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Fortea JI, Alvarado-Tapias E, Simbrunner B, Ezcurra I, Hernández-Gea V, Aracil C, Llop E, Puente A, Roig C, Reiberger T, García-Pagan JC, Calleja JL, Ferrero-Gregori A, Mandorfer M, Villanueva C, Crespo J. Carvedilol vs. propranolol for the prevention of decompensation and mortality in patients with compensated and decompensated cirrhosis. J Hepatol 2024:S0168-8278(24)02772-7. [PMID: 39701300 DOI: 10.1016/j.jhep.2024.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND & AIMS Data on the effectiveness of classical non-selective beta-blockers (cNSBBs, i.e., propranolol and nadolol) vs. carvedilol in patients with cirrhosis are scarce. In the present study, we aimed to compare their potential for preventing decompensation and mortality in patients with compensated and decompensated cirrhosis. METHODS We performed a multicenter retrospective study including patients with compensated and decompensated cirrhosis with clinically significant portal hypertension, undergoing measurement of hepatic venous pressure gradient (HVPG) to assess acute hemodynamic response to intravenous propranolol (i.e., HVPG decrease ≥10% from baseline value) prior to primary prophylaxis for variceal bleeding. Outcomes were adjusted using inverse probability of treatment weighting in a competitive risk framework. RESULTS A total of 540 patients were included, 256 with compensated (cNSBBs n = 111; carvedilol n = 145) and 284 with decompensated (cNSBBs n = 134; carvedilol n = 150) cirrhosis. Median follow-up was 36.3 (IQR 16.9-61.0) and 30.7 (IQR 13.1-52.2) months, respectively. After covariate balancing, compared to cNSBBs, carvedilol significantly reduced the risk of a first decompensation in compensated patients (subdistribution hazard ratio 0.61; 95% CI 0.41-0.92; p = 0.019) and a combined endpoint of further decompensation/death in decompensated patients (subdistribution hazard ratio 0.57; 95% CI 0.42-0.77; p <0.0001). A second HVPG was conducted on 176 (68.8%, compensated) and 177 (62.3%, decompensated) patients. Acute non-responders, both compensated (11.1% vs. 29.4%; p = 0.422) and decompensated (16.0% vs. 43.6%: p = 0.0247) patients, showed a higher likelihood of achieving a chronic hemodynamic response with carvedilol. The safety profile of each type of NSBB was comparable in both cohorts. CONCLUSIONS Our data endorse the current recommendation favoring the use of carvedilol for the prevention of a first decompensation of cirrhosis and suggest extending the recommendation to patients with decompensated cirrhosis without recurrent or refractory ascites. IMPACT AND IMPLICATIONS This study addresses a gap in the comparative effectiveness of classical non-selective beta-blockers (e.g., propranolol and nadolol) vs. carvedilol in managing cirrhosis in both compensated and decompensated stages. Our results support the preferential use of carvedilol in both settings due to its superior efficacy in reducing first and further decompensation. However, owing to the retrospective nature of the study and inherent selection biases, we advise against broadly applying these findings to patients with decompensated cirrhosis who exhibit signs of circulatory dysfunction or recurrent/refractory ascites.
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Affiliation(s)
- Jose Ignacio Fortea
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain.
| | - Edilmar Alvarado-Tapias
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain. Universitat Autònoma de Barcelona (UAB), Departament de Medicina UAB, Barcelona, Spain; Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Hepatic Hemodynamic Lab, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Iranzu Ezcurra
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain
| | - Virginia Hernández-Gea
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona. Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-RARE-LIVER), Barcelona, Spain
| | - Carles Aracil
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Digestive Diseases Unit, Hospital Arnau de Vilanova, Lleida, Spain
| | - Elba Llop
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Department of Gastroenterology and Hepatology, Puerta de Hierro University Hospital, Puerta de Hierro Health Research Institute (IDIPHIM), Universidad Autonoma de Madrid, Majadahonda, Spain
| | - Angela Puente
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain
| | - Cristina Roig
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain. Universitat Autònoma de Barcelona (UAB), Departament de Medicina UAB, Barcelona, Spain; Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Hepatic Hemodynamic Lab, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Juan Carlos García-Pagan
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona. Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-RARE-LIVER), Barcelona, Spain
| | - José Luis Calleja
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Department of Gastroenterology and Hepatology, Puerta de Hierro University Hospital, Puerta de Hierro Health Research Institute (IDIPHIM), Universidad Autonoma de Madrid, Majadahonda, Spain
| | - Andreu Ferrero-Gregori
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain. Universitat Autònoma de Barcelona (UAB), Departament de Medicina UAB, Barcelona, Spain
| | - Matthias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Hepatic Hemodynamic Lab, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Candid Villanueva
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain. Universitat Autònoma de Barcelona (UAB), Departament de Medicina UAB, Barcelona, Spain; Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla University Hospital, Santander, Spain
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Alvarado-Tapias E, Brujats A, Puente A, Ardevol A, Rodriguez-Arias A, Fajardo J, Pavel O, Garcia-Guix M, Aracil C, Poca M, Cuyàs B, Cantó E, Montañés R, Garcia-Osuna A, Escorsell À, Torras X, Villanueva C. Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial. Hepatology 2024:01515467-990000000-01072. [PMID: 39509369 DOI: 10.1097/hep.0000000000001148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND AND AIMS Carvedilol is a nonselective β-blocker (NSBB) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal pressure hepatic venous pressure gradient (HVPG). However, 35%-45% of patients still have insufficient HVPG decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal hypertension and suboptimal response to traditional NSBBs. METHODS Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v. propranolol. Suboptimal responders (HVPG decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6 weeks, repeating HVPG measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters. RESULTS Of 184 eligible patients, 82 were randomized to carvedilol + simvastatin (N = 41) or carvedilol + placebo (N = 41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol + simvastatin (18.6 ± 4 to 15.7 ± 4 mm Hg, p < 0.001) and carvedilol + placebo (18.9 ± 3 to 16.9 ± 3 mm Hg, p < 0.001). The decrease was greater with carvedilol + simvastatin (2.97 ± 2.5 vs. 2.05 ± 1.6 mm Hg, p = 0.031). An HVPG decrease ≥20% occurred in 37% versus 15% of patients, respectively (OR: 3.37, 95% CI = 1.15-9.85; p = 0.021). With test meal, HVPG increased in both groups ( p < 0.01), although carvedilol + simvastatin attenuated such increment (12 ± 8% vs. 23 ± 16%, p < 0.001). Cytokine levels (Interleukine-6, monocyte-chemoattractant protein-1, and malondialdehyde) decreased significantly more with carvedilol + simvastatin ( p < 0.01). The incidence of adverse events was similar. CONCLUSIONS In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal pressure reduction achieved with carvedilol monotherapy, improves endothelial dysfunction, and reduces proinflammatory cytokines.
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Affiliation(s)
- Edilmar Alvarado-Tapias
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Anna Brujats
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Angela Puente
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Alba Ardevol
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Javier Fajardo
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Oana Pavel
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Marta Garcia-Guix
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Carles Aracil
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Maria Poca
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Berta Cuyàs
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Elisabet Cantó
- Inflammatory Diseases Department, Institut Recerca Hospital Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Rosa Montañés
- Inflammatory Diseases Department, Institut Recerca Hospital Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
| | - Alvaro Garcia-Osuna
- Department of Biochemistry, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Àngels Escorsell
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Xavier Torras
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
| | - Càndid Villanueva
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
- Centre for Biomedical Research in Liver and Digestive Diseases Network (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain
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Garcia-Guix M, Ardevol A, Sapena V, Alvarado-Tápias E, Huertas A, Brujats A, Fajardo J, Cuyas B, Poca M, Guarner C, Torras X, Escorsell À, Villanueva C. Influence of further decompensation on survival across clinical stages of decompensated cirrhosis: The role of portal hypertension and HVPG changes. Liver Int 2024; 44:1971-1989. [PMID: 38634685 DOI: 10.1111/liv.15937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/13/2024] [Accepted: 04/02/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND AND AIMS Decompensated-cirrhosis encompasses several stages with different prognosis, such as bleeding, ascites and bleeding-plus-ascites. Development of further-decompensation worsens survival, while non-selective β-blockers (NSBBs) can modify the risk. However, how this applies to each stage is uncertain. We aimed to investigate, in each stage of decompensated-cirrhosis, the influence of further-decompensation on mortality and whether changes in portal-pressure (HVPG) under NSBBs influence these outcomes. METHODS Patients with variceal bleeding were consecutively included differentiating those with bleeding-alone from those who also had ascites. Patients with ascites and high-risk varices referred for primary-prophylaxis were also investigated. A baseline haemodynamic study was performed and was repeated after 1-3-months under NSBBs. Outcomes were investigated by competing-risk. RESULTS Totally 103 patients had bleeding-alone, 186 bleeding-plus-ascites and 187 ascites-alone. Mean follow-up was 32-months (IQR, 12-60). Patients with bleeding-plus-ascites had higher HVPG and were more hyperdynamic than patients with ascites-alone and these than those with bleeding-alone. At each stage, the mortality risk was more than twice in patients developing further-decompensation vs. those without (p < .001). In each stage, HVPG-decrease under NSBBs showed better discrimination to predict further-decompensation than the baseline MELD, Child-Pugh or HVPG, by time-dependent ROC-curves (c-statistic >70%). At each stage, patients without HVPG-decreases, either ≥10% or ≥20% from the baseline, had higher risk of further-decompensation (sHR from 2.43 to 6.73, p < .01) and worse survival. CONCLUSIONS In each stage of decompensated cirrhosis, mortality risk significantly and very markedly increase with further-decompensation. HVPG-non-response to NSBBs may adequately stratify the risk of further decompensation and death, in each stage. This suggests potential benefit with pre-emptive therapies in HVPG-non-responders at each-stage.
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Affiliation(s)
- Marta Garcia-Guix
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Alba Ardevol
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Victor Sapena
- Biostatistics Unit, Medical School, Universitat Autònoma de Barcelona, Barcelona, Spain
- Medical Statistics Core Faculty, IDIBAPS, Hospital Clinic, Barcelona, Spain
| | - Edilmar Alvarado-Tápias
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Anna Huertas
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Anna Brujats
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Javier Fajardo
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Berta Cuyas
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - María Poca
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Carlos Guarner
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Xavier Torras
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Àngels Escorsell
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Càndid Villanueva
- Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Rodrigues SG, Delgado MG, Stirnimann G, Berzigotti A, Bosch J. Hepatic Venous Pressure Gradient: Measurement and Pitfalls. Clin Liver Dis 2024; 28:383-400. [PMID: 38945633 DOI: 10.1016/j.cld.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Measurement of hepatic venous pressure gradient (HVPG) effectively mirrors the severity of portal hypertension (PH) and offers valuable insights into prognosis of liver disease, including the risk of decompensation and mortality. Additionally, HVPG offers crucial information about treatment response to nonselective beta-blockers and other medications, with its utility demonstrated in clinical trials in patients with PH. Despite the widespread dissemination and validation of noninvasive tests, HVPG still holds a significant role in hepatology. Physicians treating patients with liver diseases should comprehend the HVPG measurement procedure, its applications, and how to interpret the results and potential pitfalls.
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Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, MEM, Murtenstrasse 35 Office F807, Bern 3008, Switzerland
| | - Maria Gabriela Delgado
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, MEM, Murtenstrasse 35 Office F808, Bern 3008, Switzerland
| | - Guido Stirnimann
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, Bern 3010, Switzerland
| | - Annalisa Berzigotti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, BHH D115, Freiburgstrasse 10, Bern 3010, Switzerland
| | - Jaime Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, MEM, Murtenstrasse 35 Office F805, Bern 3008, Switzerland; CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Barcelona, Spain.
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5
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Kaplan DE, Ripoll C, Thiele M, Fortune BE, Simonetto DA, Garcia-Tsao G, Bosch J. AASLD Practice Guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology 2024; 79:1180-1211. [PMID: 37870298 DOI: 10.1097/hep.0000000000000647] [Citation(s) in RCA: 103] [Impact Index Per Article: 103.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 10/16/2023] [Indexed: 10/24/2023]
Affiliation(s)
- David E Kaplan
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA USA
| | - Cristina Ripoll
- Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Maja Thiele
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Brett E Fortune
- Department of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Jaime Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) and CIBERehd, University of Barcelona, Spain
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Qaqish F, Dimachkie R, Sasso R, Loeffler J, Hasan M, Deghani S, Abou Yassine A, Deeb L. Safety of Nonselective Beta-Blockers in Decompensated Liver Cirrhosis and Their Role in Inducing Hepatorenal Syndrome. Cureus 2024; 16:e58296. [PMID: 38752039 PMCID: PMC11094662 DOI: 10.7759/cureus.58296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2024] [Indexed: 05/18/2024] Open
Abstract
Background Nonselective beta-blockers (NSBBs) have been used in the management of portal hypertension and the prevention of initial and recurrent variceal bleeding in patients with liver cirrhosis. However, there is controversy regarding the use of NSBBs in patients with decompensated cirrhosis (DC) due to concerns over potential adverse effects, such as worsening of hepatic function and risk of hepatorenal syndrome (HRS). HRS is a serious complication of DC characterized by acute kidney injury (AKI) and progressive renal failure, and its development can lead to significant morbidity and mortality in this setting. Therefore, using NSBBs in patients with DC remains an area of ongoing research and debate. Our study aims to investigate the potential effect of NSBBs on HRS development. Methodology A retrospective chart review of 404 patients with cirrhosis was performed across all Northwell Health institutions between January 01, 2019, and December 31, 2020. An analysis was done on 516 patient encounters. Inclusion criteria included patients with an established International Classification of Diseases 10th Revision code of cirrhosis and AKI. After adjusting for clinical predictors, the Student's t-test or Mann-Whitney U-test was used to compare variables between the two outcome groups (HRS vs. no HRS) for the continuous variables. Pearson's chi-square test or Fisher's exact test was used for the categorical variables to test if an association existed between the use of NSBBs at home and HRS. A two-sided p-value <0.05 was considered statistically significant. SAS 9.4 (SAS Institute Inc., Cary, NC, USA) was used for statistical analysis. Results The primary outcome was the development of HRS during the hospital stay. With a total of 109 visits with HRS, we had 21 (23.60%) reported HRS in the 89 visits where NSBBs were used at home before the hospitalization, while 88 (20.61%) HRS were observed in the 427 visits with no NSBB use at home. The use of NSBBs at home was not significantly associated with the development of HRS (odds ratio = 1.1, 95% confidence interval = 0.6-1.9, p = 0.7321). We also found that higher serum albumin on admission is associated with lower odds of HRS. In contrast, increased serum creatinine, bilirubin, presence of ascites, and use of pressors were associated with a higher risk of HRS. Conclusions Our study highlights the relevant safety of NSBB use in end-stage liver disease. Their use did not appear to increase the risk of developing HRS during hospitalization with DC. Further randomized controlled trials are warranted to shed more light on the efficacy, dose tolerance limits, and safety of NSBBs in decompensated end-stage liver disease.
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Affiliation(s)
- Faris Qaqish
- Internal Medicine, Staten Island University Hospital, Staten Island, USA
| | - Reem Dimachkie
- Internal Medicine, Staten Island University Hospital, Staten Island, USA
| | - Roula Sasso
- Internal Medicine, Staten Island University Hospital, Staten Island, USA
| | - Jeffrey Loeffler
- Internal Medicine, Staten Island University Hospital, Staten Island, USA
| | - Mohammed Hasan
- Internal Medicine, Staten Island University Hospital, Staten Island, USA
| | - Shabnam Deghani
- Internal Medicine, Staten Island University Hospital, Staten Island, USA
| | - Ahmad Abou Yassine
- Internal Medicine, Staten Island University Hospital, Staten Island, USA
| | - Liliane Deeb
- Gastroenterology, Staten Island University Hospital, Staten Island, USA
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Danielsen KV, Nabilou P, Wiese SS, Hove JD, Bendtsen F, Møller S. Effect of beta-blockers on multiple haemodynamics in cirrhosis: A cross-over study by MR-imaging and hepatic vein catheterization. Liver Int 2023; 43:2245-2255. [PMID: 37387503 DOI: 10.1111/liv.15664] [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: 03/13/2023] [Revised: 05/25/2023] [Accepted: 06/19/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND Non-selective beta-blockers (NSBB) are widely used in the treatment of patients with cirrhosis. Only about 50% respond with a sufficient reduction in their hepatic venous pressure gradient (HVPG) and NSBB may induce detrimental cardiac and renal effects in the presence of severe decompensation. We aimed to assess the effects of NSBB on haemodynamics using magnetic resonance imaging (MRI) and to assess if these haemodynamic changes were related to the disease severity and HVPG response. METHOD A prospective cross-over study of 39 patients with cirrhosis. Patients underwent hepatic vein catheterization and MRI with assessments of HVPG, cardiac function, systemic and splanchnic haemodynamics before and after propranolol infusion. RESULTS Propranolol induced significant decreases in cardiac output (-12%) and blood flow of all vascular compartments, with the largest reductions seen in the azygos venous (-28%), portal venous (-21%), splenic (-19%) and superior mesenteric artery (-16%) blood flow. Renal artery blood flow fell by -5% in the total cohort, with a more pronounced reduction in patients without ascites than in those with ascites (-8% vs. -3%, p = .01). Twenty-four patients were NSBB responders. Their changes in HVPG after NSBB were not significantly associated with other haemodynamic changes. CONCLUSION The changes in cardiac, systemic and splanchnic haemodynamics did not differ between NSBB responders and non-responders. The effects of acute NSBB blockade on renal flow seem to depend on the severity of the hyperdynamic state, with the largest reduction in renal blood flow in compensated patients compared to decompensated patients with cirrhosis. However, future studies are needed to assess the effects of NSBB on haemodynamics and renal blood flow in patients with diuretic-resistant ascites.
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Affiliation(s)
- Karen Vagner Danielsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Department of Clinical Physiology and Nuclear Medicine, Centre of Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Puria Nabilou
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Signe Skovgaard Wiese
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jens Dahlgaard Hove
- Department of Clinical Physiology and Nuclear Medicine, Centre of Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Department of Cardiology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, Centre of Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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8
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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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9
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Ferral H, Schepis F, Gaba RC, Garcia-Tsao G, Zanetto A, Perez-Campuzano V, Haskal ZJ, Garcia-Pagan JC. Endovascular Assessment of Liver Hemodynamics in Patients with Cirrhosis Complicated by Portal Hypertension. J Vasc Interv Radiol 2023; 34:327-336. [PMID: 36516940 DOI: 10.1016/j.jvir.2022.12.014] [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: 07/29/2022] [Revised: 11/02/2022] [Accepted: 12/04/2022] [Indexed: 12/14/2022] Open
Abstract
The hepatic venous pressure gradient (HVPG) is currently considered the gold standard to assess portal hypertension (PH) in patients with cirrhosis. A meticulous technique is important to achieve accurate and reproducible results, and values obtained during measurement are applied in risk stratification of patients with PH, allocating treatment options, monitoring follow-up, and deciding management options in surgical patients. The use of portosystemic pressure gradients in patients undergoing placement of transjugular intrahepatic portosystemic shunts has been studied extensively and has great influence on decisions on shunt diameter. The purpose of this study was to describe the recommended technique to measure HVPG and portosystemic pressure gradient and to review the existing literature describing the importance of these hemodynamic measurements in clinical practice.
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Affiliation(s)
- Hector Ferral
- Section of Interventional Radiology, Department of Radiology, Louisiana State University, New Orleans, Louisiana
| | - Filippo Schepis
- Hepatic Hemodynamic Laboratory, Division of Gastroenterology, AOU of Modena and University of Modena and Reggio Emilia, Modena, Italy
| | - Ron C Gaba
- Division of Interventional Radiology, Department of Radiology, University of Illinois at Chicago, Chicago, Illinois
| | - Guadalupe Garcia-Tsao
- Digestive Disease Section, Internal Medicine, Yale School of Medicine, New Haven, Connecticut; VA-Connecticut Healthcare System, West Haven, Connecticut
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padova University Hospital, Italy
| | - Valeria Perez-Campuzano
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Madrid, Spain; Health Care Provider of the European Reference Network on Rare Liver Disorders, Hamburg, Germany
| | - Ziv J Haskal
- Department of Radiology and Medical Imaging/Interventional Radiology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Juan Carlos Garcia-Pagan
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Madrid, Spain; Health Care Provider of the European Reference Network on Rare Liver Disorders, Hamburg, Germany.
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10
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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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11
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Thabut D, Weil D, Bouzbib C, Rudler M, Cassinotto C, Castéra L, Serste T, Oberti F, Ganne-Carrié N, de Lédinghen V, Bourlière M, Bureau C. Non-invasive diagnosis and follow-up of portal hypertension. Clin Res Hepatol Gastroenterol 2022; 46:101767. [PMID: 34332128 DOI: 10.1016/j.clinre.2021.101767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/23/2021] [Indexed: 02/04/2023]
Abstract
Compensated advanced chronic liver disease (cACLD) describes the spectrum of advanced fibrosis/cirrhosis in asymptomatic patients at risk of developing clinically significant portal hypertension (CSPH, defined by a hepatic venous pressure gradient (HVPG) ≥10 mmHg). Patients with cACLD are at high risk of liver-related morbidity and mortality. In patients at risk of chronic liver disease, cACLD is strongly suggested by a liver stiffness (LSM) value >15 kPa or clinical/biological/radiological signs of portal hypertension, and ruled out by LSM <10 kPa, or Fibrotest® ≤0.58, or Fibrometer® ≤0.786. Patients with chronic liver disease (excluding vascular diseases) with a LSM <10 kPa are at low risk of developing portal hypertension complications. The presence of CSPH can be strongly suspected when LSM is ≥20 kPa. In a patient without clinical, endoscopic or radiological features of portal hypertension, measurement of the HVPG is recommended before major liver or intra-abdominal surgery, before extra-hepatic transplantation and in patients with unexplained ascites. Endoscopic screening for oesophageal varices can be avoided in patients with LSM <20 kPa and a platelet count >150 G/L (favourable Baveno VI criteria) at the time of diagnosis. There is no non-invasive method alternative for oeso-gastroduodenal endoscopy in patients with unfavourable Baveno criteria (liver stiffness ≥20 kPa or platelet count ≤50 G/l). Platelet count and liver stiffness measurements must be performed once a year in patients with cACLD with favourable Baveno VI criteria at the time of diagnosis. A screening oeso-gastroduodenal endoscopy is recommended if Baveno VI criteria become unfavourable.
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Affiliation(s)
- Dominique Thabut
- Service d'hépato-gastroentérologie, Hôpital Pitié- Salpêtrière, Sorbonne Université, APHP, 47-83 boulevard de l'Hôpital, 75013 Paris, France.
| | - Delphine Weil
- Service d'hépatologie, CHRU Besançon, Besançon, France
| | - Charlotte Bouzbib
- Service d'hépato-gastroentérologie, Hôpital Pitié- Salpêtrière, Sorbonne Université, APHP, 47-83 boulevard de l'Hôpital, 75013 Paris, France
| | - Marika Rudler
- Service d'hépato-gastroentérologie, Hôpital Pitié- Salpêtrière, Sorbonne Université, APHP, 47-83 boulevard de l'Hôpital, 75013 Paris, France
| | - Christophe Cassinotto
- Radiologie diagnostique et interventionnelle Saint Eloi, CHU Montpellier, Montpellier, France
| | - Laurent Castéra
- Service d'Hépatologie, Hôpital Beaujon, Université de Paris, APHP, Paris, France
| | - Thomas Serste
- Service d'hépato-gastroentérologie, CHU Saint-Pierre, Bruxelles, France
| | - Frédéric Oberti
- Service d'hépato-gastroentérologie et oncologie digestive, CHU Angers, Angers, France
| | - Nathalie Ganne-Carrié
- Service d'hépatologie, Hôpital Avicenne, APHP, Université Sorbonne Paris Nord, Bobigny & INSERM UMR 1138, Centre de Recherche des Cordeliers, Université de Paris, France
| | - Victor de Lédinghen
- Service d'hépato-gastroentérologie et d'oncologie digestive, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Marc Bourlière
- Service d'hépato-gastroentérologie, Hôpital Saint Joseph & INSERM UMR 1252 IRD SESSTIM Aix Marseille Université, Marseille, France
| | - Christophe Bureau
- Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse, France
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12
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Kristensen H, Kimer N, Møller S. Indications and methods for measuring portal hypertension in cirrhosis. Scand J Gastroenterol 2022; 57:1149-1157. [PMID: 35514215 DOI: 10.1080/00365521.2022.2065889] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background and objectives: Over the last decade our understanding of the pathophysiology of portal hypertension has increased. Novel diagnostic technologies have facilitated and improved the diagnosis and treatment of hepatic fibrosis and cirrhosis. With this review we aim to provide an overview of contemporary diagnostic principles of portal hypertension and indications for measuring portal pressure in cirrhosis.Methods: By review of current literature, we assessed new and old principles of measuring portal hypertension and the diagnostic values of the methods.Results: Invasive measurement of the portal pressure is still the gold standard to quantitate portal hypertension and to assess response to vasoactive treatment. The size of the portal pressure is important to assess since it contains information on the course of the disease and risk of developing hepatic decompensation, hepatocellular carcinoma, and mortality. Reliable non-invasive Elastography techniques are emerging that adequately assess portal pressure, but the available methods are not yet sufficiently accurate.Conclusion: Although elastography techniques provide valuable information and are good monitoring tools, liver vein catheterization remains valuable in diagnosing and monitoring portal hypertension, especially in combination with a trans-jugular liver biopsy.
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Affiliation(s)
- Helle Kristensen
- Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, University Hospital Hvidovre, Hvidovre, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, Center of Functional Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark.,Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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13
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Liver and spleen stiffness as assessed by vibration controlled transient elastography for diagnosing clinically significant portal hypertension in comparison with other elastography‐based techniques in adults with chronic liver disease. Cochrane Database Syst Rev 2022; 2022:CD015415. [PMCID: PMC9400388 DOI: 10.1002/14651858.cd015415] [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: 11/08/2022]
Abstract
This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows: To assess the diagnostic accuracy of liver stiffness and spleen stiffness, as well as their combination, as measured by vibration‐controlled transient elastography (VCTE) in the detection of clinically significant portal hypertension (CSPH) in adults with chronic liver disease. We will regard a combination of tests as positive when at least one is positive. To compare the diagnostic accuracy of individual tests (liver and spleen stiffness by VCTE) directly and versus the combination of both tests (liver and spleen stiffness by VCTE considered positive when at least one test is positive) in detecting CSPH. To assess the diagnostic accuracy of liver stiffness and spleen stiffness, as well as their combination, as measured by other elastography techniques (two‐dimensional shear wave elastography (2D‐SWE), point shear wave elastography (pSWE), and magnetic resonance elastography (MRE)) in the detection of CSPH in adults with chronic liver disease. We will regard a combination of tests as positive when at least one is positive. To compare the diagnostic accuracy of liver stiffness and spleen stiffness by VCTE with other techniques (2D‐SWE, pSWE, MRE) in the detection of CSPH in adults with chronic liver disease.
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14
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Hofer BS, Simbrunner B, Bauer DJM, Paternostro R, Schwabl P, Scheiner B, Semmler G, Hartl L, Jachs M, Datterl B, Staettermayer AF, Trauner M, Mandorfer M, Reiberger T. Acute hemodynamic response to propranolol predicts bleeding and nonbleeding decompensation in patients with cirrhosis. Hepatol Commun 2022; 6:2569-2580. [PMID: 35808889 PMCID: PMC9426394 DOI: 10.1002/hep4.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/17/2022] [Accepted: 05/29/2022] [Indexed: 11/29/2022] Open
Abstract
Nonselective beta‐blockers are used as prophylaxis for variceal bleeding in patients with advanced chronic liver disease (ACLD). The acute hemodynamic response to intravenous propranolol (i.e., ≥10% reduction in hepatic venous pressure gradient [HVPG]) is linked to a decreased risk of variceal bleeding. In this study, we aimed to investigate the overall prognostic value of an acute response in compensated and decompensated ACLD. We analyzed the long‐term outcome of prospectively recruited patients with ACLD following a baseline HVPG measurement with an intraprocedural assessment of the acute hemodynamic response to propranolol. Overall, we included 98 patients with ACLD (mean ± SD age, 56.4 ± 11.5 years; 72.4% decompensated; 88.8% varices; mean ± SD HVPG, 19.9 ± 4.4 mm Hg) who were followed for a median of 9.6 (interquartile range, 6.5–18.2) months. Fifty‐seven patients (58.2%) demonstrated an acute hemodynamic response to propranolol that was associated with a decreased risk of variceal bleeding (at 12 months, 3.6% vs. 15% in nonresponder; log‐rank, p = 0.038) and hepatic decompensation (at 12 months, 23% vs. 33% in nonresponder; log‐rank, p = 0.096). On multivariate analysis, the acute response was an independent predictor of first/further hepatic decompensation (adjusted hazards ratio, 0.31; 95% confidence interval [CI], 0.13–0.70; p = 0.005). Importantly, there was a tendency toward a prolonged transplant‐free survival in acute responders compared to nonresponders (34.2; 95% CI, 29.2–39.2 vs. 25.2; 95% CI, 19.8–30.6 months; log‐rank, p = 0.191). Conclusions: Patients with ACLD who achieve an acute hemodynamic response to intravenous propranolol experience a lower risk of variceal bleeding and nonbleeding hepatic decompensation events compared to nonresponders. An assessment of the acute hemodynamic response to intravenous propranolol provides important prognostic information in ACLD.
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Affiliation(s)
- Benedikt S Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - David J M Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Barbara Datterl
- Pharmacy Department, Vienna General Hospital, Vienna, Austria
| | - Albert F Staettermayer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.,Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
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15
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Chauhan A, Bhatia A. Letter: non-selective beta-blockers in cirrhosis-effect beyond portal hypertension. Aliment Pharmacol Ther 2022; 56:184-185. [PMID: 35689323 DOI: 10.1111/apt.16941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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16
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Nabilou P, Danielsen KV, Kimer N, Hove JD, Bendtsen F, Møller S. Blunted cardiovascular effects of beta-blockers in patients with cirrhosis: Relation to severity? PLoS One 2022; 17:e0270603. [PMID: 35763518 PMCID: PMC9239488 DOI: 10.1371/journal.pone.0270603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 06/13/2022] [Indexed: 11/22/2022] Open
Abstract
Aims Patients with cirrhosis and portal hypertension are at high risk of developing complications such as variceal hemorrhage, ascites, and cardiac dysfunction, the latter of which is known as cirrhotic cardiomyopathy. Since non-selective beta-blockers (NSBB) may aggravate hemodynamic complications we investigated the effect of real-time propranolol infusion on cardiac function in patients with varying degrees of cirrhosis. Methods Thirty-eight patients with Child-Pugh A (n = 17), B (n = 17) and C (n = 4) underwent liver vein catheterization and cardiac magnetic resonance imaging. We assessed the effect of real-time propranolol infusion on the hepatic venous pressure gradient, cardiac index, stroke volume, ejection fraction, heart rate, and contractility. Results Nineteen patients were classified as responders to beta-blocker therapy. In pooling Child-Pugh B and C patients, the reduction in cardiac index by beta-blockade was weaker than in Child-Pugh A patients (-8.5% vs. -20.5%, p = 0.043). The effect of NSBB on portal pressure was inversely correlated to changes in the left atrium where the left atrial volume changed by 4 mL±18 in responders compared to 15 mL±11 in non-responders (p = 0.03). Finally, the baseline ejection fraction correlated inversely with the reduction in portal pressure (r = -0.39, p = 0.02). Conclusion We found the effect of beta-blockade on cardiac index in patients with advanced cirrhosis to be less potent than in patients with early cirrhosis, indicating that underlying cirrhotic cardiomyopathy increases, and the cardiac compensatory reserve becomes more compromised, with disease progression. The differential effects of beta-blockade in the left atrium may be used to predict the effect of beta-blockers on portal pressure, but further studies are needed to investigate this possibility.
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Affiliation(s)
- Puria Nabilou
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- * E-mail:
| | - Karen Vagner Danielsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jens Dahlgaard Hove
- Department of Cardiology, Copenhagen University Hospital, Hvidovre, Denmark
- Department of Clinical Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Søren Møller
- Department of Clinical Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Dept. Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Faculty of Health Sciences, University of Copenhagen, København, Denmark
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Llop E, Perelló C, Fontanilla T, de la Revilla J, Conde MH, López M, Minaya J, Ferre C, Abad J, Carrillo CF, Martínez JL, Puga NF, Trapero M, Hajra IE, Santos E, Calleja JL. Spleen Transient Elastography and Damping Index Identify a Subgroup of Patients Without an Acute or Chronic Response to Beta-Blockers. Front Med (Lausanne) 2022; 9:900073. [PMID: 35814751 PMCID: PMC9258685 DOI: 10.3389/fmed.2022.900073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 05/30/2022] [Indexed: 11/18/2022] Open
Abstract
Background and Aims Monitoring of acute or chronic response to beta-blockers in patients with liver cirrhosis is based on the measurement of the HVPG. Our aim was to evaluate the response to beta-blockers with non-invasive techniques. Patients and Methods This is a prospective observational study. Consecutive patients with an indication of primary or secondary prophylaxis of variceal bleeding who did not meet exclusion criteria were included. Acute response and chronic response were evaluated. Baseline and after acute and chronic response hepatosplenic measurements of TE and ARFI were obtained. Contrast-enhanced Doppler ultrasound was performed before and after acute and chronic responses. Results From June 2015 to May 2018, 55 patients (14 with exclusion criteria) were included. We analyzed 41 patients, mean age 57 (SD: 8), 82.9% men, alcohol 43.9%, children A/B/C 78%/17.1%/4.9%, and 87.8% on primary prophylaxis. In all, the acute response was performed and was positive in 68.3% (CI 95: 55-85%). The chronic response was performed in 30 (73.2%) and was positive in 36.7% (CI 95: 18-55%). Basal measurements significantly related to acute response were spleen TE [responders 58.4 (SD: 23.0) KPa vs. non-responders 75 (SD: 0) KPa; p = 0.02] and damping index [non-responders 0.96 (0.8) vs. responders 0.44 (0.4), p = 0.01], and with chronic response, the spleen TE [responders 58.1 (SD: 21.4) KPa vs. non-responders 73.2 (SD: 5.5) KPa; p = 0.02], and damping index [non-chronic responders 0.8 (0.7) vs. chronic responders 0.4 (0.4), p = 0.04]. A spleen TE ≥ 74 KPa had a high sensitivity of 100% and specificity of 60% and a high NPV100% for predicting poor acute response to beta-blockers. The damping index > 0.6 showed moderate sensitivity of 67% and specificity of 69% with a high NPV of 82% for predicting poor acute response to beta-blockers. The combination of both measurements for predicting poor acute response to beta-blockers had an AUC of 0.8 (CI 95: 0.5-0.9). A spleen TE ≥ 74 KPa had a high sensitivity of 87% and specificity of 71% with a high NPV of 71% for predicting poor chronic response to beta-blockers. A damping index > 0.6 had moderate sensitivity of 60%, specificity of 82%, and NPV of 56% for predicting poor chronic response to beta-blockers. The combination of both measurements for predicting poor chronic response to beta-blockers had an AUC of 0.8 (CI 95: 0.7-0.9). Conclusion Spleen TE and damping index can identify a subgroup of patients with poor acute or chronic response to beta-blockers.
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Affiliation(s)
- Elba Llop
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Christie Perelló
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Teresa Fontanilla
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- Department of Radiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Juan de la Revilla
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Marta Hernández Conde
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Marta López
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Javier Minaya
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- Department of Radiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Carlos Ferre
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Javier Abad
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Carlos Fernández Carrillo
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - José Luís Martínez
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Natalia Fernández Puga
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - María Trapero
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
| | - Ismael El Hajra
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Elena Santos
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - José Luis Calleja
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- Instituto de Investigación Sanitaria Puerta Hierro-Segovia Arana (IDIPHISA), Madrid, Spain
- CIBERHD, Madrid, Spain
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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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19
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Rabiee A, Garcia‐Tsao G, Tapper EB. Nonselective Beta-Blockers in Portal Hypertension: Why, When, and How? Clin Liver Dis (Hoboken) 2022; 19:118-123. [PMID: 35355838 PMCID: PMC8958249 DOI: 10.1002/cld.1182] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 09/15/2021] [Accepted: 10/04/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Interview and Audio Recording.
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Affiliation(s)
- Anahita Rabiee
- Digestive Diseases SectionYale School of MedicineNew HavenCT
| | - Guadalupe Garcia‐Tsao
- Digestive Diseases SectionYale School of MedicineNew HavenCT,Digestive Diseases SectionVA‐CT Healthcare SystemWest HavenCT
| | - Elliot B. Tapper
- Division of Gastroenterology and HepatologyUniversity of MichiganAnn ArborMI,Gastroenterology SectionVA Ann Arbor Healthcare SystemAnn ArborMI
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20
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Jachs M, Reiberger T. Non-selective Beta Blockers in Liver Cirrhosis. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:127-140. [DOI: 10.1007/978-981-19-2615-0_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Agarwal S, Sharma S, Kumar M, Venishetty S, Bhardwaj A, Kaushal K, Gopi S, Mohta S, Gunjan D, Saraya A, Sarin SK. Development of a machine learning model to predict bleed in esophageal varices in compensated advanced chronic liver disease: A proof of concept. J Gastroenterol Hepatol 2021; 36:2935-2942. [PMID: 34050561 DOI: 10.1111/jgh.15560] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/19/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Risk stratification beyond the endoscopic classification of esophageal varices (EVs) to predict first episode of variceal bleeding (VB) is currently limited in patients with compensated advanced chronic liver disease (cACLD). We aimed to assess if machine learning (ML) could be used for predicting future VB more accurately. METHODS In this retrospective analysis, data from patients of cACLD with EVs, laboratory parameters and liver stiffness measurement (LSM) were used to generate an extreme-gradient boosting (XGBoost) algorithm to predict the risk of VB. The performance characteristics of ML and endoscopic classification were compared in internal and external validation cohorts. Bleeding rates were estimated in subgroups identified upon risk stratification with combination of model and endoscopic classification. RESULTS Eight hundred twenty-eight patients of cACLD with EVs, predominantly related to non-alcoholic fatty liver disease (28.6%), alcohol (23.7%) and hepatitis B (23.1%) were included, with 455 (55%) having the high-risk varices. Over a median follow-up of 24 (12-43) months, 163 patients developed VB. The accuracy of machine learning (ML) based model to predict future VB was 98.7 (97.4-99.5)%, 93.7 (88.8-97.2)%, and 85.7 (82.1-90.5)% in derivation (n = 497), internal validation (n = 149), and external validation (n = 182) cohorts, respectively, which was better than endoscopic classification [58.9 (55.5-62.3)%] alone. Patients stratified high risk on both endoscopy and model had 1-year and 3-year bleeding rates of 31-43% and 64-85%, respectively, whereas those stratified as low risk on both had 1-year and 3-year bleeding rates of 0-1.6% and 0-3.4%, respectively. Endoscopic classification and LSM were the major determinants of model's performance. CONCLUSION Application of ML model improved the performance of endoscopic stratification to predict VB in patients with cACLD with EVs.
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Affiliation(s)
- Samagra Agarwal
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Sanchit Sharma
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Manoj Kumar
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shantan Venishetty
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankit Bhardwaj
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Kanav Kaushal
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Srikanth Gopi
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Srikant Mohta
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Deepak Gunjan
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology and Liver Transplantation, Institute of Liver and Biliary Sciences, New Delhi, India
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22
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Kreisel W, Lazaro A, Trebicka J, Grosse Perdekamp M, Schmitt-Graeff A, Deibert P. Cyclic GMP in Liver Cirrhosis-Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. Int J Mol Sci 2021; 22:10372. [PMID: 34638713 PMCID: PMC8508925 DOI: 10.3390/ijms221910372] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/10/2023] Open
Abstract
The NO-cGMP signal transduction pathway plays a crucial role in tone regulation in hepatic sinusoids and peripheral blood vessels. In a cirrhotic liver, the key enzymes endothelial NO synthase (eNOS), soluble guanylate cyclase (sGC), and phosphodiesterase-5 (PDE-5) are overexpressed, leading to decreased cyclic guanosine-monophosphate (cGMP). This results in constriction of hepatic sinusoids, contributing about 30% of portal pressure. In contrast, in peripheral arteries, dilation prevails with excess cGMP due to low PDE-5. Both effects eventually lead to circulatory dysfunction in progressed liver cirrhosis. The conventional view of portal hypertension (PH) pathophysiology has been described using the "NO-paradox", referring to reduced NO availability inside the liver and elevated NO production in the peripheral systemic circulation. However, recent data suggest that an altered availability of cGMP could better elucidate the contrasting findings of intrahepatic vasoconstriction and peripheral systemic vasodilation than mere focus on NO availability. Preclinical and clinical data have demonstrated that targeting the NO-cGMP pathway in liver cirrhosis using PDE-5 inhibitors or sGC stimulators/activators decreases intrahepatic resistance through dilation of sinusoids, lowering portal pressure, and increasing portal venous blood flow. These results suggest further clinical applications in liver cirrhosis. Targeting the NO-cGMP system plays a role in possible reversal of liver fibrosis or cirrhosis. PDE-5 inhibitors may have therapeutic potential for hepatic encephalopathy. Serum/plasma levels of cGMP can be used as a non-invasive marker of clinically significant portal hypertension. This manuscript reviews new data about the role of the NO-cGMP signal transduction system in pathophysiology of cirrhotic portal hypertension and provides perspective for further studies.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Markus Grosse Perdekamp
- Institute of Forensic Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (A.L.); (P.D.)
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23
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Yao Q, Chen W, Yan C, Yu J, Jiang T, Cao H. Efficacy and Safety of Treatments for Patients With Portal Hypertension and Cirrhosis: A Systematic Review and Bayesian Network Meta-Analysis. Front Med (Lausanne) 2021; 8:712918. [PMID: 34540867 PMCID: PMC8446274 DOI: 10.3389/fmed.2021.712918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/12/2021] [Indexed: 12/19/2022] Open
Abstract
Background and Aims: Viral hepatitis are one of the main causes of liver cirrhosis. The treatment of portal hypertension caused by liver cirrhosis is difficult and diverse, and the therapeutic effect is unknown. Bayesian network meta-analysis was performed to compare the efficacy and safety of treatments for patients with portal hypertension and cirrhosis, including a transjugular intrahepatic portosystemic shunt (TIPS), endoscopic therapy, surgical therapy and medications. Methods: Eligible articles were searched for in PubMed, Embase, Cochrane Library and Web of Science databases from their inception until June 2020. Using the "gemtc-0.8.4" package in R v.3.6.3 software and the Just Another Gibbs Sampler v.4.2.0 program, network meta-analysis was performed using a random effects model within a Bayesian framework. The odds ratios for all-cause rebleeding, bleeding-related mortality, overall survival (OS), treatment failure and hepatic encephalopathy were determined within the Bayesian framework. Results: Forty randomized controlled trials were identified, including 4,006 adult patients and nine treatment strategies. Our results showed that distal splenorenal shunt and TIPS provided the best control of hemorrhage. Endoscopic variceal ligation with medication resulted in the highest OS rate. Medication alone resulted in poor OS and treatment failure. Conclusions: We performed a systematic comparison of diverse treatments for cirrhotic patients with portal hypertension. Our meta-analysis indicated that a TIPS and distal splenorenal shunt resulted in lower rates of rebleeding than did other therapies. Furthermore, drugs are more suitable for combination therapy than monotherapy.
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Affiliation(s)
- Qigu Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, China
| | - Wenyi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, China
| | - Cuilin Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiong Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, China
| | - Tian'an Jiang
- National Clinical Research Center for Infectious Diseases, Hangzhou, China
- Department of Ultrasound, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- National Clinical Research Center for Infectious Diseases, Hangzhou, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, Hangzhou, China
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24
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Danielsen KV, Hove JD, Nabilou P, Yin M, Chen J, Zhao M, Kallemose T, Teisner AS, Siebner HR, Ehman RL, Møller S, Bendtsen F. Using MR elastography to assess portal hypertension and response to beta-blockers in patients with cirrhosis. Liver Int 2021; 41:2149-2158. [PMID: 34060714 PMCID: PMC8373798 DOI: 10.1111/liv.14981] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/18/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND MR elastography can determine organ-related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post-prandially due to increased portal blood in-flow. Non-selective beta-blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed. AIMS To assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure. METHODS Fifty-two patients with cirrhosis underwent liver vein catheterization and two-dimensional (2D) MR elastography on separate days. Thirty-six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12 mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography. RESULTS HVPG showed a strong, positive, linear relationship with liver stiffness (r2 = 0.92; P < .001) and spleen stiffness (r2 = 0.94; P < .001). The cut-off points for identifying patients with a HVPG ≥ 12 mmHg were 7.7 kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5 kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5-10.4, P < .001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response (P = .75). CONCLUSIONS Two-dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.
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Affiliation(s)
- Karen Vagner Danielsen
- Centre of Gastroenterology, Medical division, Copenhagen University Hospital Hvidovre, Denmark,Dept. Clinical Physiology and Nuclear Medicine, Centre of Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jens Dahlgaard Hove
- Dept. of Cardiology, Copenhagen University Hospital Hvidovre, Denmark,Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen
| | - Puria Nabilou
- Centre of Gastroenterology, Medical division, Copenhagen University Hospital Hvidovre, Denmark
| | - Meng Yin
- Dept. of Radiology, Mayo Clinic, Rochester, cx USA
| | - Jun Chen
- Dept. of Radiology, Mayo Clinic, Rochester, cx USA
| | - Mirabella Zhao
- Centre of Gastroenterology, Medical division, Copenhagen University Hospital Hvidovre, Denmark
| | - Thomas Kallemose
- Clinical Research Department. Copenhagen University Hospital Hvidovre, Denmark
| | - Ane Søgaard Teisner
- Centre of Gastroenterology, Medical division, Copenhagen University Hospital Herlev, Denmark
| | - Hartwig Roman Siebner
- Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen,Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | | | - Søren Møller
- Dept. Clinical Physiology and Nuclear Medicine, Centre of Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark,Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen
| | - Flemming Bendtsen
- Centre of Gastroenterology, Medical division, Copenhagen University Hospital Hvidovre, Denmark,Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen
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25
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Bruno R, Cammà C, Caraceni P, D'Amico G, Grattagliano I, La Mura V, Riggio O, Schepis F, Senzolo M, Angeli P, de Franchis R. Portal Hypertension and Ascites: Patient-and Population-centered Clinical Practice Guidelines by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2021; 53:1089-1104. [PMID: 34321192 DOI: 10.1016/j.dld.2021.06.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/30/2021] [Accepted: 06/20/2021] [Indexed: 02/06/2023]
Abstract
Portal hypertension and ascites are two crucial events in the natural history of liver cirrhosis, whose appearance marks a downward shift in the prognosis of the disease. Over the years, several international and national societies have issued clinical practice guidelines for the diagnosis and management of portal hypertension and ascites. The present document addresses the needs of an updated guidance on the clinical management of these conditions. Accordingly, the AISF Governing Board appointed a multi-disciplinary committee of experts for drafting an update of the most recent EASL Clinical Practice Guidelines. The aim of this work was to adapt the EASL recommendations to national regulations and resources, local circumstances and settings, infrastructure, and cost/benefit strategies to avoid duplication of efforts and optimize resource utilization. The committee defined the objectives, the key issues and retrieved the relevant evidence by performing a systematic review of the literature. Finally, the committee members (chosen on the basis of their specific expertise) identified the guidelines' key questions and developed them following the PICO format (Population, Intervention, Comparison, Outcomes). For each of the PICO questions, the systematic review of the literature was made on the most important scientific databases (Pubmed, Scopus, Embase).
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26
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Rittig N, Aagaard NK, Villadsen GE, Sandahl TD, Jessen N, Grønbaek H, George J. Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2021; 54:320-328. [PMID: 34165199 DOI: 10.1111/apt.16460] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/17/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect. AIMS To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion. METHODS In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90 minutes after ingestion of 1000-mg metformin (n = 16) or placebo (n = 16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow. RESULTS The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time × group interaction, P = 0.008). In patients with baseline HVPG ≥12 mm Hg clinically significant improvements in HVPG (HVPG <12 mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P = 0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O2 uptake or inflammation markers between groups. CONCLUSIONS A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Nikolaj Rittig
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.,Department and Laboratories of Diabetes and Hormone diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Kristian Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | - Niels Jessen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark.,Research laboratories for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, Australia
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27
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He L, Lou L. Letter: the need to reconsider the liver-specific benefit of carvedilol. Aliment Pharmacol Ther 2021; 54:348. [PMID: 34236095 DOI: 10.1111/apt.16383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Lu He
- Department of Infectious Diseases, YiWu Central Hospital, Zhejiang, China
| | - Lianqing Lou
- Department of Infectious Diseases, YiWu Central Hospital, Zhejiang, China
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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: 31] [Impact Index Per Article: 7.8] [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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29
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Gonzalo Bada N, Suárez Parga JM, Hernández Cabrero T, Ponce Dorrego D, Zarauza Soto Y, Abadía Barnó M, Olveira Martín A, Novo Torres J, Rodríguez Díaz R, Fernández Rodríguez L, Mora Sanz P, Froilán Torres C. Hemodynamic changes after endoscopic variceal ligation: a cohort study. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 112:456-461. [PMID: 32450703 DOI: 10.17235/reed.2020.6656/2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND there is controversy about the need to maintain vasoconstrictor treatment after adequate haemostasis is achieved through endoscopic band ligation (EBL) in bleeding esophageal varices (BEV). Measuring a "before and after urgent-EBL" hepatic venous pressure gradient (HVPG) in acute variceal hemorrhage is very difficult. Thus, the goal of this study was to determine hemodynamic variations after an EBL session. A "before" HVPG (PRE) was performed and another one 24 hours "after-ligation" (POST), in cirrhotic patients undergoing endoscopic band ligation as BEV prophylaxis. PATIENTS AND METHODS this was a single-center, cohort, prospective study. Patients followed a program of repeated sessions of EBL until eradication of their varices and underwent a basal hepatic venous pressure gradient (PRE HVPG), without changing their usual treatment with beta-blockers. Subsequently, an endoscopic ligation session was performed, following the clinical practices guidelines. A second pressure measurement (POST HVPG) was taken 24 hours after the endoscopic treatment. RESULTS 30 patients were included. PRE and POST HVPG median results were 16.5 mmHg (14-20) and 19.5 mmHg (17-21), respectively, with a significant increase after the procedure (p < 0.001). Percentage variations in portal pressure, based on the baseline gradient values (12, 16 and 20 mmHg), were higher for patients with a lower basal HVPG versus a higher HVPG for any of the categories compared (p = 0.087, p = 0.016 and p < 0.001, respectively). In our series, 36.7 % of patients showed a ≥ 20 % gradient increase after ligation. CONCLUSION endoscopic band ligation causes an increase in portal pressure, at least for a transitional period, determined by the hepatic venous pressure gradient.
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Non-invasive laboratory, imaging and elastography markers in predicting varices with high risk of bleeding in cirrhotic patients. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MÉDECINE INTERNE 2021; 59:194-200. [PMID: 33544557 DOI: 10.2478/rjim-2021-0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Indexed: 11/21/2022]
Abstract
Introduction. Upper digestive tract endoscopy remains the gold-standard for detecting esophageal or gastric varices and assessment of bleeding risk, but this method is invasive. The aim of the study was to identify non-invasive factors that could be incorporated into an algorithm for estimating the risk of variceal bleeding.Methods. A prospective study was performed on 130 cirrhotic patients. Tests were performed on all patients which included liver enzymes, complete blood count and coagulation parameters, abdominal ultrasound, elastography of both the liver and the spleen. Upper gastrointestinal endoscopy was performed in all patients included in the study and the results were classified, in accordance with Baveno VI into 2 outcome groups: Group 1 - patients with low bleeding risk and Group 2 - patients with varices needing treatment.Results. The study lot (130 patients) was divided into: Group I (low bleeding risk - 102 patients), and Group II (high bleeding risk - 28 patients). Parameters found to have significant differences in univariate analysis were transaminases, platelet count, spleen size, INR, portal vein diameter and both liver and spleen elastography. Calculating AUROC for each parameter identifies spleen elastography as having the best result, followed by INR, AST and platelet count. Liver elastography had the worst AUROC. Independent variables identified by logistic regression included spleen elastography, INR, platelet count, spleen diameter, ALT, age, and gender.Conclusions. Spleen stiffness is the best single parameter predicting the presence of high-risk esophageal varices.
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Veldhuijzen van Zanten D, Buganza E, Abraldes JG. The Role of Hepatic Venous Pressure Gradient in the Management of Cirrhosis. Clin Liver Dis 2021; 25:327-343. [PMID: 33838853 DOI: 10.1016/j.cld.2021.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Quantifying the degree of portal hypertension provides useful information to estimate prognosis and to evaluate new therapies for portal hypertension. This quantification is done in clinical practice with the measurement of the hepatic venous pressure gradient. This article addresses the applications of measuring portal pressure in cirrhosis, including the differential diagnosis of portal hypertension; estimation of prognosis in cirrhosis, including preoperative evaluation before hepatic and extrahepatic surgery; assessment of the response to drug therapy (mainly in the context of drug development); and assessing the regression of portal hypertension syndrome.
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Affiliation(s)
- Daniel Veldhuijzen van Zanten
- Department of Medicine, University of Alberta, 13-103 Clinical Sciences Building, 11350-83 Avenue, Edmonton, Alberta T6G 2G3, Canada
| | - Elizabeth Buganza
- Division of Gastroenterology, Zeidler Ledcor Centre, University of Alberta, 8540 112 St NW, Edmonton, Alberta T6G 2X8, Canada
| | - Juan G Abraldes
- Division of Gastroenterology, University of Alberta, 8540 112 St NW, 1-38 Zeidler Ledcor Centre, Edmonton, Alberta T6G 2X8, Canada.
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Abstract
Liver cirrhosis is a major healthcare problem. Acute decompensation, and in particular its interplay with dysfunction of other organs, is responsible for the majority of deaths in patients with cirrhosis. Acute decompensation has different courses, from stable decompensated cirrhosis over unstable decompensated cirrhosis to pre-acute-on-chronic liver failure and finally acute-on-chronic liver failure, a syndrome with high short-term mortality. This review focuses on the recent developments in the field of acute decompensation and acute-on-chronic liver failure.
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Affiliation(s)
- Philip Ferstl
- Department for Internal Medicine I, University Hospital, Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany
| | - Jonel Trebicka
- Department for Internal Medicine I, University Hospital, Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main 60590, Germany; European Foundation for the Study of Chronic Liver Failure, Travesera de Gracia 11, 08021 Barcelona, Spain.
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Jachs M, Reiberger T. Prevention of Variceal Bleeding and Rebleeding by Nonselective Beta-Blockers: A Tailored Approach. Clin Liver Dis 2021; 25:311-326. [PMID: 33838852 DOI: 10.1016/j.cld.2021.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Indexed: 01/31/2023]
Abstract
Nonselective beta-blockers represent the mainstay of medical therapy in the prophylaxis of variceal bleeding and rebleeding in patients with portal hypertension. Their efficacy has been demonstrated by numerous trials; however, there exist safety concerns in advanced disease, such as in patients with refractory ascites. Importantly, nonselective beta-blockers also exert nonhemodynamic beneficial effects that may contribute to a prolonged decompensation-free survival, as recently shown in the PREDESCI trial. This review summarizes the current evidence on nonselective beta-blocker therapy and proposes a tailored, patient-centered approach for the use of nonselective beta-blockers in patients with portal hypertension.
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Affiliation(s)
- Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
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Ishikawa T, Sasaki R, Nishimura T, Matsuda T, Iwamoto T, Saeki I, Hidaka I, Takami T, Sakaida I. Splenic non-infarction volume determines a clinically significant hepatic venous pressure gradient response to partial splenic embolization in patients with cirrhosis and hypersplenism. J Gastroenterol 2021; 56:382-394. [PMID: 33629147 DOI: 10.1007/s00535-021-01762-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 01/17/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND This study aimed to investigate changes in the hepatic venous pressure gradient (HVPG) by partial splenic embolization (PSE) and to identify the determinants of a clinically meaningful postoperative HVPG reduction. METHODS Sixty-eight patients with cirrhosis and hypersplenism who underwent PSE at our department between September 2007 and June 2020 were included. The HVPG was evaluated pre- and immediately post-PSE. The patients were divided into three groups according to their preprocedural HVPG: low-HVPG (< 10 mmHg, n = 22), intermediate-HVPG (10 mmHg ≤ HVPG < 16 mmHg, n = 33), and high-HVPG (≥ 16 mmHg, n = 13). RESULTS Overall, PSE significantly reduced HVPG from 12.2 ± 4.0 to 9.4 ± 3.6 mmHg (p < 0.01) with a relative decrease of 22.2 ± 20.4%. In addition, HVPG reductions were 19.4 ± 28.7%, 24.0 ± 15.9%, and 22.5 ± 13.3% in the low-, intermediate-, and high-HVPG groups, respectively, indicating no significant difference in HVPG reduction between the groups. An HVPG decrease of ≥ 20% from the baseline, defined in this study as a clinically significant HVPG response to PSE, was achieved in 55.9% of all patients. Multivariate logistic regression and receiver operating characteristic curve analyses identified splenic non-infarction volume as an independent determinant of a 20% decrease in HVPG (p < 0.05), with a cut-off of 139.2 cm3 (sensitivity, 76.3%; specificity, 60.0%; p < 0.05). CONCLUSIONS The splenic non-infarction volume, namely the residual functional spleen volume, independently determines a clinically significant HVPG response to PSE in patients with cirrhosis and hypersplenism.
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Affiliation(s)
- Tsuyoshi Ishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan.
| | - Ryo Sasaki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Tatsuro Nishimura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Takashi Matsuda
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Takuya Iwamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Issei Saeki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Isao Hidaka
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
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Ferrusquía-Acosta J, Bassegoda O, Turco L, Reverter E, Pellone M, Bianchini M, Pérez-Campuzano V, Ripoll E, García-Criado Á, Graupera I, García-Pagán JC, Schepis F, Senzolo M, Hernández-Gea V. Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis. J Hepatol 2021; 74:811-818. [PMID: 33068638 DOI: 10.1016/j.jhep.2020.10.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/29/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Wedge hepatic vein pressure (WHVP) accurately estimates portal pressure (PP) in alcohol- or viral hepatitis-related cirrhosis. Whether this also holds true in cirrhosis caused by non-alcoholic steatohepatitis (NASH) is unknown. We aimed to evaluate the agreement between WHVP and PP in patients with NASH cirrhosis in comparison to patients with alcohol- or HCV-related cirrhosis. METHODS All consecutive patients with NASH cirrhosis treated with a transjugular intrahepatic portosystemic shunt (TIPS) in 3 European centres were included (NASH group; n = 40) and matched with 2 controls (1 with alcohol-related and 1 with HCV-related cirrhosis) treated with TIPS contemporaneously (control group; n = 80). Agreement was assessed by Pearson's correlation (R), intra-class correlation coefficient (ICC), and Bland-Altman method. Disagreement between WHVP and PP occurred when both pressures differed by >10% of PP value. A binary logistic regression analysis was performed to identify factors associated with this disagreement. RESULTS Correlation between WHVP and PP was excellent in the control group (R 0.92; p <0.001; ICC 0.96; p <0.001) and moderate in the NASH group (R 0.61; p <0.001; ICC 0.74; p <0.001). Disagreement between WHVP and PP was more frequent in the NASH group (37.5% vs. 14%; p = 0.003) and was mainly because of PP underestimation. In uni- and multivariate analyses, only NASH aetiology was associated with disagreement between WHVP and PP (odds ratio 4.03; 95% CI 1.60-10.15; p = 0.003). CONCLUSIONS In patients with decompensated NASH cirrhosis, WHVP does not estimate PP as accurately as in patients with alcohol- or HCV-related cirrhosis, mainly because of PP underestimation. Further studies aimed to assess this agreement in patients with compensated NASH cirrhosis are needed. LAY SUMMARY Portal pressure is usually assessed by measuring wedge hepatic vein pressure because of solid evidence demonstrating their excellent agreement in alcohol- and viral hepatitis-related cirrhosis. Our results show that in patients with decompensated cirrhosis caused by non-alcoholic steatohepatitis, wedge hepatic vein pressure estimates portal pressure with less accuracy than in patients with other aetiologies of cirrhosis, mainly because of portal pressure underestimation.
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Affiliation(s)
- José Ferrusquía-Acosta
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain; Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Octavi Bassegoda
- Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Laura Turco
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria di Modena and University of Modena and Reggio Emilia, Modena, Italy; PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Enric Reverter
- Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Monica Pellone
- University Hospital of Padua, Multivisceral Transplant Unit, Gastroenterology, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver) Padua, Italy
| | - Marcello Bianchini
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria di Modena and University of Modena and Reggio Emilia, Modena, Italy
| | - Valeria Pérez-Campuzano
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain; Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Enric Ripoll
- Centre de Diagnostic per l'Imatge, Hospital Clínic, Barcelona, Spain
| | | | - Isabel Graupera
- Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain; Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Filippo Schepis
- Division of Gastroenterology, Azienda Ospedaliero-Universitaria di Modena and University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Senzolo
- University Hospital of Padua, Multivisceral Transplant Unit, Gastroenterology, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver) Padua, Italy
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain; Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Centro de Investigación Biomédica Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.
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Garcia Garcia de Paredes A, Manicardi N, Tellez L, Ibañez L, Royo F, Bermejo J, Blanco C, Fondevila C, Fernandez Lanza V, Garcia-Bermejo L, Falcon-Perez JM, Bañares R, Gracia-Sancho J, Albillos A. Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature. Hepatol Commun 2021; 5:309-322. [PMID: 33553977 PMCID: PMC7850302 DOI: 10.1002/hep4.1642] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/27/2020] [Accepted: 10/23/2020] [Indexed: 02/04/2023] Open
Abstract
Noninvasive staging of decompensated cirrhosis is an unmet clinical need. The aims of this study were to characterize and validate a novel microRNA (miRNA) signature to stage decompensated cirrhosis and predict the portal pressure and systolic cardiac response to nonselective beta-blockers (NSBBs). Serum samples from patients with decompensated cirrhosis (n = 36) and healthy controls (n = 36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes and for three miRNAs (miR-192-5p, miR-34a-5p, and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, which was refractory in 18 (50%), and were placed on NSBBs for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient, and an echocardiogram study were performed before and 1 month after NSBBs. Patients with cirrhosis had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p, and miR-29a-5p (P < 0.05). Baseline serum miR-452-5p and miR-429 levels were lower in NSBB responders (P = 0.006). miR-181b-5p levels were greater in refractory ascites than in diuretic-sensitive ascites (P = 0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (ρ = -0.46, P = 0.007; and ρ = -0.41, P = 0.01, respectively) and with diminished systolic contractility (ρ = -0.55, P = 0.02; and ρ = -0.55, P = 0.02, respectively) in patients with refractory ascites after NSBBs. Conclusion: Analysis of a miRNA signature in serum discriminates between patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade and those more likely to benefit from NSBBs.
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Affiliation(s)
- Ana Garcia Garcia de Paredes
- Gastroenterology and Hepatology DepartmentHospital Universitario Ramon y CajalInstituto Ramon y Cajal de Investigacion Biosanitaria (IRYCIS)Universidad de AlcalaMadridSpain
| | - Nicolo Manicardi
- Liver Vascular Biology Research GroupAugust Pi i Sunyer Biomedical Research InstituteBarcelonaSpain
| | - Luis Tellez
- Gastroenterology and Hepatology DepartmentHospital Universitario Ramon y CajalInstituto Ramon y Cajal de Investigacion Biosanitaria (IRYCIS)Universidad de AlcalaMadridSpain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
| | - Luis Ibañez
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Gastroenterology and Hepatology DepartmentHospital Universitario Gregorio MarañonInstituto de Investigacion Sanitaria Gregorio Marañon (IiSGM)Universidad Complutense de MadridMadridSpain
| | - Felix Royo
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Exosomes LaboratoryCenter for Cooperative Research in BioscienciesBasque Research and Technology Alliance DerioDerioSpain
| | - Javier Bermejo
- Cardiology DepartmentHospital Universitario Gregorio MarañonIiSGMUniversidad Complutense de MadridMadridSpain
| | | | - Constantino Fondevila
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Liver Surgery and Transplantation UnitHospital ClinicBarcelonaSpain
| | | | | | - Juan Manuel Falcon-Perez
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Exosomes LaboratoryCenter for Cooperative Research in BioscienciesBasque Research and Technology Alliance DerioDerioSpain.,IKERBASQUE-Basque Foundation for ScienceBilbaoSpain
| | - Rafael Bañares
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Gastroenterology and Hepatology DepartmentHospital Universitario Gregorio MarañonInstituto de Investigacion Sanitaria Gregorio Marañon (IiSGM)Universidad Complutense de MadridMadridSpain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research GroupAugust Pi i Sunyer Biomedical Research InstituteBarcelonaSpain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
| | - Agustin Albillos
- Gastroenterology and Hepatology DepartmentHospital Universitario Ramon y CajalInstituto Ramon y Cajal de Investigacion Biosanitaria (IRYCIS)Universidad de AlcalaMadridSpain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
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Piccolo Serafim L, Simonetto DA. Primary Prophylaxis of Variceal Bleeding in Liver Cirrhosis. VARICEAL BLEEDING IN LIVER CIRRHOSIS 2021:67-75. [DOI: 10.1007/978-981-15-7249-4_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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38
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Sharma S, Agarwal S, Gunjan D, Kaushal K, Anand A, Gopi S, Mohta S, Saraya A. Outcomes of Portal Pressure-Guided Therapy in Decompensated Cirrhosis With Index Variceal Bleed in Asian Cohort. J Clin Exp Hepatol 2021; 11:443-452. [PMID: 34276151 PMCID: PMC8267357 DOI: 10.1016/j.jceh.2020.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS Hemodynamic response to pharmacotherapy improves survival in patients with cirrhosis post variceal bleeding, but long-term outcomes remain unexplored especially in this part of the world. We aimed to study the long-term impact of portal pressure reduction on liver-related outcomes after index variceal bleed. METHODS Patients with hepatic venous pressure gradient (HVPG) more than 12 mm Hg after index variceal bleed were given non-selective beta-blockers in combination with variceal band ligation. HVPG response was assessed after 4 weeks. Patients were followed up for rebleed events, survival, additional decompensation events and safety outcomes. Rebleed and other decompensations were compared using competing risks analysis, taking death as competing event, and survival was compared using Kaplan-Meier analysis. RESULTS Forty-eight patients (29 responders and 19 non-responders) were followed up for a median duration of 45 (24-56) months. Rebleeding rates at 1, 3 and 5 years were 10.3%, 20.7% and 20.7% in responders and 15.8%, 44.7% and 51.1% in non-responders, respectively (Gray's test, P = 0.044). Survival rates at 1, 3 and 5 years were 89.7%, 72.1% and 51.9% in responders and 89.5%, 44% and 37.7% in non-responders, respectively (log-rank test, P = 0.1). Both severity of liver disease (MELD score, multivariate sub-distributional hazards ratio: 1.166 [1.014-1.341], P = 0.030) and HVPG non-response (multivariate sub-distributional hazards ratio: 2.476 [1.87-7.030], P = 0.045) predicted rebleeding risk while survival was dependent only on severity of liver disease (MELD > 12, multivariate hazards ratio: 2.36 [1.04-5.38], P = 0.041). CONCLUSION Baseline severity of liver disease predicted survival and rebleed in these patients. Hemodynamic response, although associated with lower rebleeding rate, had limited impact on survival.
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Key Words
- ACLF, acute on chronic liver failure
- AFP, alpha-fetoprotein
- AVB, acute variceal bleed
- CT, computed tomography
- CTP, Child–Turcotte–Pugh
- EASL-CLIF, European Association of Study of Liver Disease – Chronic Liver Failure Consortium
- EBL, endoscopic band ligation
- EGD, esophagogastroduodenoscopy
- HE, hepatic encephalopathy
- HRS, hepatorenal syndrome
- HVPG, hepatic venous pressure gradient
- MELD, model for end-stage liver disease
- NSBB, non-selective beta-blockers
- SBP, spontaneous bacterial peritonitis
- acute variceal bleed
- hemodynamic response and carvedilol
- hepatic venous pressure gradient
- non-selective beta-blockers
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Affiliation(s)
| | | | | | | | | | | | | | - Anoop Saraya
- Address for correspondence: Anoop Saraya, Professor and Head of Department, Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium. J Hepatol 2021; 74:200-219. [PMID: 32896580 DOI: 10.1016/j.jhep.2020.08.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/09/2020] [Accepted: 08/02/2020] [Indexed: 12/15/2022]
Abstract
Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.
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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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Affiliation(s)
- Vincenzo La Mura
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Medicina Generale - Emostasi e Trombosi, Milano, and Dipartimento di scienze Biomediche per la Salute, Università degli studi di Milano, Milano, Italy
| | - Candid Villanueva
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Autonomous University, Barcelona, Spain
| | - Juan G Abraldes
- Swiss Liver, University Clinic for Visceral Medicine and Surgery, Inselspital, University of Bern, Hepatology, Bern, Switzerland
| | - Jaime Bosch
- Division of Gastroenterology, University of Alberta, CEGIIR, Edmonton, AB, Canada
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Clinical Decompensation and Outcomes in Patients With Compensated Cirrhosis and a Hepatic Venous Pressure Gradient ≥20 mm Hg. Am J Gastroenterol 2020; 115:1624-1633. [PMID: 32453061 DOI: 10.14309/ajg.0000000000000653] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Hepatic venous pressure gradient (HVPG) of ≥10 mm Hg predicts clinical decompensation (CD) in compensated cirrhosis. A proportion of cirrhotic patients at presentation have high HVPG (≥20 mm Hg) and are compensated. The natural history, spectrum of CD, and mortality in this group is largely unknown. METHODS Consecutive compensated cirrhotic patients with HVPG ≥6 mm Hg (n = 741) were followed up for 3-6 months for the development of any CD. Patients were classified based on the baseline HVPG (6 to <12 mm Hg [low HVPG, Gr.A, n = 163], 12 to <20 mm Hg [intermediate HVPG, Gr.B, n = 437] and ≥20 mm Hg [high HVPG, Gr.C, n = 141]). We analyzed the predictors of first CD, HVPG response to carvedilol, and mortality in these groups. RESULTS CD developed in 217 (29.3%) patients during a mean follow-up of 1.6 ± 0.4 years, and those who developed CD had higher baseline HVPG (17.02 ± 4.79 vs 14.28 ± 4.86; P < 0.001). First CD was seen earlier (1.3 ± 0.7 years vs 1.5 ± 0.6 years and 1.6 ± 0.5 years, P = 0.02) and more frequently (44.7% vs 11% and 31.1%, P < 0.01) in high HVPG groups compared with low and intermediate HVPG groups, with higher mortality rates. Patients in the high HVPG group compared with the low HVPG group more often had NASH-cirrhosis (35.5% vs 19.6%; P 0.001), higher liver stiffness values (45.06 ± 20.46 vs 20.09 ± 5.47 kPa, P < 0.001), and lower platelet counts (113.37 ± 72.57 vs 151.7 ± 87.30/cmm, P < 0.001). Patients with HVPG ≥12 mm Hg received carvedilol, and a repeat HVPG performed in a proportion after 9.3 ± 2.4 months showed response (≥20% reduction in HVPG or <12 mm Hg) in 31.6% patients (Gr. B, 44.9% > Gr. C, 22.2%, P < 0.05). Baseline HVPG (HVPG ≥12 to <20 mm Hg [Hazard ratio: 2.73] and HVPG ≥20 mm Hg [Hazard ratio: 4.48], P < 0.001) independently predicted CD. DISCUSSION HVPG ≥20 mm Hg in patients with compensated cirrhosis independently predicts early and more frequent CD and poor outcomes. These patients should be labeled as "high-risk compensated cirrhosis," and early and effective interventions to reduce portal pressure should be initiated to improve long-term outcomes.
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Ishikawa T, Hamamoto K, Sasaki R, Nishimura T, Matsuda T, Iwamoto T, Takami T, Sakaida I. Significant improvement in portal-systemic liver failure symptoms and successful management of portal-splenic venous hemodynamics by the combination of interventional radiology and pharmacotherapy. Hepatol Res 2020; 50:1201-1208. [PMID: 32609922 DOI: 10.1111/hepr.13545] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/10/2020] [Accepted: 06/26/2020] [Indexed: 02/08/2023]
Abstract
This study describes a case of hepatitis C virus-related decompensated cirrhosis with portal-systemic liver failure and refractory encephalopathy. It was successfully managed with a combination of interventional radiology and pharmacotherapy, to improve hepatic function, including hyperammonemia and to control portal-splenic venous hemodynamics with hepatic venous pressure gradient (HVPG) monitoring. A man in his late 50s presented with a Child-Pugh score of 13, Model for End-Stage Liver Disease-sodium (MELD-Na) score of 19 and blood ammonia level of 185 μg/dL. He underwent balloon-occluded retrograde transvenous obliteration (BRTO) followed by partial splenic embolization (PSE) and non-selective beta-blocker (NSBB) administration. BRTO induced drastic changes in the portal-splenic venous hemodynamics, resulting in dramatically improved hepatic function and reduced hyperammonemia. However, the procedure resulted in increased HVPG from 13.6 mmHg at baseline to 23.5 mmHg at 1-month post-BRTO, accompanied by ascites retention and development of portal hypertensive gastropathy. Thereafter, PSE was performed, followed by NSBB administration, to control the elevated portal venous pressure following BRTO. Postoperatively, the patient's ascites and portal hypertensive gastrophy improved after splenic artery embolization, which eventually disappeared after the additional administration of NSBBs 1 month later. The HVPG finally decreased to 16.9 mmHg; the Child-Pugh score, MELD-Na score and blood ammonia level improved to 7, 11 and 22 μg/dL, respectively, after all therapies. BRTO significantly improved the symptoms of portal-systemic liver failure with refractory encephalopathy. PSE and NSBB administration could contribute to additional amelioration of hepatic function and successful management of complications induced by portal hemodynamic changes following BRTO.
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Affiliation(s)
- Tsuyoshi Ishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Kaori Hamamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Ryo Sasaki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Tatsuro Nishimura
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Takashi Matsuda
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Takuya Iwamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube-Yamaguchi, 7558505, Japan
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Magaz M, Baiges A, Hernández-Gea V. Precision medicine in variceal bleeding: Are we there yet? J Hepatol 2020; 72:774-784. [PMID: 31981725 DOI: 10.1016/j.jhep.2020.01.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 12/14/2022]
Abstract
Variceal bleeding is one of the most feared complications of portal hypertension in patients with cirrhosis because of its deleterious impact on prognosis. Adequate management of patients at risk of developing variceal bleeding includes the prevention of the first episode of variceal bleeding and rebleeding, and is crucial in modifying prognosis. The presence of clinically significant portal hypertension is the main factor determining the risk of development of varices and other liver-related decompensations; therefore, it should be carefully screened for and monitored. Treating patients with clinically significant portal hypertension based on their individual risk of portal hypertension-related bleeding undoubtedly improves prognosis. The evaluation of liver haemodynamics and liver function can stratify patients according to their risk of bleeding and are no question useful tools to guide therapy in an individualised manner. That said, recent data support the idea that tailoring therapy to patient characteristics may effectively impact on prognosis and increase survival in all clinical scenarios. This review will focus on evaluating the available evidence supporting the use of individual risk characteristics for clinical decision-making and their impact on clinical outcome and survival. In primary prophylaxis, identification and treatment of patients with clinically significant portal hypertension improves decompensation-free survival. In the setting of acute variceal bleeding, the risk of failure and rebleeding can be easily predicted, allowing for early escalation of treatment (i.e. pre-emptive transjugular intrahepatic portosystemic shunt) which can improve survival in appropriate candidates. Stratifying the risk of recurrent variceal bleeding based on liver function and haemodynamic response to non-selective beta-blockers allows for tailored treatment, thereby increasing survival and avoiding adverse events.
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Affiliation(s)
- Marta Magaz
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain
| | - Anna Baiges
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - Virginia Hernández-Gea
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain.
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Møller S, Kimer N, Barløse M, Bendtsen F. Pathophysiological-based treatments of complications of cirrhosis. Scand J Gastroenterol 2020; 55:383-394. [PMID: 32233873 DOI: 10.1080/00365521.2020.1744709] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Detailed knowledge and understanding of the pathophysiological mechanisms and changes in hepatic and splanchnic function leading to the development of haemodynamic changes and portal hypertension in patients with cirrhosis are essential since it guides the search for targets to ameliorate liver-related abnormalities. Recent research has focused on the gut-liver axis, changes in intestinal permeability, translocation of bacterial products, and inflammation as important drivers of haemodynamic alterations and thereby targets for treatment. Additionally, treatment strategies should focus on microbiotic modulation, antiangiogenics, anti-inflammatory strategies, and modulation of bile acid metabolism. This paper aims to review contemporary pathophysiological-based treatment principles of the major complications of cirrhosis and portal hypertension and future targets for treatment.
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Affiliation(s)
- Søren Møller
- Department Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, Hvidovre Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.,Bridge Translational Excellence Programme, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Mads Barløse
- Department Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Hvidovre Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Gifford FJ, Dunne PDJ, Weir G, Ireland H, Graham C, Tuck S, Hayes PC, Fallowfield JA. A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP). Trials 2020; 21:260. [PMID: 32164767 PMCID: PMC7066808 DOI: 10.1186/s13063-020-4203-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 02/24/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure. METHODS In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) > 10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2 h of peripheral i.v. serelaxin infusion (80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed. RESULTS A total of 17 participants were screened, 15 were randomised and 11 completed the study (n = 9 serelaxin, n = 2 placebo). Reasons for withdrawal were baseline HVPG < 10 mmHg (n = 2) and technical failure (n = 2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43-69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n = 10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6-14). The mean baseline HVPG was 16.3 (range 10.3-21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h of i.v. serelaxin (arithmetic mean of difference ± SD was 0.4 ± 3.5 mmHg (95% CI -2.3, 3.1; p = 0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events. CONCLUSION In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG. TRIAL REGISTRATION ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.
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Affiliation(s)
| | | | - Graeme Weir
- Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Hamish Ireland
- Department of Radiology, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Catriona Graham
- Wellcome Trust Clinical Research Facility, University of Edinburgh, Edinburgh, UK
| | - Sharon Tuck
- Wellcome Trust Clinical Research Facility, University of Edinburgh, Edinburgh, UK
| | - Peter C Hayes
- Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Jonathan A Fallowfield
- Centre for Inflammation Research, University of Edinburgh, BioQuarter, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
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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: 95] [Impact Index Per Article: 19.0] [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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Turco L, Villanueva C, La Mura V, García-Pagán JC, Reiberger T, Genescà J, Groszmann RJ, Sharma BC, Merkel C, Bureau C, Alvarado E, Abraldes JG, Albillos A, Bañares R, Peck-Radosavljevic M, Augustin S, Sarin SK, Bosch J, García-Tsao G. Lowering Portal Pressure Improves Outcomes of Patients With Cirrhosis, With or Without Ascites: A Meta-Analysis. Clin Gastroenterol Hepatol 2020; 18:313-327.e6. [PMID: 31176013 DOI: 10.1016/j.cgh.2019.05.050] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 05/24/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS In unselected patients with cirrhosis, those with reductions in hepatic venous pressure gradient (HVPG) to below a defined threshold (responders) have a reduced risk of variceal hemorrhage (VH) and death. We performed a meta-analysis to compare this effect in patients with vs without ascites. METHODS We collected data from 15 studies of primary or secondary prophylaxis of VH that reported data on VH and death in responders vs nonresponders. We included studies in which data on ascites at baseline and on other relevant outcomes during follow-up evaluation were available. We performed separate meta-analyses for patients with vs without ascites. RESULTS Of the 1113 patients included in the studies, 968 patients (87%) had been treated with nonselective β-blockers. In 993 patients (89%), HVPG response was defined as a decrease of more than 20% from baseline (>10% in 11% of patients) or to less than 12 mm Hg. In the 661 patients without ascites, responders (n = 329; 50%) had significantly lower odds of events (ascites, VH, or encephalopathy) than nonresponders (odds ratio [OR], 0.35; 95% CI, 0.22-0.56). Odds of death or liver transplantation were also significantly lower among responders than nonresponders (OR, 0.50, 95% CI, 0.32-0.78). In the 452 patients with ascites, responders (n = 188; 42%) had significantly lower odds of events (VH, refractory ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome) than nonresponders (OR, 0.27; 95% CI, 0.16-0.43). Overall, odds of death or liver transplantation were lower among responders (OR, 0.47; 95% CI, 0.29-0.75). No heterogeneity was observed among studies. CONCLUSIONS In a meta-analysis of clinical trials, we found that patients with cirrhosis with and without ascites who respond to treatment with nonselective β-blockers (based on reductions in HVPG) have a reduced risk of events, death, or liver transplantation.
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Affiliation(s)
- Laura Turco
- Division of Gastroenterology, Azienda Ospedaliero, Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy; PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Candid Villanueva
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Vincenzo La Mura
- Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda, Ospedale Maggiore Policlinico, Medicina Generale - Emostasi e Trombosi, Milano, Italy; Centro Ricerca e Cura "Angela Maria ed Antonio Migliavacca" per lo Studio e la Cura delle Malattie del Fegato and Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milano, Italy
| | - Juan Carlos García-Pagán
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Joan Genescà
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Department of Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Roberto J Groszmann
- Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut; Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, Connecticut
| | - Barjesh C Sharma
- Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education & Research, New Delhi, India
| | - Carlo Merkel
- Department of Medicine Dipartimento di Medicina and Centro Interdipartimentale di Ricerca sulla Modellistica delle Alterazioni Neuropsichiche in Medicina Clinica, University of Padua, Padua, Italy
| | - Christophe Bureau
- Service d'Hépato-Gastroentérologie, Hôpital Purpan Centre Hospitalier Universitaire Toulouse, Université Paul Sabatier, Toulouse, France
| | - Edilmar Alvarado
- Department of Gastroenterology, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
| | - Juan Gonzalez Abraldes
- Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit), University of Alberta, Centre of Excellence for Gastrointestinal Inflammation and Immunity Research, Edmonton, Canada
| | - Agustin Albillos
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, University of Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain
| | - Rafael Bañares
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Markus Peck-Radosavljevic
- Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Klinikum Klagenfurth am Wörthersee, Klagenfurth, Austria
| | - Salvador Augustin
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Department of Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Shiv K Sarin
- Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education & Research, New Delhi, India
| | - Jaime Bosch
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain; Swiss Liver Center, Hepatology, University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Guadalupe García-Tsao
- Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut; Section of Digestive Diseases, VA Connecticut Healthcare System, West Haven, Connecticut.
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49
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Liu C, Liu Y, Shao R, Wang S, Wang G, Wang L, Zhang M, Hou J, Zhang C, Qi X. The predictive value of baseline hepatic venous pressure gradient for variceal rebleeding in cirrhotic patients receiving secondary prevention. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:91. [PMID: 32175384 PMCID: PMC7049047 DOI: 10.21037/atm.2019.12.143] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 12/06/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Baseline hepatic venous pressure gradient (HVPG) has been applied for prediction of variceal rebleeding in patients after acute variceal bleeding. However, for patients receiving secondary prevention, there still lacks evidence about the predictive performance of baseline-HVPG for rebleeding. This study aims to investigate the predictive value of baseline-HVPG for variceal rebleeding in cirrhotic patients receiving secondary prevention. METHODS This retrospective study included 122 patients with cirrhosis accepting secondary prevention of variceal rebleeding in a university hospital. All the included patients had HVPG measurements before rebleeding and had at least 1-year follow-up after HVPG measurement unless the rebleeding occurred. The rebleeding rate in patients with different HVPG levels and time-dependent predictive performance of baseline-HVPG were analysed. A Cox regression model and P for trend were used to assess the rebleeding risk. RESULTS Variceal rebleeding occurred in 22 (18.0%) patients during 1-year follow-up. No significant difference was observed in rebleeding rate between patients with HVPG <16 mmHg and HVPG ≥16 mmHg (17.91% vs. 26.41%, P=0.200). A decreasing trend was observed in area under the curve of HVPG for predicting rebleeding by time. The multivariate Cox model showed an overall decreasing trend in hazard ratio of rebleeding (vs. patients with HVPG <12 mmHg) for patients with 12≤ HVPG <16 mmHg, 16≤ HVPG <20 mmHg and HVPG ≥20 mmHg; besides, an increasing P for trend was observed. CONCLUSIONS A single baseline-HVPG measurement was insufficient for predicting rebleeding in patients with cirrhosis who received secondary prevention.
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Affiliation(s)
- Chuan Liu
- Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yanna Liu
- Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ruoyang Shao
- Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Sining Wang
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan 250012, China
| | - Guangchuan Wang
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan 250012, China
| | - Lifen Wang
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan 250012, China
| | - Mingyan Zhang
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan 250012, China
| | - Jinlin Hou
- Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chunqing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital, Shandong University, Jinan 250012, China
| | - Xiaolong Qi
- Department of Hepatology Unit and Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou 730000, China
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50
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Lichtenegger P, Schiefer J, Graf A, Berlakovich G, Faybik P, Baron DM, Baron-Stefaniak J. The association of pre-operative anaemia with survival after orthotopic liver transplantation. Anaesthesia 2019; 75:472-478. [PMID: 31701527 PMCID: PMC7078747 DOI: 10.1111/anae.14918] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2019] [Indexed: 12/15/2022]
Abstract
Anaemia is common in patients with end-stage liver disease. Pre-operative anaemia is associated with greater mortality after major surgery. We analysed the association of pre-operative anaemia (World Health Organization classification) with survival and complications after orthotopic liver transplantation using Cox and logistic regression models. We included patients undergoing their first orthotopic liver transplantation between 2004 and 2016. Out of 599 included patients, 455 (76%) were anaemic before transplantation. Pre-operative anaemia was not associated with the survival of 485/599 (81%) patients to 1 year after liver transplantation, OR (95%CI) 1.04 (0.64-1.68), p = 0.88. Pre-operative anaemia was associated with higher rates of intra-operative blood transfusions and acute postoperative kidney injury on multivariable analysis, OR (95%CI) 1.70 (0.82-2.59) and 1.72 (1.11-2.67), respectively, p < 0.001 for both. Postoperative renal replacement therapy was associated with pre-operative anaemia on univariate analysis, OR (95%CI) 1.87 (1.11-3.15), p = 0.018.
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Affiliation(s)
- P Lichtenegger
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - J Schiefer
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - A Graf
- Section for Medical Statistics, Centre for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - G Berlakovich
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - P Faybik
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - D M Baron
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna, Austria
| | - J Baron-Stefaniak
- Department of Anaesthesia, Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna, Austria
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