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Kumar R, Kumar A, Kumar S. Sepsis in liver failure patients: Diagnostic challenges and recent advancements. World J Crit Care Med 2025; 14:101587. [DOI: 10.5492/wjccm.v14.i2.101587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/19/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
Acute liver failure (ALF) and acute-on-chronic LF (ACLF) are prevalent hepatic emergencies characterized by an increased susceptibility to bacterial infections (BI), despite significant systemic inflammation. Literature indicates that 30%–80% of ALF patients and 55%–81% of ACLF patients develop BI, attributed to immunological dysregulation. Bacterial sepsis in these patients is associated with adverse clinical outcomes, including prolonged hospitalization and increased mortality. Early detection of bacterial sepsis is critical; however, distinguishing between sterile systemic inflammation and sepsis poses a significant challenge due to the overlapping clinical presentations of LF and sepsis. Conventional sepsis biomarkers, such as procalcitonin and C-reactive protein, have shown limited utility in LF patients due to inconsistent results. In contrast, novel biomarkers like presepsin and sTREM-1 have demonstrated promising discriminatory performance in this population, pending further validation. Moreover, emerging research highlights the potential of machine learning-based approaches to enhance sepsis detection and characterization. Although preliminary findings are encouraging, further studies are necessary to validate these results across diverse patient cohorts, including those with LF. This article provides a comprehensive review of the magnitude, impact, and diagnostic challenges associated with BI in LF patients, focusing on novel advancements in early sepsis detection and characterization.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Abhishek Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Sudhir Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
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Haedge F, Bruns T. Antibiotics in decompensated liver disease - who, when and for how long? Expert Rev Gastroenterol Hepatol 2025; 19:111-130. [PMID: 39921440 DOI: 10.1080/17474124.2025.2464044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
INTRODUCTION Bacterial infections are a leading cause of hospitalization and mortality in patients with decompensated cirrhosis. Antibiotic prophylaxis in cirrhotic patients has demonstrated significant short-term reductions in bacterial infections in randomized controlled trials, but at the cost of drug resistance and with uncertain survival benefits. AREAS COVERED This review examines antibiotic use in cirrhosis, focusing on patients most likely to benefit from antibiotic prophylaxis, management strategies for infections through risk-based antibiotic selection and timely treatment initiation, challenges posed by the emergence of multidrug-resistant organisms, and principles of antimicrobial stewardship. EXPERT OPINION The efficacy of prophylaxis has decreased over time, and current registry data have questioned its use, emphasizing the need for better risk-based individualized strategies. When bacterial infections occur, the efficacy of antimicrobial therapies depends heavily on local epidemiological patterns and individual patient risk factors, necessitating tailored antibiotic selection based on regional resistance data and specific clinical scenarios. Nosocomial infections, colonization with multidrug-resistant organisms, and prior exposure to systemic antibiotics are key risk factors that should guide empirical therapy selection. Until evidence-based algorithms are available, clinicians should continue to adopt individualized approaches, guided by available evidence, local specificities, and antimicrobial stewardship principles to optimize patient outcomes.
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Affiliation(s)
- Frederic Haedge
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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Kulkarni AV, Premkumar M, Arab JP, Kumar K, Sharma M, Reddy ND, Padaki NR, Reddy RK. Early Diagnosis and Prevention of Infections in Cirrhosis. Semin Liver Dis 2022; 42:293-312. [PMID: 35672014 DOI: 10.1055/a-1869-7607] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Strategies to prevent infection and improve outcomes in patients with cirrhosis. HAV, hepatitis A virus; HBV, hepatitis B virus; COVID-19, novel coronavirus disease 2019; NSBB, nonselective β-blocker; PPI, proton pump inhibitors.Cirrhosis is a risk factor for infections. Majority of hospital admissions in patients with cirrhosis are due to infections. Sepsis is an immunological response to an infectious process that leads to end-organ dysfunction and death. Preventing infections may avoid the downstream complications, and early diagnosis of infections may improve the outcomes. In this review, we discuss the pathogenesis, diagnosis, and biomarkers of infection; the incremental preventive strategies for infections and sepsi; and the consequent organ failures in cirrhosis. Strategies for primary prevention include reducing gut translocation by selective intestinal decontamination, avoiding unnecessary proton pump inhibitors' use, appropriate use of β-blockers, and vaccinations for viral diseases including novel coronavirus disease 2019. Secondary prevention includes early diagnosis and a timely and judicious use of antibiotics to prevent organ dysfunction. Organ failure support constitutes tertiary intervention in cirrhosis. In conclusion, infections in cirrhosis are potentially preventable with appropriate care strategies to then enable improved outcomes.
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Affiliation(s)
- Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Juan P Arab
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Karan Kumar
- Department of Hepatology, Mahatma Gandhi Medical College and Hospital, Jaipur, Rajasthan, India
| | - Mithun Sharma
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Nageshwar D Reddy
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Nagaraja R Padaki
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India
| | - Rajender K Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
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Philips CA, Ahamed R, Rajesh S, George T, Mohanan M, Augustine P. Update on diagnosis and management of sepsis in cirrhosis: Current advances. World J Hepatol 2020; 12:451-474. [PMID: 32952873 PMCID: PMC7475781 DOI: 10.4254/wjh.v12.i8.451] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 05/18/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023] Open
Abstract
Sepsis and septic shock are catastrophic disease entities that portend high mortality in patients with cirrhosis. In cirrhosis, hemodynamic perturbations, immune dysregulation, and persistent systemic inflammation with altered gut microbiota in the background of portal hypertension enhance the risk of infections and resistance to antimicrobials. Patients with cirrhosis develop recurrent life-threatening infections that progress to multiple organ failure. The definition, pathophysiology, and treatment options for sepsis have been ever evolving. In this exhaustive review, we discuss novel advances in the understanding of sepsis, describe current and future biomarkers and scoring systems for sepsis, and delineate newer modalities and adjuvant therapies for the treatment of sepsis from existing literature to extrapolate the same concerning the management of sepsis in cirrhosis. We also provide insights into the role of gut microbiota in initiation and progression of sepsis and finally, propose a treatment algorithm for management of sepsis in patients with cirrhosis.
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Affiliation(s)
- Cyriac Abby Philips
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682028, Kerala, India.
| | - Rizwan Ahamed
- Gastroenterology and Advanced G.I Endoscopy, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682028, Kerala, India
| | - Sasidharan Rajesh
- Division of Hepatobiliary Interventional Radiology, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682028, Kerala, India
| | - Tom George
- Division of Hepatobiliary Interventional Radiology, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682028, Kerala, India
| | - Meera Mohanan
- Anaesthesia and Critical Care, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682028, Kerala, India
| | - Philip Augustine
- Gastroenterology and Advanced G.I Endoscopy, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi 682028, Kerala, India
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Yan H, Jin S, Liang L, Du J, Aithal GP, Li L. Pro-adrenomedullin in acute decompensation of liver cirrhosis: relationship with acute-on-chronic liver failure and short-term survival. Scand J Gastroenterol 2020; 55:606-614. [PMID: 32476510 DOI: 10.1080/00365521.2020.1764616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background and aim: Acute-on-chronic liver failure (ACLF) is characterized by the presence of acute decompensation (AD) of cirrhosis, organ failures, and high short-term mortality rates. In present study, we explored whether Pro-adrenomedullin (Pro-ADM), a biomarker of sepsis, is a potential marker of outcome in patients admitted for AD or ACLF and whether it might be of additional value to conventional prognostic scoring systems in these patients.Methods: 332 consecutive patients with AD of cirrhosis were prospectively enrolled. Pro-ADM was measured for all patients at baseline. Cox regression analysis was used to evaluate the impact of pro-ADM on short-term survival and developing ACLF during hospital stay.Results: Serum pro-ADM levels were significantly high in non-survivors (p < .001) and showed significant correlation with ALT (r = 0.181, p = .001), INR (r = 0.144, p = .009), TB (r = 0.368, p < .001), Creatinine (r = 0.145, p = .004), MELD score (r = 0.334, p = <.001) and CLI-C OF score (r = 0.375, p= <.001). Serum pro-ADM at admission was shown to be a predictor of 28-day mortality independently of MELD and CLIF-C OF scores. Prognostic models incorporating pro-ADM achieved high C index for predicting 28-day mortality in AD patients of cirrhosis. Moreover, baseline pro-ADM was found to be predictive of ACLF development during hospital stay.Conclusions: Serum pro-ADM levels correlate with multiorgan failure and are independently associated with short-term survival and ACLF development in patients admitted for AD or ACLF.
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Affiliation(s)
- Huadong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Department of Hepatology, Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Hwamei Hospital, Ningbo No.2 Hospital, University of Chinese Academy of Sciences, Ningbo, China.,Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Susu Jin
- Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Lili Liang
- Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Jingyuan Du
- Department of Hepatology, Hwamei Hospital, Ningbo No.2 Hospital, Ningbo University School of Medicine, Ningbo, China
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Centre for Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Conti F, Dall'Agata M, Gramenzi A, Biselli M. Biomarkers for the early diagnosis of bacterial infection and the surveillance of hepatocellular carcinoma in cirrhosis. Biomark Med 2015; 9:1343-51. [PMID: 26580585 DOI: 10.2217/bmm.15.100] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The early detection of bacterial infections and hepatocellular carcinoma (HCC) could ameliorate the prognosis of cirrhosis. C-reactive protein and procalcitonin are under investigation in the setting of cirrhosis as markers of sepsis. In the attempt to discriminate bacterial infection from systemic inflammation, the role of novel biomarkers such as lypopolysaccharide binding-protein, mid-regional fragment of pro-adrenomedullin and delta neutrophil index are currently in development. Concerning HCC, many studies attempted to evaluate biomarkers in the hope of ameliorating the accuracy of the surveillance based on ultrasound. The use of α-fetoprotein (AFP) has been extensively investigated, as well as other biomarkers expressed in the serum of HCC patients like lens culinaris agglutinin-reactive fraction of AFP, des-γ-carboxy prothrombin, glypican-3, α-l-fucosidase and their combined use.
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Affiliation(s)
- Fabio Conti
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Marco Dall'Agata
- Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Università di Ferrara, Ferrara, Italy
| | - Annagiulia Gramenzi
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Maurizio Biselli
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
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Reuken PA, Kussmann A, Kiehntopf M, Budde U, Stallmach A, Claus RA, Bruns T. Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis. Liver Int 2015; 35:37-45. [PMID: 25113276 DOI: 10.1111/liv.12657] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 08/05/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Systemic inflammation in advanced cirrhosis represents a spectrum ranging from subclinical pathological bacterial translocation and immune activation to overt bacterial infection and sepsis. We hypothesized that systemic inflammation in cirrhosis is accompanied by a failure of ADAMTS13 to control the prothrombotic function of von Willebrand factor (VWF), which is increased in portal hypertension and hepatic fibrosis. METHODS Patients with Child A cirrhosis (n = 25), Child B/C cirrhosis without clinical features of systemic inflammation (n = 31), and Child B/C cirrhosis with overt bacterial infections or systemic inflammatory response syndrome (n = 24) were analysed for ADAMTS13 and associated parameters and were followed to determine transplant-free survival. RESULTS Plasma concentration and activity of ADAMTS13 were decreased in patients with systemic inflammation. Furthermore, ADAMTS13 inversely correlated with the extent of bacterial translocation and the severity of acute-phase reaction. As a function of reduced ADAMTS13 activity and increased VWF antigen, plasma from patients with superimposed inflammation strongly aggregated the platelet receptor glycoprotein Ib in presence of ristocetin. VWF:RCo correlated with higher concentrations of leucocytes and lipopolysaccharide-binding protein, organ dysfunction, augmented turnover of cross-linked intravascular fibrin, and the occurrence of acute kidney injury during follow-up. VWF:RCo of 390% or more predicted transplant-free survival in univariate analysis [HR = 8.24 (3.30-20.54)] and after adjustment for MELD [HR = 3.58 (1.30-9.88)]. However, adverse outcome was not associated with the accumulation of high-molecular weight VWF multimers. CONCLUSIONS Systemic inflammation complicating advanced cirrhosis is accompanied by reduced activity of ADAMTS13 promoting a prothrombotic function of VWF, which can be employed to predict clinical outcome.
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Affiliation(s)
- Philipp A Reuken
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Friedrich Schiller University, Jena, Germany; Integrated Research and Treatment Center - Center for Sepsis Control and Care (CSCC), Jena University Hospital, Friedrich Schiller University, Jena, Germany
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Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, Stadlbauer V, Gustot T, Bernardi M, Canton R, Albillos A, Lammert F, Wilmer A, Mookerjee R, Vila J, Garcia-Martinez R, Wendon J, Such J, Cordoba J, Sanyal A, Garcia-Tsao G, Arroyo V, Burroughs A, Ginès P. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014; 60:1310-24. [PMID: 24530646 DOI: 10.1016/j.jhep.2014.01.024] [Citation(s) in RCA: 633] [Impact Index Per Article: 57.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/30/2013] [Accepted: 01/26/2014] [Indexed: 02/08/2023]
Abstract
Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.
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Affiliation(s)
- Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital, UK
| | - Javier Fernandez
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Reiner Wiest
- Department of Gastroenterology, UVCM, Inselspital, 3010 Bern, Switzerland
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Richard Moreau
- INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, UMRS 773, Université Paris-Diderot Paris, Service d'Hépatologie, Hôpital Beaujon, APHP, Clichy, France
| | - Paolo Angeli
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, University of Padova, Italy
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Austria
| | - Thierry Gustot
- Department of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Rafael Canton
- Department of Microbiology, Hospital Universitario Ramón y Cajal and Intituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
| | - Agustin Albillos
- Gastroenterology Service, University Hospital Ramon y Cajal, Madrid, Spain
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Alexander Wilmer
- Medical Intensive Care Unit, University Hospital Gasthuisberg, Leuven, Belgium
| | - Rajeshwar Mookerjee
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital, UK
| | - Jordi Vila
- Department of Microbiology, Hospital Clínic, School of Medicine, University of Barcelona, Barcelona, Spain
| | - Rita Garcia-Martinez
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Julia Wendon
- Institute of Liver Studies and Critical Care, Kings College London, Kings College Hospital, UK
| | - José Such
- Department of Clinical Medicine, Miguel Hernández University, Alicante, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan Cordoba
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Arun Sanyal
- Charles Caravati Professor of Medicine, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Guadalupe Garcia-Tsao
- Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Vicente Arroyo
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Andrew Burroughs
- The Royal Free Shelia Sherlock Liver Centre and University Department of Surgery, University College London and Royal Free Hospital, UK
| | - Pere Ginès
- Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
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Bruns T, Zimmermann HW, Stallmach A. Risk factors and outcome of bacterial infections in cirrhosis. World J Gastroenterol 2014; 20:2542-2554. [PMID: 24627590 PMCID: PMC3949263 DOI: 10.3748/wjg.v20.i10.2542] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 01/05/2014] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Viable and non-viable pathological bacterial translocation promote a self-perpetuating circle of dysfunctional immune activation and systemic inflammation facilitating infections and organ failure in advanced cirrhosis. Bacterial infections and sepsis are now recognized as a distinct stage in the natural progression of chronic liver disease as they accelerate organ failure and contribute to the high mortality observed in decompensated cirrhosis. The increasing knowledge of structural, immunological and hemodynamic pathophysiology in advanced cirrhosis has not yet translated into significantly improved outcomes of bacterial infections over the last decades. Therefore, early identification of patients at the highest risk for developing infections and infection-related complications is required to tailor the currently available measures of surveillance, prophylaxis and therapy to the patients in need in order to improve the detrimental outcome of bacterial infections in cirrhosis.
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Zimmermann HW, Reuken PA, Koch A, Bartneck M, Adams DH, Trautwein C, Stallmach A, Tacke F, Bruns T. Soluble urokinase plasminogen activator receptor is compartmentally regulated in decompensated cirrhosis and indicates immune activation and short-term mortality. J Intern Med 2013; 274:86-100. [PMID: 23432143 DOI: 10.1111/joim.12054] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis. DESIGN, SETTING AND PARTICIPANTS We examined the associations between serum and ascitic fluid (AF) suPAR and liver function, bacterial infection, and short-term mortality in 162 consecutive patients with decompensated cirrhosis undergoing diagnostic paracentesis in a tertiary health care centre in Germany. MAIN OUTCOME MEASURE Twenty-eight-day mortality. RESULTS Circulating suPAR levels were increased in patients with decompensated cirrhosis and correlated with the severity of liver dysfunction and systemic inflammation but were not indicative of bacterial infection. Circulating suPAR levels >14.4 ng mL(-1) predicted 28-day mortality, even after adjustment for liver function and confounders [HR = 3.05 (1.35-6.90); P = 0.0076] equal to the MELD score (AUC = 0.71; 95% CI = 0.61-0.81; P < 0.001). Cut-off levels derived from cohorts without liver disease were not applicable due to the low specificity. AF suPAR levels were elevated during spontaneous bacterial peritonitis (SBP), but not during episodes in which bacteria or bacterial DNA was translocated into the ascites. AF suPAR levels correlated poorly with systemic suPAR but were associated with a more severe course of SBP and a worse outcome. In vitro experiments revealed that monocytes, and to a lesser extent neutrophils, secrete suPAR after Toll-like-receptor ligation, which led to rapid urokinase plasminogen activator receptor cleavage followed by increased synthesis. CONCLUSION Blood and ascitic suPAR levels provide distinct, but relevant prognostic information on the severity of complications in patients with end-stage liver disease.
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Affiliation(s)
- H W Zimmermann
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
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