dysfunction in patients with cirrhosis necessitated a revision of CCM criteria. Changes in CCM criteria included the removal of blunted contractile or heart rate response on stress testing and the addition of global longitudinal systolic strain. The refinement of criteria for diastolic dysfunction was also incorporated into the new diagnostic approach. Since 2020, the prevalence of the disorder and clinical considerations for pretransplant, peritransplant, and posttransplant patients with cirrhosis have been further evaluated, and CCM was found to adversely impact clinical outcomes during all 3 phases of care. Future research considerations should address the timing of universal echocardiographic screening for patients with cirrhosis, the utility of biomarkers in aiding CCM diagnosis, the impact of CCM on right heart function, and the role of anti-remodeling agents after liver transplant.
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Affiliation(s)
- Sarah Myers
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Deepak K Gupta
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Manhal Izzy
- Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Davis BC, Lin KC, Shahub S, Ramasubramanya A, Fagan A, Muthukumar S, Prasad S, Bajaj JS. A novel sweat sensor detects inflammatory differential rhythmicity patterns in inpatients and outpatients with cirrhosis. NPJ Digit Med 2024; 7:382. [PMID: 39733165 DOI: 10.1038/s41746-024-01404-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/20/2024] [Indexed: 12/30/2024] Open
Abstract
Patients with cirrhosis have high systemic inflammation (TNFα, CRP, and IL-6) that is associated with poor outcomes. These biomarkers need continuous non-invasive monitoring, which is difficult with blood. We studied the AWARE sweat-sensor to measure these in passively expressed sweat in healthy people (N = 12) and cirrhosis (N = 32, 10 outpatients/22 inpatients) for 3 days. Blood CRP, TNFα, IL6, levels, and liver function and quality of life were measured. We found that CRP, TNFα, and IL6 were correlated in sweat and serum among both groups and were evaluated in inpatients versus outpatients/controls. IL6 is associated with lower transplant-free survival. Sweat monitoring nocturnal CRP/IL6 elevations in cirrhosis versus controls. Outpatients with cirrhosis had inflammation levels that elevated during the evening and peaked towards the early night periods. The levels start to fall much later at night and early morning. These data suggest that further investigation of continuous measurement of sweat biomarkers in cirrhosis is warranted.
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Affiliation(s)
- Brian C Davis
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA
| | - Kai-Chun Lin
- University of Texas at Dallas, Richardson, TX, USA
| | - Sarah Shahub
- University of Texas at Dallas, Richardson, TX, USA
| | | | - Andrew Fagan
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA
| | | | | | - Jasmohan S Bajaj
- Richmond Veterans Affairs (VA) Medical Center and Virginia Commonwealth University, Richmond, VA, USA.
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Chou TS, Lin Y, Tsai ML, Tseng CJ, Dai JW, Yang NI, Lin CL, Chen LW, Hung MJ, Chen TH. Efficacy and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Liver Cirrhosis. J Clin Gastroenterol 2024:00004836-990000000-00374. [PMID: 39495818 DOI: 10.1097/mcg.0000000000002089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 09/22/2024] [Indexed: 11/06/2024]
Abstract
OBJECTIVE Comparing direct oral anticoagulants (DOACs) and warfarin's efficacy and safety in patients with nonvalvular atrial fibrillation (AF) and liver cirrhosis (LC). BACKGROUND Evidence of the pharmacodynamics of DOACs is limited in patients with AF and LC. METHODS A retrospective cohort study was conducted in the largest hospital system in Taiwan, involving patients with AF and LC for the years 2012 to 2021. Hazards of thromboembolic events (ischemic stroke, transient ischemic attack, and systemic embolism), intracranial hemorrhage, gastrointestinal, major bleeding, and all-cause mortality were investigated with a new-user, active comparator design. Inverse probability of treatment weighting was applied to balance potential confounders between treatment groups. RESULTS In total, 478 DOAC users and 247 warfarin users were included. DOACs and warfarin demonstrated similar trends in preventing thromboembolic events, namely ischemic stroke [adjusted hazard ratio (aHR), 1.05 (95% CI: 0.42-2.61)], transient ischemic attack [aHR, 1.36 (95% CI: 0.18-10.31)], and systemic embolism [aHR, 0.49 (95% CI: 0.14-1.70)]. DOAC use was associated with a similar risk of intracranial hemorrhage [aHR, 0.65 (95% CI: 0.26-1.59)] and gastrointestinal bleeding [aHR, 0.64 (95% CI: 0.39-1.03)], a decreased risk of major bleeding [aHR, 0.64 (95% CI: 0.42-0.99)], and a reduction in mortality [aHR, 0.73 (95% CI: 0.54-0.99)]. DOAC users exhibited a significant reduction in major bleeding risk in patients with Child-Pugh class A (aHR, 0.48; 95% CI: 0.33-0.70). CONCLUSIONS DOACs showed potential safety advantages over warfarin for patients with nonvalvular AF and LC, particularly in reducing major bleeding risk in those with Child-Pugh class A.
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Affiliation(s)
- Tien-Shin Chou
- Division of Gastroenterology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yuan Lin
- Department of Emergency Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Lung Tsai
- Division of Cardiology, Department of Internal Medicine, New Taipei Municipal TuCheng Hospital, New Taipei City, Taiwan
| | - Chin-Ju Tseng
- Division of Cardiology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Jhih-Wei Dai
- Division of Cardiology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ning-I Yang
- Division of Cardiology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Chih-Lang Lin
- Division of Gastroenterology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Li-Wei Chen
- Division of Gastroenterology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ming-Jui Hung
- Division of Cardiology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Tien-Hsing Chen
- Division of Cardiology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- Centre of Data Science and Biostatistics, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Elsheikh M, El Sabagh A, Mohamed IB, Bhongade M, Hassan MM, Jalal PK. Frailty in end-stage liver disease: Understanding pathophysiology, tools for assessment, and strategies for management. World J Gastroenterol 2023; 29:6028-6048. [PMID: 38130738 PMCID: PMC10731159 DOI: 10.3748/wjg.v29.i46.6028] [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: 09/13/2023] [Revised: 11/08/2023] [Accepted: 12/01/2023] [Indexed: 12/13/2023] Open
Abstract
Frailty and sarcopenia are frequently observed in patients with end-stage liver disease. Frailty is a complex condition that arises from deteriorations across various physiological systems, including the musculoskeletal, cardiovascular, and immune systems, resulting in a reduced ability of the body to withstand stressors. This condition is associated with declined resilience and increased vulnerability to negative outcomes, including disability, hospitalization, and mortality. In cirrhotic patients, frailty is influenced by multiple factors, such as hyperammonemia, hormonal imbalance, malnutrition, ascites, hepatic encephalopathy, and alcohol intake. Assessing frailty is crucial in predicting morbidity and mortality in cirrhotic patients. It can aid in making critical decisions regarding patients' eligibility for critical care and transplantation. This, in turn, can guide the development of an individualized treatment plan for each patient with cirrhosis, with a focus on prioritizing exercise, proper nutrition, and appropriate treatment of hepatic complications as the primary lines of treatment. In this review, we aim to explore the topic of frailty in liver diseases, with a particular emphasis on pathophysiology, clinical assessment, and discuss strategies for preventing frailty through effective treatment of hepatic complications. Furthermore, we explore novel assessment and management strategies that have emerged in recent years, including the use of wearable technology and telemedicine.
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Affiliation(s)
- Mazen Elsheikh
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Ahmed El Sabagh
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Islam B Mohamed
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Megha Bhongade
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Manal M Hassan
- Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Prasun Kumar Jalal
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, United States
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Sayaf K, Zanotto I, Gabbia D, Alberti D, Pasqual G, Zaramella A, Fantin A, De Martin S, Russo FP. Sex Drives Functional Changes in the Progression and Regression of Liver Fibrosis. Int J Mol Sci 2023; 24:16452. [PMID: 38003640 PMCID: PMC10671597 DOI: 10.3390/ijms242216452] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/28/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Liver fibrosis is a common and reversible feature of liver damage associated with many chronic liver diseases, and its onset is influenced by sex. In this study, we investigated the mechanisms of liver fibrosis and regeneration, focusing on understanding the mechanistic gaps between females and males. We injected increasing doses of carbon tetrachloride into female and male mice and maintained them for a washout period of eight weeks to allow for liver regeneration. We found that male mice were more prone to developing severe liver fibrosis as a consequence of early chronic liver damage, supported by the recruitment of a large number of Ly6Chigh MoMφs and neutrophils. Although prolonged liver damage exacerbated the fibrosis in mice of both sexes, activated HSCs and Ly6Chigh MoMφs were more numerous and active in the livers of female mice than those of male mice. After eight weeks of washout, only fibrotic females reported no activated HSCs, and a phenotype switching of Ly6Chigh MoMφs to anti-fibrogenic Ly6Clow MoMφs. The early stages of liver fibrosis mostly affected males rather than females, while long-term chronic liver damage was not influenced by sex, at least for liver fibrosis. Liver repair and regeneration were more efficient in females than in males.
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Affiliation(s)
- Katia Sayaf
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy
| | - Ilaria Zanotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35128 Padova, Italy (D.G.); (S.D.M.)
| | - Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35128 Padova, Italy (D.G.); (S.D.M.)
| | - Dafne Alberti
- Laboratory of Synthetic Immunology, Department of Surgery Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy (G.P.)
- Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Giulia Pasqual
- Laboratory of Synthetic Immunology, Department of Surgery Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy (G.P.)
- Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Alice Zaramella
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, University of Padova, 35128 Padova, Italy;
| | - Alberto Fantin
- Gastroenterology Unit, Veneto Institute of Oncology IOV-IRCCS, University of Padova, 35128 Padova, Italy;
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35128 Padova, Italy (D.G.); (S.D.M.)
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35131 Padova, Italy
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Philips CA, Ahamed R, Abduljaleel JK, Rajesh S, Augustine P. Identification and Analysis of Gut Microbiota and Functional Metabolism in Decompensated Cirrhosis with Infection. J Clin Transl Hepatol 2023; 11:15-25. [PMID: 36406325 PMCID: PMC9647106 DOI: 10.14218/jcth.2021.00428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 01/05/2022] [Accepted: 05/10/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS Intestinal dysbiosis play a role in the adverse outcomes of sepsis and septic shock. However, variations in bacterial diversity and microbiota-related functional metabolic alterations within the gut microbiome in decompensated cirrhosis (DC) patients with infection remain unknown. METHODS We conducted 16-srRNA sequencing on stool samples (n=51: sepsis, 27/no sepsis, 24) collected from consecutive DC patients upon admission. Bacterial diversity, significant taxa, and respective metabolic profiling were performed based on subgroup comparisons. Conet/Cytoscape was utilized to identify significant non-random patterns of bacterial copresence and mutual exclusion for clinical events. RESULTS Genera associated with pathogenicity in conditions of immune exhaustion (Corynebacterium, Lautropia) were predominant in patients with sepsis. Metabolic pathways associated with oxidative stress and endotoxemia [lipopolysaccharide (LPS) synthesis and sulfur relay] were significantly upregulated in sepsis. Specific taxa were associated with sites of infection in DC patients. Protective oxidant pathways that increase glutathione were upregulated in those without sepsis. Gammaproteobacteria family of sulfur-metabolizing bacteria, exaggeration of orally predominant pathogens (Prevotella), and pathways of severe LPS-related hyperinflammatory stress were notable in those with interleukin-6 levels >1,000 pg/dL. Pathogenic genera related to an immune deficient state was significant in DC with ≥2 infection episodes. Megamonas was associated with survival during the same admission. CONCLUSIONS Specific gut microbiota and their metabolites were associated with sepsis and related events in patients with DC. Identifying beneficial strains that reduce immune exhaustion and supplementation of favorable metabolites could improve therapeutics for DC and sepsis, for which larger prospective, well controlled population-based studies remain an unmet need.
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Affiliation(s)
- Cyriac Abby Philips
- Clinical and Translational Hepatology, Monarch Liver Laboratory, The Liver Institute, Center of Excellence in GI Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Rizwan Ahamed
- Gastroenterology and Advanced GI Endoscopy, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Jinsha K.P. Abduljaleel
- Gastroenterology and Advanced GI Endoscopy, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Sasidharan Rajesh
- Diagnostic and Interventional Gastroenterology and Hepatology, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
| | - Philip Augustine
- Gastroenterology and Advanced GI Endoscopy, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
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Xu X, Jin J, Liu Y, Li H. Analysis of related factors of portal vein thrombosis in liver cirrhosis. BMC Gastroenterol 2023; 23:26. [PMID: 36717769 PMCID: PMC9887918 DOI: 10.1186/s12876-022-02632-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 12/20/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND AND AIMS To investigate the usefulness of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), protein C (PC), and thromboelastography (TEG) to serve as a predictor of portal vein thrombosis (PVT) in patients with liver cirrhosis. Additionally, we examined the clinical significance of the above indicators in terms of disease progression. METHODS A total of 123 patients with liver cirrhosis were recruited from May 2021 to December 2021, according to the imaging findings. They were divided into the PVT group (n = 52) and the non-PVT group (n = 71). Furthermore, patients with PVT were divided into plasma transfusion groups (n = 13) and non-plasma transfusion groups (n = 39). The basic general information, past medical history, laboratory, and imaging examination data were collected and analyzed. RESULTS In univariate analysis, there was no significant difference between the two groups in IL-6, PC, reaction time (R), alpha angle (Angle), maximum amplitude, or coagulation index (CI) (P > 0.05). TNF-α in the PVT group was significantly lower than that in the non-PVT group (P = 0.001). K-time (K) in the PVT group was significantly higher than that in the non-PVT group (P = 0.031). There was no significant difference in IL-6, TNF-α, PC, or TEG between different Child-Pugh classification groups (P > 0.05). There were no significant differences in TEG between the plasma transfusion group and the non-plasma transfusion group. In Binary logistic regression analysis, TNF-α (OR = 0.9881, 95%CI = 0.971, 0.990, P < 0.001), K(OR = 1.28, 95% = 1.053, 1.569, P = 0.014), activate partial thromboplastin time (APTT) (OR = 0.753, 95%CI = 0.656, 0.865, P < 0.001), portal vein diameter (OR = 1.310, 95%CI = 1.108, 1.549, P = 0.002)and the history of splenectomy or embolism (OR = 7.565, 95%CI = 1.514, 37.799, P = 0.014)were related to the formation of PVT. CONCLUSIONS TNF-α, K, APTT, portal vein diameter, and splenectomy or embolism history were associated with PVT formation, but IL-6 was not.
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Affiliation(s)
- Xiaotong Xu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Jinglan Jin
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China.
| | - Yuwei Liu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Hang Li
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
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Buonomo EL, Mei S, Guinn SR, Leo IR, Peluso MJ, Nolan MA, Schildberg FA, Zhao L, Lian C, Xu S, Misdraji J, Kharchenko PV, Sharpe AH. Liver stromal cells restrict macrophage maturation and stromal IL-6 limits the differentiation of cirrhosis-linked macrophages. J Hepatol 2022; 76:1127-1137. [PMID: 35074474 DOI: 10.1016/j.jhep.2021.12.036] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 12/01/2021] [Accepted: 12/17/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Myeloid cells are key regulators of cirrhosis, a major cause of mortality worldwide. Because stromal cells can modulate the functionality of myeloid cells in vitro, targeting stromal-myeloid interactions has become an attractive potential therapeutic strategy. We aimed to investigate how human liver stromal cells impact myeloid cell properties and to understand the utility of a stromal-myeloid coculture system to study these interactions in the context of cirrhosis. METHODS Single-cell RNA-sequencing analyses of non-cirrhotic (n = 7) and cirrhotic (n = 5) human liver tissue were correlated to the bulk RNA-sequencing results of in vitro cocultured human CD14+ and primary liver stromal cells. Complimentary mechanistic experiments and flow cytometric analysis were performed on human liver stromal-myeloid coculture systems. RESULTS We found that stromal-myeloid coculture reduces the frequency CD14+ cell subsets transcriptionally similar to liver macrophages, showing that stromal cells inhibit the maturation of monocytes into macrophages. Stromal cells also influenced in vitro macrophage differentiation by skewing away from cirrhosis-linked CD9+ scar-associated macrophage-like cells and towards CD163+ Kupffer cell-like macrophages. We identify IL-6 production as a mechanism by which stromal cells limit CD9+ macrophage differentiation and find that local IL-6 levels are decreased in early-stage human liver disease compared to healthy liver tissue, suggesting a protective role for local IL-6 in the healthy liver. CONCLUSIONS Our work reveals an unanticipated role for liver stromal cells in impeding the maturation and altering the differentiation of macrophages and should prompt investigations into the role of local IL-6 production in the pathogenesis of liver disease. These studies provide a framework for investigating macrophage-stromal interactions during cirrhosis. LAY SUMMARY The impact of human liver stromal cells on myeloid cell maturation and differentiation in liver disease is incompletely understood. In this study, we present a mechanistic analysis using a primary in vitro human liver stromal-myeloid coculture system that is translated to liver disease using single-cell RNA sequencing analysis of cirrhotic and non-cirrhotic human liver tissue. Our work supports a role for stromal cell contact in restricting macrophage maturation and for stromal-derived IL-6 in limiting the differentiation of a cirrhotic macrophage subset.
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Affiliation(s)
- Erica L Buonomo
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
| | - Shenglin Mei
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Samantha R Guinn
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Current Address: The Bloomberg-Kimmel Institute for Cancer Immunotherapy, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Isabelle R Leo
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Current Address: Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23A, 171 65 Solna, Sweden
| | - Michael J Peluso
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
| | - Mei-An Nolan
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
| | - Frank A Schildberg
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, 53127 Bonn, Germany
| | - Lei Zhao
- Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Christine Lian
- Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Shuyun Xu
- Department of Pathology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Peter V Kharchenko
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge MA, USA
| | - Arlene H Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
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Kronsten VT, Woodhouse CA, Zamalloa A, Lim TY, Edwards LA, Martinez-Llordella M, Sanchez-Fueyo A, Shawcross DL. Exaggerated inflammatory response to bacterial products in decompensated cirrhotic patients is orchestrated by interferons IL-6 and IL-8. Am J Physiol Gastrointest Liver Physiol 2022; 322:G489-G499. [PMID: 35195033 PMCID: PMC8993594 DOI: 10.1152/ajpgi.00012.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cirrhosis-associated immune dysfunction (CAID) contributes to disease progression and organ failure development. We interrogated immune system function in nonseptic compensated and decompensated cirrhotic patients using the TruCulture whole blood stimulation system, a novel technique that allows a more accurate representation than traditional methods, such as peripheral blood mononuclear cell culture, of the immune response in vivo. Thirty cirrhotics (21 decompensated and 9 compensated) and seven healthy controls (HCs) were recruited. Whole blood was drawn directly into three TruCulture tubes [unstimulated to preloaded with heat-killed Escherichia coli 0111:B4 (HKEB) or lipopolysaccharide (LPS)] and incubated in dry heat blocks at 37°C for 24 h. Cytokine analysis of the supernatant was performed by multiplex assay. Cirrhotic patients exhibited a robust proinflammatory response to HKEB compared with HCs, with increased production of interferon-γ-induced protein 10 (IP-10) and IFN-λ1, and to LPS, with increased production of IFN-λ1. Decompensated patients demonstrated an augmented immune response compared with compensated patients, orchestrated by an increase in type I, II, and III interferons, and higher levels of IL-1β, IL-6, and IL-8 post-LPS stimulation. IL-1β, TNF-α, and IP-10 post-HKEB stimulation and IP-10 post-LPS stimulation negatively correlated with biochemical markers of liver disease severity and liver disease severity scores. Cirrhotic patients exposed to bacterial products exhibit an exaggerated inflammatory response orchestrated by IFNs, IL-6, and IL-8. Poststimulation levels of a number of proinflammatory cytokines negatively correlate with markers of liver disease severity raising the possibility that the switch to an immunodeficient phenotype in CAID may commence earlier in the course of advanced liver disease. NEW & NOTEWORTHY Decompensated cirrhotic patients, compared with compensated patients, exhibit a greater exaggerated inflammatory response to bacterial products orchestrated by interferons, IL-6, and IL-8. Postbacterial product stimulation levels of a number of pro-inflammatory cytokines negatively correlate with liver disease severity biomarkers and liver disease severity scores raising the possibility that the switch to an immunodeficient phenotype in cirrhosis-associated immune dysfunction may commence earlier in the course of advanced liver disease.
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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, London, United Kingdom
| | - Charlotte A. Woodhouse
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Ane Zamalloa
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Tiong Yeng Lim
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Lindsey A. Edwards
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Marc Martinez-Llordella
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - 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, London, United Kingdom
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10
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Kronsten VT, Tranah TH, Pariante C, Shawcross DL. Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J Hepatol 2022; 76:665-680. [PMID: 34800610 DOI: 10.1016/j.jhep.2021.11.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/13/2021] [Accepted: 11/08/2021] [Indexed: 02/08/2023]
Abstract
Depression and chronic liver disease (CLD) are important causes of disability, morbidity and mortality worldwide and their prevalence continues to rise. The rate of depression in CLD is high compared to that of the general population and is comparable to the increased rates observed in other medical comorbidities and chronic inflammatory conditions. Notably, a comorbid diagnosis of depression has a detrimental effect on outcomes in cirrhosis. Systemic inflammation is pivotal in cirrhosis-associated immune dysfunction - a phenomenon present in advanced CLD (cirrhosis) and implicated in the development of complications, organ failure, disease progression, increased infection rates and poor outcome. The presence of systemic inflammation is also well-documented in a cohort of patients with depression; peripheral cytokine signals can result in neuroinflammation, behavioural change and depressive symptoms via neural mechanisms, cerebral endothelial cell and circumventricular organ signalling, and peripheral immune cell-to-brain signalling. Gut dysbiosis has been observed in both patients with cirrhosis and depression. It leads to intestinal barrier dysfunction resulting in increased bacterial translocation, in turn activating circulating immune cells, leading to cytokine production and systemic inflammation. A perturbed gut-liver-brain axis may therefore explain the high rates of depression in patients with cirrhosis. The underlying mechanisms explaining the critical relationship between depression and cirrhosis remain to be fully elucidated. Several other psychosocial and biological factors are likely to be involved, and therefore the cause is probably multifactorial. However, the role of the dysfunctional gut-liver-brain axis as a driver of gut-derived systemic inflammation requires further exploration and consideration as a target for the treatment of depression in patients with cirrhosis.
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Affiliation(s)
- Victoria T Kronsten
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK.
| | - Thomas H Tranah
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Carmine Pariante
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, The Maurice Wohl Clinical Neuroscience Institute, Cutcombe Road, London, SE5 9RT, UK
| | - Debbie L Shawcross
- Institute of Liver Studies, 1(st) Floor James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, 125 Coldharbour Lane, London, SE5 9NU, UK
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11
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Systemic inflammation as a risk factor for portal vein thrombosis in cirrhosis: a prospective longitudinal study. Eur J Gastroenterol Hepatol 2021; 33:e108-e113. [PMID: 33208682 DOI: 10.1097/meg.0000000000001982] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND AND AIMS Various risk factors for portal vein thrombosis (PVT) development in patients with cirrhosis have been identified, but the role of systemic inflammatory reaction is unknown. The study aims to assess the association between markers of systemic inflammation and PVT in cirrhosis. METHODS Between January 2014 and October 2015, 107 outpatients with cirrhosis and no PVT were recruited, and followed till February 2017. White blood cell count, serum concentrations of high-sensitive C-reactive protein, ferritin, tumor necrosis factor-alpha and interleukin-6 (IL-6) were evaluated at baseline and every 3 or 6 months till PVT diagnosis or end of follow-up. RESULTS Median age, model for end-stage liver disease (MELD) score and follow-up period of the studied population was 55 years (IQR 46-62 years), 9.6 points (IQR 7.5-12 points) and 19 months (12-24 months), respectively. PVT developed in 10.3% of the patients. Lymphocyte count below 1.2 ´ 109/L [hazard ratio, 6.04; 95% confidence interval (CI), 1.29-28.2; P = 0.022], IL-6 above 5.5 pg/mL (hazard ratio, 5.64; 95% CI, 1.21-26.33; P = 0.028) and neutrophil-to-lymphocyte ratio (hazard ratio, 1.46; 95% CI, 1.04-2.04; P = 0.028) were associated with a higher risk of PVT development. IL-6 and lymphopenia remained associated with subsequent PVT development after adjustment for nonselective beta-blockers, spleen size, portosystemic collaterals, oesophageal varices (grade ≥2) and ascites, but also with alcohol as the cause for cirrhosis and MELD ≥13. CONCLUSION In patients with cirrhosis, markers of systemic inflammation IL-6 and lymphopenia are predictive of PVT independently of markers of portal hypertension. These results draw our attention on a factor so far overlooked in the pathogenesis of PVT.
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12
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Ranjan R, Rampal S, Jaiman A, Ali Tokgöz M, Kit Koong J, Ramayah K, Rajaram R. Common musculoskeletal disorders in chronic liver disease patients. Jt Dis Relat Surg 2021; 32:818-823. [PMID: 34842121 PMCID: PMC8650659 DOI: 10.52312/jdrs.2021.25] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/16/2021] [Indexed: 12/24/2022] Open
Abstract
Chronic liver disease (CLD) is the commonest ailment affecting the hepatobiliary system. Six significant pathologies related to CLD include hepatic osteodystrophy (HO), increased infection susceptibility, sarcopenia, osteonecrosis of the femoral head (OFH), increased risk of periprosthetic complications and fracture. Hepatic osteodystrophy, which comprises osteopenia, osteoporosis, and osteomalacia, refers to alterations in bone mineral metabolism found in patients with CLD. The HO prevalence ranges from 13 to 95%. Low complement levels, poor opsonization capacity, portosystemic shunting, decreased albumin levels, and impaired reticuloendothelial system make the cirrhotic patients more susceptible to developing infectious diseases. Septic arthritis, osteomyelitis, prosthetic joint infection, and cellulitis were common types of CLD-associated infectious conditions. The incidence of septic arthritis is 1.5 to 2-fold higher in patients with cirrhosis. Sarcopenia, also known as muscle wasting, is one of the frequently overlooked manifestations of CLD. Sarcopenia has been shown to be independent predictor of longer mechanical ventilation, hospital stay, and 12-month mortality of post-transplantation. Alcohol and steroid abuse commonly associated with CLD are the two most important contributory factors for non-traumatic osteonecrosis. However, many studies have identified cirrhosis alone to be an independent cause of atraumatic osteonecrosis. The risk of developing OFH in cirrhosis patients increases by 2.4 folds and the need for total hip arthroplasty increases by 10 folds. Liver disease has been associated with worse outcomes and higher costs after arthroplasty. Cirrhosis is a risk factor for arthroplasty complications and is associated with a prolonged hospital stay, higher costs, readmission rates, and increased mortality after arthroplasty. Greater physician awareness of risk factors associated with musculoskeletal complications of CLD patients would yield earlier interventions, lower healthcare costs, and better overall clinical outcomes for this group of patients.
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Affiliation(s)
- Rajat Ranjan
- Integral Institute of Medical Sciences & Research, Integral University, Lucknow, India
| | - Sanjiv Rampal
- Department of Orthopaedics and Traumatology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Selangor, Malaysia
| | - Ashish Jaiman
- Vardhman Mahavir Medical College & Safdarjung Hospital, Central Institute of Orthopaedics, New Delhi, India
| | - Mehmet Ali Tokgöz
- Ankara Keçiören Training and Research Hospital, Consultant Orthopaedic Surgeon, Ankara, Turkey
| | - Jun Kit Koong
- Department of Surgery, Malaya University Medical Faculty, Kuala Lumpur, Malaysia
| | - Kamarajan Ramayah
- Department of Surgery, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Ruveena Rajaram
- Department of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia
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13
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Kronsten VT, Shawcross DL. Hepatic encephalopathy and depression in chronic liver disease: is the common link systemic inflammation? Anal Biochem 2021; 636:114437. [PMID: 34715068 DOI: 10.1016/j.ab.2021.114437] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/26/2021] [Accepted: 10/22/2021] [Indexed: 02/08/2023]
Abstract
Hepatic encephalopathy and depression share a number of clinical features, such as cognitive impairment and psychomotor retardation, and are highly prevalent in patients with chronic liver disease. Both conditions signify a poor prognosis, carry an increased mortality and are major determinants of reduced health related quality of life. The pathophysiology of hepatic encephalopathy is complex. Whilst cerebral accumulation of ammonia is well-recognised as being central to the development of hepatic encephalopathy, systemic inflammation, which acts in synergy with hyperammonaemia, is emerging as a key driver in its development. The pro-inflammatory state is also widely documented in depression, and peripheral to brain communication occurs resulting in central inflammation, behavioural changes and depressive symptoms. Gut dysbiosis, with a similar reduction in beneficial bacteria, increase in pathogens and decreased bacterial diversity, has been observed in both hepatic encephalopathy and depression, and it may be that the resultant increased bacterial translocation causes their shared inflammatory pathophysiology. Whilst the literature on a positive association between hepatic encephalopathy and depression in cirrhosis remains to be substantiated, there is evolving evidence that treatment with psychobiotics may be of dual benefit, improving cognition and mood in cirrhosis.
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Affiliation(s)
- Victoria Tatiana Kronsten
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK.
| | - Debbie Lindsay Shawcross
- Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, UK
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14
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Dragomir MP, Tudor S, Lacatus M, Stanciulea O, Trandafir B, Diaconu A, Coriu D, Colita A, Droc G, Purnichescu-Purtan R, Calin G, Vasilescu C. TNF-alpha releasing capacity of the whole blood drops after open total splenectomy, but increases after partial/subtotal or minimally invasive splenectomy. Acta Chir Belg 2021; 122:346-356. [PMID: 33886417 DOI: 10.1080/00015458.2021.1916282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND The mechanisms that induce immunodeficiency after splenectomy remain unknown. The aim of this study was to measure the cytokine releasing capacity of the whole blood as an expression of the innate immunity after total (TS) and subtotal/partial splenectomy (S/PS) in order to assess the impact of splenectomy on the individual cytokine reactivity. METHODS We prospectively collected blood before (D0) and at multiple time points after splenectomy (7 days - D7, 30 days - D30, 90 days - D90, 180 days - D180, and 360 days - D360) and measured the cytokines releasing capacity of IL-6, TNF-alpha and IL-10 from whole blood under LPS stimulation which we normalized to the monocytes number. RESULTS When analyzing all splenectomies at D0, D7 and D30, normalized ΔTNF-alpha significantly dropped after splenectomy (p = .0038) and normalized ΔIL-6 and ΔIL-10 did not significantly change. More specifically, normalized ΔTNF-alpha dropped after TS (p = .0568) and significantly increased after S/PS (p = .0388). Open surgery induced a decrease in normalized ΔTNF-alpha (p = .0970), whereas minimally invasive (MI) surgery significantly increased the normalized ΔTNF-alpha releasing capacity (p = .0178). The cytokine levels were heterogenous between pathologies at D0, and ΔIL-6 dropped mainly in cirrhotic patients after splenectomy (all underwent TS), ΔTNF-alpha dropped in immune thrombocytopenic purpura patients (all underwent TS), but increased in spherocytosis (91% underwent S/PS) after splenectomy. CONCLUSIONS Splenectomy induces a decrease of the pro-inflammatory cytokine TNF-alpha and if splenic parenchyma is spared and the surgery is performed MI, this change is hindered.
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Affiliation(s)
- Mihnea P. Dragomir
- Department of General Surgery, Fundeni Clinical Institute, Bucharest, Romania
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Stefan Tudor
- Department of General Surgery, Fundeni Clinical Institute, Bucharest, Romania
- Faculty of Medicine, Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Monica Lacatus
- Department of General Surgery, Fundeni Clinical Institute, Bucharest, Romania
- Faculty of Medicine, Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Oana Stanciulea
- Department of General Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Bogdan Trandafir
- Department of General Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Adriana Diaconu
- Department of Pediatric Bone Marrow Transplantation, Fundeni Hospital, Bucharest, Romania
| | - Daniel Coriu
- Faculty of Medicine, Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Department of Hematology, Fundeni Clinical Institute, Bucharest, Romania
| | - Anca Colita
- Faculty of Medicine, Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Department of Pediatric Bone Marrow Transplantation, Fundeni Hospital, Bucharest, Romania
| | - Gabriela Droc
- Faculty of Medicine, Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Intensive Care Department, Fundeni Clinical Instutute, Bucharest, Romania
| | - Raluca Purnichescu-Purtan
- Department of Mathematical Methods and Models, Faculty of Applied Sciences, Politehnica University of Bucharest, Bucharest, Romania
| | - George Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Catalin Vasilescu
- Department of General Surgery, Fundeni Clinical Institute, Bucharest, Romania
- Faculty of Medicine, Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
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15
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Hwang W, Lee J. Pathophysiologic Implications of Cytokines Secretion during Liver Transplantation Surgery. Int J Med Sci 2018; 15:1737-1745. [PMID: 30588198 PMCID: PMC6299421 DOI: 10.7150/ijms.28382] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 10/18/2018] [Indexed: 12/29/2022] Open
Abstract
We introduce the following issues of the cytokines secretion during liver transplantation surgery in this review article; 1) the aspect of cytokines secretion during liver transplantation surgery, 2) the evidences of association of cytokines concentration with post-transplantation graft survival, 3) a variety of factors that may influence the secretion of cytokines during liver transplantation, 4) pro-inflammatory and anti-inflammatory cytokine balance during the surgery, and 5) the issues of T helper 1 and T helper 2, and T helper 17 and regulatory T cell signature cytokines secretion and their ratio during liver transplantation surgery. Primary failure of the liver is associated with the secondary dysfunction of virtually all other organ systems, including the cardiovascular, pulmonary, renal, coagulation and central nervous systems. In addition, liver transplantation surgery itself is a major surgical procedure with accompanying life-threatening hemorrhage, massive transfusion, clamping and unclamping of great vessels and resulting ischemia-reperfusion injury and cardiovascular instability. Both the underlying liver failure and the surgical events act as stressors and promote the secretion of various cytokines. So it is clinically important to understand above issues regarding the cytokines secretion during liver transplantation surgery. As cytokines secretion has clear relationship with post-transplantation clinical outcomes, future study directions for artificially manipulating cytokines secretion is also suggested for enhancing outcomes of the patients.
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Affiliation(s)
- Wonjung Hwang
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea
| | - Jaemin Lee
- Department of Anesthesiology and Pain Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea
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16
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Eslamparast T, Montano-Loza AJ, Raman M, Tandon P. Sarcopenic obesity in cirrhosis-The confluence of 2 prognostic titans. Liver Int 2018; 38:1706-1717. [PMID: 29738109 DOI: 10.1111/liv.13876] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 04/17/2018] [Indexed: 02/13/2023]
Abstract
Sarcopenia and obesity are 2 major health conditions with a growing prevalence in cirrhosis. The concordance of these 2 conditions, sarcopenic obesity, is associated with higher rates of mortality and impact on the metabolic profile and physical function than either condition alone. To date, there is little consensus surrounding the diagnostic criteria for sarcopenia, obesity or as a result, sarcopenic obesity in patients with cirrhosis. Cross-sectional imaging, although the most accurate diagnostic technique, has practical limitations for routine use in clinical practice. Management strategies are focused on increasing muscle mass and strength. The present review provides an overview of the diagnosis, pathophysiology, prognostic implications and management strategies available for sarcopenic obesity in cirrhosis. We also discuss the associated condition myosteatosis, the pathological accumulation of fat in skeletal muscle. Much work needs to be done to advance both clinical care and research in this area. Future directions require consensus definitions for sarcopenia, obesity and sarcopenic obesity, an expansion of our understanding of the complex pathogenesis of the muscle-liver-adipose tissue axis in cirrhosis and evidence to support management recommendations for nutrition, exercise and pharmacological therapies.
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Affiliation(s)
| | | | - Maitreyi Raman
- Department of Medicine, University of Calgary, Calgary, AB, Canada
| | - Puneeta Tandon
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
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17
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Ferrarese A, Zanetto A, Becchetti C, Sciarrone SS, Shalaby S, Germani G, Gambato M, Russo FP, Burra P, Senzolo M. Management of bacterial infection in the liver transplant candidate. World J Hepatol 2018; 10:222-230. [PMID: 29527258 PMCID: PMC5838441 DOI: 10.4254/wjh.v10.i2.222] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 12/29/2017] [Accepted: 01/23/2018] [Indexed: 02/06/2023] Open
Abstract
Bacterial infection (BI) is a common cause of impairment of liver function in patients with cirrhosis, especially in the liver transplant candidates. These patients share an immunocompromised state and increased susceptibility to develop community and hospital-acquired infections. The changing epidemiology of BI, with an increase of multidrug resistant strains, especially in healthcare-associated settings, represents a critical issue both in the waiting list and in the post-operative management. This review focused on the role played by BI in patients awaiting liver transplantation, evaluating the risk of drop-out from the waiting list, the possibility to undergo liver transplantation after recovery from infection or during a controlled infection.
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Affiliation(s)
- Alberto Ferrarese
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Chiara Becchetti
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Salvatore Stefano Sciarrone
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Sarah Shalaby
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua 35128, Italy
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18
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Liu CW, Huang CC, Tsai HC, Su YB, Huang SF, Lee KC, Hsieh YC, Li TH, Tsai CY, Chong LW, Ou SM, Yang YY, Fan WC, Hou MC, Lin HC, Lee SD. Serum adrenomedullin and urinary thromboxane B 2 help early categorizing of acute kidney injury in decompensated cirrhotic patients: A prospective cohort study. Hepatol Res 2018; 48:E9-E21. [PMID: 28544540 DOI: 10.1111/hepr.12917] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 05/15/2017] [Accepted: 05/15/2017] [Indexed: 02/08/2023]
Abstract
AIMS Increases in the systemic vasodilator adrenomedullin and the renal vasoconstrictors thromboxane A2 in cirrhotic patients are pathogenic factors for the development of functional acute kidney injury (AKI), including pre-renal azotemia (PRA) and hepatorenal syndrome (HRS), which is associated with high mortality. This study aims to find biomarkers that can diagnose HRS at an early stage, to enable treatment as soon as possible. METHODS Acute decompensated cirrhotic patients who had been admitted to hospital were enrolled in this prospective cohort study. Blood and urinary samples were collected immediately after admission. In addition to initially categorizing AKI cases into PRA, acute tubular necrosis (ATN), and HRS groups, their final diagnosis was adjudicated by a nephrologist and a hepatologist who checked the corrected and misclassification rates for significant biomarkers. RESULTS The cut-off values for serum adrenomedullin and urinary thromboxane B2 (TXB2 ), when used as predictors for functional AKI (adrenomedullin >283 pg/mL, urinary TXB2 >978 [pg/mg urinary creatinine]), for HRS (adrenomedullin >428, urinary TXB2 >1604), and for good terlipressin plus albumin treatment responders (adrenomedullin >490, urinary TXB2 >1863), were observed. Patients with HRS who could be treated, due to high mortality, had significantly higher serum adrenomedullin and urinary TXB2 levels compared to HRS patients receiving standard treatment. In addition to predicting 60-day mortality, a combination of these two markers further increased diagnostic accuracy for HRS among functional AKI. CONCLUSIONS Prompt diagnosis of HRS by differentiating it from PRA and ATN can be achieved by using serum adrenomedullin and urinary TXB2 in acute decompensated cirrhotic patients. In combination with severe clinical courses, these two markers are useful to select HRS patients who cannot be treated.
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Affiliation(s)
- Chih-Wei Liu
- Division of Allergy and Immunology and Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chia-Chang Huang
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Hung-Cheng Tsai
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yen-Bo Su
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shiang-Fen Huang
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Infection, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuei-Chuan Lee
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yun-Cheng Hsieh
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tzu-Hao Li
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Chia-Yi Branch of Taichung Veterans General Hospital, Chiayi, Taiwan
| | - Chang-Youh Tsai
- Division of Allergy and Immunology and Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Lee-Won Chong
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Shuo-Ming Ou
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Nephrology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ying-Ying Yang
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wen-Chien Fan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Ming-Chih Hou
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Han-Chieh Lin
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shou-Dong Lee
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Cheng Hsin General Hospital, Taipei, Taiwan
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19
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Kimer N, Pedersen JS, Tavenier J, Christensen JE, Busk TM, Hobolth L, Krag A, Al-Soud WA, Mortensen MS, Sørensen SJ, Møller S, Bendtsen F. Rifaximin has minor effects on bacterial composition, inflammation, and bacterial translocation in cirrhosis: A randomized trial. J Gastroenterol Hepatol 2018; 33:307-314. [PMID: 28671712 DOI: 10.1111/jgh.13852] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/30/2017] [Accepted: 06/18/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Decompensated cirrhosis is characterized by disturbed hemodynamics, immune dysfunction, and high risk of infections. Translocation of viable bacteria and bacterial products from the gut to the blood is considered a key driver in this process. Intestinal decontamination with rifaximin may reduce bacterial translocation (BT) and decrease inflammation. A randomized, placebo-controlled trial investigated the effects of rifaximin on inflammation and BT in decompensated cirrhosis. METHODS Fifty-four out-patients with cirrhosis and ascites were randomized, mean age 56 years (± 8.4), and model for end-stage liver disease score 12 (± 3.9). Patients received rifaximin 550-mg BD (n = 36) or placebo BD (n = 18). Blood and fecal (n = 15) sampling were conducted at baseline and after 4 weeks. Bacterial DNA in blood was determined by real-time qPCR 16S rRNA gene quantification. Bacterial composition in feces was analyzed by 16S rRNA gene sequencing. RESULTS Circulating markers of inflammation, including tumor necrosis factor alpha, interleukins 6, 10, and 18, stromal cell-derived factor 1-α, transforming growth factor β-1, and high sensitivity C-reactive protein, were unaltered by rifaximin treatment. Rifaximin altered abundance of bacterial taxa in blood marginally, only a decrease in Pseudomonadales was observed. In feces, rifaximin decreased bacterial richness, but effect on particular species was not observed. Subgroup analyses on patients with severely disturbed hemodynamics (n = 34) or activated lipopolysaccharide binding protein (n = 37) revealed no effect of rifaximin. CONCLUSION Four weeks of treatment with rifaximin had no impact on the inflammatory state and only minor effects on BT and intestinal bacterial composition in stable, decompensated cirrhosis (NCT01769040).
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Affiliation(s)
- Nina Kimer
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Julie S Pedersen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Juliette Tavenier
- Clinical Research Centre, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jeffrey E Christensen
- Vaiomer SAS, Toulouse, France.,Institute of Cardiovascular and Metabolic Diseases (I2MC), INSERM U1048, Toulouse, France
| | - Troels M Busk
- Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Lise Hobolth
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.,Department of Gastroenterology and Hepatology, Copenhagen University Hospital Bispebjerg, Bispebjerg, Denmark
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Waleed Abu Al-Soud
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Martin S Mortensen
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Søren J Sørensen
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Søren Møller
- Centre of Diagnostic Imaging and Research, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
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20
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Rogal SS, Udawatta V, Akpan I, Moghe A, Chidi A, Shetty A, Szigethy E, Bielefeldt K, DiMartini A. Risk factors for hospitalizations among patients with cirrhosis: A prospective cohort study. PLoS One 2017; 12:e0187176. [PMID: 29149171 PMCID: PMC5693413 DOI: 10.1371/journal.pone.0187176] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/14/2017] [Indexed: 12/13/2022] Open
Abstract
This study was designed to assess unique baseline factors associated with subsequent hospitalizations in a cohort of outpatients with cirrhosis. A cohort of 193 patients with cirrhosis was recruited from an outpatient liver disease clinic at a single, tertiary medical center. Comorbidities, prescription medications, liver disease symptoms and severity, and psychiatric and pain symptoms were assessed at baseline using validated instruments. Inflammatory markers were measured using standardized Luminex assays. Subsequent hospitalizations and the primary admission diagnoses were collected via chart review. Multivariable models were used to evaluate which baseline factors were associated with time to hospitalization and number of hospitalizations. The cohort consisted of 193 outpatients, with an average age of 58±9 and model for end-stage liver disease (MELD) score of 12±5. Over follow-up, 57 (30%) were admitted to the hospital. The factors associated with time to hospitalization included the severity of liver disease (HR/MELD point:1.10, 95% CI:1.04,1.16), ascites (HR: 1.90, 95% CI: 1.01, 3.58), baseline symptoms of depression (HR:2.34, 95% CI:1.28,4.25), sleep medications (HR:1.81, 95% CI:1.01, 3.22) and IL-6 (HR:1.43, 95% CI: 1.10, 1.84). Similarly the number admissions was significantly associated with MELD (IIR: 1.08, CI: 1.07,1.09), ascites (IIR: 4.15, CI:3.89, 4.43), depressive symptoms (IIR:1.54, CI:1.44,1.64), IL-6 (IIR:1.26, CI:1.23,1.30), sleep medications (IIR:2.74, CI:2.57, 2.93), and widespread pain (IIR: 1.61, CI: 1.50, 1.73). In conclusion, consistent with prior studies, MELD and ascites were associated with subsequent hospitalization. However, this study also identified other factors associated with hospitalization including inflammation, depressive symptoms, sleep medication use, and pain.
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Affiliation(s)
- Shari S. Rogal
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States of America
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States of America
- * E-mail:
| | - Viyan Udawatta
- Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Imo Akpan
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Akshata Moghe
- Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Alexis Chidi
- Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States of America
- Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Amit Shetty
- University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States of America
| | - Eva Szigethy
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Klaus Bielefeldt
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Andrea DiMartini
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States of America
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States of America
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21
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Abstract
Alcohol-related liver disease (ALD) remains the most important cause of death due to alcohol. Infections, particularly bacterial infections, are one of the most frequent and severe complications of advanced ALDs, such as alcoholic cirrhosis and severe alcoholic hepatitis (sAH). The specific mechanisms responsible for this altered host defence are yet to be deciphered. The aim of the present study is to review the current knowledge of infectious complications in ALD and its pathophysiological mechanisms, distinguishing the role of alcohol consumption and the contribution of different forms of ALD. To date, corticosteroids are the only treatment with proven efficacy in sAH, but their impact on the occurrence of infections remains controversial. The combination of an altered host defence and corticosteroid treatment in sAH has been suggested as a cause of opportunistic fungal and viral infections. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic or preemptive strategies in this high-risk population might be a preferable option, because of the high short-term mortality rate despite adequate therapies. However, these strategies should be assessed in well-designed trials before clinical implementation.
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22
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Kao JT, Yu CJ, Feng CL, Tsai SM, Chen YL, Wu YY. IL-6 significantly correlates with p-STAT3 expression and presents high variceal bleeding with mortality in cirrhotic patients: A cross-sectional study. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2017; 50:286-296. [PMID: 25899133 DOI: 10.1016/j.jmii.2015.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 02/06/2015] [Accepted: 03/05/2015] [Indexed: 01/27/2023]
Abstract
BACKGROUND/PURPOSE Effective mediators activate downstream transducers regulating inflammation and angiogenesis. Correlation among mediators IL-6, IL-27, TNF-α, and VEGF with STAT proteins at diverse clinical-pathologic stages of cirrhotic patients remains limited. METHODS Plasma mediators were assayed from 158 naïve liver cirrhosis (LC-total group) and 144 non-LC individuals. The LC-total group included 69 hepatitis B virus-infected (LC-HBV) patients, 40 hepatitis C virus-infected (LC-HCV) patients, and 49 patients without HBV-/HCV- infection (LC-NBNC). Another 144 non-LC individuals comprised 54 healthy persons (HG) and 90 chronic hepatitis patients (CH-total) as the control group. To correlate with plasma mediators, 52 paired liver tissues (CH: 41 and LC: 11 cases) served for p-STAT1 and p-STAT3 immunostaining. RESULTS Although IL-6, IL-27, TNF-α, and VEGF were expressed significantly in CH-total versus HG (p = 0.011, p < 0.001, p = 0.007, p = 0.004, respectively) and overall viral hepatitis patients versus HG (p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively), only IL-6 presented the strongest correlation in cirrhotic patients than noncirrhotic patients (LC-HBV vs. HG, p < 0.001, vs. CH-HBV, p = 0.001; LC-HCV vs. HG, p = 0.001, vs. CH-HCV, p = 0.031; LC-NBNC vs. HG, p < 0.001). Over-expressed IL-6 linked with poorer liver function (albumin: r = -0.346, p < 0.001; bilirubin: r = 0.271, p = 0.001; INR: r = 0.308, p < 0.001; Child-Turcotte-Pugh Classification C vs. A or B, p = 0.001, p = 0.007, respectively), variceal severity (p = 0.045), and bleeding (p = 0.047), as well as patients' mortality (p = 0.005). Furthermore, plasma IL-6 significantly correlated with tissues p-STAT3 expression (r = 0.737, p = 0.010) (IL-27: r = 0.078, p = 0.820; TNF-α: r = -0.145, p = 0.670; VEGF: r = 0.142, p = 0.678) in cirrhotic patients than noncirrhotic patients. CONCLUSION Over-expression of IL-6 reflects hepatic dysfunction and varices bleeding with mortality, as well as correlates p-STAT3 expression in cirrhotic patients.
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Affiliation(s)
- Jung-Ta Kao
- School of Medicine, China Medical University, Taichung, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Ju Yu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Lung Feng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shu-Mei Tsai
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yao-Li Chen
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Yi-Ying Wu
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
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23
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Fischer J, Silva TE, Soares E Silva PE, Colombo BS, Silva MC, Wildner LM, Bazzo ML, Rateke ECM, Frode TS, Mello SVD, Rosa JS, Dantas-Correa EB, Narciso-Schiavon JL, Schiavon LL. From stable disease to acute-on-chronic liver failure: Circulating cytokines are related to prognosis in different stages of cirrhosis. Cytokine 2017; 91:162-169. [PMID: 28082235 DOI: 10.1016/j.cyto.2016.12.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 11/24/2016] [Accepted: 12/21/2016] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Although both pro- and anti-inflammatory circulating cytokines are known to be elevated in liver cirrhosis, its clinical significance is not completely recognized. Our aim was to evaluate the prognostic significance of circulating cytokines interleukin (IL)-6, IL-17 and IL-10 in different stages of cirrhosis. METHODS This prospective study included two cohorts: (1) stable cirrhosis attended in the Outpatient Clinic (n=118), and (2) subjects hospitalized for acute decompensation (AD) (n=130). Thirty healthy subjects served as control group. RESULTS Patients with cirrhosis exhibited higher levels of cytokines as compared to controls. In stable cirrhosis, during a median follow-up of 17months, liver-related events occurred in 26 patients. Higher IL-10 levels and Child-Pugh B/C were independently associated with reduced event-free survival. In AD cohort, death after 90days of follow-up occurred in 39 patients and was independently associated with ascites, higher IL-6 and model for end-stage liver disease. IL-6 levels also showed higher AUROC than CRP for predicting bacterial infection in the AD cohort (0.831±0.043vs. 0.763±0.048, respectively). IL-17 decreased at third day of hospitalization only in patients who progressed to death. Higher IL-6 levels were observed in acute-on-chronic liver failure (ACLF) patients even in the absence of bacterial infection whereas IL-10 was higher only in subjects with infection-related ACLF. Higher IL-10 and IL-17 levels were associated with progression to death in ACLF. CONCLUSIONS The pattern of immune response seems to vary according to the phase of cirrhosis and is related to prognosis, from stable disease to ACLF.
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Affiliation(s)
- Josiane Fischer
- Division of Gastroenterology, Federal University of Santa Catarina, Brazil
| | | | | | | | | | | | - Maria Luiza Bazzo
- Department of Clinical Analysis, Federal University of Santa Catarina, Brazil
| | | | - Tania Silvia Frode
- Department of Clinical Analysis, Federal University of Santa Catarina, Brazil
| | | | - Júlia S Rosa
- Department of Clinical Analysis, Federal University of Santa Catarina, Brazil
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24
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Tsai CF, Chu CJ, Wang YP, Liu PY, Huang YH, Lin HC, Lee FY, Lu CL. Increased serum interleukin-6, not minimal hepatic encephalopathy, predicts poor sleep quality in nonalcoholic cirrhotic patients. Aliment Pharmacol Ther 2016; 44:836-45. [PMID: 27518472 DOI: 10.1111/apt.13765] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/07/2016] [Accepted: 07/24/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Sleep-wake disturbances are common in patients with cirrhosis and have a considerable effect on health-related quality of life; however, the underlying mechanism behind the phenomenon is unclear. Cytokines are involved in the mediation of signalling pathways regulating fibrogenesis, leading to cirrhosis. In addition, increased cytokines could contribute to sleep disturbances. AIM To determine the relationship between pro-inflammatory cytokines and sleep disturbance in cirrhotic patients. METHODS Ninety-eight nonalcoholic cirrhotic patients without overt hepatic encephalopathy were enrolled in this cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. The Psychometric Hepatic Encephalopathy Score (PHES) was used to examine cognitive performance and define minimal hepatic encephalopathy (MHE). The Hospital Anxiety and Depression Scale (HADS) was used to evaluate the mood status of the patients. Pro-inflammatory cytokines that include interleukin 6 (IL-6) and tumour necrosis factor-α, as well as HBV-DNA or HCV-RNA levels were determined in patients. RESULTS A total of 56 (57%) cirrhotic patients were identified as 'poor' sleepers (PSQI > 5). After multivariate analysis, IL-6 (P = 0.001) and HADS scores (P = 0.002) were found to be independent predictive factors of poor sleep quality. No significant relationships were observed between the sleep indices and the presence of MHE. HCV-RNA, but not HBV-DNA, viraemia was associated with sleep disturbance in cirrhotic patients. CONCLUSIONS Sleep disturbance is found commonly in cirrhotic patients and a high serum IL-6 level is predictive of poor sleep quality. Minimal hepatic encephalopathy by itself may not contribute to sleep dysfunction in cirrhotic patients.
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Affiliation(s)
- C-F Tsai
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - C-J Chu
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Y-P Wang
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - P-Y Liu
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
| | - Y-H Huang
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - H-C Lin
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - F-Y Lee
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - C-L Lu
- Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan. , .,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. , .,Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan. , .,Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. ,
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25
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Deleuran T, Overgaard S, Vilstrup H, Jepsen P. Cirrhosis is a risk factor for total hip arthroplasty for avascular necrosis. Acta Orthop 2016; 87:231-4. [PMID: 26900635 PMCID: PMC4900083 DOI: 10.3109/17453674.2016.1151122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Background and purpose - There are limited data on risk factors for avascular necrosis of the hip, but cirrhosis has been proposed as a risk factor. We examined the association between cirrhosis and incidence of total hip arthroplasty for avascular necrosis. Methods - We used nationwide healthcare data to identify all Danish residents diagnosed with cirrhosis in 1994-2011, and matched them 1:5 by age and sex to non-cirrhotic reference individuals from the general population. We excluded people with a previous total hip arthroplasty, a previous hip fracture, or a previous diagnosis of avascular necrosis. We used stratified Cox regression to estimate the hazard ratio (HR) for cirrhosis patients relative to reference individuals, adjusting for potential confounders. We used the cumulative incidence function to compute 5-year risks. Results - We included 25,421 cirrhosis patients and 114,052 reference individuals. Their median age was 57 years, and 65% were men. 45 cirrhosis patients and 44 reference individuals underwent total hip arthroplasty for avascular necrosis. Cirrhosis patients' HR for a total hip arthroplasty for avascular necrosis was 10 (95% CI: 6-17), yet their 5-year risk of avascular necrosis was only 0.2%. For the reference individuals, the 5-year risk was 0.02%. Interpretation - Cirrhosis is a strong risk factor for avascular necrosis of the hip, but it is rare even in cirrhosis patients.
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Affiliation(s)
- Thomas Deleuran
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus,,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus,,Correspondence:
| | - Søren Overgaard
- Department of Orthopedic Surgery and Traumatology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus,
| | - Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus,,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus,
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26
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Grønbæk H, Rødgaard-Hansen S, Aagaard NK, Arroyo V, Moestrup SK, Garcia E, Solà E, Domenicali M, Piano S, Vilstrup H, Møller HJ. Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure (ACLF). J Hepatol 2016; 64:813-22. [PMID: 26639396 DOI: 10.1016/j.jhep.2015.11.021] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Revised: 10/21/2015] [Accepted: 11/17/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Activation of liver macrophages plays a key role in liver and systemic inflammation and may be involved in development and prognosis of acute-on-chronic liver failure (ACLF). We therefore measured the circulating macrophage activation markers soluble sCD163 and mannose receptor (sMR) and related them to the short-(1-3 months) and long-term (6 months) mortality in the cirrhosis patients of the CANONIC study. METHODS Eighty-six cirrhosis patients had no ascites and no ACLF, 580 had ascites but no ACLF; 100, 66, and 19 had ACLF-grade-I (ACLF-I), ACLF-II, and ACLF-III, respectively. The patients' clinical course was registered and their MELD, CLIF-C Acute Decompensation (AD), and CLIF-C ACLF-scores computed at inclusion. RESULTS We found a stepwise increase (p<0.001) in median sCD163 (5.68 (IQR: 3.86-9.60); 8.26 (5.02-12.34); 9.50 (5.37-17.91); 15.68 (10.12-19.42); 20.18 (15.26-32.20) mg/L) and sMR (0.60 (0.40-0.84); 0.81 (0.57-1.12); 0.81 (0.61-1.26); 1.17 (0.89-1.62); 1.41 (1.14-1.79)mg/L) with increasing grades of ACLF. Both sCD163 and sMR were independently associated with short and long-term mortality and showed equal or higher predictive accuracy than MELD, CLIF-C ACLF and CLIF-C AD scores. Addition of the macrophage markers to the clinical scores improved the prognostic efficacy: In ACLF patients sCD163 improved prediction of short-term mortality (C-index: 0.74 (0.67-0.80)) and in patients without ACLF sMR improved prediction of long-term mortality (C-index: 0.80 (0.76-0.85)). CONCLUSIONS The severity related increase in sCD163 and sMR and close association with mortality suggest a primary importance of inflammatory activation of liver macrophages in the emergence and course of ACLF. Accordingly, supplementation of the macrophage biomarkers to the platform of the clinical scores improved the prognostic performance beyond that of the original scores.
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Affiliation(s)
- Henning Grønbæk
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | | | - Niels Kristian Aagaard
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | - Søren K Moestrup
- Department of Biomedicine, Aarhus University, Aarhus & Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | | | - Elsa Solà
- Liver Unit, Hospital Clinic de Barcelona, Unviersity of Barcelona, IDIBAPS, CIBEReHD, Barcelona, Spain
| | - Marco Domenicali
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Salvatore Piano
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Hendrik Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
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Gnauck A, Lentle RG, Kruger MC. Chasing a ghost?--Issues with the determination of circulating levels of endotoxin in human blood. Crit Rev Clin Lab Sci 2016; 53:197-215. [PMID: 26732012 DOI: 10.3109/10408363.2015.1123215] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Reliable quantification of bacterial products such as endotoxin is important for the diagnosis of Gram-negative infection and for the monitoring of its treatment. Further, it is important to identify patients with persistent subclinical level of bacterial products in their systemic circulation as data from animal studies also suggest this may be correlated with the onset of metabolic syndrome. In this review, we first aim to describe the principles of the Limulus amoebocyte lysate (LAL) test, an assay that is used to quantify endotoxin, and the various shortcomings that must be addressed before it can become a reliable means of quantifying endotoxin in samples derived from blood. We then review published data regarding endotoxin levels in healthy subjects and those with sepsis, inflammatory bowel disease, liver disorders and metabolic disorders such as obesity and diabetes. We also review the evidence regarding influence of macronutrients in augmenting the levels of systemic endotoxin. The results of this review show that reported mean levels of endotoxin in the systemic circulation of healthy humans and of those with various clinical disorders vary over a wide range. Further, this review shows that a significant proportion of this variation can be related to the method that was used to prepare plasma and serum samples prior to assay and its ability to reduce the effect of various blood borne factors that interfere with the LAL assay.
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Affiliation(s)
- Anne Gnauck
- a Physiology Group, School of Food and Nutrition, College of Health, Massey University , Palmerston North , New Zealand
| | - Roger Graham Lentle
- a Physiology Group, School of Food and Nutrition, College of Health, Massey University , Palmerston North , New Zealand
| | - Marlena Cathorina Kruger
- a Physiology Group, School of Food and Nutrition, College of Health, Massey University , Palmerston North , New Zealand
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28
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Liver Failure Impairs the Intrahepatic Elimination of Interleukin-6, Tumor Necrosis Factor-Alpha, Hepatocyte Growth Factor, and Transforming Growth Factor-Beta. BIOMED RESEARCH INTERNATIONAL 2015; 2015:934065. [PMID: 26090463 PMCID: PMC4454738 DOI: 10.1155/2015/934065] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 04/23/2015] [Accepted: 04/27/2015] [Indexed: 11/17/2022]
Abstract
The strategic location of the liver and its metabolic activity make it a key organ regulating homeostasis. Our purpose was to examine its participation in removal of cytokines: interleukin-6 (Il-6), tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-β) from the portal circulation in human. 20 liver donors and 20 patients with end-stage liver failure were included in the study. Their blood was collected during liver transplantation from the portal, hepatic, and peripheral vein, and the hepatic artery and cytokines' concentrations were determined. Using the results the mathematical model of cytokine elimination by the liver was developed. In donors significantly lower levels of IL-6, TNF-α, HGF, and TGF-β were detected in portal blood compared to hepatic vein. In patients with cirrhosis there were no significant differences of IL-6, TNF-α, and TGF-β levels between portal and hepatic veins. Significantly higher level of HGF in hepatic compared to portal vein was observed. In healthy liver elimination of the cytokines prevailed over their synthesis, as reflected by the positive values of the elimination ratios. In the cirrhotic liver elimination ratios of Il-6, HGF, and TGF-β were negative indicating the prevalence of intrahepatic synthesis of cytokines over their removal.
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29
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Fukui H. Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia. World J Hepatol 2015; 7:425-442. [PMID: 25848468 PMCID: PMC4381167 DOI: 10.4254/wjh.v7.i3.425] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 12/14/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
A “leaky gut” may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin, activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.
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30
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Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61:1385-96. [PMID: 25135860 DOI: 10.1016/j.jhep.2014.08.010] [Citation(s) in RCA: 837] [Impact Index Per Article: 76.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 07/27/2014] [Accepted: 08/09/2014] [Indexed: 02/06/2023]
Abstract
The term cirrhosis-associated immune dysfunction refers to the main syndromic abnormalities of immune function, immunodeficiency and systemic inflammation that are present in cirrhosis. The course of advanced cirrhosis, regardless of its aetiology, is complicated by cirrhosis-associated immune dysfunction and this constitutes the pathophysiological hallmark of an increased susceptibility to bacterial infection, distinctive of the disease. Cirrhosis impairs the homeostatic role of the liver in the systemic immune response. Damage to the reticulo-endothelial system compromises the immune surveillance function of the organ and the reduced hepatic synthesis of proteins, involved in innate immunity and pattern recognition, hinders the bactericidal ability of phagocytic cells. Systemic inflammation, in form of activated circulating immune cells and increased serum levels of pro-inflammatory cytokines, is the result of persistent episodic activation of circulating immune cells from damage-associated molecular patterns, released from necrotic liver cells and, as cirrhosis progresses, from pathogen-associated molecular patterns, released from the leaky gut. Cirrhosis-associated immune dysfunction phenotypes switch from predominantly "pro-inflammatory" to predominantly "immunodeficient" in patients with stable ascitic cirrhosis and in patients with severely decompensated cirrhosis and extra-hepatic organ failure (e.g. acute-on-chronic liver failure), respectively. These cirrhosis-associated immune dysfunction phenotypes represent the extremes of a spectrum of reversible dynamic events that take place during the course of cirrhosis. Systemic inflammation can affect the functions of tissue somatic cells and modify the clinical manifestation of cirrhosis. The best characterized example is the contribution of systemic inflammation to the haemodynamic derangement of cirrhosis, which correlates negatively with prognosis.
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Affiliation(s)
- Agustín Albillos
- Department of Medicine, Universidad de Alcalá, Madrid, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Service of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
| | - Margaret Lario
- Department of Medicine, Universidad de Alcalá, Madrid, Spain
| | - Melchor Álvarez-Mon
- Department of Medicine, Universidad de Alcalá, Madrid, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Service of Immune Diseases and Oncology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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Arroyo V, García-Martinez R, Salvatella X. Human serum albumin, systemic inflammation, and cirrhosis. J Hepatol 2014; 61:396-407. [PMID: 24751830 DOI: 10.1016/j.jhep.2014.04.012] [Citation(s) in RCA: 407] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 04/04/2014] [Accepted: 04/06/2014] [Indexed: 12/16/2022]
Abstract
Human serum albumin (HSA) is one of the most frequent treatments in patients with decompensated cirrhosis. Prevention of paracentesis-induced circulatory dysfunction, prevention of type-1 HRS associated with bacterial infections, and treatment of type-1 hepatorenal syndrome are the main indications. In these indications treatment with HSA is associated with improvement in survival. Albumin is a stable and very flexible molecule with a heart shape, 585 residues, and three domains of similar size, each one containing two sub-domains. Many of the physiological functions of HSA rely on its ability to bind an extremely wide range of endogenous and exogenous ligands, to increase their solubility in plasma, to transport them to specific tissues and organs, or to dispose of them when they are toxic. The chemical structure of albumin can be altered by some specific processes (oxidation, glycation) leading to rapid clearance and catabolism. An outstanding feature of HSA is its capacity to bind lipopolysaccharide and other bacterial products (lipoteichoic acid and peptidoglycan), reactive oxygen species, nitric oxide and other nitrogen reactive species, and prostaglandins. Binding to NO and prostaglandins are reversible, so they can be transferred to other molecules at different sites from their synthesis. Through these functions, HSA modulates the inflammatory reaction. Decompensated cirrhosis is a disease associated systemic inflammation, which plays an important role in the pathogenesis of organ or system dysfunction/failure. Although, the beneficial effects of HAS have been traditionally attributed to plasma volume expansion, they could also relate to its effects modulating systemic and organ inflammation.
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Affiliation(s)
- Vicente Arroyo
- Liver Unit, Hospital Clinic, Centre Esther Koplowitz, IDIBAPS, University of Barcelona, Barcelona, Spain; EASL-Cronic Liver Failure Consortium, Fundació Clinic, Barcelona, Spain.
| | | | - Xavier Salvatella
- ICREA and BSC-CRG-IRB Research Programme in Computational Biology, IRB Barcelona (IRB), Barcelona, Spain
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Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver cirrhosis. J Hepatol 2014; 60:197-209. [PMID: 23993913 DOI: 10.1016/j.jhep.2013.07.044] [Citation(s) in RCA: 551] [Impact Index Per Article: 50.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 06/20/2013] [Accepted: 07/19/2013] [Indexed: 12/11/2022]
Affiliation(s)
- Reiner Wiest
- Department Gastroenterology, Inselspital, University Hospital, Bern 3010, Switzerland.
| | - Melissa Lawson
- Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern, Bern 3010, Switzerland
| | - Markus Geuking
- Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern, Bern 3010, Switzerland
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Petrtyl J, Dvorak K, Jachymova M, Vitek L, Lenicek M, Urbanek P, Linhart A, Jansa P, Bruha R. Functional variants of eNOS and iNOS genes have no relationship to the portal hypertension in patients with liver cirrhosis. Scand J Gastroenterol 2013; 48:592-601. [PMID: 23452051 DOI: 10.3109/00365521.2013.773459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Nitric oxide is an important vasoactive mediator. Changes in NO production, caused by functional variants of both endothelial and inducible NO synthase (eNOS, iNOS), might play a role in portal hypertension. The aim was to study the significance of functional eNOS and iNOS gene variants in cirrhotic patients and their interrelationship to both inflammatory and endothelial activation parameters. MATERIAL AND METHODS One hundred and thirty-two patients with liver cirrhosis (age 36-72 years) and 101 controls were examined for functional variants of eNOS (E298D, 27bpintr4, 786T/C) and iNOS (R221W, S608L) genes. Inflammatory (IL6, IL8, IL10) and vasoactive (sVCAM-1, E-selectin) cytokines were measured using ELISA kits. RESULTS The frequency of E298D (GG 12%, GT 41%, TT 47%), 28bpintr4 (AA 6%, AB 28%, BB 66%), 786T/C genotypes (CC 17%, CT 45%, TT 38%), as well as R221W (CC 93%, CT 7%, TT 0%), and S608L (CC 65%, CT 32%, TT 3%) genotypes in cirrhotic patients did not differ from the controls (p > 0.05 for all comparisons). No relationship was found between the frequency of these genotypes and the severity of portal hypertension, or either inflammatory or vasoactive cytokines. A positive correlation was found between hepatic venous pressure gradient and cytokine concentration: sVCAM-1, IL6, IL8, IL10. CONCLUSIONS Examined eNOS and iNOS variants have no relationship to pathogenesis of liver cirrhosis. Severity of portal hypertension was associated with the changes in endothelial activation.
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Affiliation(s)
- Jaromir Petrtyl
- Charles University in Prague, 1st Faculty of Medicine, 4th Department of Internal Medicine, U Nemocnice 2, Prague 2, Czech Republic
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Huang HC, Haq O, Utsumi T, Sethasine S, Abraldes JG, Groszmann RJ, Iwakiri Y. Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure. J Cell Mol Med 2012; 16:1125-33. [PMID: 21801303 PMCID: PMC3213314 DOI: 10.1111/j.1582-4934.2011.01399.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Increased levels of intestinal VEGF are thought to worsen portal hypertension. The cause of the increase in the level of intestinal VEGF found during cirrhosis is not known. The aim of this study is to demonstrate a relationship between portal pressure (PP) and intestinal/ plasma VEGF levels in different stages of fibrosis/cirrhosis. In this experiment, rats were exposed to carbon tetrachloride (CCl4) for 6, 8 and 12 weeks. At the end of exposure, the three groups of rats exhibited three different stages of pathology: non-cirrhotic, early fibrotic and cirrhotic, respectively. For those rats and their age-matched controls, PP and intestinal/plasma VEGF levels were measured. Rats inhaling CCl4 for 12 weeks developed portal hypertension (18.02 ± 1.07 mmHg), while those exposed for 6 weeks (7.26 ± 0.58 mmHg) and for 8 weeks (8.55 ± 0.53 mmHg) did not. The rats exposed for 12 weeks also showed a 40% increase in the level of intestinal VEGF compared to the controls (P < 0.05), while those rats exposed to CCl4 inhalation for 6 and 8 weeks did not. There was a significant positive correlation between PP and intestinal VEGF levels (r2 = 0.4, P < 0.005). Plasma VEGF levels were significantly elevated in those rats exposed to 12 weeks of CCl4 inhalation (63.7 pg/ml, P < 0.01), compared to the controls (8.5 pg/ml). However, no correlation was observed between PP and plasma VEGF levels. It is concluded that portal pressure modulates intestinal VEGF levels during the development of cirrhosis.
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Affiliation(s)
- Hui-Chun Huang
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
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Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. Clin Gastroenterol Hepatol 2012; 10:815-8. [PMID: 22391344 DOI: 10.1016/j.cgh.2012.02.025] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Revised: 02/16/2012] [Accepted: 02/20/2012] [Indexed: 02/07/2023]
Abstract
Circulating levels of endotoxin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α increase with intestinal bacterial overgrowth and translocation, and are believed to be involved in the pathogenesis of hyperdynamic circulatory syndrome and functional renal failure in patients with advanced cirrhosis. We investigated the effects of the antibiotic rifaximin on systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. We measured mean arterial pressure, cardiac output (CO) by Doppler ultrasound, systemic vascular resistance (as the ratio of mean arterial pressure:CO), plasma renin activity, levels of plasma aldosterone, the glomerular filtration rate by plasma clearance of technetium-99m-DTPA, natriuresis, levels of plasma endotoxin, and serum levels of IL-6 and TNF-α in 13 patients at baseline and after 4 weeks of treatment with rifaximin. Rifaximin treatment significantly reduced CO and significantly increased systemic vascular resistance, in association with a significant decrease in plasma rennin activity. The therapy also significantly increased the glomerular filtration rate and natriuresis while reducing levels of endotoxin, IL-6, and TNF-α. Intestinal decontamination with rifaximin improved systemic hemodynamics and renal function in patients with advanced cirrhosis.
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Estrogen suppresses heptatic IκB expression during short-term alcohol exposure. Inflamm Res 2012; 61:1053-61. [DOI: 10.1007/s00011-012-0497-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 04/25/2012] [Accepted: 05/22/2012] [Indexed: 02/07/2023] Open
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Kalambokis GN, Mouzaki A, Rodi M, Pappas K, Korantzopoulos P, Tsianos EV. Circulating endotoxin and interleukin-6 levels are associated with Doppler-evaluated pulmonary vascular resistance in cirrhotic patients. Hepatol Int 2012. [PMID: 26201526 DOI: 10.1007/s12072-011-9337-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
PURPOSE Endotoxin and interleukin-6 levels (IL-6) have been involved in the development of pulmonary hypertension (PH) in non-cirrhotic experimental models and subjects. High circulating levels of both substances have been detected in cirrhosis. The association between circulating endotoxin and IL-6 levels and echocardiographically evaluated pulmonary vascular resistance (PVR) in cirrhotic patients are investigated. METHODS Thirty-seven cirrhotic patients were studied: 25 with PVR <120 dynes s cm(-5) (group 1) and 12 with PVR >120 dynes s cm(-5) (group 2). Plasma endotoxin and serum IL-6 levels were measured. The PVR and cardiac output (CO) by Doppler ultrasound, mean arterial pressure (MAP), and systemic vascular resistance (SVR) as the ratio MAP/CO were evaluated. RESULTS Child-Pugh scores, MAP, CO, and SVR were similar in both groups. Endotoxin levels were correlated significantly with IL-6 levels (r = 0.342; P = 0.03). Endotoxin and IL-6 levels were significantly higher in group 2 compared to group 1 (2.26 [0.39-8.4] vs. 0.85 [0.37-7.6] EU/mL; P = 0.04 and 37.4 [7.85-106.5] vs. 8.36 [3.15-53.7] pg/mL; P < 0.001, respectively). The PVR was correlated significantly with endotoxin levels in group 2 (r = 0.587; P = 0.04) and with IL-6 levels in group 1 (r = 0.529; P = 0.01) and group 2 (r = 0.760; P = 0.004), respectively. CONCLUSIONS Our results suggest that endotoxin and IL-6 may contribute to cirrhosis-associated PH. In this regard, modulation of these substances could improve pulmonary pressures in cirrhotic patients.
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Affiliation(s)
- Georgios N Kalambokis
- First Division of Internal Medicine and Hepato-Gastroenterology Unit, Medical School of Ioannina, University Hospital, 45110, Ioannina, Greece.
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Maria Rodi
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | | | | | - Epameinondas V Tsianos
- First Division of Internal Medicine and Hepato-Gastroenterology Unit, Medical School of Ioannina, University Hospital, 45110, Ioannina, Greece.
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Peters L, Neuhaus J, Mocroft A, Soriano V, Rockstroh J, Dore G, Puoti M, Tedaldi E, Clotet B, Kupfer B, Lundgren JD, Klein MB. Hyaluronic acid levels predict increased risk of non-AIDS death in hepatitis-coinfected persons interrupting antiretroviral therapy in the SMART Study. Antivir Ther 2012; 16:667-75. [PMID: 21817188 DOI: 10.3851/imp1815] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND In the SMART study, HIV-viral-hepatitis-coinfected persons were, compared with HIV-monoinfected persons, at higher risk of non-AIDS death if randomized to the antiretroviral therapy (ART) interruption strategy. We hypothesized that a marker of liver fibrosis, hyaluronic acid (HA), would be predictive of development of non-AIDS-related outcomes in coinfected participants in the SMART study. METHODS All participants positive for HCV RNA or hepatitis B surface antigen (HBsAg) and with stored plasma samples were included (n=675). Plasma samples were tested for HA (normal range 0-75 ng/ml) at baseline and months 6, 12 and 24 during follow-up in the drug conservation (DC; interrupt ART until CD4(+) T-cell count <250) group and the viral suppression (VS; continued use of ART) group. Time to non-AIDS death was investigated using Kaplan-Meier analysis. RESULTS Overall, 52 (31 in DC and 21 in VS) coinfected participants died during follow-up. Coinfected participants who were randomized to the DC group with baseline HA>75 ng/ml had a cumulative risk of non-AIDS death of 24.6% after 36 months of follow-up compared with 9.3% for participants randomized to the VS group (P=0.005), while the cumulative risk for coinfected participants with HA ≤ 75 ng/ml was 4.1% (DC) and 4.7% (VS; P=0.76). The change in HA from baseline to month 24 was 8.3 ng/ml and 4.7 ng/ml in the DC and VS group (P=0.56), respectively. CONCLUSIONS Interruption of ART was particularly unsafe in HIV-hepatitis-coinfected individuals if plasma HA was increased. HA changed very little during follow-up and was not influenced by differences in CD4(+) T-cell count or HIV viral load.
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The Effect of Caffeic Acid Phenethyl Ester (CAPE) Against Cholestatic Liver Injury in Rats. J Surg Res 2010; 159:674-9. [DOI: 10.1016/j.jss.2008.10.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2008] [Revised: 10/16/2008] [Accepted: 10/27/2008] [Indexed: 01/07/2023]
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Shiraki M, Terakura Y, Iwasa J, Shimizu M, Miwa Y, Murakami N, Nagaki M, Moriwaki H. Elevated serum tumor necrosis factor-alpha and soluble tumor necrosis factor receptors correlate with aberrant energy metabolism in liver cirrhosis. Nutrition 2009; 26:269-75. [PMID: 19695831 DOI: 10.1016/j.nut.2009.04.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Revised: 04/22/2009] [Accepted: 04/22/2009] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Protein-energy malnutrition is frequently observed in patients with liver cirrhosis and is associated with their poor prognosis. Tumor necrosis factor-alpha (TNF-alpha) is elevated in those patients and may contribute to the alterations of energy metabolism. Our aim was to characterize the aberrant energy metabolism in cirrhotic patients with regard to TNF-alpha. METHODS Twenty-four patients (mean age 65 +/- 6 y) with viral liver cirrhosis who did not have hepatocellular carcinoma or acute infections were studied. Twelve healthy volunteers were recruited after matching for age, gender, and body mass index with the patients and served as controls (59 +/- 8 y). Serum levels of TNF-alpha, soluble 55-kDa TNF receptor (sTNF-R55), soluble 75-kDa TNF receptor (sTNF-R75), and leptin were determined by immunoassay. Substrate oxidation rates of carbohydrate and fat were estimated by indirect calorimetry after overnight bedrest and fasting. RESULTS In cirrhotic patients, serum levels of TNF-alpha, sTNF-R55, and sTNF-R75 were significantly higher than those in the controls and correlated with the increasing grade of disease severity as defined by Child-Pugh classification. Serum leptin concentration was not different between cirrhotics and controls but correlated with their body mass index. The decrease in substrate oxidation rate of carbohydrate and the increase in substrate oxidation rate of fat significantly correlated with serum TNF-alpha, sTNF-R55, and sTNF-R75 concentrations. CONCLUSION Tumor necrosis factor-alpha might be associated with the aberrant energy metabolism in patients with liver cirrhosis.
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Affiliation(s)
- Makoto Shiraki
- Department of Internal Medicine, Gifu University School of Medicine, Yanagido, Gifu, Japan.
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Riordan SM, Skinner NA, McIver CJ, Liu Q, Bengmark S, Bihari D, Visvanathan K. Synbiotic-associated improvement in liver function in cirrhotic patients: Relation to changes in circulating cytokine messenger RNA and protein levels. MICROBIAL ECOLOGY IN HEALTH AND DISEASE 2009. [DOI: 10.1080/08910600601178709] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Stephen M. Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, Australia
| | - Narelle A. Skinner
- Department of Infectious Diseases, Monash Medical Centre and Monash University, Melbourne, Australia
| | - Christopher J. McIver
- Department of Microbiology, Prince of Wales Hospital and University of New South Wales, Sydney, Australia
| | - Qing Liu
- Gastrointestinal and Liver Unit, Prince of Wales Hospital and University of New South Wales, Sydney, Australia
| | - Stig Bengmark
- Institute of Hepatology, University College London, UK
| | - David Bihari
- Department of Intensive Care, Prince of Wales Hospital and University of New South Wales, Sydney, Australia
| | - Kumar Visvanathan
- Department of Infectious Diseases, Monash Medical Centre and Monash University, Melbourne, Australia
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Grünhage F, Rezori B, Neef M, Lammert F, Sauerbruch T, Spengler U, Reichel C. Elevated soluble tumor necrosis factor receptor 75 concentrations identify patients with liver cirrhosis at risk of death. Clin Gastroenterol Hepatol 2008; 6:1255-62. [PMID: 18995216 DOI: 10.1016/j.cgh.2008.06.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2007] [Revised: 06/17/2008] [Accepted: 06/23/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Elevated levels of the soluble 75-kd receptor for tumor necrosis factor-alpha (sTNF-R 75) are better predictors of mortality in cirrhosis than the Child-Turcotte-Pugh (CTP) score. Thus, we compared sTNF-R 75 with the Model for End-Stage Liver Disease (MELD), CTP, and the sTNF-R 75/55 ratio. METHODS Ninety-two patients with liver cirrhosis (mean age, 55 years; range, 19-76 years; male, 66%; CTP stage C, 41%) were included in our prospective single-center survival study. The study setting was a tertiary care university clinic. Soluble TNF-R levels were determined, and the primary end point was death. RESULTS During > or =730 days, 44 patients died. Multivariate Cox regression analysis revealed sTNF-R 75 (> or =14 ng/mL) as an independent predictor of mortality (hazard ratio, 2.53; P = .006). By receiver operating characteristic, MELD and sTNF-R 75 were more accurate in predicting 6-, 15-, and 24-month mortality than CTP and sTNF-R 75/55. This was significant for 6 months (MELD, 0.78; sTNF-R 75, 0.75 vs sTNF-R 75/55, 0.60). In patients with high MELD scores (> or =15), survival was further reduced if sTNF-R 75 values were elevated (P = .035). CONCLUSIONS Elevated sTNF-R 75 levels independently predicted mortality and improved MELD on the basis of evaluation of prognosis, especially in patients with high MELD scores. Thus, sTNF-R 75 levels might be a useful cytokine-based prognostic marker in patients with liver cirrhosis.
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Affiliation(s)
- Frank Grünhage
- Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Bonn, Germany
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Lee S, Son SC, Han MJ, Kim WJ, Kim SH, Kim HR, Jeon WK, Park KH, Shin MG. Increased intestinal macromolecular permeability and urine nitrite excretion associated with liver cirrhosis with ascites. World J Gastroenterol 2008; 14:3884-90. [PMID: 18609714 PMCID: PMC2721447 DOI: 10.3748/wjg.14.3884] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine intestinal permeability, the serum tumor necrosis factor (TNF)-α level and urine nitric oxide (NO) metabolites are altered in liver cirrhosis (LC) with or without ascites.
METHODS: Fifty-three patients with LC and 26 healthy control subjects were enrolled in the study. The intestinal permeability value is expressed as the percentage of polyethylene glycol (PEG) 400 and 3350 retrieval in 8-h urine samples as determined by high performance liquid chromatography. Serum TNF-α concentrations and urine NO metabolites were determined using an enzyme-linked immunosorbent assay (ELISA) and Greiss reaction method, respectively.
RESULTS: The intestinal permeability index was significantly higher in patients with LC with ascites than in healthy control subjects or patients with LC without ascites (0.88 ± 0.12 vs 0.52 ± 0.05 or 0.53 ± 0.03, P < 0.05) and correlated with urine nitrite excretion (r = 0.98). Interestingly, the serum TNF-α concentra-tion was significantly higher in LC without ascites than in control subjects or in LC with ascites (198.9 ± 55.8 pg/mL vs 40.9 ± 12.3 pg/mL or 32.1 ± 13.3 pg/mL, P < 0.05). Urine nitrite excretion was significantly higher in LC with ascites than in the control subjects or in LC without ascites (1170.9 ± 28.7 &mgr;mol/L vs 903.1 ± 55.1 &mgr;mol/L or 956.7 ± 47.7 &mgr;mol/L, P < 0.05).
CONCLUSION: Increased intestinal macromolecular permeability and NO is probably of importance in the pathophysiology and progression of LC with ascites, but the serum TNF-α concentration was not related to LC with ascites.
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Auguet T, Vidal F, López-Dupla M, Broch M, Gutiérrez C, Olona M, Oltra C, Aguilar C, González E, Quer JC, Sirvent JJ, Richart C. A study on the TNF-alpha system in Caucasian Spanish patients with alcoholic liver disease. Drug Alcohol Depend 2008; 92:91-9. [PMID: 17728075 DOI: 10.1016/j.drugalcdep.2007.07.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2007] [Revised: 06/21/2007] [Accepted: 07/01/2007] [Indexed: 12/20/2022]
Abstract
BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) is thought to be a critical driving force of inflammatory damage in alcoholic liver disease (ALD). We aimed to establish whether there is a correlation between plasma levels of the soluble TNF-alpha receptors 1 and 2 (sTNFR1 and sTNFR2) and the severity of liver damage in patients with ALD. We also aimed to elucidate whether functionally active polymorphisms in the promoter region of the TNF-alpha gene modulate the development of ALD. DESIGN We studied 614 Spaniards. Of these, 278 were alcoholics (103 without liver histologic abnormalities, 89 with non-cirrhotic liver disease and 86 with cirrhosis) and 336 were non-alcoholics (115 healthy controls, 114 with non-alcoholic non-cirrhotic liver disease and 107 with cirrhosis unrelated to alcohol). Plasma levels of sTNFR1 and sTNFR2 were determined by ELISA and results were expressed in ng/mL and subsequently converted in log(10). TNF-alpha gene promoter region polymorphisms at the positions -238, -308 and -863 were assessed by restriction fragment length polymorphisms (RFLPs) on white cell DNA. Differences in plasma sTNFR1 and sTNFR2 levels between groups were compared with the one-way and two-factor analysis of variance test, and Student's t-test. Genotype distribution and allele frequencies in the different groups were compared using the chi(2) test or Fisher's exact test. RESULTS sTNFR1 and sTNFR2 plasma levels were significantly higher in patients with cirrhosis than in those with non-cirrhotic liver disease (p<0.001) and individuals without liver disease (p<0.001), both in the alcoholic and the non-alcoholic group. Among cirrhotics, sTNFR1 and sTNFR2 levels had a significant positive correlation with the severity of the liver disease, graded with the Child-Pugh's score (p=0.003 and p<0.001, respectively). TNF-alpha genotype distribution and allele frequencies of the three loci assessed were similar in the groups studied, hence no particular genotype or haplotype could be linked to ALD. CONCLUSIONS The TNF-alpha system is activated in patients with cirrhosis of the liver irrespective of aetiology. TNF-alpha polymorphisms at positions -238, -308 and -863 are not linked to ALD.
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MESH Headings
- Aged
- Alcohol Drinking/psychology
- DNA/genetics
- Female
- Genotype
- Humans
- Liver Diseases, Alcoholic/epidemiology
- Liver Diseases, Alcoholic/genetics
- Male
- Middle Aged
- Polymorphism, Restriction Fragment Length/genetics
- Polymorphism, Single Nucleotide/genetics
- Promoter Regions, Genetic/genetics
- Prospective Studies
- Receptors, Tumor Necrosis Factor, Type I/blood
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type II/blood
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Spain/epidemiology
- Tumor Necrosis Factor-alpha/genetics
- White People
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Affiliation(s)
- Teresa Auguet
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain; Universitat Rovira i Virgili, Tarragona, Spain.
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Horiguchi N, Ishac EJN, Gao B. Liver regeneration is suppressed in alcoholic cirrhosis: correlation with decreased STAT3 activation. Alcohol 2007; 41:271-80. [PMID: 17630087 PMCID: PMC1986734 DOI: 10.1016/j.alcohol.2007.04.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2007] [Revised: 04/18/2007] [Accepted: 04/18/2007] [Indexed: 02/06/2023]
Abstract
UNLABELLED Liver regeneration is suppressed in alcoholic patients; however, the underlying mechanisms are not fully understood. We examined liver regeneration and signal transducer and activator of transcription 3 (STAT3) activation (an important signal for liver regeneration) in cirrhotic livers from alcoholics, hepatitis C virus (HCV) infection, and alcoholic plus HCV infection. Liver regeneration and STAT3 activation were determined by immunohistochemistry analysis of Ki67 and STAT3 phosphorylation, respectively, in 20 alcoholic cirrhosis, 13 HCV cirrhosis, 13 alcoholic+HCV cirrhosis. Alcoholic or alcoholic plus HCV cirrhotic livers had significantly lower Ki67+ and phospho-STAT3+ (pSTAT3+) hepatocytes and bile duct cells than HCV cirrhotic livers. The pSTAT3 positive staining did not correlate with liver injury (elevation of serum levels of aspartate transaminase [AST] and alkaline phosphatase [ALP]) but correlated positively with cell proliferation (Ki67 positive staining). IN CONCLUSION liver regeneration is suppressed in alcoholic cirrhotic livers, which may be partly due to decreased STAT3 activation.
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Affiliation(s)
- Norio Horiguchi
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892
| | - Edward JN Ishac
- Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Bin Gao
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892
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Elsing C, Harenberg S, Stremmel W, Herrmann T. Serum levels of soluble Fas, nitric oxide and cytokines in acute decompensated cirrhotic patients. World J Gastroenterol 2007; 13:421-5. [PMID: 17230612 PMCID: PMC4065898 DOI: 10.3748/wjg.v13.i3.421] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate plasma levels of nitrite/nitrate (NOx), soluble Fas (sFas) antigen, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in patients with compensated and acute decompensated cirrhosis and to evaluate mediators causing acute decompensation in liver cirrhosis.
METHODS: This prospective study was conducted in the medical intensive care unit of an academic tertiary center. Fifty-five patients with acute decompensation (gastrointestinal hemorrhage, encephalopathy, hydropic decompensation) and twenty-five patients with compensated liver cirrhosis were included. Blood samples were taken for analyses of sFas, Nox, IL-6, TNF-α. Liver enzymes and kidney functions were also tested.
RESULTS: In patients with acute decompensation, plasma sFas levels were higher than in non-decompensated patients (15 305 ± 4646 vs 12 458 ± 4322 pg/mL, P < 0.05). This was also true for the subgroup of patients with alcoholic liver cirrhosis (P < 0.05). The other mediators were not different and none of the parameters predicted survival, except for ALT (alanine-aminotransferase). In patients with portal-hypertension-induced acute hemorrhage, NOx levels were significantly lower than in patients with other forms of decompensation (70.8 ± 48.3 vs 112.9 ± 74.9 pg/mL, P < 0.05). When NOx levels were normalized to creatinine levels, the difference disappeared. IL-6, TNF-α and sFas were not different between bleeders and non-bleeders. In decompensated patients sFas, IL-6 and NOx levels correlated positively with creatinine levels, while IL-6 levels were dependent on Child class.
CONCLUSION: In acute decompensated cirrhotic patients sFas is increased, suggesting a role of apoptosis in this process and patients with acute bleeding have lower NOx levels. However, in this acute complex clinical situation, kidney function seems to have a predominant influence on mediator levels.
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Affiliation(s)
- Christoph Elsing
- Gastroenterology, Department of Medicine, St. Elisabeth-Hospital, PO Box 580, Dorsten 46225, Germany.
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48
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Yilmaz M, Ara C, Isik B, Karadag N, Yilmaz S, Polat A, Coban S, Duzova H. The effect of aminoguanidine against cholestatic liver injury in rats. Cell Biochem Funct 2007; 25:625-32. [PMID: 16892451 DOI: 10.1002/cbf.1359] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
We investigated the protective role of aminoguanidine (AG) in rat liver injury induced by chronic biliary obstruction. Secondary biliary cirrhosis was induced by bile duct ligation for 14 days. Swiss albino rats were divided into three groups: Common bile duct ligated (CBDL) rats; Group A, CBDL rats treated with AG as Group B and simple laparotomy group known as the Sham group; Group C. Group B received 200 mg/kg of AG intraperitoneally daily throughout 14 days. The present data showed decreased gama glutamyl transferase (GGT), aspartate aminotransferase (AST), bilirubin and alanine aminotransferase (ALT) levels in the AG treated rats, when compared with CBDL rats (p < 0.05). In the AG treated rats, tissue levels of malondialdehyde (MDA) were significantly lower than that in CBDL rats (p < 0.001). Although the levels of glutathione (GSH) in AG treated rats were higher and myeloperoxidase (MPO) were lower than that in CBDL rats, the difference was not statistically significant (p > 0.05). The levels of interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) were significantly lower and although the levels of interleukin-6 (IL-6) were lower in AG treated rats than that in CBDL rats, the difference was not statistically significant. Administration of AG in the rats with biliary obstruction resulted in inhibition of ductular proliferation and portal inflammation. The present study demonstrates that intraperitoneal administration of AG in CBDL rats maintains antioxidant defenses, reduces liver oxidative and cytokine damage and ductular proliferation and portal inflammation. This effect of AG may be useful in the preservation of liver injury in cholestasis.
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Affiliation(s)
- Mehmet Yilmaz
- Department of General Surgery, Inonu University School of Medicine, Turkey
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49
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Bruha R, Vitek L, Petrtyl J, Lenicek M, Urbanek P, Zelenka J, Jachymova M, Svestka T, Kalab M, Dousa M, Marecek Z. Effect of carvedilol on portal hypertension depends on the degree of endothelial activation and inflammatory changes. Scand J Gastroenterol 2006; 41:1454-63. [PMID: 17101577 DOI: 10.1080/00365520600780403] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Bleeding from esophageal varices is a major complication of liver cirrhosis. Non-selective beta-blockers exert an influence on the functional part of portal hypertension, thereby reducing the risk of bleeding. Direct measurement of this functional part is not possible; nevertheless, pro-inflammatory markers as well as parameters of endothelial dysfunction might serve as surrogate markers. The aim of study was to assess the correlation between the therapeutic efficacy of carvedilol and markers of endothelial dysfunction and systemic inflammation in patients with liver cirrhosis and portal hypertension. MATERIAL AND METHODS Thirty-six patients with cirrhosis and portal hypertension were given carvedilol, 25 mg q.i.d. for 30 days. Hepatic venous pressure gradient (HVPG) and biochemical determinations were performed prior to and after the treatment. Eight healthy individuals served as controls for comparison of biochemical markers. RESULTS In the whole group of cirrhotic patients, HVPG decreased from 17.7+/-3.8 to 14.9+/-4.8 mmHg (p<0.001). Complete response was seen in 15 patients (42%). Baseline serum levels of E-selectin were significantly higher in responders than in non-responders (119.8+/-70.6 versus 52.6+/-25.7 ng/ml; p=0.023) and in controls (28.8+/-22.2 ng/ml; p=0.004). Furthermore, baseline TNF-alpha levels were significantly higher in responders than in non-responders (22.8+/-15.7 versus 7+/-8.9; p=0.047) and in controls (5.5+/-5.9 pg/ml; p=0.005). Serum levels of ICAM-1 showed the same trend (4360+/-2870 versus 2861+/-1577 versus 651+/-196 ng/ml), although differences did not reach statistical significance. CONCLUSIONS Markers of systemic inflammation and endothelial dysfunction seem to predict the hypotensive effect of carvedilol on portal hypertension in patients with liver cirrhosis and may be useful in the assessment of the efficacy of the therapy.
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Affiliation(s)
- Radan Bruha
- 4th Medical Department, General Teaching Hospital, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
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Kiki I, Yilmaz O, Erdem F, Gundogdu M, Demircan B, Bilici M. Tumour necrosis factor-alpha levels in hepatitis B virus-related chronic active hepatitis and liver cirrhosis and its relationship to Knodell and Child-Pugh scores. Int J Clin Pract 2006; 60:1075-9. [PMID: 16939549 DOI: 10.1111/j.1742-1241.2006.00936.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Although both chronic active hepatitis-B (CAH-B) and liver cirrhosis (LC) are characterised by various degrees of inflammation and hepatocyte necrosis, in advanced stage cirrhosis, marked fibrosis develops and inflammation and tissue necrosis diminishes. In this study, we aimed to investigate serum tumour necrosis factor-alpha (TNF-alpha) concentration in patients with CAH-B and LC and its relationship to disease activity. Serum samples were taken from 30 patients with CAH-B and 30 with LC at different stages of the disease. TNF-alpha concentrations were measured by the ELISA technique. Results were compared with those of 30 healthy controls. Mean plasma TNF-alpha levels were found as 2.47 +/- 2.98, 0.8 +/- 1.21 and 0.72 +/- 1.08 pg/ml in CAH-B, LC and control groups, respectively. TNF-alpha levels were significantly higher in CAH-B group than LC and control groups (p <0.01 and p < 0.05, respectively). Although mean plasma TNF-alpha level of cirrhotic patients at Child-A stage was markedly high (3.31 +/- 0.15), no significant difference has been found between LC and control groups (p > 0.05). TNF-alpha concentrations were positively correlated with hepatitis activity index (Knodell's score) in CAH-B group whereas negatively correlated with Child-Pugh score in LC group (r =0.73, p < 0.01 and r = -0.42, p < 0.05, respectively). Our study showed that TNF-alpha level increases in patients with CAH-B correlated with histologic activity index. So it can be used to evaluate disease activity. Additionally, marked reduction of TNF-alpha concentration in advanced cirrhosis suggested that TNF-alpha production is determined by hepatic damage and inflammation.
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Affiliation(s)
- I Kiki
- Department of Internal Medicine, Medical Faculty, Atatürk University, Erzurum, Turkey.
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