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Lai JCT, Dai J, Liang LY, Wong GLH, Wong VWS, Yip TCF. Pharmacological Treatment of Ascites: Challenges and Controversies. Pharmaceuticals (Basel) 2025; 18:339. [PMID: 40143117 PMCID: PMC11945444 DOI: 10.3390/ph18030339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 02/20/2025] [Accepted: 02/25/2025] [Indexed: 03/28/2025] Open
Abstract
Ascites is the most common complication from cirrhosis related to portal hypertension and depicts the onset of hepatic decompensation. Ranging from uncomplicated to refractory ascites, the progression carries prognostic value by reflecting the deterioration of underlying cirrhosis and portal hypertension. Diuretics have been the mainstay of treatment to control ascites, but the side effects heighten when the dosage is escalated. Non-selective beta-blockers (NSBBs) are widely used nowadays to prevent hepatic decompensation and variceal hemorrhage. However, with worsening systemic vasodilation and inflammation when ascites progresses, patients on NSBBs are at risk of hemodynamic collapse leading to renal hypoperfusion and thus hepatorenal syndrome. Long-term albumin infusion was studied to prevent the progression of ascites. However, the results were conflicting. Sodium-glucose cotransporter-2 inhibitors are under investigation to control refractory ascites. With that, patients with refractory ascites may require regular large-volume paracentesis. With an aging population, more patients are put on anti-thrombotic agents and their risks in decompensated cirrhosis and invasive procedures have to be considered. In general, decompensated cirrhosis with ascites poses multiple issues to pharmacological treatment. In the present review, we discuss the challenges and controversies in the pharmacological treatment of ascites.
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Affiliation(s)
- Jimmy Che-To Lai
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Junlong Dai
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lilian Yan Liang
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Lai-Hung Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Center, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; (J.C.-T.L.); (J.D.); (L.Y.L.); (G.L.-H.W.); (V.W.-S.W.)
- State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
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Dunne PDJ, Manship T, Sinha R, Stanley AJ, Lachlan N, Shams A, Forrest EH, Hayes P. Long-term follow-up of a randomised clinical trial: standard of care versus pre-emptive transjugular intrahepatic portosystemic shunt (TIPSS) in patients with cirrhosis and oesophageal variceal bleeding. Frontline Gastroenterol 2025:flgastro-2024-102858. [DOI: 10.1136/flgastro-2024-102858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2025] Open
Abstract
Background and aimsPre-emptive transjugular intrahepatic portosystemic shunt (pTIPSS) within 72 hours following acute oesophageal variceal bleeding has potential survival benefit. However, there is uncertainty whether pTIPSS is advantageous over standard of care (SOC) and long-term outcomes remain unstudied.ApproachPatients recruited to a Scottish randomised control trial were allocated to SOC or pTIPSS and had follow-up extended to 3 years. The primary outcome was 3-year transplant-free survival on intention to treat and per-protocol analysis.Results58 patients were initially recruited, 29 patients per group. Of the 29 in the pTIPSS group, only 23 received TIPSS placement due to logistical reasons. On intention to treat analysis, 3-year transplant-free survival rate in the SOC group was significantly higher than that of the pTIPSS group (55.2% vs 20.1%, p=0.006, HR 2.5, 95% CI 1.3 to 4.87). On per-protocol analysis, 3-year transplant-free survival rate in the SOC group was significantly higher than that of the pTIPSS group (55.2% vs 15.4%, p=0.03, HR 2.93, 95% CI 1.27 to 7.94). There were significantly higher rates of sepsis-related death or sepsis-induced liver failure-related death in the pTIPSS group compared with the SOC group (48.2% vs 3.6%, p<0.001, reciprocal of RR 13.0, 95% CI 2.46 to 75.45). There were no differences in other outcomes associated with portal hypertension on intention to treat analysis.ConclusionpTIPSS was associated with significantly reduced rates of transplant-free survival at 3 years compared with SOC. This may be due to higher rates of sepsis. Further large studies are required to validate these findings.
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Albillos A, Bañares R, Hernández-Gea V. Portal hypertension: recommendations for diagnosis and treatment. Consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Centre for Liver and Digestive Diseases (CIBERehd). GASTROENTEROLOGIA Y HEPATOLOGIA 2025; 48:502208. [PMID: 39756832 DOI: 10.1016/j.gastrohep.2024.502208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/07/2024] [Accepted: 04/09/2024] [Indexed: 01/07/2025]
Abstract
Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of CSPH and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad de Alcalá, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
| | - Rafael Bañares
- Servicio de Medicina de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Universidad Complutense, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
| | - Virginia Hernández-Gea
- Servicio de Hepatología, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, España.
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Albillos A, Bañares R, Hernández-Gea V. Portal hypertension: recommendations for diagnosis and treatment. Consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd). REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2025; 117:14-57. [PMID: 39350672 DOI: 10.17235/reed.2024.10805/2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of clinically significant portal hypertension and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, España
| | - Rafael Bañares
- Servicio de Medicina de Aparato Digestivo, Hospital General Universitario Gregorio Marañón
| | - Virginia Hernández-Gea
- Servicio de Hepatología, Hospital Clínic. Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
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Xu X, Gao F, Wang T, Yang Z, Zhao Q, Qi X. Association of non-selective β blockers with the development of renal dysfunction in liver cirrhosis: a systematic review and meta-analysis. Ann Med 2024; 56:2305935. [PMID: 38271554 PMCID: PMC10812853 DOI: 10.1080/07853890.2024.2305935] [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: 04/03/2023] [Revised: 10/14/2023] [Accepted: 01/09/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND & AIMS Non-selective β blockers (NSBBs) may negatively influence renal function through decreasing heart rate and cardiac output. This study aimed to systematically investigate their association. METHODS PubMed, EMBASE, and Cochrane library databases were searched to identify all relevant studies evaluating the association of NSBBs with renal dysfunction in cirrhotic patients. Unadjusted and adjusted data were separately extracted. Odds ratios (ORs) and hazard ratios (HRs) were pooled. Subgroup meta-analyses were performed according to the proportions of ascites and Child-Pugh class B/C and the mean model for end-stage liver disease (MELD) score. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework. RESULTS Fourteen studies were finally included. Based on unadjusted data, NSBBs significantly increased the risk of developing renal dysfunction (OR = 1.49; p = 0.03), and this association remained significant in subgroup analyses of studies where the proportions of ascites was >70% and Child-Pugh class B/C was 100%. Based on adjusted data with propensity score matching (adjusted OR = 0.61; p = 0.08) and multivariable regression modelling (adjusted HR = 0.86; p = 0.713), NSBBs did not increase the risk of developing renal dysfunction, and this association remained not significant in subgroup analyses of studies where the proportions of ascites was >70% and <70%, the proportion of Child-Pugh class B/C was <100%, and the mean MELD score was <15. The quality of evidence was very low for all meta-analyses. CONCLUSIONS NSBBs may not be associated with the development of renal dysfunction in liver cirrhosis. However, more evidence is required to clarify their association in specific populations.
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Affiliation(s)
- Xiangbo Xu
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Fangbo Gao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Ting Wang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Zuyao Yang
- Division of Epidemiology, The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China
| | - Qingchun Zhao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Xingshun Qi
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
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Wang T, Wang X, Jia S, Zhao H, Wang L, Zhang X, Fang X, He Y, Li H, Tacke F, Qi X. Impact of non-selective beta blockers on further decompensation and death in decompensated cirrhosis: Benefit and risk stratification by MELD score. Aliment Pharmacol Ther 2024; 60:1409-1420. [PMID: 39300691 DOI: 10.1111/apt.18261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/24/2024] [Accepted: 08/29/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Non-selective beta blockers (NSBBs) can reduce the risk of decompensation, but their impact on further decompensation has been rarely investigated. AIMS The aim is to evaluate the impact of NSBBs on further decompensation and death in decompensated cirrhosis stratified by the severity of liver disease. METHODS Overall, 332 decompensated cirrhotic patients were retrospectively included, of whom 149 used NSBBs. Kaplan-Meier and Nelson-Aalen cumulative risk curves as well as Cox regression and competing risk analyses were used to estimate the associations of NSBBs with further decompensation and death, if appropriate. Hazard ratio (HR) and sub-distribution HR (sHR) were calculated. Subgroup analyses were performed based on the model for end-stage liver disease (MELD) score at admission. RESULTS In the overall analysis, the use of NSBBs was not significantly associated with further decompensation in multivariate competing risk analysis (sHR = 1.09, p = 0.580). In the subgroup analysis of patients with a MELD score of ≤9, the use of NSBBs was significantly associated with decreased risk of further decompensation in multivariate competing risk analysis (sHR = 0.57, p = 0.021). In the subgroup analysis of patients with a MELD score of >9, the use of NSBBs was associated with increased risk of further decompensation in multivariate competing risk analysis (sHR = 1.45, p = 0.044). Regardless of overall and subgroup analyses, the use of NSBBs was not significantly associated with death in multivariate Cox regression analyses. CONCLUSION NSBBs may be beneficial for the prevention of further decompensation in cirrhotic patients with a MELD score of ≤9, but deleterious in those with a MELD score of >9.
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Affiliation(s)
- Ting Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Xueying Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Postgraduate College, Jinzhou Medical University, Jinzhou, China
| | - Siqi Jia
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Haitao Zhao
- Medical Ethical Committee, General Hospital of Northern Theater Command, Shenyang, China
| | - Le Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Postgraduate College, China Medical University, Shenyang, China
| | - Xianxian Zhang
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaohui Fang
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Yong He
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Hongyu Li
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Postgraduate College, China Medical University, Shenyang, China
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command (Teaching Hospital of Shenyang Pharmaceutical University), Shenyang, China
- Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
- Postgraduate College, Jinzhou Medical University, Jinzhou, China
- Postgraduate College, China Medical University, Shenyang, China
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Maia AG, Palhares LFN, Maia IG, Braulino PDM, Pereira LMMB. NON-SELECTIVE BETA-BLOCKERS IN CIRRHOTIC PATIENTS WITH REFRACTORY ASCITES: WHERE ARE WE? ARQUIVOS DE GASTROENTEROLOGIA 2024; 61:e23157. [PMID: 39046001 DOI: 10.1590/s0004-2803.24612023157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/24/2024] [Indexed: 07/25/2024]
Abstract
BACKGROUND The established use of non-selective beta-blockers (NSBB) in the primary and secondary prevention of esophageal varices has recently been questioned in the subgroup of patients with diuretic-refractory ascites. OBJECTIVE Critically analyze the body of evidence on the topic in order to assist clinical decisions. METHODS A literature review was carried out in the Pubmed® and Scielo® databases. In total, 20 articles between 2010 and 2023 were read by independent researchers. CONCLUSION It remains doubtful whether the use of NSBB is deleterious in cirrhotic patients with refractory ascites, however our literature review allows us to conclude that these drugs should not be proscribed in these patients. On the contrary, a doctor-patient decision based on tolerability and hemodynamic parameters certainly seems to be a safe conduct.
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Muñoz-Restrepo AM, Navas MC, Daza J, Girala M, Ridruejo E, Gerken G, Teufel A. Prevention in Hepatology. J Pers Med 2024; 14:132. [PMID: 38392566 PMCID: PMC10890057 DOI: 10.3390/jpm14020132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/01/2024] [Accepted: 01/09/2024] [Indexed: 02/24/2024] Open
Abstract
The prevention of liver disease has improved significantly in the last few decades, to the point that it can now be considered a true success story. The wide variety of interventions, including comprehensive vaccination strategies, novel medications, lifestyle changes, and even preventive surgeries, have reduced the morbidity and mortality of chronic liver diseases. However, the prevalence of chronic liver diseases is increasing worldwide. Currently, fatty liver disease alone is estimated to be present in as much as 30% of the adult population. Furthermore, there is a trend towards increasing incidences of chronic hepatitis B, and a global lack of success in efforts to eliminate chronic hepatitis C. Thus, improving and efficiently rolling out existing and successful prevention strategies for chronic liver diseases will play an essential role in healthcare throughout the upcoming decades. In this review, we summarize the current options and concepts for preventing chronic liver diseases, highlight their limitations, and provide an outlook on probable future developments to improve awareness, integrated care, and the analysis of big data.
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Affiliation(s)
- Ana-Maria Muñoz-Restrepo
- Department of Medicine II, Division of Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (A.-M.M.-R.); (J.D.)
- Grupo Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, UdeA, Calle 70 # 52-21, Medellin 050010, Colombia;
| | - Maria-Cristina Navas
- Grupo Gastrohepatología, Facultad de Medicina, Universidad de Antioquia, UdeA, Calle 70 # 52-21, Medellin 050010, Colombia;
| | - Jimmy Daza
- Department of Medicine II, Division of Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (A.-M.M.-R.); (J.D.)
| | - Marcos Girala
- Department of Hepatology, Universidad Nacional de Asunción, San Lorenzo 111421, Paraguay;
| | - Ezequiel Ridruejo
- Hepatology Section, Department of Medicine, Center for Medical Education and Clinical Research, Norberto Quirno CEMIC, Buenos Aires 1431, Argentina;
| | - Guido Gerken
- Department of Gastroenterology, University Hospital Essen, 45147 Essen, Germany;
| | - Andreas Teufel
- Department of Medicine II, Division of Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; (A.-M.M.-R.); (J.D.)
- Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine, and Digital Health (CPD), Medical Faculty Mannheim, Heidelberg University, 69117 Mannheim, Germany
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Mingpun W, Sobhonslidsuk A, Chumnumwat S. Optimal resting heart rate and ascites-related death in patients with cirrhosis and ascites using nonselective beta-blockers (ORCA). Clin Transl Sci 2024; 17:e13681. [PMID: 37950532 PMCID: PMC10766015 DOI: 10.1111/cts.13681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/09/2023] [Accepted: 11/05/2023] [Indexed: 11/12/2023] Open
Abstract
Nonselective beta-blockers (NSBBs) may exacerbate ascites by impairing cardiac function. This study evaluated the impact of achieving a heart rate target of 55-60 beats per minute (bpm) on ascites-related death and complications from worsening ascites in patients with cirrhosis and diuretic-responsive ascites using NSBBs. A retrospective study was conducted at the Faculty of Medicine Ramathibodi Hospital, Mahidol University (2012-2022) and analyzed patients with cirrhosis and diuretic-responsive ascites using NSBBs (propranolol/carvedilol) for variceal bleeding prophylaxis. The outcomes were incidence of ascites-related death and complications from worsening ascites, comparing the achievable target group (heart rate 55-60 bpm) and the unachievable target group (heart rate >60 bpm). A total of 206 patients were included in the study, with a median follow-up time of 20 months. The patients were divided into an achievable target group (n = 75, median heart rate = 58.0 bpm) and an unachievable target group (n = 131, median heart rate = 73.6 bpm). Propranolol was the most used NSBB (95.1%). The adjusted hazard ratio (HR) for ascites-related death from spontaneous bacterial peritonitis (SBP) or refractory ascites (RA) or hepatorenal syndrome (HRS) or hepatic encephalopathy (HE) showed no difference between the groups (adjusted HR 0.59 [0.23-1.54]; p = 0.28). Additionally, no significant difference was found in the incidence of complications between groups, including SBP, RA, HRS, and HE. Achieving a heart rate target of 55-60 bpm with NSBBs for variceal bleeding prophylaxis is safe in patients with diuretic-responsive ascites and cirrhosis.
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Affiliation(s)
- Warunee Mingpun
- Department of Pharmacy, Faculty of PharmacyMahidol UniversityBangkokThailand
- Department of Pharmaceutical Care, Faculty of PharmacyChiang Mai UniversityChiang MaiThailand
| | - Abhasnee Sobhonslidsuk
- Division of Gastroenterology and Hepatology, Faculty of Medicine, Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Supatat Chumnumwat
- Department of Pharmacy, Faculty of PharmacyMahidol UniversityBangkokThailand
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Karagiannakis DS, Karakousis ND, Androutsakos T. B-Blockers in Liver Cirrhosis: A Wonder Drug for Every Stage of Portal Hypertension? A Narrative Review. Biomedicines 2023; 12:57. [PMID: 38255164 PMCID: PMC10813395 DOI: 10.3390/biomedicines12010057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/24/2024] Open
Abstract
In cirrhotic patients, non-selective b-blockers (NSBBs) constitute the reference treatment of choice as monotherapy or combined with band ligation for the prevention of first variceal bleeding and rebleeding, respectively. Furthermore, the last Baveno VII guidelines recommended carvedilol, a b-blocker with additional anti-a1 receptor activity, in all compensated cirrhotics with clinically significant portal hypertension, to prevent liver decompensation. Interestingly enough, NSBBs have been reported to have a potentially positive impact on the short-term mortality of patients with acute-on-chronic liver failure. However, concerns remain about the use of b-blockers in the presence of severe complications, such as refractory ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, or established cirrhotic cardiomyopathy. In addition, it has not been verified yet whether carvedilol supersedes all the other NSBBs in every stage of liver disease, even when severe complications have developed. Therefore, this review aims to illustrate recent data regarding the potential role of b-blockers across all stages of liver disease, beyond the primary and secondary prophylaxis of variceal bleeding, and address the authors' proposals on the use of NSBBs concerning the severity of liver disease and the patient's performance status.
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Affiliation(s)
- Dimitrios S. Karagiannakis
- Academic Department of Gastroenterology, Laiko General Medicine, Medical School of National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Theodoros Androutsakos
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
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Balafar M, Ghojazadeh M, Shahsavarinia K, Parsian Z, Hamedani S, Soleimanpour H. Association Between Proton Pump Inhibitor Use and Spontaneous Bacterial Peritonitis or Hepatic Encephalopathy in Cirrhotic Patients: A Systematic Review and Meta-analysis. HEPATITIS MONTHLY 2023; 23. [DOI: 10.5812/hepatmon-132642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Context: There is a link between proton pump inhibitors (PPIs) use and the occurrence of spontaneous bacterial peritonitis (SBP) in cirrhotic patients in some studies; however, in other studies, such a link does not exist. Objectives: The aim of the current systematic review and meta-analysis was to evaluate the association between PPI and the occurrence of SBP or hepatic encephalopathy (HE) in cirrhotic patients. Data Sources: A systematic search of sources was conducted in order to evaluate for any relationship between PPI and the risk of SBP in patients with liver diseases. Medline, Scopus, Ovid, ProQuest, Google Scholar, and Web of Science were searched to find any evidence in this regard from 1980 to November of 2021. Study Selection: The articles were evaluated by two independent reviewers according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses). After deleting the duplicates, first, the titles of the studies were evaluated, and then the full texts were evaluated. Any disagreement between the two researchers was solved by discussion or a third reviewer. Data Extraction: Appropriate Critical Appraisal Checklists of Joanna Briggs Institute (JBI) were used for the quality assessment of eligible studies. Statistical analysis was performed by CMA software (version 2.0), and a P-value of less than 0.05 was considered a significant level. Results: In the systematic search of sources, 3705 articles were identified. Finally, 33 studies were included in this meta-analysis study. A total of 6370 PPI users and 8037 patients in the control group experienced at least one of the complications of liver cirrhosis, including SBP or HE. According to meta-analysis, the risk of SBP or HE in the intervention group was 1.95 times higher than in the control group (RR = 1.95; 95% confidence interval [CI]: 1.53 - 2.48, P < 0.001). Conclusions: The use of PPIs is associated with a higher risk of SBP and HE in cirrhotic patients. However, the quality of included studies in the current systematic review and meta-analysis was moderate, and high-quality studies with a larger sample size are required.
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12
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Singh V, De A, Mehtani R, Angeli P, Maiwall R, Satapathy S, Singal AK, Saraya A, Sharma BC, Eapen CE, Rao PN, Shukla A, Shalimar, Choudhary NS, Alcantara-Payawal D, Arora V, Aithal G, Kulkarni A, Roy A, Shrestha A, Mamun Al Mahtab, Niriella MA, Siam TS, Zhang CQ, Huei LG, Yu ML, Roberts SK, Peng CY, Chen T, George J, Wong V, Yilmaz Y, Treeprasertsuk S, Kurniawan J, Kim SU, Younossi ZM, Sarin SK. Asia-Pacific association for study of liver guidelines on management of ascites in liver disease. Hepatol Int 2023; 17:792-826. [PMID: 37237088 DOI: 10.1007/s12072-023-10536-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 04/08/2023] [Indexed: 05/28/2023]
Affiliation(s)
- Virendra Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India.
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
| | - Arka De
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rohit Mehtani
- Department of Hepatology, Amrita Institute of Medical Sciences and Research, Faridabad, India
| | - Paolo Angeli
- Department of Internal Medicine and Hepatology, University of Padova, Padua, Italy
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sanjaya Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY, USA
| | - Ashwini K Singal
- University of South Dakota Sanford School of Medicine, Sioux Falls, USA
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - B C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, Delhi, India
| | - C E Eapen
- Department of Hepatology, Christian Medical College, Vellore, India
| | - P N Rao
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Akash Shukla
- Department of Gastroenterology, Lokmanya Tilak Municipal General Hospital and Lokmanya Tilak Municipal Medical College, Sion, Mumbai, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | | | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guru Aithal
- Biomedical Research Unit, NIHR Nottingham Digestive Diseases, Nottingham, UK
| | - Anand Kulkarni
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Akash Roy
- Institute of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, India
| | - Ananta Shrestha
- Department of Hepatology, The Liver Clinic, Liver Foundation, Kathmandu, Nepal
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Madunil A Niriella
- Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka
| | - Tan Soek Siam
- Department of Hepatology, Hospital Selayang, Selangor Darul Ehsan, Malaysia
| | - Chun-Qing Zhang
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Lee Guan Huei
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Ming-Lung Yu
- School of Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | | | - Cheng-Yuan Peng
- Centre for Digestive Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Tao Chen
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jacob George
- University of Sydney School of Medicine, Sydney, Australia
| | - Vincent Wong
- Mok Hing Yiu Professor of Medicine, Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Yusuf Yilmaz
- Liver Research Unit, Institute of Gastroenterology, Marmara University, Istanbul, Turkey
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
| | | | - Juferdy Kurniawan
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital Jakarta, Jakarta, Indonesia
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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13
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Wong F. Management of Portal Hypertension in Patients with Acute-on-Chronic Liver Disease. Clin Liver Dis 2023; 27:717-733. [PMID: 37380294 DOI: 10.1016/j.cld.2023.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Portal hypertension is central to the pathogenesis of complications of cirrhosis, including acute-on-chronic liver failure (ACLF). Both nonselective beta-blockers and preemptive transjugular portal-systemic stent shunt can lower portal pressure, reducing the risk of variceal bleeding, a known trigger for ACLF. However, in patients with advanced cirrhosis, both could potentially induce ACLF by causing hemodynamic instability and hepatic ischemia, respectively, and therefore must be used with caution. Lowering portal pressure with vasoconstrictor such as terlipressin can reverse the kidney failure but careful patient selection is key for success, with careful monitoring for complications.
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Affiliation(s)
- Florence Wong
- Department of Medicine, Division of Gastroenterology & Hepatology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
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14
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Albillos A, Krag A. Beta-blockers in the era of precision medicine in patients with cirrhosis. J Hepatol 2023; 78:866-872. [PMID: 36529293 DOI: 10.1016/j.jhep.2022.12.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/04/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022]
Abstract
For decades, non-selective beta-blockers (NSBBs) have been the standard of care for the primary and secondary prevention of bleeding from oesophageal varices. However, several questions regarding the best clinical use of NSBBs remain unanswered and new data continue to emerge. Herein, we aim to delineate the therapeutic window of NSBBs in cirrhosis from a more individualised perspective. We address the current controversy of widening the therapeutic window and prescribing NSBBs to all patients with clinically significant portal hypertension. Although transient elastography is useful to rule-in clinically significant portal hypertension, we lack robust data supporting the use of NSBBs in patients without varices. While most data are based on propranolol, accumulating evidence suggests that carvedilol is superior and should be the first-line treatment until the decompensated stage. The clinical risk-to-benefit ratio appears to deteriorate in advanced decompensated stages and the risk of harm is high in patients with refractory ascites, low blood pressure and renal impairment, which clinically define closure of the therapeutic window. We also critically review non-invasive surrogates and biomarkers for predicting the haemodynamic response to NSBBs and confirm that the absence of reliable non-invasive methods is one of the main challenges facing the field.
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Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto Salud Carlos III, Madrid, Spain.
| | - Aleksander Krag
- Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
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15
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Gillespie SL, Hanrahan TP, Rockey DC, Majumdar A, Hayes PC. Review article: controversies surrounding the use of carvedilol and other beta blockers in the management of portal hypertension and cirrhosis. Aliment Pharmacol Ther 2023; 57:454-463. [PMID: 36691947 DOI: 10.1111/apt.17380] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/03/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Advanced chronic liver disease is an increasing cause of premature morbidity and mortality in the UK. Portal hypertension is the primary driver of decompensation, including the development of ascites, hepatic encephalopathy and variceal haemorrhage. Non-selective beta blockers (NSBB) reduce portal pressure and are well established in the prevention of variceal haemorrhage. Carvedilol, a newer NSBB, is more effective at reducing portal pressure due to additional α-adrenergic blockade and has additional anti-oxidant, anti-inflammatory and anti-fibrotic effects. AIM To summarise the available evidence on the use of beta blockers, specifically carvedilol, in cirrhosis, focussing on when and why to start METHODS: We performed a comprehensive literature search of PubMed for relevant publications. RESULTS International guidelines advise the use of NSBB in primary prophylaxis against variceal haemorrhage in those with high-risk varices, with substantial evidence of efficacy comparable with endoscopic band ligation (EBL). NSBB are also well established in secondary prophylaxis, in combination with EBL. More controversial is their use in patients without large varices, but with clinically significant portal hypertension. However, there is gathering evidence that NSBB, particularly carvedilol, reduce the risk of decompensation and improve survival. While caution is advised in patients with advanced cirrhosis and refractory ascites, recent evidence suggests that NSBB can continue to be used safely, and that premature discontinuation may be detrimental. CONCLUSIONS With increasing evidence of benefit independent of variceal bleeding, namely retardation of decompensation and improvement in survival, it is time to consider whether carvedilol should be offered to all patients with advanced chronic liver disease.
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Affiliation(s)
| | - Timothy P Hanrahan
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Avik Majumdar
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.,The University of Melbourne, Melbourne, Australia
| | - Peter C Hayes
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
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16
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Sauerbruch T, Hennenberg M, Trebicka J, Schierwagen R. Beta-blockers in patients with liver cirrhosis: Pragmatism or perfection? Front Med (Lausanne) 2023; 9:1100966. [PMID: 36743678 PMCID: PMC9891090 DOI: 10.3389/fmed.2022.1100966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/12/2022] [Indexed: 01/11/2023] Open
Abstract
With increasing decompensation, hyperdynamic circulatory disturbance occurs in liver cirrhosis despite activation of vasoconstrictors. Here, the concept of a therapy with non-selective beta-blockers was established decades ago. They lower elevated portal pressure, protect against variceal hemorrhage, and may also have pleiotropic immunomodulatory effects. Recently, the beneficial effect of carvedilol, which blocks alpha and beta receptors, has been highlighted. Carvedilol leads to "biased-signaling" via recruitment of beta-arrestin. This effect and its consequences have not been sufficiently investigated in patients with liver cirrhosis. Also, a number of questions remain open regarding the expression of beta-receptors and its intracellular signaling and the respective consequences in the intra- and extrahepatic tissue compartments. Despite the undisputed role of non-selective beta-blockers in the treatment of liver cirrhosis, we still can improve the knowledge as to when and how beta-blockers should be used in which patients.
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Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Robert Schierwagen
- Department of Internal Medicine B, University of Münster, Münster, Germany
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17
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Tittanegro T, China L, Forrest E, Kallis Y, Ryder SD, Wright G, Freemantle N, O'Brien A. Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial. EClinicalMedicine 2023; 55:101716. [PMID: 36407574 PMCID: PMC9672423 DOI: 10.1016/j.eclinm.2022.101716] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Nonselective B-blockers (NSBBs) are believed to have pleiotropic effects beyond reducing portal pressure. However, studies also report potential harm in patients hospitalized with cirrhosis and ascites. We therefore investigated whether NSBB use at ATTIRE trial entry (Albumin to prevent infection in chronic liver failure, 2016-19) was associated with increased renal or cardiovascular dysfunction, compared the incidence of infection and plasma markers of systemic inflammation, and examined mortality at 28-days, 3 and 6-months. METHODS In ATTIRE patients grouped by NSBB use at trial entry, we studied infection at baseline, hospital acquired infection and organ dysfunction during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. FINDINGS There were no differences in renal or cardiovascular dysfunction between patients treated with NSBBs or not, during days 3-15 of hospitalization, despite elevated serum creatinine in NSBB patients at hospitalisation. Use of NSBBs was associated with a significant reduction in infection at hospitalization (p = 0.006), lower white cell counts throughout hospital stay (p < 0.001) and reduced plasma procalcitonin (p = 0.009) and interlukin-8 levels (p = 0.04) at baseline, but markers of bacterial translocation and systemic inflammation were the same in treatment groups. There was no reduction in hospital acquired infections in patients taking NSBBs and no beneficial impact on mortality at 28-days, 3 and 6-months. INTERPRETATIONS Our real-world data from a completed randomised trial show that use of NSBBs in decompensated cirrhosis patients is safe during hospitalisation. We also show a potential anti-inflammatory role for NSBBs which may be mediated by a downregulation of IL-8 induced leucocytosis, that was associated with reduced infection at baseline but not a survival benefit. FUNDING Wellcome Trust and Department of Health and Social Care.
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Affiliation(s)
- Thais Tittanegro
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Louise China
- Institute of Liver and Digestive Health, University College London, United Kingdom
| | - Ewan Forrest
- Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Yiannis Kallis
- Barts and the London School of Medicine and Dentistry Queen Mary University of London, United Kingdom
| | - Stephen D. Ryder
- National Institute for Health Research Nottingham Biomedical Research Centre at Nottingham University Hospitals NHS Trust, and the University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom
| | - Gavin Wright
- Mid and South Essex NHS Foundation Trust, Basildon & Thurrock University Hospitals NHS Foundation Trust, The Royal Free Hospital, University College London, Kings College London, United Kingdom
| | - Nick Freemantle
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
| | - Alastair O'Brien
- Institute of Liver and Digestive Health, University College London, United Kingdom
- Comprehensive Clinical Trials Unit, University College London, United Kingdom
- Corresponding author. UCL Institute for Liver and Digestive Health, Upper 3rd Floor, Division of Medicine, Royal Free Campus, Rowland Hill Street London NW3 2PF, United Kingdom. a.o'
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18
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Dunne PDJ, Young D, Chuah CS, Hayes PC, Tripathi D, Leithead J, Smith LA, Gaya DR, Forrest E, Stanley AJ. Carvedilol versus endoscopic band ligation for secondary prophylaxis of variceal bleeding-long-term follow-up of a randomised control trial. Aliment Pharmacol Ther 2022; 55:1581-1587. [PMID: 35322892 DOI: 10.1111/apt.16901] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/06/2022] [Accepted: 03/12/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Carvedilol reduces rates of variceal bleeding and rebleeding by lowering portal pressure. However, an associated pleiotropic survival benefit has been proposed. We aimed to assess long-term survival in a cohort of patients previously randomised to receive either carvedilol or endoscopic band ligation (EBL) following oesophageal variceal bleeding (OVB). METHODS The index study randomised 64 cirrhotic patients with OVB between 2006 and 2011 to receive either carvedilol or EBL. Follow-up was undertaken to April 2020 by review of electronic patient records. The primary outcome was survival. Other outcomes including variceal rebleeding and liver decompensation events were compared. RESULTS 26 out of 33 participants received carvedilol in the follow-up period and 28 out of 31 attended regular EBL sessions. The median number of follow-up days for all patients recruited was 1459 (SE = 281.74). On the intention to treat analysis, there was a trend towards improved survival in the carvedilol group (p = 0.09). On per-protocol analysis, carvedilol use was associated with improved long-term survival (p = 0.005, HR 3.083, 95% CI 1.397-6.809), fewer liver-related deaths (0% vs 22.57%, p = 0.013, OR ∞, 95%CI 1.565-∞) and fewer admissions with decompensated liver disease (12% vs 64.29%, p = 0.0002, OR 13.2, 95% CI 3.026-47.23) compared to the EBL group. There was no statistically significant difference in variceal rebleeding rates. CONCLUSION Following OVB in cirrhotic patients, carvedilol use is associated with survival benefit, fewer liver-related deaths and fewer hospital admissions with decompensated liver disease. Further studies are needed to validate this finding.
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Affiliation(s)
- Philip D J Dunne
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - David Young
- Department of Statistics, Strathclyde University, Glasgow, UK
| | - Cher Shiong Chuah
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Peter C Hayes
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
- University of Edinburgh, Edinburgh, UK
| | - Dhiraj Tripathi
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Joanna Leithead
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Forth Valley Royal Hospital, UK
| | - Lyn A Smith
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - Daniel R Gaya
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| | - Ewan Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| | - Adrian J Stanley
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
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19
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Caccamo G, Franzè MS, Saffioti F, Pitrone C, Porcari S, Alibrandi A, Filomia R, Mondello P, Cacciola I, Saitta C, Squadrito G, Raimondo G, Maimone S. Cirrhotic Patients with Bacterial Infection and Negative Cultures Have a More Advanced Disease and an Increased Short-Term Mortality Rate. Dig Dis Sci 2022; 67:2655-2665. [PMID: 34041650 DOI: 10.1007/s10620-021-07047-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 05/09/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND The negative clinical impact of bacterial infections (BI) in patients with cirrhosis is well documented. In cirrhotic patients, failure to isolate the pathogen is a frequent event, occurring in 30-40% of cases. AIM The aim of this study was to compare the clinical characteristics, early (30-day) and short-term (90-day) mortality rates, in a cohort of cirrhotic patients with BI, between those with positive (C-pos) and those with negative (C-neg) microbiological cultures. METHODS We retrospectively enrolled 279 consecutive hospitalized cirrhotic patients with BI. Survival and predictors of 30-day and 90-day mortality were assessed by Kaplan-Meier curves and logistic regression analysis, respectively. RESULTS Cultures tested negative in 108/279 (38.7%) patients. C-neg patients were more frequently males (p = 0.035), had higher Child-Pugh-Turcotte (CPT; p = 0.007) and model for end-stage liver disease-sodium (MELD-Na; p = 0.043) scores, and had more frequently decompensated liver disease (p = 0.04). Mortality rate was higher in C-neg than in C-pos patients, both at 30 days (22.2% versus 11.7%, p = 0.024) and 90 days (46.3% versus 33.3%, p = 0.030). MELD-Na score and non-selective beta-blockers (NSBBs) were independent risk factors for 30-day and 90-day mortality. In particular, the use of NSBBs was independently associated with a lower 30-day and 90-day mortality risk (OR 0.41, CI95% 0.17-0.94, p = 0.040; and OR 0.43, CI95% 0.25-0.75, p = 0.003, respectively). CONCLUSIONS Cirrhotic patients with BI and negative microbiological cultures have significantly higher mortality compared to those with positive cultures. Early mortality and short-term mortality are mainly influenced by the underlying severity of liver disease. In this contest, therapy with NSBBs has a positive impact on short-term survival.
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Affiliation(s)
- Gaia Caccamo
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy.
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy.
| | - Maria Stella Franzè
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Windmill Road, Heading, Oxford, OX1 HP, UK
| | - Concetta Pitrone
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Serena Porcari
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Division of Gastroenterology and Inflammatory Bowel Diseases, University Hospital of Messina, Via Consolare Valeria 1, 98124, Messina, Italy
| | - Angela Alibrandi
- Department of Economics Unit of Statistical and Mathematical Science, University of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Roberto Filomia
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Placido Mondello
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Division of Infectious Diseases, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Irene Cacciola
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Carlo Saitta
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Giovanni Squadrito
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Division of Internal Medicine, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Giovanni Raimondo
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Clinical and Experimental Medicine, University of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
| | - Sergio Maimone
- Division of Medicine and Hepatology, University Hospital of Messina "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
- Department of Medical Sciences, University Hospital of Messina, "Policlinico G. Martino", Via Consolare Valeria 1, 98124, Messina, Italy
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20
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Téllez L, Albillos A. Non-selective beta-blockers in patients with ascites: The complex interplay among the liver, kidney and heart. Liver Int 2022; 42:749-761. [PMID: 35051310 DOI: 10.1111/liv.15166] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/31/2021] [Accepted: 01/09/2022] [Indexed: 12/12/2022]
Abstract
Non-selective beta-blockers (NSBBs) are the cornerstone of the primary and secondary prophylaxis of variceal bleeding in cirrhotic patients. They additionally prevent ascites development and death in compensated patients with clinically significant portal hypertension. After ascites onset, NSBBs remain beneficial for preventing further decompensations. However, as the cirrhosis progresses, the inflammation increases, systemic vasodilatation worsens, ascites turns refractory and cardiodynamic equilibrium becomes extremely fragile. In this scenario, NSBBs can critically impair the cardiac reserve and facilitate a haemodynamic breakdown, imperilling renal perfusion. Consequently, NSBB treatment should be carefully monitored or even avoided in such patients, and other options for portal hypertension management should be considered. In the present review, we explore the effects of NSBBs in patients with ascites and discuss the complex interplay among their hepatic, systemic and renal haemodynamic effects in this scenario.
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Affiliation(s)
- Luis Téllez
- Department of Gastroenterology and Hepatology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
| | - Agustín Albillos
- Department of Gastroenterology and Hepatology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, Spain
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21
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Bartell N, Al-Judaibi B. Beta-blocker therapy in refractory ascites: A steady march towards the truth. Saudi J Gastroenterol 2022; 28:83-84. [PMID: 35295065 PMCID: PMC9007079 DOI: 10.4103/sjg.sjg_87_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Nicholas Bartell
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Rochester, Rochester, New York, USA,Address for correspondence: Dr. Nicholas Bartell, Department of Medicine, Division of Gastroenterology and Hepatology, University of Rochester, Rochester, New York, USA. E-mail:
| | - Bandar Al-Judaibi
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Rochester, Rochester, New York, USA
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22
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Chen YC, Li YD, Lu CM, Huang WC, Kao SS, Chen WC. Propranolol use in patients with cirrhosis and refractory ascites: A nationwide study. Saudi J Gastroenterol 2022; 28:108-114. [PMID: 35295067 PMCID: PMC9007076 DOI: 10.4103/sjg.sjg_586_21] [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] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The impact of propranolol on patients with cirrhosis and refractory ascites is controversial. We conducted a nationwide longitudinal cohort study to compare the survival between patients with cirrhosis and refractory ascites, with and without using propranolol. METHODS Data of patients with cirrhosis and refractory ascites using propranolol, and controls matched by age and gender, were extracted from The National Health Insurance Research Database of Taiwan. The baseline demographic characteristics were compared between groups. Cox regression analysis was used to examine the predictors of mortality. RESULTS In this study, 1788 patients were enrolled in each group; 1304 patients (72.9%) in the propranolol group and 1445 patients (80.8%) in the control group died (P < 0.001). The mean survival was 34.3 ± 31.2 months in the propranolol group and 20.8 ± 26.6 months in the control group (P < 0.001). Propranolol (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.55-0.64, P < 0.001), statins (HR: 0.43, 95% CI: 0.34-0.56, P < 0.001), age (HR: 1.02, 95% CI: 1.01-1.02, P < 0.001), and diabetes mellitus (HR: 1.14, 95% CI: 1.05-1.24, P = 0.002) were the independent predictors for mortality. CONCLUSIONS Use of propanolol was associated with reduced mortality, compared with controls, in this nationwide cohort of patients with cirrhosis and refractory ascites.
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Affiliation(s)
- Yen-Chun Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan,Division of Gastroenterology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan
| | - Yun-Da Li
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chia-Ming Lu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wei-Chun Huang
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Division of Cardiology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan,Institute of Biomedical Sciences, College of Science, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Sung-Shuo Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan,Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wen-Chi Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan,Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Institute of Biomedical Sciences, College of Science, National Sun Yat-sen University, Kaohsiung, Taiwan,Address for correspondence: Dr. Wen-Chi Chen, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, No. 386, Ta-Chung 1st. Rd., Kaohsiung City 813, Taiwan. E-mail:
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23
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Zanetto A, Shalaby S, Feltracco P, Gambato M, Germani G, Russo FP, Burra P, Senzolo M. Recent Advances in the Management of Acute Variceal Hemorrhage. J Clin Med 2021; 10:3818. [PMID: 34501265 PMCID: PMC8432221 DOI: 10.3390/jcm10173818] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/21/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal bleeding is one of the most relevant causes of death in patients with cirrhosis and clinically significant portal hypertension, with gastroesophageal varices being the most frequent source of hemorrhage. Despite survival has improved thanks to the standardization on medical treatment aiming to decrease portal hypertension and prevent infections, mortality remains significant. In this review, our goal is to discuss the most recent advances in the management of esophageal variceal hemorrhage in cirrhosis with specific attention to the treatment algorithms involving the use of indirect measurement of portal pressure (HVPG) and transjugular intrahepatic portosystemic shunt (TIPS), which aim to further reduce mortality in high-risk patients after acute variceal hemorrhage and in the setting of secondary prophylaxis.
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Affiliation(s)
- Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (F.P.R.); (P.B.)
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (F.P.R.); (P.B.)
| | - Paolo Feltracco
- Anesthesiology and Intensive Care Unit, Department of Medicine, Padova University Hospital, 35128 Padova, Italy;
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (F.P.R.); (P.B.)
| | - Giacomo Germani
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (F.P.R.); (P.B.)
| | - Francesco Paolo Russo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (F.P.R.); (P.B.)
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (F.P.R.); (P.B.)
| | - Marco Senzolo
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Via Giustiniani 2, 35128 Padova, Italy; (A.Z.); (S.S.); (M.G.); (G.G.); (F.P.R.); (P.B.)
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24
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Biggins SW, Angeli P, Garcia-Tsao G, Ginès P, Ling SC, Nadim MK, Wong F, Kim WR. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2021; 74:1014-1048. [PMID: 33942342 DOI: 10.1002/hep.31884] [Citation(s) in RCA: 431] [Impact Index Per Article: 107.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022]
Affiliation(s)
- Scott W Biggins
- Division of Gastroenterology and Hepatology, and Center for Liver Investigation Fostering discovEryUniversity of WashingtonSeattleWA
| | - Paulo Angeli
- Unit of Hepatic Emergencies and Liver TransplantationDepartment of MedicineDIMEDUniversity of PadovaPaduaItaly
| | - Guadalupe Garcia-Tsao
- Department of Internal MedicineSection of Digestive DiseasesYale UniversityNew HavenCT
- VA-CT Healthcare SystemWest HavenCT
| | - Pere Ginès
- Liver Unit, Hospital Clinic, and Institut d'Investigacions Biomèdiques August Pi i SunyerUniversity of BarcelonaBarcelonaSpain
- Centro de Investigación Biomèdica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)MadridSpain
| | - Simon C Ling
- The Hospital for Sick Children, Division of Gastroenterology, Hepatology and Nutrition, and Department of PaediatricsUniversity of TorontoTorontoOntarioCanada
| | - Mitra K Nadim
- Division of NephrologyUniversity of Southern CaliforniaLos AngelesCA
| | - Florence Wong
- Division of Gastroenterology and HepatologyUniversity Health NetworkUniversity of TorontoTorontoOntarioCanada
| | - W Ray Kim
- Division of Gastroenterology and HepatologyStanford UniversityPalo AltoCA
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25
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Pfisterer N, Unger LW, Reiberger T. Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis. World J Hepatol 2021; 13:731-746. [PMID: 34367495 PMCID: PMC8326161 DOI: 10.4254/wjh.v13.i7.731] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 05/14/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension (PH), a common complication of liver cirrhosis, results in development of esophageal varices. When esophageal varices rupture, they cause significant upper gastrointestinal bleeding with mortality rates up to 20% despite state-of-the-art treatment. Thus, prophylactic measures are of utmost importance to improve outcomes of patients with PH. Several high-quality studies have demonstrated that non-selective beta blockers (NSBBs) or endoscopic band ligation (EBL) are effective for primary prophylaxis of variceal bleeding. In secondary prophylaxis, a combination of NSBB + EBL should be routinely used. Once esophageal varices develop and variceal bleeding occurs, standardized treatment algorithms should be followed to minimize bleeding-associated mortality. Special attention should be paid to avoidance of overtransfusion, early initiation of vasoconstrictive therapy, prophylactic antibiotics and early endoscopic therapy. Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding, and potentially in Child B patients with active bleeding at endoscopy. The use of carvedilol, safety of NSBBs in advanced cirrhosis (i.e. with refractory ascites) and assessment of hepatic venous pressure gradient response to NSBB is discussed. In the present review, we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.
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Affiliation(s)
- Nikolaus Pfisterer
- Medizinische Abteilung für Gastroenterologie und Hepatologie, Klinik Landstraße/Krankenanstalt Rudolfstiftung, Vienna 1030, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1090, Austria
| | - Lukas W Unger
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna 1090, Austria
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, United Kingdom.
| | - Thomas Reiberger
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1090, Austria
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna 1090, Austria
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna 1090, Austria
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26
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Garcia-Pagan JC, Francoz C, Montagnese S, Senzolo M, Mookerjee RP. Management of the major complications of cirrhosis: Beyond guidelines. J Hepatol 2021; 75 Suppl 1:S135-S146. [PMID: 34039484 DOI: 10.1016/j.jhep.2021.01.027] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/17/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023]
Abstract
Along with a growing understanding of the pathophysiology of cirrhosis and its complications, new therapies and management strategies have emerged in recent years. Many of these advances have helped inform the current EASL clinical practice guidelines1 on the management of some of the key complications of cirrhosis, such as ascites, variceal bleeding and infection. However, there are still some aspects of management where the evidence base is less clear, and/or where opinions amongst practitioners remain divided. Some of these more controversial areas are explored in this section, wherein we present evidence culminating in a suggested management approach based on expert opinion and extending beyond the current guidelines.
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Affiliation(s)
- Juan Carlos Garcia-Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Spain
| | - Claire Francoz
- Hepatology and Liver Intensive Care Unit, Hôpital Beaujon, INSERM. Clichy; France
| | | | - Marco Senzolo
- Gastroenterology, Multi-visceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Italy
| | - Rajeshwar P Mookerjee
- Institute for Liver and Digestive Health, University College London, UK; Department of Hepatology and Gastroenterology, Aarhus University, Denmark.
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27
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Calès P, Bertrais S, Boursier J, Fouchard I, Oberti F. Non-selective beta-blockers increase overall and liver mortality in alcoholic cirrhosis with MELD ≥ 12 over 5 years of follow-up. Liver Int 2021; 41:168-179. [PMID: 32979020 DOI: 10.1111/liv.14674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Non-cardioselective beta-blocker (NSBB) effects on mortality in cirrhosis are controversial. We evaluated the impact of NSBBs on mortality according to liver severity and mortality cause. METHODS Two hundred and fifty-eight patients with alcoholic cirrhosis were included in a retroprospective cohort: 129 NSBB-treated and 129 controls. The NSBB group had the following significant baseline differences: higher MELD, more frequent previous gastrointestinal bleeding, large oesophageal varices (OV) and lower heart rate. Propranolol dose was 160 mg/d in 81% of NSBB patients. RESULTS (i) Liver function: during 5.3 ± 2.6 years of follow-up, MELD progression was higher in NSBB patients: 1 (-1-4) than in controls: 0 (-1-1) (P = .017). (ii) Overall survival: no significant differences were observed between NSBBs and controls (Kaplan-Meier curves: P = .291). In multivariate Cox analysis, baseline MELD interacted with NSBB (P = .011). Thus, the NSBB hazard ratio (HR) was 0.99 (0.50-1.98) in MELD < 12 vs 3.17 (1.19-8.42) in MELD ≥ 12. (iii) Liver survival: NSBB decreased liver survival (Kaplan-Meier: P = .031). In multivariate Cox analysis, baseline MELD interacted with NSBB (P < .001). The NSBB HR was 0.81 (0.30-2.19) in MELD < 12 vs 6.23 (1.94-20.0) in MELD ≥ 12. In competing risk multivariate analysis for liver mortality, the MELD-NSBB interaction was significant (P < .001): the NSBB HR was 1.02 (0.36-2.91) in MELD < 12 vs 9.24 (3.18-26.9) in MELD ≥ 12. 4) Non-liver survival: contrastingly, non-liver survival was increased by NSBBs, especially in MELD ≥ 12 (competing Kaplan-Meier: P = .044). These results were confirmed in propensity risk score (PRS)-matched patients. CONCLUSION In alcoholic cirrhosis with rather high propranolol doses, overall and liver survival are significantly aggravated when MELD is ≥12.
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Affiliation(s)
- Paul Calès
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Sandrine Bertrais
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Jérôme Boursier
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Isabelle Fouchard
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
| | - Frédéric Oberti
- Liver-Gastroenterology Department, University Hospital, HIFIH Laboratory, Angers University, Angers, France
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28
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Gallo A, Dedionigi C, Civitelli C, Panzeri A, Corradi C, Squizzato A. Optimal Management of Cirrhotic Ascites: A Review for Internal Medicine Physicians. J Transl Int Med 2020; 8:220-236. [PMID: 33511049 PMCID: PMC7805288 DOI: 10.2478/jtim-2020-0035] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Clinical history of liver cirrhosis is characterised by two phases: the asymptomatic phase, also termed 'compensated cirrhosis', and the phase of complications due to the development of portal hypertension and liver dysfunction, also termed 'decompensated cirrhosis', in which patients may develop ascites, the most frequent and clinically relevant complication of liver cirrhosis. Ascites can be classified into uncomplicated and complicated according to the development of refractoriness, spontaneous bacterial peritonitis (SBP) or the association with hepatorenal syndrome (HRS). In this narrative review, we will extensively discuss the optimal pharmacological and non-pharmacological management of cirrhotic ascites with the aim to offer an updated practical guide to Internal Medicine physicians. According to the amount of fluid in the abdominal cavity, uncomplicated ascites is graded from 1 to 3, and the cornerstone of its management consists of restriction of salt intake, diuretics and large-volume paracentesis (LVP); in recent years, long-term administration of human albumin has acquired a new interesting role. Refractory ascites is primarily managed with LVP and transjugular intrahepatic portosystemic shunt (TIPS) placement in selected patients. The occurrence of renal impairment, especially HRS, worsens the prognosis of patients with cirrhotic ascites and deserves a specific treatment. Also, the management of SBP faces the rising and alarming spread of antibiotic resistance. Hepatic hydrothorax may even complicate the course of the disease and its management is a challenge. Last but not least, liver transplantation (LT) is the ultimate and more effective measure to offer to patients with cirrhotic ascites, particularly when complications occur.
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Affiliation(s)
- Andrea Gallo
- Department of Medicine and Surgery, University of Insubria, Como/Varese, Italy
| | - Cristina Dedionigi
- Department of Medicine and Surgery, University of Insubria, Como/Varese, Italy
| | - Chiara Civitelli
- Department of Medicine and Surgery, University of Insubria, Como/Varese, Italy
| | - Anna Panzeri
- Department of Medicine and Surgery, University of Insubria, Como/Varese, Italy
- Hepatology Center, Ospedale Sant’Anna, Como, Italy
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29
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Beta-blockers in refractory ascites - is it truly the end of the road? J Hepatol 2020; 73:1290-1291. [PMID: 32861511 DOI: 10.1016/j.jhep.2020.06.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 12/04/2022]
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30
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Alvarado-Tapias E, Ardevol A, Garcia-Guix M, Montañés R, Pavel O, Cuyas B, Graupera I, Brujats A, Vilades D, Colomo A, Poca M, Torras X, Guarner C, Concepción M, Aracil C, Torres F, Villanueva C. Short-term hemodynamic effects of β-blockers influence survival of patients with decompensated cirrhosis. J Hepatol 2020; 73:829-841. [PMID: 32298768 DOI: 10.1016/j.jhep.2020.03.048] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of β-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis. METHODS Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting β-blockers and again after 1 to 3 months of treatment (short-term). RESULTS Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under β-blockers, decompensated patients had lower portal pressure decrease (10 ± 18% vs. 15 ± 12%; p <0.05) and had greater reductions in heart rate (p <0.001) and CO (17 ± 15% vs. 10 ± 21%; p <0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with β-blockers than survivors (21 ± 14% vs. 15 ± 16%; p <0.05) and CO under β-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66-0.83). Death risk was higher in decompensated patients with CO <5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25-0.77; p = 0.004). CONCLUSIONS In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to β-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of β-blockers on CO might adversely influence survival in decompensated cirrhosis. LAY SUMMARY β-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of β-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of β-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis.
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Affiliation(s)
- Edilmar Alvarado-Tapias
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain
| | - Alba Ardevol
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain
| | - Marta Garcia-Guix
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Rosa Montañés
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Oana Pavel
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Berta Cuyas
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Isabel Graupera
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Anna Brujats
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - David Vilades
- Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain; Cardiac imaging unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Alan Colomo
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Maria Poca
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Xavier Torras
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain
| | - Carlos Guarner
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain
| | - Mar Concepción
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Carles Aracil
- Hospital Universitari Arnau de Vilanova, Lleida, Institut de Recerca Biomèdica (IRBLleida)
| | - Ferran Torres
- Medical Statistics Core Facility, IDIBAPS, Hospital Clinic, Barcelona; and Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Càndid Villanueva
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain.
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Mattos AA, Wiltgen D, Jotz RF, Dornelles CMR, Fernandes MV, Mattos ÂZ. Spontaneous bacterial peritonitis and extraperitoneal infections in patients with cirrhosis. Ann Hepatol 2020; 19:451-457. [PMID: 32533951 DOI: 10.1016/j.aohep.2020.04.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/22/2020] [Accepted: 04/07/2020] [Indexed: 02/04/2023]
Abstract
Infections are a frequent complication and a major cause of death among patients with cirrhosis. The important impact of infections in general and especially spontaneous bacterial peritonitis on the course of disease and prognosis of patients with cirrhosis has been recognized for many years. Nevertheless, such importance has recently increased due to the comprehension of infection as one of the most prominent risk factors for patients to develop acute-on-chronic liver failure. Furthermore, the issue of infections in cirrhosis is a focus of increasing attention because of the spreading of multidrug resistant bacteria, which is an emerging concern among physicians assisting patients with cirrhosis. In the present paper, we will review the current epidemiology of infections in patients with cirrhosis and particularly that of infections caused by resistant bacteria, demonstrating the relevance of the subject. Besides, we will discuss the current recommendations on diagnosis and treatment of different kinds of infections, including spontaneous bacterial peritonitis, and we will highlight the importance of knowing local microbiological profiles and choosing empirical antibiotic therapy wisely. Finally, we will debate the existing evidences regarding the role of volume expansion with albumin in patients with cirrhosis and extraperitoneal infections, and that of antibiotic prophylaxis of spontaneous bacterial peritonitis.
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Affiliation(s)
- Angelo A Mattos
- Federal University of Health Sciences of Porto Alegre, Graduate Program in Medicine: Hepatology, Brazil; Irmandade Santa Casa de Misericórdia de Porto Alegre, Brazil
| | - Denusa Wiltgen
- Irmandade Santa Casa de Misericórdia de Porto Alegre, Brazil; Federal University of Health Sciences of Porto Alegre, Brazil
| | - Raquel F Jotz
- Federal University of Health Sciences of Porto Alegre, Brazil
| | | | | | - Ângelo Z Mattos
- Federal University of Health Sciences of Porto Alegre, Graduate Program in Medicine: Hepatology, Brazil; Irmandade Santa Casa de Misericórdia de Porto Alegre, Brazil.
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Wong YJ, Kalki RC, Lin KW, Kumar R, Tan J, Teo EK, Li JW, Ang TL. Short- and long-term predictors of spontaneous bacterial peritonitis in Singapore. Singapore Med J 2020; 61:419-425. [PMID: 31363784 PMCID: PMC7926584 DOI: 10.11622/smedj.2019085] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Spontaneous bacterial peritonitis (SBP) is the commonest complication of liver cirrhosis. Timely and appropriate treatment of SBP is crucial, particularly with the rising worldwide prevalence of multidrug-resistant organisms (MDROs). We aimed to investigate the clinical outcomes of SBP in Singapore. METHODS All cirrhotic patients with SBP diagnosed between January 2014 and December 2017 were included. Nosocomial SBP (N-SBP) was defined as SBP diagnosed more than 48 hours after hospitalisation. Clinical outcomes were analysed as categorical outcomes using univariate and multivariate analysis. RESULTS There were 33 patients with 39 episodes of SBP. Their mean age was 64.5 years and 69.7% were male. The commonest aetiology of cirrhosis was hepatitis B (27.3%). The Median Model for End-stage Liver Disease (MELD) score was 17; 33.3% had acute-on-chronic liver failure and 60.6% had septic shock at presentation. N-SBP occurred in 25.6% of SBP cases. N-SBP was more commonly associated with MDROs, previous antibiotic use in the past three months (p = 0.014) and longer length of stay (p = 0.011). The 30-day and 90-day mortality among SBP patients was 30.8% and 51.3%, respectively. MELD score > 20 was a predictor for 30-day mortality. N-SBP and MELD score > 20 were predictors for 90-day mortality. CONCLUSION N-SBP was significantly associated with recent antibiotic use, longer hospitalisation, more resistant organisms and poorer survival among patients with SBP. N-SBP and MELD score predict higher mortality in SBP. Judicious use of antibiotics may reduce N-SBP and improve survival among cirrhotic patients.
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Affiliation(s)
- Yu Jun Wong
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | | | - Kenneth Weicong Lin
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Rahul Kumar
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Jessica Tan
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Eng Kiong Teo
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - James Weiquan Li
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
| | - Tiing Leong Ang
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore
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Carvedilol Combined With Ivabradine Improves Left Ventricular Diastolic Dysfunction, Clinical Progression, and Survival in Cirrhosis. J Clin Gastroenterol 2020; 54:561-568. [PMID: 31305281 DOI: 10.1097/mcg.0000000000001219] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Left ventricular diastolic dysfunction (LVDD) refers to impaired cardiac diastolic relaxation and may be improved by targeted heart rate reduction (THR). The authors evaluated whether a combination of carvedilol and ivabradine, an If channel blocker that reduces heart rate without affecting blood pressure, could improve LVDD and outcomes in cirrhosis. PATIENTS AND METHODS THR was defined as heart rate reduction to 55 to 65 beats per minute. Of 260 patients with cirrhosis, 189 (72%) with LVDD were randomized to THR [group (Gr.)A; n=94; carvedilol±ivabradine)] or standard care (Gr.B; n=95; no β-blockers) and followed for 12 months. RESULTS In Gr.A, THR was achieved at 4 weeks in 88 (93%) patients (responders, R): 48 (61.5%) with carvedilol alone and 40 (86.9%) of 46 patients with additional ivabradine. In Gr.A, LVDD reversed in 16 (20.5%) and improved from grade 2 to 1 in 34 (35.4%)], whereas in Gr.B, it progressed from grade 1 to 2 in 10 (10.5%) patients. At 12 months, 21 (11.1%) patients died, 6 (14%) in Gr.A and 15 (18%) in Gr.B (P=0.240), but no mortality was seen in those who had persistent THR at 1 year (n=78; P=0.000). In multivariate analysis, model for end-stage liver disease [hazard ratio (HR), 1.52; 95% confidence interval (CI), 1.22-2.75; P=0.034] and E-wave transmitral/early diastolic mitral annular velocity (HR, 1.28; 95% CI, 1.23-2.42; P=0.048) predicted 1-year mortality. Nonresponders had an increased mortality risk (HR, 1.3; 95% CI, 1.2-1.8; P=0.046) independent of age, gender, and baseline model for end-stage liver disease. Levels of norepinephrine, N terminal brain natriuretic peptide, plasma renin activity, and aldosterone were reduced (P<0.01) in responders. More patients in Gr.B developed acute kidney injury (odds ratio, 4.2; 95% CI, 2.8-10.5; P=0.027) and encephalopathy (odds ratio, 6.6; 95% CI, 1.9-9.7; P=0.040). CONCLUSIONS Ivabradine combined with carvedilol improves LVDD, achieves THR more often and reduces risk of encephalopathy, acute kidney injury with improved survival in patients with cirrhosis.
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Wu CK, Yang SC, Liang CM, Li YC, Yeh WS, Tai WC, Lee CH, Yang YH, Hsu CN, Tsai TH, Chuah SK. The role of antibiotics in upper gastrointestinal bleeding among cirrhotic patients without major complications after endoscopic hemostasis. J Gastroenterol Hepatol 2020; 35:777-787. [PMID: 31674688 DOI: 10.1111/jgh.14873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/09/2019] [Accepted: 09/14/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Antibiotic prophylaxis should be instituted for cirrhotic patients with upper gastrointestinal bleeding (UGIB), but the benefit on compensated patients remains undetermined. We aimed to compare the clinical outcomes between cirrhotic patients without major complications with UGIB with and without antibiotic prophylaxis. METHODS We conducted this population-based cohort study by using Taiwanese Longitudinal Health Insurance Database 2000 (LHID2000, between 1997 to 2013), aged 18 years or older with a hospital discharge diagnosis of cirrhosis (n = 64,506), UGIB (n = 7,784), and endoscopic therapy (n = 2,292). After strict exclusions, 1205 patients were enrolled and were divided into antibiotic exposure (n = 558) and non-exposure (n = 647) groups. The outcomes were rebleeding and mortality. RESULTS After completing the analysis adjusted by death, the rebleeding rates within 4 weeks were significantly lower in patients with antibiotic prophylaxis (3.05% versus 6.03%, P = 0.0142) and those with endoscopic therapy (0.72% vs 3.09%, P = 0.0033) but not significant after 3 months and onwards. Male patients aged > 55, high CCI score ≧ 4, and UGIB of variceal etiologies were benefited from rebleeding. The use of antibiotics did not significantly impact 6-week mortality (adjusted hazard ratio: 1.07, 95%CI: 0.41~2.75; P = 0.8943). Old age, multiple comorbidities, and UGIB of variceal etiologies were risk factors of all-cause mortality. CONCLUSIONS The current study suggested that cirrhotic patients without major complications who suffered from UGIB were benefited by the use of antibiotics to prevent rebleeding within 4 weeks after endoscopic treatment of UGIB especially for those with age > 55, high CCI score ≧ 4, and UGIB of variceal etiologies.
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Affiliation(s)
- Cheng-Kun Wu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Shih-Cheng Yang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Ming Liang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Chi Li
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wen-Shuo Yeh
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Wei-Chen Tai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chen-Hsiang Lee
- Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan.,Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tzu-Hsien Tsai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Seng-Kee Chuah
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Low dose of propranolol treatment is associated with better survival in cirrhotic patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol 2020; 32:365-372. [PMID: 31688303 DOI: 10.1097/meg.0000000000001511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The use of nonselective beta blockers in cirrhotic patients experiencing complications is controversial. We aimed to investigate the association between propranolol treatment and outcomes for cirrhotic patients with hepatic encephalopathy. METHODS Using data from the Taiwan National Health Insurance Research Database, we identified 4754 cirrhotic patients newly diagnosed with hepatic encephalopathy between 2001 and 2010. Among them, 519 patients received propranolol treatment and the other 519 patients without exposure to propranolol were enrolled into our study, both of which were matched by sex, age, and propensity score. The Kaplan-Meier method and time-dependent-modified Cox proportional hazards models were employed for survival and multivariate-stratified analyses. RESULTS The median overall survival (OS) was significantly longer in the propranolol-treated cohort than in the untreated cohort (3.46 versus 1.88 years, P < 0.001). A dose-dependent increase in survival was observed (median OS: 4.49, 3.29, and 2.46 years in patients treated with propranolol more than 30 , 20-30 , and less than 20 mg/day, respectively [P < 0.001, P = 0.001, and P = 0.079 versus the untreated group]). In addition to reduce the risk of mortality (adjusted hazard ratio, 0.58; P < 0.001), propranolol also diminished the risk of sepsis-related death (adjusted hazard ratio, 0.31; P = 0.006) according to the multivariate analysis. However, the risk of circulatory or hepatic failure was nonsignificantly altered by propranolol treatment. CONCLUSION Low dose of propranolol treatment was associated with a better OS in cirrhotic patients with hepatic encephalopathy and its effects were dose dependent.
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Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: Evidence-based indications and limitations. JHEP Rep 2020; 2:100063. [PMID: 32039404 PMCID: PMC7005550 DOI: 10.1016/j.jhepr.2019.12.001] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/29/2019] [Accepted: 12/03/2019] [Indexed: 02/07/2023] Open
Abstract
Non-selective beta-blockers (NSBBs) are the mainstay of treatment for portal hypertension in the setting of liver cirrhosis. Randomised controlled trials demonstrated their efficacy in preventing initial variceal bleeding and subsequent rebleeding. Recent evidence indicates that NSBBs could prevent liver decompensation in patients with compensated cirrhosis. Despite solid data favouring NSBB use in cirrhosis, some studies have highlighted relevant safety issues in patients with end-stage liver disease, particularly with refractory ascites and infection. This review summarises the evidence supporting current recommendations and restrictions of NSBB use in patients with cirrhosis.
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Key Words
- ACLF
- ACLF, acute-on-chronic liver failure
- AKI, acute kidney injury
- ALD, alcohol-related liver disease
- ARD, absolute risk difference
- AV, atrioventricular
- EBL, endoscopic band ligation
- GOV, gastroesophageal varices
- HRS, hepatorenal syndrome
- HVPG, hepatic venous pressure gradient
- IGV, isolated gastric varices
- IRR, incidence rate ratio
- ISMN, isosorbide mononitrate
- MAP, mean arterial pressure
- NASH, non-alcoholic steatohepatitis
- NNH, number needed to harm
- NNT, number needed to treat
- NR, not reported
- NSBBs
- NSBBs, non-selective beta-blockers
- OR, odds ratio
- PH, portal hypertension
- PHG, portal hypertensive gastropathy
- RCT, randomised controlled trials
- RR, risk ratio
- SBP, spontaneous bacterial peritonitis
- SCL, sclerotherapy
- TIPS, transjugular intrahepatic portosystemic shunt
- ascites
- cirrhosis
- portal hypertension
- spontaneous bacterial peritonitis
- varices
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Affiliation(s)
- Susana G. Rodrigues
- Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Yuly P. Mendoza
- Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Jaime Bosch
- Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland
- Corresponding author. Address: Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland.
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Yoo JJ, Kim SG, Kim YS, Lee B, Jeong SW, Jang JY, Lee SH, Kim HS, Jun BG, Kim YD, Cheon GJ. Propranolol plus endoscopic ligation for variceal bleeding in patients with significant ascites: Propensity score matching analysis. Medicine (Baltimore) 2020; 99:e18913. [PMID: 32000397 PMCID: PMC7004788 DOI: 10.1097/md.0000000000018913] [Citation(s) in RCA: 7] [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] [Indexed: 12/15/2022] Open
Abstract
The use of beta-blockers in decompensated cirrhosis accompanying ascites is still under debate. The aim of this study was to compare overall survival (OS) and incidence of cirrhotic complications between endoscopic variceal ligation (EVL) only and EVL + non-selective beta-blocker (NSBB) combination therapy in cirrhotic patients with significant ascites (≥grade 2).This retrospective study included 271 consecutive cirrhotic patients with ascites who were treated with EVL only or EVL + NSBB combination therapy as a primary prophylaxis of esophageal varices. The primary outcome was all-cause mortality. Propensity score matching was performed between the 2 groups to minimize baseline difference.Median observation period was 42.1 months (interquartile range, 18.4-75.1 months). All patients had deteriorated liver function: 81.1% Child-Pugh class B and 18.9% Child-Pugh class C. All-cause mortality was significantly higher in the EVL + NSBB group than in the EVL only group not only in non-matched cohort, but also in matched cohort (48.9% vs 31.2%; P = .039). More people died from hepatic failure in the EVL + NSBB group than that in the EVL only group (40.5% vs 20.0%; P = .020). However, the incidence of variceal bleeding, hepatorenal syndrome (HRS), or spontaneous bacterial peritonitis (SBP) was not significantly different between the 2 groups.The use of NSBB might worsen the prognosis of cirrhotic patients with significant ascites. These results suggest that EVL alone is a more appropriate treatment option for prophylaxis of esophageal varices than propranolol combination therapy when patients have significant ascites.
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Affiliation(s)
- Jeong-Ju Yoo
- Department of Gastroenterology and Hepatology, Soon Chun Hyang University School of Medicine
| | - Sang Gyune Kim
- Department of Gastroenterology and Hepatology, Soon Chun Hyang University School of Medicine
| | - Young Seok Kim
- Department of Gastroenterology and Hepatology, Soon Chun Hyang University School of Medicine
| | - Bora Lee
- Department of Statistics, Graduate School, Chung-Ang University, Seoul
| | - Soung Won Jeong
- Department of Gastroenterology and Hepatology, Soon Chun Hyang University School of Medicine
| | - Jae Young Jang
- Department of Gastroenterology and Hepatology, Soon Chun Hyang University School of Medicine
| | - Sae Hwan Lee
- Department of Gastroenterology and Hepatology, Soon Chun Hyang University School of Medicine
| | - Hong Soo Kim
- Department of Gastroenterology and Hepatology, Soon Chun Hyang University School of Medicine
| | - Baek-Gyu Jun
- Department of Internal Medicine, Gangneug Asan Hospital, Republic of Korea
| | - Young Don Kim
- Department of Internal Medicine, Gangneug Asan Hospital, Republic of Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, Gangneug Asan Hospital, Republic of Korea
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Zanetto A, Garcia-Tsao G. Gastroesophageal Variceal Bleeding Management. THE CRITICALLY ILL CIRRHOTIC PATIENT 2020:39-66. [DOI: 10.1007/978-3-030-24490-3_4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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The Role of Non-Selective β-Blockers in Compensated Cirrhotic Patients without Major Complications. ACTA ACUST UNITED AC 2019; 56:medicina56010014. [PMID: 31905956 PMCID: PMC7022668 DOI: 10.3390/medicina56010014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 12/22/2019] [Accepted: 12/22/2019] [Indexed: 12/17/2022]
Abstract
Background and Objectives: Non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in cirrhotic patients with clinically significant portal hypertension (CSPH), but remained uncertain for compensated cirrhotic patients without major complications. We aimed to compare the clinical outcomes between propranolol users and non-users of a CC group without major complications. Material and Methods: We conducted this population-based cohort study by using the Taiwanese Longitudinal Health Insurance Database 2000. Propranolol users (classified as cumulative defined daily dose (cDDD)) and non-PPL users were matched with a 1:1 propensity score in both cohorts. Results: This study comprised 6896 propranolol users and 6896 non-propranolol users. There was no significant impact on the development of spontaneous bacterial peritonitis between the two groups (aHR: 1.24, 95% confidence interval (CI): 0.88~1.75; p = 0.2111). Male gender, aged condition, and non-liver related diseases (peripheral vascular disease, cerebrovascular disease, dementia, pulmonary disease, and renal disease) were the independent risk factors of mortality. PPL users had significantly lower incidence of HCC development than non-users (aHR: 0.81, p = 0.0580; aHR: 0.80, p = 0.1588; and aHR: 0.49, p < 0.0001 in the groups of 1–28, 29–90, and >90 cDDD, respectively). Conclusion: The current study suggested that high cumulative doses of propranolol could decrease the risk of hepatocellular carcinoma among compensated cirrhotic patients without major complications. Further large-scale prospective studies are still required to confirm the findings in this study. Results: It remained uncertain whether non-selective β-blockers (NSBB) could prevent decompensation and hepatocellular carcinoma (HCC) in compensatory cirrhotic patients without major complications. This study aimed to compare the clinical outcomes between propranolol users and non-users of the CC group without major complications.
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Bultas AC, Teshome B, Richter SK, Schafers S, Cooke E, Call WB. Use of Nonselective β-Blockers in Patients With End-Stage Liver Disease and Select Complications. Ann Pharmacother 2019; 54:583-593. [PMID: 31810371 DOI: 10.1177/1060028019893092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Objective: To review the literature and recommendations for nonselective β-blockers (NSBBs) in the setting of variceal bleeding prophylaxis and decompensated liver disease. Data Sources: Literature search of MEDLINE was performed (1988 to October 2019) using the following search terms: cirrhosis, advanced cirrhosis, β-blocker, decompensation, prophylaxis. Abstracts, peer-reviewed publications, clinical practice guidelines, and product monographs were reviewed. Study Selection and Data Extraction: Relevant English language studies and those conducted in humans were considered for analysis and inclusion. Data Synthesis: Evidence that suggests that NSBBs are harmful in advanced cirrhosis is overshadowed by confounding variables and small patient populations. The majority of the available evidence suggests neutral or beneficial effects on mortality with continuation of NSBBs despite liver disease progression. Based on the available literature, guidelines, and expert consensuses, NSBBs can be considered within this patient population and may have a positive impact on the majority of these patients. Relevance to Patient Care and Clinical Practice: This review summarizes current place in therapy for NSBBs in the setting of cirrhosis and variceal bleeding prophylaxis. It also includes a discussion of the literature for use of NSBBs within the setting of different acute decompensations in which the data and recommendations for use are less clear. Conclusions: Recent evidence shows neutral or positive results for NSBB use in particular decompensation subgroups, which suggests that NSBBs can be used cautiously with close monitoring in patients with advanced cirrhosis. Questions still remain regarding optimal agent and dose and whether agents can be safely restarted after an acute decompensation episode.
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Affiliation(s)
| | | | | | | | - Emily Cooke
- Barnes-Jewish Hospital, Saint Louis, MO, USA
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Tergast TL, Kimmann M, Laser H, Gerbel S, Manns MP, Cornberg M, Maasoumy B. Systemic arterial blood pressure determines the therapeutic window of non-selective beta blockers in decompensated cirrhosis. Aliment Pharmacol Ther 2019; 50:696-706. [PMID: 31373713 DOI: 10.1111/apt.15439] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/10/2019] [Accepted: 07/05/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND The safety of non-selective β-blockers in patients with advanced cirrhosis has been questioned in recent years. It was hypothesised that there is a particular therapeutic window. However, the specific limits still need to be determined. AIM To evaluate potential limits of the therapeutic window of non-selective β-blocker therapy in patients with cirrhosis and ascites METHODS: The impact of non-selective β-blockers on 28-day transplant-free survival was analysed in a cohort of 624 consecutive patients with decompensated cirrhosis and ascites. Three potential limits were investigated: spontaneous bacterial peritonitis, acute-on-chronic liver failure, mean arterial blood pressure ≤ 82 and < 65 mm Hg. RESULTS Treatment with non-selective β-blockers was associated with a higher 28-day transplant-free survival in the overall cohort (hazard ratio: 0.621; P = .035) as well as in patients with acute-on-chronic liver failure (hazard ratio: 0.578; P = .031) and those with spontaneous bacterial peritonitis (hazard ratio: 0.594; P = .073). In contrast, survival benefits were markedly attenuated in patients with a mean arterial blood pressure ≤ 82 mm Hg and completely lost in those with mean arterial blood pressure < 65 mm Hg (P = .536). In spontaneous bacterial peritonitis patients with a mean arterial blood pressure < 65 mm Hg non-selective β-blocker treatment was associated with renal impairment. Of note, among those with a mean arterial blood pressure ≥ 65 mm Hg non-selective β-blocker intake was consistently associated with superior transplant-free survival (hazard ratio: 0.582; P = .029) irrespective of the presence of spontaneous bacterial peritonitis (hazard ratio: 0.435; P = .028) or acute-on-chronic liver failure (hazard ratio: 0.480 P = .034). CONCLUSIONS Ascites, acute-on-chronic liver failure and spontaneous bacterial peritonitis do not limit the safe use of non-selective β-blockers in patients with cirrhosis. Mean arterial blood pressure might represent a better indicator to determine the therapeutic window of non-selective β-blocker treatment.
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Affiliation(s)
- Tammo L Tergast
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Kimmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hans Laser
- Hannover Medical School, Centre for Information Management (ZIMt), Hannover, Germany
| | - Svetlana Gerbel
- Hannover Medical School, Centre for Information Management (ZIMt), Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany.,Centre for Individualised Infection Medicine (CIIM), Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany.,Centre for Individualised Infection Medicine (CIIM), Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung DZIF), Partner-site Hannover-Braunschweig, Hannover, Germany
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Abstract
Gastrointestinal bleeding is one of the major causes of death in patients with cirrhosis, and gastroesophageal varices represent the main source of hemorrhage. Even though in the last decades survival has been improved because of the widespread adoption of effective treatments and optimization of general medical care, mortality is still significantly high, and decompensated patients pose a complex challenge requiring a multidisciplinary approach that is crucial to improve survival. The aims of this commentary are to review the most recent advances in the management of esophageal variceal bleeding and to highlight useful information to aid hepatologists in clinical practice.
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Affiliation(s)
- Alberto Zanetto
- Digestive Disease Section, Yale University School of Medicine, 333 Cedar Street 1080 LMP New Haven, Connecticut, 06520-8019, USA.,VA-CT Healthcare System, 950 Campbell Ave, West Haven, Connecticut, 06516, USA
| | - Guadalupe Garcia-Tsao
- Digestive Disease Section, Yale University School of Medicine, 333 Cedar Street 1080 LMP New Haven, Connecticut, 06520-8019, USA.,VA-CT Healthcare System, 950 Campbell Ave, West Haven, Connecticut, 06516, USA
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43
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Mandorfer M, Hernández-Gea V, Reiberger T, García-Pagán JC. Hepatic Venous Pressure Gradient Response in Non-Selective Beta-Blocker Treatment—Is It Worth Measuring? ACTA ACUST UNITED AC 2019. [DOI: 10.1007/s11901-019-00469-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Low-Dose Propranolol as Secondary Prophylaxis for Varix Bleeding Decreases Mortality and Rebleeding Rate in Patients with Tense Ascites. J Clin Med 2019; 8:jcm8050573. [PMID: 31035484 PMCID: PMC6571569 DOI: 10.3390/jcm8050573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/20/2019] [Accepted: 04/24/2019] [Indexed: 12/25/2022] Open
Abstract
Background and Aim: The risk and benefit of non-selective propranolol in patients with tense ascites are controversial. This study aimed to investigate the effect of propranolol as secondary prophylaxis on varix rebleeding and overall mortality in patients with tense ascites. Methods: This study used a database of the Health Insurance Review and Assessment Service (HIRAS), which provides health insurance to 97.2% of the total population in Korea. A total of 80,071 patients first variceal bleeding as the first decompensated complication enrolled from 2007 to 2014. Results: There were 2274 patients with large-volume ascites prescribed propranolol as secondary prophylaxis after first varix bleeding. The average prescription dose of propranolol as secondary prophylaxis was 74 mg/day in patients with large-volume ascites. The mean duration of rebleeding was 22.8 months. Result of analysis showed that low-dose propranolol (40–120 mg/day) compared to inadequate propranolol dose (<40 mg/day) as secondary prophylaxis decreased overall mortality and varix rebleeding in patients with tense ascites. Conclusions: Low-dose propranolol (40–120 mg/day) as secondary prophylaxis for variceal re-bleeding decreased overall mortality and varix rebleeding recurrence in patients with tense ascites.
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45
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Zhang F, Xu H, Chen M, Zhang M, Xiao J, Wang Y, He Q, Zhang W, Yin X, Zou X, Zhuge Y. Dose-dependent effect of propranolol on the hemodynamic response in cirrhotic patients with gastroesophageal varices. Eur J Gastroenterol Hepatol 2019; 31:368-374. [PMID: 30422868 PMCID: PMC6380447 DOI: 10.1097/meg.0000000000001293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 09/18/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Propranolol is always titrated to the maximum tolerated dose to prevent gastroesophageal variceal bleeding. However, some patients do not achieve a hemodynamic response and experience more intolerance and discontinuation. This study evaluated the dose-dependent effect of propranolol on hemodynamic response and tolerance in cirrhotic patients. PATIENTS AND METHODS This retrospective study included 95 consecutive patients recruited from our prospective database. After hepatic venous pressure gradient measurement, patients received propranolol 10 mg, twice daily increased 10 mg daily until to 80 or 120 mg/day. Secondary hepatic venous pressure gradient was also measured. For nonresponders at 80 mg/day, propranolol was titrated to 120 mg/day. RESULTS For 58 patients, propranolol was titrated to 80 mg/day, whereas for 37 patients, it was titrated to 120 mg/day. Hemodynamic response was similar in both groups (50 vs. 54.1%, P=0.700). Eighteen of the 29 nonresponders at propranolol 80 mg/day received a dose of 120 mg/day. Two patients achieved a hemodynamic response, but two could not tolerate the dose. Nine (15.5%) patients achieved the target dose of propranolol at 80 mg/day, whereas 16 (43.2%) patients at 120 mg/day achieved this (P=0.003). The difference in patients achieving the target dose between responders and nonresponders was not significant (14 vs. 14, P=0.642). Reduction or discontinuation was required by two (6.9%) patients using 80 mg/day propranolol and six (30%) patients using 120 mg/day propranolol (P=0.032). CONCLUSION There is no dose-dependent effect of 80-120 mg/day of propranolol on the hemodynamic response in cirrhotic patients with gastroesophageal varices. This indicates that low-dose propranolol below the target dose might lead to a considerable hemodynamic response and is much safer and well tolerated.
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Affiliation(s)
- Feng Zhang
- Department of Gastroenterology, Nanjing Medical University Drum Tower Clinical Medical School
| | - Hui Xu
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Min Chen
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Ming Zhang
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Jiangqiang Xiao
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yi Wang
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Qibin He
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wei Zhang
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaochun Yin
- Department of Gastroenterology, Nanjing Medical University Drum Tower Clinical Medical School
| | - Xiaoping Zou
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yuzheng Zhuge
- Department of Gastroenterology, Nanjing Medical University Drum Tower Clinical Medical School
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46
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Kim HY, So YH, Kim W, Ahn DW, Jung YJ, Woo H, Kim D, Kim MY, Baik SK. Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices. J Hepatol 2019; 70:412-422. [PMID: 30389550 DOI: 10.1016/j.jhep.2018.10.018] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/15/2018] [Accepted: 10/21/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Non-selective beta-blockers (NSBBs) are the mainstay of primary prophylaxis of esophageal variceal bleeding in patients with liver cirrhosis. We investigated whether non-invasive markers of portal hypertension correlate with hemodynamic responses to NSBBs in cirrhotic patients with esophageal varices. METHODS In this prospective cohort study, 106 cirrhotic patients with high-risk esophageal varices in the derivation cohort received carvedilol prophylaxis, and completed paired measurements of hepatic venous pressure gradient, liver stiffness (LS), and spleen stiffness (SS) at the beginning and end of dose titration. LS and SS were measured using acoustic radiation force impulse imaging. A prediction model for hemodynamic response was derived, and subject to an external validation in the validation cohort (63 patients). RESULTS Hemodynamic response occurred in 59 patients (55.7%) in the derivation cohort, and in 33 patients (52.4%) in the validation cohort, respectively. Multivariate logistic regression analysis identified that ΔSS was the only significant predictor of hemodynamic response (odds ratio 0.039; 95% confidence interval 0.008-0.135; p <0.0001). The response prediction model (ModelΔSS = 0.0490-2.8345 × ΔSS; score = (exp[ModelΔSS])/(1 + exp[ModelΔSS]) showed good predictive performance (area under the receiver-operating characteristic curve [AUC] = 0.803) using 0.530 as the threshold value. The predictive performance of the ModelΔSS in the validation set improved using the same threshold value (AUC = 0.848). CONCLUSION A new model based on dynamic changes in SS exhibited good performance in predicting hemodynamic response to NSBB prophylaxis in patients with high-risk esophageal varices. LAY SUMMARY Non-selective beta-blockers are the mainstay of primary prophylaxis to prevent variceal bleeding in patients with cirrhosis and high-risk esophageal varices. This prospective study showed that a prediction model based on changes in spleen stiffness before vs. after dose titration might be a non-invasive marker for response to prophylactic non-selective beta-blocker (carvedilol) therapy in patients with cirrhosis and high-risk esophageal varices. ClinicalTrials.gov Identifier: NCT01943318.
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Affiliation(s)
- Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Young Ho So
- Department of Radiology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea.
| | - Dong-Won Ahn
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Yong Jin Jung
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Hyunsik Woo
- Department of Radiology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
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Kockerling D, Nathwani R, Forlano R, Manousou P, Mullish BH, Dhar A. Current and future pharmacological therapies for managing cirrhosis and its complications. World J Gastroenterol 2019; 25:888-908. [PMID: 30833797 PMCID: PMC6397723 DOI: 10.3748/wjg.v25.i8.888] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 01/17/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
Due to the restrictions of liver transplantation, complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis. This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications, together with discussion of current controversies and potential future directions. PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety, efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis. Non-selective beta-blockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices, but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation. Recent observational studies suggest protective, haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation. The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy; recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis. Diuretics remain the mainstay of uncomplicated ascites treatment, and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites. Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications. Despite initial hepatotoxicity concerns, safety of statin administration has been demonstrated in compensated cirrhosis. Furthermore, statins are suggested to have protective effects upon fibrosis progression, decompensation and mortality. Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting. Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis, and may impede hepatic fibrogenesis and decompensation. Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management, nutritional optimisation and patient education.
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Affiliation(s)
- David Kockerling
- Liver Unit/Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London W2 1NY, United Kingdom
| | - Rooshi Nathwani
- Liver Unit/Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London W2 1NY, United Kingdom
| | - Roberta Forlano
- Liver Unit/Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London W2 1NY, United Kingdom
| | - Pinelopi Manousou
- Liver Unit/Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London W2 1NY, United Kingdom
| | - Benjamin H Mullish
- Liver Unit/Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London W2 1NY, United Kingdom
| | - Ameet Dhar
- Liver Unit/Division of Integrative Systems Medicine and Digestive Disease, Imperial College London, London W2 1NY, United Kingdom
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48
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Safi W, Elnegouly M, Schellnegger R, Umgelter K, Geisler F, Reindl W, Saugel B, Hapfelmeier A, Umgelter A. Infection and Predictors of Outcome of Cirrhotic Patients after Emergency Care Hospital Admission. Ann Hepatol 2018; 17:948-958. [PMID: 30600289 DOI: 10.5604/01.3001.0012.7195] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIMS We aimed to explore the impact of infection diagnosed upon admission and of other clinical baseline parameters on mortality of cirrhotic patients with emergency admissions. MATERIAL AND METHODS We performed a prospective observational monocentric study in a tertiary care center. The association of clinical parameters and established scoring systems with short-term mortality up to 90 days was assessed by univariate and multivariable Cox regression analysis. Akaike's Information Criterion (AIC) was used for automated variable selection. Statistical interaction effects with infection were also taken into account. RESULTS 218 patients were included. 71.2% were male, mean age was 61.1 ± 10.5 years. Mean MELD score was 16.2 ± 6.5, CLIF-consortium Acute on Chronic Liver Failure-score was 34 ± 11. At 28, 90 and 365 days, 9.6%, 26.0% and 40.6% of patients had died, respectively. In multivariable analysis, respiratory organ failure [Hazard Ratio (HR) = 0.15], albumin substitution (HR = 2.48), non-HCC-malignancy (HR = 4.93), CLIF-C-ACLF (HR = 1.10), HCC (HR = 3.70) and first episode of ascites (HR = 0.11) were significantly associated with 90-day mortality. Patients with infection had a significantly higher 90-day mortality (36.3 vs. 20.1%, p = 0.007). Cultures were positive in 32 patients with resistance to cephalosporins or quinolones in 10, to ampicillin/sulbactam in 14 and carbapenems in 6 patients. CONCLUSION Infection is common in cirrhotic ED admissions and increases mortality. The proportion of resistant microorganisms is high. The predictive capacity of established scoring systems in this setting was low to moderate.
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Affiliation(s)
- Wajima Safi
- 4th Medical Department, Klinikum Süd, Friedrich-Alexander-University Erlangen-Nuremberg, Germany
| | - Mayada Elnegouly
- 2nd Medical Department, Technische Universität München, Klinikum rechts der Isar, Germany
| | | | - Katrin Umgelter
- Department of Anaesthesiology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany, Klinik für operative Intensivmedizin, Vivantes Humboldt Klinikum, Berlin, Germany
| | - Fabian Geisler
- 2nd Medical Department, Technische Universität München, Klinikum rechts der Isar, Germany
| | - Wolfgang Reindl
- 2nd Medical Department, Universitätsmedizin Mannheim, Germany
| | - Bernd Saugel
- Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center, Hamburg-Eppendorf, Germany
| | - Alexander Hapfelmeier
- Institute of Medical Statistics and Epidemiology, Technische Universität München, Germany
| | - Andreas Umgelter
- 2nd Medical Department, Technische Universität München, Klinikum rechts der Isar, Germany
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49
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Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, Krag A, Laleman W, Gines P. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018; 69:406-460. [PMID: 29653741 DOI: 10.1016/j.jhep.2018.03.024] [Citation(s) in RCA: 1759] [Impact Index Per Article: 251.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 03/28/2018] [Indexed: 02/06/2023]
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50
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Facciorusso A, Roy S, Livadas S, Fevrier-Paul A, Wekesa C, Kilic ID, Chaurasia AK, Sadeq M, Muscatiello N. Nonselective Beta-Blockers Do Not Affect Survival in Cirrhotic Patients with Ascites. Dig Dis Sci 2018; 63:1737-1746. [PMID: 29725793 DOI: 10.1007/s10620-018-5092-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 04/24/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND The role of nonselective beta-blockers in cirrhotic patients with ascites has been recently questioned; however, definitive evidence in this regard is still lacking. AIMS To analyze published data on the influence of nonselective beta-blockers as compared to control group on survival of cirrhotic patients with ascites. METHODS Computerized bibliographic search on the main databases was performed. Hazard ratios from Kaplan-Meier curves were extracted in order to perform an unbiased comparison of survival estimates. Secondary outcomes were mortality in patients with refractory ascites, pooled rate of nonselective beta-blockers interruption, spontaneous bacterial peritonitis and hepato-renal syndrome incidence. RESULTS Three randomized controlled trials and 13 observational studies with 8279 patients were included. Overall survival was comparable between the two groups (hazard ratio = 0.86, 0.71-1.03, p = 0.11). Study design resulted as the main source of heterogeneity in sensitivity analysis and meta-regression. Mortality in refractory ascites patients was similar in the two groups (odds ratio = 0.90, 0.45-1.79; p = 0.76). No difference in spontaneous bacterial peritonitis (odds ratio = 0.78, 0.47-1.29, p = 0.33) and hepato-renal syndrome incidence (odds ratio = 1.22, 0.48-3.09; p = 0.67) was observed. Pooled rate of nonselective beta-blockers interruption was 18.6% (5.2-32.1%). CONCLUSIONS Based on our findings, nonselective beta-blockers should not be routinely withheld in patients with cirrhosis and ascites, even if refractory.
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Affiliation(s)
- Antonio Facciorusso
- Gastroenterology Unit, Department of Medical Sciences, University of Foggia, AOU Ospedali Riuniti, Viale Pinto, 1, 71100, Foggia, Italy.
| | - Sunil Roy
- Belhoul Speciality Hospital, Dubai, United Arab Emirates
| | | | | | | | | | | | - Mina Sadeq
- National Institute of Hygiene, Rabat, Morocco
| | - Nicola Muscatiello
- Gastroenterology Unit, Department of Medical Sciences, University of Foggia, AOU Ospedali Riuniti, Viale Pinto, 1, 71100, Foggia, Italy
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