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1. A robust clustering strategy for stratification unveils unique patient subgroups in acutely decompensated cirrhosis

Author

Sara Palomino-Echeverria, Estefania Huergo, Asier Ortega-Legarreta, Eva M. Uson Raposo, Ferran Aguilar, Carlos de la Peña-Ramirez, Cristina López-Vicario, Carlo Alessandria, Wim Laleman, Alberto Queiroz Farias, Richard Moreau, Javier Fernandez, Vicente Arroyo, Paolo Caraceni, Vincenzo Lagani, Cristina Sánchez-Garrido, Joan Clària, Jesper Tegner, Jonel Trebicka, Narsis A. Kiani, Nuria Planell, Pierre-Emmanuel Rautou, and David Gomez-Cabrero

Subjects
Stratification, Clustering, Complex diseases, Cirrhosis, ACLF, Patient heterogeneity, Medicine
Abstract

Abstract Background Patient heterogeneity poses significant challenges for managing individuals and designing clinical trials, especially in complex diseases. Existing classifications rely on outcome-predicting scores, potentially overlooking crucial elements contributing to heterogeneity without necessarily impacting prognosis. Methods To address patient heterogeneity, we developed ClustALL, a computational pipeline that simultaneously faces diverse clinical data challenges like mixed types, missing values, and collinearity. ClustALL enables the unsupervised identification of patient stratifications while filtering for stratifications that are robust against minor variations in the population (population-based) and against limited adjustments in the algorithm’s parameters (parameter-based). Results Applied to a European cohort of patients with acutely decompensated cirrhosis (n = 766), ClustALL identified five robust stratifications, using only data at hospital admission. All stratifications included markers of impaired liver function and number of organ dysfunction or failure, and most included precipitating events. When focusing on one of these stratifications, patients were categorized into three clusters characterized by typical clinical features; notably, the 3-cluster stratification showed a prognostic value. Re-assessment of patient stratification during follow-up delineated patients’ outcomes, with further improvement of the prognostic value of the stratification. We validated these findings in an independent prospective multicentre cohort of patients from Latin America (n = 580). Conclusions By applying ClustALL to patients with acutely decompensated cirrhosis, we identified three patient clusters. Following these clusters over time offers insights that could guide future clinical trial design. ClustALL is a novel and robust stratification method capable of addressing the multiple challenges of patient stratification in most complex diseases.

Published
2024
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2. Impact of Sarcopenia on the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib

Author

Maurizio Biselli, Nicola Reggidori, Massimo Iavarone, Matteo Renzulli, Lorenzo Lani, Alessandro Granito, Fabio Piscaglia, Stefania Lorenzini, Eleonora Alimenti, Giulio Vara, Paolo Caraceni, Angelo Sangiovanni, Massimo Marignani, Elia Gigante, Nicolò Brandi, Annagiulia Gramenzi, and Franco Trevisani

Subjects
hepatocellular carcinoma, sarcopenia, sorafenib, skeletal muscle index, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background and aims: Sarcopenia has been associated with poor outcomes in patients with cirrhosis and hepatocellular carcinoma. We investigated the impact of sarcopenia on survival in patients with advanced hepatocellular carcinoma treated with Sorafenib. Methods: A total of 328 patients were retrospectively analyzed. All patients had an abdominal CT scan within 8 weeks prior to the start of treatment. Two cohorts of patients were analyzed: the “Training Group” (215 patients) and the “Validation Group” (113 patients). Sarcopenia was defined by reduced skeletal muscle index, calculated from an L3 section CT image. Results: Sarcopenia was present in 48% of the training group and 50% of the validation group. At multivariate analysis, sarcopenia (HR: 1.47, p = 0.026 in training; HR 1.99, p = 0.033 in validation) and MELD > 9 (HR: 1.37, p = 0.037 in training; HR 1.78, p = 0.035 in validation) emerged as independent prognostic factors in both groups. We assembled a prognostic indicator named “SARCO-MELD” based on the two independent prognostic factors, creating three groups: group 1 (0 prognostic factors), group 2 (1 factor) and group 3 (2 factors), the latter with significantly worse survival and shorter time receiving treatment.

Published
2024
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3. The Role of Transjugular Intrahepatic Portosystemic Shunt for the Management of Ascites in Patients with Decompensated Cirrhosis

Author

Giulia Iannone, Enrico Pompili, Clara De Venuto, Dario Pratelli, Greta Tedesco, Maurizio Baldassarre, Paolo Caraceni, and Giacomo Zaccherini

Subjects
cirrhosis, large volume paracentesis, ascites, portal hypertension, TIPS, systemic inflammation, Medicine
Abstract

The development and progression of ascites represent a crucial event in the natural history of patients with cirrhosis, predisposing them to other complications and carrying a heavy impact on prognosis. The current standard of care for the management of ascites relies on various combinations of diuretics and large-volume paracenteses. Periodic long-term albumin infusions on top of diuretics have been recently shown to greatly facilitate the management of ascites. The insertion of a transjugular intrahepatic portosystemic shunt (TIPS), an artificial connection between the portal and caval systems, is indicated to treat patients with refractory ascites. TIPS acts to decrease portal hypertension, thus targeting an upstream event in the pathophysiological cascade of cirrhosis decompensation. Available evidence shows a significant benefit on ascites control/resolution, with less clear results on patient survival. Patient selection plays a crucial role in obtaining better clinical responses and avoiding TIPS-related adverse events, the most important of which are hepatic encephalopathy, cardiac overload and failure, and liver failure. At the same time, some recent technical evolutions of available stents appear promising but deserve further investigations. Future challenges and perspectives include (i) identifying the features for selecting the ideal candidate to TIPS; (ii) recognizing the better timing for TIPS placement; and (iii) understanding the most appropriate role of TIPS within the framework of all other available treatments for the management of patients with decompensated cirrhosis.

Published
2024
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4. Landscape of alcohol-related hepatocellular carcinoma in the last 15 years highlights the need to expand surveillance programs

Author

Nicola Reggidori, Laura Bucci, Valentina Santi, Benedetta Stefanini, Lorenzo Lani, Davide Rampoldi, Giorgia Ghittoni, Fabio Farinati, Alberto Masotto, Bernardo Stefanini, Andrea Mega, Elisabetta Biasini, Francesco Giuseppe Foschi, Gianluca Svegliati-Baroni, Angelo Sangiovanni, Claudia Campani, Giovanni Raimondo, Gianpaolo Vidili, Antonio Gasbarrini, Ciro Celsa, Mariella Di Marco, Edoardo G. Giannini, Rodolfo Sacco, Maurizia Rossana Brunetto, Francesco Azzaroli, Donatella Magalotti, Filomena Morisco, Gian Ludovico Rapaccini, Gerardo Nardone, Alessandro Vitale, Franco Trevisani, Maurizio Biselli, Paolo Caraceni, Annagiulia Gramenzi, Francesca Benevento, Alessandro Granito, Luca Muratori, Fabio Piscaglia, Francesco Tovoli, Gloria Allegrini, Calogero Cammà, Giuseppe Cabibbo, Carmelo Marco Giacchetto, Paolo Giuffrida, Maria Vittoria Grassini, Mauro Grova, Gabriele Rancatore, Caterina Stornello, Valentina Adotti, Tancredi Li Cavoli, Fabio Marra, Martina Rosi, Vittoria Bevilacqua, Alberto Borghi, Lucia Napoli, Fabio Conti, G.L. Frassineti, Maria Teresa Migliano, Nicoletta de Matthaeis, Francesca Romana Ponziani, Gabriele Missale, Andrea Olivani, Mario Capasso, Valentina Cossiga, Maria Guarino, Ester Marina Cela, Antonio Facciorusso, Camilla Graziosi, Valentina Lauria, Giorgio Pelecca, Marta Schirripa, Fabrizio Chegai, Armando Raso, Alessio Bozzi, Maria Stella Franzè, Carlo Saitta, Assunta Sauchella, Elton Dajti, Federico Ravaioli, Maria Corina Plaz Torres, Giulia Pieri, Filippo Oliveri, Gabriele Ricco, Veronica Romagnoli, Alessandro Inno, Fabiana Marchetti, Pietro Coccoli, Antonio Malerba, Alberta Cappelli, Rita Golfieri, Cristina Mosconi, and Matteo Renzulli

Subjects
Hepatocellular carcinoma, Alcohol abuse, ITA.LI.CA staging system, Metabolic dysfunction-associated fatty liver disease, Surveillance programs, Oesophageal varices, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006–2020) in Italy. Methods: Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006–2010; 2011–2015; 2016–2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Results: Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia,

Published
2023
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5. Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study

Author

Oliviero Riggio, Ciro Celsa, Vincenza Calvaruso, Manuela Merli, Paolo Caraceni, Sara Montagnese, Vincenzina Mora, Martina Milana, Giorgio Maria Saracco, Giovanni Raimondo, Antonio Benedetti, Patrizia Burra, Rodolfo Sacco, Marcello Persico, Filippo Schepis, Erica Villa, Antonio Colecchia, Stefano Fagiuoli, Mario Pirisi, Michele Barone, Francesco Azzaroli, Giorgio Soardo, Maurizio Russello, Filomena Morisco, Sara Labanca, Anna Ludovica Fracanzani, Antonello Pietrangelo, Gabriele Di Maria, Silvia Nardelli, Lorenzo Ridola, Antonio Gasbarrini, and Calogero Cammà

Subjects
hepatic encephalopathy, decompensated cirrhosis, orthotopic liver transplant, hospital readmission, mortality, Medicine (General), R5-920
Abstract

IntroductionHepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE.MethodsWe prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT).ResultsDuring follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission.ConclusionIn patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.

Published
2023
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6. Low haemoglobin level predicts early hospital readmission in patients with cirrhosis and acute decompensation

Author

Enrico Pompili, Maurizio Baldassarre, Giacomo Zaccherini, Manuel Tufoni, Giulia Iannone, Dario Pratelli, Francesco Palmese, Luca Vizioli, Chiara Faggiano, Giorgio Bedogni, Marco Domenicali, and Paolo Caraceni

Subjects
Early readmission, Hospitalisation, Haemoglobin, Anaemia, Systemic inflammation, MELD score, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Patients with decompensated cirrhosis present frequent hospitalisations with a relevant clinical and socio-economic impact. This study aims to characterise unscheduled readmissions up to 1-year follow-up and identify predictors of 30-day readmission after an index hospitalisation for acute decompensation (AD). Methods: We performed a secondary analysis of a prospectively collected cohort of patients admitted for AD. Laboratory and clinical data at admission and at discharge were collected. Timing and causes of unscheduled readmissions and mortality were recorded up to 1 year. Results: A total of 329 patients with AD were included in the analysis. Acute-on-chronic liver failure was diagnosed in 19% of patients at admission or developed in an additional 9% of patients during the index hospitalisation. During the 1-year follow-up, 182 patients (55%) were rehospitalised and 98 (30%) more than once. The most frequent causes of readmission were hepatic encephalopathy (36%), ascites (22%), and infection (21%). Cumulative incidence of readmission was 20% at 30 days, 39% at 90 days, and 63% at 1 year. Fifty-four patients were readmitted for emergent liver-related causes within 30 days. Early readmission was associated with a higher 1-year mortality (47 vs. 32%, p = 0.037). Multivariable Cox regression analysis showed that haemoglobin (Hb) ≤8.7 g/dl (hazard ratio 2.63 [95% CI 1.38–5.02], p = 0.003) and model for end-stage liver disease-sodium score (MELD-Na) >16 at discharge (hazard ratio 2.23 [95% CI 1.27–3.93], p = 0.005), were independent predictors of early readmission. In patients with MELD-Na >16 at discharge, the presence of Hb ≤8.7 g/dl doubles the risk of early rehospitalisation (44% vs. 22%, p = 0.02). Conclusion: Besides MELD-Na, a low Hb level (Hb ≤8.7 g/dl) at discharge emerged as a new risk factor for early readmission, contributing to identification of patients who require closer surveillance after discharge. Impact and Implications: Patients with decompensated cirrhosis face frequent hospitalisations. In the present study, type and causes of readmissions were analysed during 1-year follow-up in patients discharged after the index hospitalisation for an acute decompensation of the disease. Early (30-day) liver-related readmission was associated with higher 1-year mortality. The model for end-stage liver disease-sodium score and low haemoglobin at discharge were identified as independent risk factors for early readmissions. Haemoglobin emerged as a new easy-to-use parameter associated with early readmission warranting further investigation.

Published
2023
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7. Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis

Author

Elisa Pose, Elsa Solà, Juan J. Lozano, Adrià Juanola, Julia Sidorova, Giacomo Zaccherini, Koos deWit, Frank Uschner, Marta Tonon, Konstantin Kazankov, Cesar Jiménez, Daniela Campion, Laura Napoleone, Ann T. Ma, Marta Carol, Manuel Morales‐Ruiz, Carlo Alessandria, Ulrich Beuers, Paolo Caraceni, Claire Francoz, François Durand, Rajeshwar P. Mookerjee, Jonel Trebicka, Victor Vargas, Salvatore Piano, Hugh Watson, Juan G. Abraldes, Patrick S. Kamath, Mark M. Davis, Pere Ginès, and for the investigators of the LIVERHOPE Consortium

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Patients with decompensated cirrhosis, particularly those with acute‐on‐chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE‐SAFETY randomized, double‐blind, placebo‐controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography–tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan–kynurenine and carnitine beta‐oxidation pathways. An ACLF‐specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan–kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.

Published
2022
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8. Prediction of nosocomial acute-on-chronic liver failure in patients with cirrhosis admitted to hospital with acute decompensation

Author

Giacomo Zaccherini, Maurizio Baldassarre, Michele Bartoletti, Manuel Tufoni, Sonia Berardi, Mariarosa Tamè, Lucia Napoli, Antonio Siniscalchi, Angela Fabbri, Lorenzo Marconi, Agnese Antognoli, Giulia Iannone, Marco Domenicali, Pierluigi Viale, Franco Trevisani, Mauro Bernardi, and Paolo Caraceni

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Nosocomial acute-on-chronic liver failure (nACLF) develops in at least 10% of patients with cirrhosis hospitalized for acute decompensation (AD), greatly worsening their prognosis. In this prospective observational study, we aimed to identify rapidly obtainable predictors at admission, which allow for the early recognition and stratification of patients at risk of nACLF. Methods: A total of 516 consecutive patients hospitalized for AD of cirrhosis were screened: those who did not present ACLF at admission (410) were enrolled and surveilled for the development of nACLF. Results: Fifty-nine (14%) patients developed nALCF after a median of 7 (IQR 4–18) days. At admission, they presented a more severe disease and higher degrees of systemic inflammation and anemia than those (351; 86%) who remained free from nACLF. Competing risk multivariable regression analysis showed that baseline MELD score (sub-distribution hazard ratio [sHR] 1.15; 95% CI 1.10–1.21; p ≪0.001), hemoglobin level (sHR 0.81; 95% CI 0.68–0.96; p = 0.018), and leukocyte count (sHR 1.11; 95% CI 1.06–1.16; p ≪0.001) independently predicted nACLF. Their optimal cut-off points, determined by receiver-operating characteristic curve analysis, were: 13 points for MELD score, 9.8 g/dl for hemoglobin, and 5.6x109/L for leukocyte count. These thresholds were used to stratify patients according to the cumulative incidence of nACLF, being 0, 6, 21 and 59% in the presence of 0, 1, 2 or 3 risk factors (p ≪0.001). Nosocomial bacterial infections only increased the probability of developing nACLF in patients with at least 1 risk factor, rising from 3% to 29%, 16% to 50% and 52% to 83% in patients with 1, 2 or 3 risk factors, respectively. Conclusions: Easily available laboratory parameters, related to disease severity, systemic inflammation, and anemia, can be used to identify, at admission, hospitalized patients with AD at increased risk of developing nACLF. Lay summary: More than 10% of patients with cirrhosis hospitalized because of an acute decompensation develop acute-on-chronic liver failure, which is associated with high short-term mortality, during their hospital stay. We found that the combination of 3 easily obtainable variables (model for end-stage liver disease score, leukocyte count and hemoglobin level) help to identify and stratify patients according to their risk of developing nosocomial acute-on-chronic liver failure, from nil to 59%. Moreover, if a nosocomial bacterial infection occurs, such an incidence proportionally increases from nil to 83%. This simple approach helps to identify patients at risk of developing nosocomial acute-on-chronic liver failure at admission to hospital, enabling clinicians to put in place preventive measures. Keywords: Anemia, Systemic inflammation, MELD score, Liver cirrhosis, Hospitalizations, Organ failures, Nosocomial infections

Published
2019
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9. The cost-effectiveness of albumin in the treatment of decompensated cirrhosis in Germany, Italy, and Spain

Author

M. Chris Runken, Paolo Caraceni, Javier Fernandez, Alexander Zipprich, Rashad Carlton, and Martin Bunke

Subjects
Albumin, Decompensated cirrhosis, Cost-effectiveness, Medicine (General), R5-920
Abstract

Abstract Background Albumin is frequently prescribed in cirrhotic patients with acute decompensation. However, the true cost effectiveness of albumin use in cirrhotic patients is still under debate. Objective To evaluate the cost-effectiveness of albumin in the treatment of decompensated cirrhosis in Germany, Italy, and Spain. Methods A decision-tree economic model was developed to evaluate treatments for decompensated cirrhosis from the hospital perspective over a typical inpatient admission. The treatments for large volume paracentesis (LVP) were albumin vs saline, gelatin, or no fluid. The treatments for spontaneous bacterial peritonitis (SBP) were albumin plus antibiotics vs antibiotics alone. The treatments for hepatorenal syndrome (HRS) were albumin plus a vasoconstrictor vs a vasoconstrictor alone. Effectiveness inputs were literature-based. Cost inputs included pharmacy costs and medical complication costs of decompensated cirrhosis. The primary model assessments were incremental cost-effectiveness ratios (ICERs) per life saved and per quality-adjusted life-year (QALY). Results Albumin was found to be both less costly and more effective relative to saline, gelatin, and no fluid for the treatment of LVP across all 3 countries. For SBP, albumin plus antibiotics was more clinically effective than antibiotics alone in all 3 countries. The combination of albumin plus antibiotics was less costly than antibiotics alone in Germany and Italy, making albumin a dominant treatment (ie, less costly and more effective). In the management of SBP in Spain, albumin plus antibiotics compared to antibiotics alone resulted in ICERs of €1516 per life saved and €3369 per QALY gained. Albumin plus a vasoconstrictor was both less costly and more effective than vasoconstrictor alone in the treatment of HRS across all 3 countries. Conclusion This analysis demonstrates that albumin is cost-effective in terms of lives saved and QALYs gained in the management of decompensated cirrhosis associated with LVP, SBP, or HRS.

Published
2019
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10. Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal

Author

Emanuel Raschi, Michele Fusaroli, Milo Gatti, Paolo Caraceni, Elisabetta Poluzzi, and Fabrizio De Ponti

Subjects
drug-induced liver injury, FAERS, spontaneous reporting system, pharmacovigilance, disproportionality, pharmacokinetics, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration’s Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15–7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis.

Published
2022
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11. Management of Ascites in Patients with Cirrhosis: An Update

Author

Giacomo Zaccherini, Manuel Tufoni, Giulia Iannone, and Paolo Caraceni

Subjects
decompensated cirrhosis, portal hypertension, effective hypovolemia, anti-mineralocorticoids, loop diuretics, vaptans, Medicine
Abstract

Ascites represents a critical event in the natural history of liver cirrhosis. From a prognostic perspective, its occurrence marks the transition from the compensated to the decompensated stage of the disease, leading to an abrupt worsening of patients’ life expectancy. Moreover, ascites heralds a turbulent clinical course, characterized by acute events and further complications, frequent hospitalizations, and eventually death. The pathophysiology of ascites classically relies on hemodynamic mechanisms, with effective hypovolemia as the pivotal event. Recent discoveries, however, integrated this hypothesis, proposing systemic inflammation and immune system dysregulation as key mechanisms. The mainstays of ascites treatment are represented by anti-mineralocorticoids and loop diuretics, and large volume paracentesis. When ascites reaches the stage of refractoriness, however, diuretics administration should be cautious due to the high risk of adverse events, and patients should be treated with periodic execution of paracentesis or with the placement of a trans-jugular intra-hepatic portosystemic shunt (TIPS). TIPS reduces portal hypertension, eases ascites control, and potentially modify the clinical course of the disease. Further studies are required to expand its indications and improve the management of complications. Long-term human albumin administration has been studied in two RCTs, with contradictory results, and remains a debated issue worldwide, despite a potential effectiveness both in ascites control and long-term survival. Other treatments (vaptans, vasoconstrictors, or implantable drainage systems) present some promising aspects but cannot be currently recommended outside clinical protocols or a case-by-case evaluation.

Published
2021
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12. Prevention of Cirrhosis Complications: Looking for Potential Disease Modifying Agents

Author

Giacomo Zaccherini, Manuel Tufoni, Mauro Bernardi, and Paolo Caraceni

Subjects
decompensated cirrhosis, portal hypertension, ascites, non-selective beta-blockers, TIPS, rifaximin, Medicine
Abstract

The current therapeutic strategies for the management of patients with cirrhosis rely on the prevention or treatment of specific complications. The removal of the causative agents (i.e., viruses or alcohol) prevents decompensation in the vast majority of patients with compensated cirrhosis. In contrast, even when etiological treatment has been effective, a significant proportion of patients with decompensated cirrhosis remains at risk of further disease progression. Therefore, therapies targeting specific key points in the complex pathophysiological cascade of decompensated cirrhosis could represent a new approach for the management of these severely ill patients. Some of the interventions currently employed for treating or preventing specific complications of cirrhosis or used in other diseases (i.e., poorly absorbable oral antibiotics, statins, albumin) have been proposed as potential disease-modifying agents in cirrhosis (DMAC) since clinical studies have shown their capacity of improving survival. Additional multicenter, large randomized clinical trials are awaited to confirm these promising results. Finally, new drugs able to antagonize key pathophysiological mechanisms are under pre-clinical development or at the initial stages of clinical assessment.

Published
2021
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13. Nutrition in Patients with Type 2 Diabetes: Present Knowledge and Remaining Challenges

Author

Maria Letizia Petroni, Lucia Brodosi, Francesca Marchignoli, Anna Simona Sasdelli, Paolo Caraceni, Giulio Marchesini, and Federico Ravaioli

Subjects
behaviour, diet, lifestyle, nutrition supplements, sarcopenia, type 2 diabetes, Nutrition. Foods and food supply, TX341-641
Abstract

Unhealthy behaviours, including diet and physical activity, coupled with genetic predisposition, drive type 2 diabetes (T2D) occurrence and severity; the present review aims to summarise the most recent nutritional approaches in T2D, outlining unmet needs. Guidelines consistently suggest reducing energy intake to counteract the obesity epidemic, frequently resulting in sarcopenic obesity, a condition associated with poorer metabolic control and cardiovascular disease. Various dietary approaches have been proposed with largely similar results, with a preference for the Mediterranean diet and the best practice being the diet that patients feel confident of maintaining in the long term based on individual preferences. Patient adherence is indeed the pivotal factor for weight loss and long-term maintenance, requiring intensive lifestyle intervention. The consumption of nutritional supplements continues to increase even if international societies do not support their systematic use. Inositols and vitamin D supplementation, as well as micronutrients (zinc, chromium, magnesium) and pre/probiotics, result in modest improvement in insulin sensitivity, but their use is not systematically suggested. To reach the desired goals, patients should be actively involved in the collaborative development of a personalised meal plan associated with habitual physical activity, aiming at normal body weight and metabolic control.

Published
2021
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15. Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis

Author

Jonel Trebicka, Alex Amoros, Carla Pitarch, Esther Titos, José Alcaraz-Quiles, Robert Schierwagen, Carmen Deulofeu, Javier Fernandez-Gomez, Salvatore Piano, Paolo Caraceni, Karl Oettl, Elsa Sola, Wim Laleman, Jane McNaughtan, Rajeshwar P. Mookerjee, Minneke J. Coenraad, Tania Welzel, Christian Steib, Rita Garcia, Thierry Gustot, Miguel A. Rodriguez Gandia, Rafael Bañares, Agustin Albillos, Stefan Zeuzem, Victor Vargas, Faouzi Saliba, Frederic Nevens, Carlo Alessandria, Andrea de Gottardi, Heinz Zoller, Pere Ginès, Tilman Sauerbruch, Alexander Gerbes, Rudolf E. Stauber, Mauro Bernardi, Paolo Angeli, Marco Pavesi, Richard Moreau, Joan Clària, Rajiv Jalan, and Vicente Arroyo

Subjects
acute decompensation, cirrhosis, signature, ACLF, organ failure, organ dysfunction, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients.Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine

Published
2019
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16. The Analysis of Food Intake in Patients with Cirrhosis Waiting for Liver Transplantation: A Neglected Step in the Nutritional Assessment

Author

Francesco Palmese, Ilaria Bolondi, Ferdinando Antonino Giannone, Giacomo Zaccherini, Manuel Tufoni, Maurizio Baldassarre, and Paolo Caraceni

Subjects
malnutrition, cirrhosis, liver transplantation, food records, caloric intake, macronutrients intakes, patient adherence, Nutrition. Foods and food supply, TX341-641
Abstract

Patients with cirrhosis waiting for liver transplantation (LT) frequently present a nutritional disorder, which represents an independent predictor of morbidity and mortality before and after transplantation. Thus, a proper assessment of the food intake by using different methods, such as food records, food frequency questionnaires, and 24 h recall, should be deemed an important step of the nutritional management of these patients. The available published studies indicate that the daily food intake is inadequate in the majority of waitlisted patients. These findings were confirmed by our experience, showing that the daily intake of total calories, proteins and carbohydrates was inadequate in approximately 85−95% of patients, while that of lipids and simple carbohydrates was inadequate in almost 50% of them. These data highlight the need to implement an effective educational program provided by certified nutritionists or dieticians, who should work in close collaboration with the hepatologist to provide a nutritional intervention tailored to the individual patient requirements.

Published
2019
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17. A case of pneumonia and sepsis in cirrhosis as paradigm of the problems in the management of bacterial infections in cirrhosis and of the limitations of current knowledge

Author

Manuel Tufoni, Alessandra Tovoli, Caterina Maggioli, Lucia Napoli, Carmen Serena Ricci, Marianna Mastroroberto, Giacomo Zaccherini, and Paolo Caraceni

Subjects
cirrhosis, sepsis, bacterial infection, healthcare related pneumonia, hepatorenal syndrome., Medicine
Abstract

Bacterial infections are a major problem in the management of liver cirrhosis. They represent the first precipitating cause of death since patients with cirrhosis carry an increased risk of sepsis, sepsis-induced organ failure and death. Although the clinical presentation is often misleading, the presence of bacterial infection should always be actively searched and ruled out with certainty whenever a cirrhotic patient is admitted to the hospital with an acute clinical deterioration. Major changes in the epidemiology of bacterial infections have also occurred in the last decade making the choice of empirical antibiotic therapy a challenge. We report a paradigmatic case of a 54-year old man with hepatitis C-related cirrhosis admitted to the hospital for worsening of his ascites and onset of hepatic encephalopathy, an excellent example for the difficulties of management of sepsis in cirrhosis and the limits of current knowledge.

Published
2013
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18. Hyposplenism as a cause of pneumococcal meningoencephalitis in an adult patient with coeliac disease

Author

Paolo Caraceni, Barbara Benazzi, Giacono Caio, Giacomo Zaccherini, Marco Domenicali, and Umberto Volta

Subjects
Coeliac disease, Hyposplenism, Streptococcus pneumoniae meningoencephalitis., Medicine
Abstract

Introduction: Coeliac disease can be associated with hyposplenism and splenic atrophy, which may increase the patient’s risk for fatal infections caused by Streptococcus pneumoniae or Pneumococcus. It is general opinion that many more patients with coeliac disease have died from hyposplenism-related infections than those reported in literature. Case report: A 62-year-old woman with recently diagnosed coeliac disease was hospitalized with high fever, disorientation, and nuchal rigidity. Cerebral computed tomography was negative. Laboratory tests showed an elevated leukocyte count and very high levels of C reactive protein. The cerebrospinal fluid (CSF) contained an increased number of mononuclear cells associated with a low glucose level and high protein concentrations. The CSF culture was positive for Streptococcus pneumoniae. Neurological conditions rapidly deteriorated with the onset of coma, and magnetic resonance imaging of the brain revealed initial signs of encephalitis extending above and below the tentorium. Abdominal ultrasonography disclosed splenic hypotrophy that raised the suspicion of hyposplenism. The diagnosis of hyposplenism was confirmed by demonstration of Howell-Jolly bodies in a peripheral blood smear. Discussion: This is the first reported case of pneumococcal meningoencephalitis caused by splenic hypofunction in a patient with coeliac disease. When coeliac disease is diagnosed with a marked delay in an elderly patient, spleen function should always be assessed. If impaired, the patient should undergo vaccination with pneumococcal conjugate vaccine to prevent pneumococcal infections.

Published
2013
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19. Liver Cirrhosis in a Patient with Sickle Cell Trait (Hb Sβ+ Thalassemia) without Other Known Causes of Hepatic Disease

Author

Luca Santi, Giancarlo Montanari, Sonia Berardi, Corrado Patti, Marta Frigerio, Claudia Sama, Paolo Caraceni, and Mauro Bernardi

Subjects
Liver cirrhosis, Sickle cell disease, Sickle cell trait, Iron overload, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Liver involvement in patients with sickle cell anemia/trait includes a wide range of alterations, from mild liver function test abnormalities to cirrhosis and acute liver failure. Approximately 15–30% of patients with sickle cell anemia present cirrhosis at autopsy. The pathogenesis of cirrhosis is usually related to chronic hepatitis B or C infection or to iron overload resulting from the many transfusions received by these patients in their lifetime. Thus, cirrhosis has been described almost exclusively in patients with sickle cell anemia, while only mild liver abnormalities have been associated with the sickle cell trait. In the present case study, we describe a young Mediterranean man carrying a sickle cell trait (Hb Sβ+ thalassemia) who developed liver cirrhosis being negative for hepatitis C and B viruses or for other causes of cirrhosis and not receiving chronic blood transfusions.

Published
2009
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20. Acute Liver Failure Caused by Amanita phalloides Poisoning

Author

Luca Santi, Caterina Maggioli, Marianna Mastroroberto, Manuel Tufoni, Lucia Napoli, and Paolo Caraceni

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Mushroom poisoning is a relatively rare cause of acute liver failure (ALF). The present paper analyzes the pathogenesis, clinical features, prognostic indicators, and therapeutic strategies of ALF secondary to ingestion of Amanita phalloides, which represents the most common and deadly cause of mushroom poisoning. Liver damage from Amanita phalloides is related to the amanitins, powerful toxins that inhibit RNA polymerase II resulting in a deficient protein synthesis and cell necrosis. After an asymptomatic lag phase, the clinical picture is characterized by gastrointestinal symptoms, followed by the liver and kidney involvement. Amatoxin poisoning may progress into ALF and eventually death if liver transplantation is not performed. The mortality rate after Amanita phalloides poisoning ranges from 10 to 20%. The management of amatoxin poisoning consists of preliminary medical care, supportive measures, detoxification therapies, and orthotopic liver transplantation. The clinical efficacy of any modality of treatment is difficult to demonstrate since randomized, controlled clinical trials have not been reported. The use of extracorporeal liver assist devices as well as auxiliary liver transplantation may represent additional therapeutic options.

Published
2012
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21. An Innovative Hyperbaric Hypothermic Machine Perfusion Protects the Liver from Experimental Preservation Injury

Author

Ferdinando A. Giannone, Davide Treré, Marco Domenicali, Ignazio Grattagliano, Alessandra Baracca, Gianluca Sgarbi, Caterina Maggioli, Pasquale Longobardi, Giancarlo Solaini, Massimo Derenzini, Mauro Bernardi, and Paolo Caraceni

Subjects
Technology, Medicine, Science
Abstract

Purpose. Hypothermic machine perfusion systems seem more effective than the current static storage to prevent cold ischemic liver injury. Thus, we test an innovative hyperbaric hypothermic machine perfusion (HHMP), which combines hyperbaric oxygenation of the preservation solution and continuous perfusion of the graft. Methods. Rat livers were preserved with Celsior solution according to 4 different modalities: normobaric static preservation; hyperbaric static preservation at 2 atmosphere absolute (ATA); normobaric dynamic preservation, with continuous perfusion; hyperbaric dynamic preservation, with continuous perfusion at 2 ATA. After 24 h cold preservation, we assessed different parameters. Results. Compared to baseline, livers preserved with the current static storage showed severe ultrastructural damage, glycogen depletion and an increased oxidative stress. Normobaric perfused livers showed improved hepatocyte ultrastructure and ameliorated glycogen stores, but they still suffered a significant oxidative damage. The addition of hyperbaric oxygen produces an extra benefit by improving oxidative injury and by inducing endothelial NO synthase (eNOS) gene expression. Conclusions. Preservation by means of the present innovative HHMP reduced the liver injury occurring after the current static cold storage by lowering glycogen depletion and oxidative damage. Interestingly, only the use of hyperbaric oxygen was associated to a blunted oxidative stress and an increased eNOS gene expression.

Published
2012
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22. A Case of Prolonged Cholestatic Hepatitis Induced by Azithromycin in a Young Woman

Author

Caterina Maggioli, Luca Santi, Giacomo Zaccherini, Vittoria Bevilacqua, Francesca Giunchi, and Paolo Caraceni

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Azithromycin, a semisynthetic macrolides, is frequently prescribed for the treatment of middle ear and upper respiratory tract infections, bronchitis, and community-acquired pneumonia. This antibiotic is usually well tolerated, and a rapid resolving cholestatic hepatitis has been described up to now only in six patients all, except one, over 65 years of age. We here report the case of a prolonged cholestatic hepatitis after administration of azithromycin in a young woman with no history of liver disease.

Published
2011
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23. Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors

Author

Benedetta Stefanini, Laura Bucci, Valentina Santi, Nicola Reggidori, Davide Rampoldi, Lorenzo Lani, Alessandro Granito, Angelo Sangiovanni, Giuseppe Cabibbo, Fabio Farinati, Claudia Campani, Francesco Giuseppe Foschi, Gianluca Svegliati-Baroni, Giovanni Raimondo, Antonio Gasbarrini, Andrea Mega, Elisabetta Biasini, Rodolfo Sacco, Filomena Morisco, Eugenio Caturelli, Gianpaolo Vidili, Francesco Azzaroli, Edoardo G. Giannini, Gian Ludovico Rapaccini, Maurizia Rossana Brunetto, Alberto Masotto, Gerardo Nardone, Mariella Di Marco, Donatella Magalotti, Franco Trevisani, Maurizio Biselli, Paolo Caraceni, Annagiulia Gramenzi, Francesco Tovoli, Luca Muratori, Francesca Benevento, Gloria Allegrini, Calogero Cammà, Ciro Celsa, Paolo Giuffrida, Caterina Stornello, Mauro Grova, Carmelo Marco Giacchetto, Gabriele Rancatore, Maria Vittoria Grassini, Valentina Adotti, Stefano Gitto, Fabio Marra, Martina Rosi, Vittoria Bevilacqua, Alberto Borghi, Andrea Casadei Gardini, Fabio Conti, Anna Chiara Dall'Aglio, Giorgio Ercolani, Federica Mirici, Nicoletta de Matthaeis, Francesca Romana Ponziani, Gabriele Missale, Andrea Olivani, Maria Guarino, Valentina Cossiga, Mario Capasso, Ester Marina Cela, Antonio Facciorusso, Valentina Lauria, Giorgia Ghittoni, Giorgio Pelecca, Fabrizio Chegai, Fabio Coratella, Mariano Ortenzi, Serena Dell'Isola, Maria Stella Franzè, Carlo Saitta, Assunta Sauchella, Elton Dajti, Federico Ravaioli, Giulia Pieri, Maria Corina Plaz Torres, Filippo Oliveri, Gabriele Ricco, Veronica Romagnoli, Alessandro Inno, Fabiana Marchetti, Pietro Coccoli, Antonio Malerba, Alberta Cappelli, Rita Golfieri, Cristina Mosconi, null Matteo Renzulli, Stefanini, B., Bucci, L., Santi, V., Reggidori, N., Rampoldi, D., Lani, L., Granito, A., Sangiovanni, A., Cabibbo, G., Farinati, F., Campani, C., Foschi, F. G., Svegliati-Baroni, G., Raimondo, G., Gasbarrini, A., Mega, A., Biasini, E., Sacco, R., Morisco, F., Caturelli, E., Vidili, G., Azzaroli, F., Giannini, E. G., Rapaccini, G. L., Brunetto, M. R., Masotto, A., Nardone, G., Di Marco, M., Magalotti, D., Trevisani, F., Biselli, M., Caraceni, P., Gramenzi, A., Tovoli, F., Muratori, L., Benevento, F., Allegrini, G., Camma, C., Celsa, C., Giuffrida, P., Stornello, C., Grova, M., Giacchetto, C. M., Rancatore, G., Grassini, M. V., Adotti, V., Gitto, S., Marra, F., Rosi, M., Bevilacqua, V., Borghi, A., Gardini, A. C., Conti, F., Dall'Aglio, A. C., Ercolani, G., Mirici, F., de Matthaeis, N., Ponziani, F. R., Missale, G., Olivani, A., Guarino, M., Cossiga, V., Capasso, M., Cela, E. M., Facciorusso, A., Lauria, V., Ghittoni, G., Pelecca, G., Chegai, F., Coratella, F., Ortenzi, M., Dell'Isola, S., Franze, M. S., Saitta, C., Sauchella, A., Dajti, E., Ravaioli, F., Pieri, G., Torres, M. C. P., Oliveri, F., Ricco, G., Romagnoli, V., Inno, A., Marchetti, F., Coccoli, P., Malerba, A., Cappelli, A., Golfieri, R., Mosconi, C., Matteo, Renzulli, Stefanini, Benedetta, Bucci, Laura, Santi, Valentina, Reggidori, Nicola, Rampoldi, Davide, Lani, Lorenzo, Granito, Alessandro, Sangiovanni, Angelo, Cabibbo, Giuseppe, Farinati, Fabio, Campani, Claudia, Foschi, Francesco Giuseppe, Svegliati-Baroni, Gianluca, Raimondo, Giovanni, Gasbarrini, Antonio, Mega, Andrea, Biasini, Elisabetta, Sacco, Rodolfo, Morisco, Filomena, Caturelli, Eugenio, Vidili, Gianpaolo, Azzaroli, Francesco, Giannini, Edoardo G, Rapaccini, Gian Ludovico, Brunetto, Maurizia Rossana, Masotto, Alberto, Nardone, Gerardo, Di Marco, Mariella, Magalotti, Donatella, and Trevisani, Franco

Subjects
Atezolizumab-bevacizumab, Clinical Trials as Topic, Antineoplastic Combined Chemotherapy Protocol, Carcinoma, Hepatocellular, Systemic therapy, Hepatology, Hepatocellular carcinoma, Tirosin-kinase inhibitor, Liver Neoplasms, Gastroenterology, Bevacizumab, Feasibility Studie, Tyrosine, Human
Abstract

Background: The combination of atezolizumab-bevacizumab has been proven to be superior to sorafenib for the treatment of unresectable hepatocellular carcinoma not amenable to locoregional treatments, be-coming the standard of care of systemic therapy.Aim: This study aimed at assessing real-world feasibility of atezolizumab-bevacizumab in patients treated with tyrosine-kinase inhibitors.Methods: Among 1447 patients treated with tyrosine-kinase inhibitors from January 2010 to December 2020, we assessed the percentage of those potentially eligible to atezolizumab-bevacizumab (according to IMbrave-150 trial criteria), and the overall survival of eligible and non-eligible patients.Results: 422 (29%) patients were qualified for atezolizumab-bevacizumab therapy. The main exclusion causes were Child-Pugh class and Performance Status. Adopting the more permissive inclusion criteria of SHARP trial, 535 patients became eligible. The median overall survival of tyrosine-kinase inhibitors patients was 14.9 months, longer in eligible patients than in their counterpart due to better baseline liver function and oncological features.Conclusion: Real-world data indicate that less than one-third of hepatocellular carcinoma patients treated with tyrosine-kinase inhibitors are potentially eligible to atezolizumab-bevacizumab according to the reg-istration trial criteria. These patients have a longer survival than the non-eligible ones. If the selection criteria of atezolizumab-bevacizumab trial are maintained in clinical practice, tyrosine-kinase inhibitors will remain the most used systemic therapy for hepatocellular carcinoma patients.(c) 2022 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Published
2022

24. Predictive factors of inhospital mortality for ICU patients with acute-on-chronic liver failure undergoing liver transplantation

Author

Cristiana Laici, Chiara Guizzardi, Maria Cristina Morelli, Giovanni Vitale, Paolo Caraceni, Matteo Cescon, Matteo Ravaioli, Maria Letizia Bacchi Reggiani, Maurizio Baldassarre, and Antonio Siniscalchi

Subjects
Liver Cirrhosis, Intensive Care Units, Hepatology, Lactates, Gastroenterology, Acute-On-Chronic Liver Failure, Humans, Hospital Mortality, Prognosis, Liver Transplantation, Retrospective Studies
Abstract

Liver transplantation (LT) is the only effective treatment for acute-on-chronic liver failure (ACLF), but it is limited by organ availability. This study aims to identify predictive factors of mortality for LT candidates based on parameters measured at the admission into the ICU.Sixty-four patients diagnosed with ACLF, admitted consecutively into ICU between 2015 and 2019, were retrospectively enrolled in the study. Data were assessed using univariate and multivariate regression analyses to identify risk factors for inhospital mortality and 1-year mortality.A total of 67% of patients were diagnosed with ACLF grade 3, and 25 and 8% with grades 2 and 1. Thirty percent received LT with a 1-year mortality rate of 16%, whereas for nontransplanted patients it reached 90%. Clinical features were compared according to transplant eligibility. In the univariate analysis model, lung failure (HR, 3.01; 95% CI, 1.48-6.09; P = 0.002), high lactate levels (HR, 1.03; 95% CI, 1.02-1.04; P0.001) and CLIF-ACLF score (HR, 1.04; 95% CI, 1.01-1.09; P = 0.026) were independently correlated to increased inhospital mortality. LT reduced mortality risk (HR, 0.16; 95% CI, 0.04-0.72; P = 0.016).Lung failure, CLIF-ACLF score and blood lactate levels at admission were the only statistically significant independent predictors of inhospital mortality, more accurate in determining transplant success than ACLF grade.

Published
2022

26. Untargeted lipidomics uncovers lipid signatures that distinguish severe from moderate forms of acutely decompensated cirrhosis

Author

Maria Vinaixa, Cristina López-Vicario, Vicente Arroyo, Florence Castelli, Jonel Trebicka, Juan José Lozano, Paolo Caraceni, Rajiv Jalan, Ferran Aguilar, Anna Curto, Paolo Angeli, Oscar Yanes, Joan Clària, Ingrid W. Zhang, Benoit Colsch, Christophe Junot, François Fenaille, Richard Moreau, Javier Fernández, Claria J., Curto A., Moreau R., Colsch B., Lopez-Vicario C., Lozano J.J., Aguilar F., Castelli F.A., Fenaille F., Junot C., Zhang I., Vinaixa M., Yanes O., Caraceni P., Trebicka J., Fernandez J., Angeli P., Jalan R., Arroyo V., Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Male, medicine.medical_specialty, Cirrhosis, Fibrosi, Prognosi, Systemic inflammation, Severity of Illness Index, Gastroenterology, or-gan failures, Cohort Studies, chemistry.chemical_compound, Internal medicine, Lipidomics, medicine, Humans, organ failure, Decompensation, Aged, systemic inflammation, Clinical Deterioration, Hepatology, business.industry, decompensated cirrhosi, Lipidomic, Albumin, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Lipid, Middle Aged, Lipidome, Prognosis, medicine.disease, Lipids, Fibrosis, chemistry, Cohort, Cholesteryl ester, Female, Cohort Studie, medicine.symptom, business, decompensated cirrhosis, Human
Abstract

Background & Aims: Acute decompensation (AD) of cirrhosis is a heterogeneous clinical entity associated with moderate mortality. In some patients, this condition develops quickly into the more deadly acute-on-chronic liver failure (ACLF), in which other organs such as the kidneys or brain fail. The aim of this study was to characterize the blood lipidome in a large series of patients with cirrhosis and identify specific signatures associated with AD and ACLF development. Methods: Serum untargeted lipidomics was performed in 561 patients with AD (518 without and 43 with ACLF) (discovery cohort) and in 265 patients with AD (128 without and 137 with ACLF) in whom serum samples were available to perform repeated measurements during the 28-day follow-up (validation cohort). Analyses were also performed in 78 patients with AD included in a therapeutic albumin trial (43 patients with compensated cirrhosis and 29 healthy individuals). Results: The circulating lipid landscape associated with cirrhosis was characterized by a generalized suppression, which was more manifest during AD and in non-surviving patients. By computing discriminating accuracy and the variable importance projection score for each of the 223 annotated lipids, we identified a sphingomyelin fingerprint specific for AD of cirrhosis and a distinct cholesteryl ester and lysophosphatidylcholine finger-print for ACLF. Liver dysfunction and infections were the prin-cipal net contributors to these fingerprints, which were dynamic and interchangeable between patients with AD whose condition worsened to ACLF and those who improved. Notably, blood lysophosphatidylcholine levels increased in these patients after albumin therapy. Conclusions: Our findings provide insights into the lipid land-scape associated with decompensation of cirrhosis and ACLF progression and identify unique non-invasive diagnostic bio-markers of advanced cirrhosis. Lay summary: Analysis of lipids in blood from patients with advanced cirrhosis reveals a general suppression of their levels in the circulation of these patients. A specific group of lipids known as sphingomyelins are useful to distinguish between patients with compensated and decompensated cirrhosis. Another group of lipids designated cholesteryl esters further distinguishes patients with decompensated cirrhosis who are at risk of developing organ failures. (c) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Published
2021

27. Determination of Effective Albumin in Patients With Decompensated Cirrhosis: Clinical and Prognostic Implications

Author

Paolo Caraceni, Anna Baldan, Pierluigi Viale, Katja Waterstradt, Paola Paterini, Marina Naldi, Marco Domenicali, Martina Gagliardi, Michele Bartoletti, Mauro Bernardi, Simona Leoni, Manuel Tufoni, Giacomo Zaccherini, Maurizio Baldassarre, Manuela Bartolini, Agnese Antognoli, Franco Trevisani, Maristella Laggetta, Baldassarre M., Naldi M., Zaccherini G., Bartoletti M., Antognoli A., Laggetta M., Gagliardi M., Tufoni M., Domenicali M., Waterstradt K., Paterini P., Baldan A., Leoni S., Bartolini M., Viale P., Trevisani F., Bernardi M., and Caraceni P.

Subjects
Liver Cirrhosis, Male, 0301 basic medicine, Cirrhosis, Kaplan-Meier Estimate, Severity of Illness Index, Gastroenterology, 0302 clinical medicine, Glycation, biology, Middle Aged, Prognosis, Italy, Biomarker (medicine), Original Article, Protein Structural Elements, Female, 030211 gastroenterology & hepatology, Human, Protein Binding, Spectrometry, Mass, Electrospray Ionization, medicine.medical_specialty, Liver Cirrhosi, Serum albumin, Reproducibility of Result, Serum Albumin, Human, 03 medical and health sciences, Protein Structural Element, Internal medicine, medicine, Humans, Protein Degradation End Product, Decompensation, In patient, Hepatology, business.industry, Albumin, Reproducibility of Results, Acute-On-Chronic Liver Failure, Original Articles, Liver Failure/Cirrhosis/Portal Hypertension, Protein Degradation End Products, Biomarker, Decompensated cirrhosis, medicine.disease, 030104 developmental biology, biology.protein, business, Biomarkers, Chromatography, Liquid
Abstract

Background and Aims: Circulating albumin in cirrhosis can be dysfunctional because of accumulating structural damages, leading to the concept of effective albumin concentration (eAlb), referring to the albumin portion presenting structural and functional integrity. We aimed to estimate eAlb in patients with decompensated cirrhosis and analyze its relationships with albumin function and clinical outcomes as compared to total albumin concentration (tAlb). Approach and Results: We evaluated 319 patients with cirrhosis hospitalized for acute decompensation (AD) with and without acute-on-chronic liver failure (ACLF) and 18 age- and sex-comparable outpatients with compensated cirrhosis. tAlb was quantified by standard assay, whereas eAlb was estimated combining liquid chromatography/electrospray ionization/mass spectrometry and standard methods. Albumin binding and detoxification efficiency were evaluated by electron paramagnetic resonance analysis. Circulating albumin in patients with decompensated cirrhosis displayed multiple structural abnormalities, with reversible oxidation and glycation being the most frequent. As a result, eAlb progressively declined with the worsening of cirrhosis and was superior to tAlb in stratifying patients between compensated cirrhosis, AD, and ACLF, as well as patients with and without complications. Moreover, eAlb, but not tAlb, was closely associated with binding capacities in ACLF. Finally, eAlb at admission predicted the occurrence of ACLF within 30 days and mortality at 90 days better than tAlb. Conclusions: This large, observational study provides the evidence in patients with decompensated cirrhosis that eAlb can be quantified and differentiated from tAlb routinely measured in clinical practice. As compared to tAlb, eAlb is more closely associated with disease severity and albumin dysfunction and carries a greater prognostic power. These results prompt future research assessing eAlb as a biomarker for predicting prognosis and treatment response.

Published
2021

28. Mortality and its association with chronic alcohol-related diseases in patients admitted to the emergency department for acute alcoholic intoxication: retrospective cohort study

Author

Francesco Palmese, Maria Elena Bonavita, Enrico Pompili, Maria Teresa Migliano, Nicola Reggidori, Cecilia Di Stefano, Marta Grieco, Stefano Colazzo, Manuel Tufoni, Maurizio Baldassarre, Paolo Caraceni, Francesco Giuseppe Foschi, Fabrizio Giostra, Gabriele Farina, Rossella Del Toro, Giorgio Bedogni, and Marco Domenicali

Subjects
Emergency Medicine, Internal Medicine
Abstract

We assessed long-term mortality and its association with chronic alcohol-related diseases in patients admitted to the emergency department (ED) because of acute alcoholic intoxication (AAI). A retrospective cohort study was performed at the ED of Sant’Orsola-Malpighi Hospital, Bologna, Italy. 3304 patients, corresponding to 6415 admissions for AAI, who accessed the ED from January 1, 2005, to December 31, 2017, were studied. The ED electronic registry system was used to assess living status on 08 May 2020 and to obtain the prespecified potential predictors, i.e., age at first admission, sex, alcohol use disorder (AUD), substance use disorder (SUD), more than 1 admission to ED for trauma, mental and behavioral disorders, neurological disorders, and cardiovascular disease. The median follow-up time was 9.3 years and the time on risk was 30,053 person years (PY) with a death rate corresponding to 4.42 (95% CI 3.74–5.26) per 1000 PY (n = 133 deaths). The death rate was higher in patients with AUD (17.30) than in those without AUD (1.98) and in those with SUD (13.58) than in those without SUD (3.80). Lastly, there was a clearly higher death rate among AUD+ SUD+ (20.89) compared to AUD–SUD–patients (1.74). At multivariable Cox regression, AUD, SUD, and liver cirrhosis were strong and independent predictors of time-to-death. Using standardized mortality ratios, a clear excess of mortality was evident for all the age bands from (40–45] to (60–65] years. Mortality is higher in AAI than in the general population and chronic alcohol-related diseases are strongly associated with it.

Published
2022

29. Clinical features and evolution of bacterial infection-related acute-on-chronic liver failure

Author

Carlo Alessandria, Carmine Gambino, Javier Fernández, Hans Van Vlierberghe, Sophie Restellini, Marcos Girala, Luis Colombato, Tae Hee Lee, Nikolaos Pyrsopoulos, Eduardo Fassio, Sang Gyune Kim, Gisela Pinero, Paolo Caraceni, Shivaram Prasad Singh, Do Seon Song, Ji Won Park, Julio Vorobioff, Dong Joon Kim, C. Toledo, Aleksander Krag, Liane Rabinowich, Preetam Nath, Robert A. de Man, Elza Cotrim Soares, Xavier Verhelst, Tiago Sevá Pereira, Gustavo Romero, Macarena Simón-Talero, Sung Eun Kim, Michele Bartoletti, Alexander L. Gerbes, Sebastián Marciano, Tony Bruns, Hyoung Su Kim, Ki Tae Suk, Nicolas M. Intagliata, Annette Dam Fialla, Adrià Juanola, Manuela Merli, Rita de Cassia Ribeiro Barea, Laure Elkrief, Rakhi Maiwall, Laurentius A Lesmana, Pere Ginès, Vikas Gautam, E.L. Yoon, M. Marino, Paolo Angeli, Kalyan Ram Bhamidimarri, Victor Vargas, Virendra Singh, Juan Pablo Roblero, François Durand, Cosmas A. Rinaldi Lesmana, M. V. Maevskaya, Gustavo Navarro, Adrian Gadano, Florence Wong, Pramod Kumar, Tae Hun Kim, Daniela Campion, Salvatore Piano, Giacomo Zaccherini, Barbara Lattanz, Jae Seok Hwang, Sun Young Yim, Thomas D. Boyer, Jeong Han Kim, Carlos Brodersen, Wong F., Piano S., Singh V., Bartoletti M., Maiwall R., Alessandria C., Fernandez J., Soares E.C., Kim D.J., Kim S.E., Marino M., Vorobioff J., Barea R.D.C.R., Merli M., Elkrief L., Vargas V., Krag A., Singh S.P., Lesmana L.A., Toledo C., Marciano S., Verhelst X., Intagliata N., Rabinowich L., Colombato L., Kim S.G., Gerbes A., Durand F., Roblero J.P., Bruns T., Yoon E.L., Girala M., Pyrsopoulos N.T., Kim T.H., Yim S.Y., Juanola A., Gadano A., Angeli P., Bhamidimarri K., Boyer T.D., Brodersen C., Campion D., Caraceni P., de Man R.A., Fassio E., Fialla A.D., Gambino C., Gautam V., Gines P., Hwang J.S., Kim H.S., Kim J.H., Kumar P., Lattanz B., Lee T.H., Rinaldi Lesmana C.A., Maevskaya M., Nath P., Navarro G., Park J.-W., Pinero G., Restellini S., Romero G., Seva -Pereira T., Simon-Talero M., Song D.S., Suk K.T., Van Vlierberghe H., and Zaccherini G.

Subjects
Male, 0301 basic medicine, Cirrhosis, Organ Dysfunction Scores, Antibiotic resistance, medicine.medical_treatment, Liver transplantation, Severity of Illness Index, 0302 clinical medicine, ACLF, MDR, Epidemiology, Cross Infection, Mortality rate, Age Factors, Bacterial Infections, Middle Aged, Prognosis, Community-Acquired Infections, Europe, Hospitalization, Female, 030211 gastroenterology & hepatology, Alcohol-Related Disorders, medicine.medical_specialty, Sepsi, India, Risk Assessment, Sepsis, 03 medical and health sciences, Sex Factors, Spontaneous bacterial peritonitis, Internal medicine, medicine, Humans, XDR, Cirrhosi, Hepatology, business.industry, Acute-On-Chronic Liver Failure, medicine.disease, Pneumonia, 030104 developmental biology, antibiotic resistance, liver transplantation, sepsis, business
Abstract

Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p

Published
2021

31. Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)

Author

Emmanuel Weiss, Carlos de la Peña-Ramirez, Ferran Aguilar, Juan-Jose Lozano, Cristina Sánchez-Garrido, Patricia Sierra, Pedro Izquierdo-Bueno Martin, Juan Manuel Diaz, François Fenaille, Florence A Castelli, Thierry Gustot, Wim Laleman, Agustín Albillos, Carlo Alessandria, Marco Domenicali, Paolo Caraceni, Salvatore Piano, Faouzi Saliba, Stefan Zeuzem, Alexander L Gerbes, Julia A Wendon, Christian Jansen, Wenyi Gu, Maria Papp, Raj Mookerjee, Carmine Gabriele Gambino, Cesar Jiménez, Ilaria Giovo, Giacomo Zaccherini, Manuela Merli, Antonella Putignano, Frank Erhard Uschner, Thomas Berg, Tony Bruns, Christian Trautwein, Alexander Zipprich, Rafael Bañares, José Presa, Joan Genesca, Victor Vargas, Javier Fernández, Mauro Bernardi, Paolo Angeli, Rajiv Jalan, Joan Claria, Christophe Junot, Richard Moreau, Jonel Trebicka, and Vicente Arroyo

Subjects
cirrhosis, liver failure, Gastroenterology, liver metabolism
Abstract

Background and aimsCurrent prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models.MethodsTwo prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling.ResultsThree prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality.ConclusionsModels including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.

Published
2023

32. Correction and Prevention of Hyponatremia in Patients With Cirrhosis and Ascites: Post Hoc Analysis of the ANSWER Study Database

Author

Giacomo, Zaccherini, Maurizio, Baldassarre, Manuel, Tufoni, Silvia, Nardelli, Salvatore, Piano, Carlo, Alessandria, Sergio, Neri, Francesco Giuseppe, Foschi, Fabio, Levantesi, Giorgio, Bedogni, Marco, Domenicali, Mauro, Bernardi, and Paolo, Caraceni

Subjects
Hepatology, Gastroenterology
Abstract

We assessed the impact of long-term albumin administration to hyponatremic patients with ascites enrolled in the ANSWER trial.The normalization rate of baseline hyponatremia and the 18-month incidence rate of at least moderate hyponatremia were evaluated.The hyponatremia normalization rate was higher with albumin than with standard medical treatment (45% vs 28%, P = 0.042 at 1 month). Long-term albumin ensured a lower incidence of at least moderate hyponatremia than standard medical treatment (incidence rate ratio: 0.245 [CI 0.167-0.359], P0.001).Long-term albumin administration improves hyponatremia and reduces episodes of at least moderate hyponatremia in outpatients with cirrhosis and ascites.

Published
2022

33. Serious adverse events with tocilizumab: Pharmacovigilance as an aid to prioritize monitoring in COVID‐19

Author

Paolo Caraceni, Michele Fusaroli, Emanuel Raschi, Fabrizio De Ponti, Milo Gatti, Elisabetta Poluzzi, Gatti M., Fusaroli M., Caraceni P., Poluzzi E., De Ponti F., and Raschi E.

Subjects
Male, Databases, Factual, Pulmonary Fibrosis, disproportionality, 030226 pharmacology & pharmacy, Pharmacovigilance, chemistry.chemical_compound, Adverse Event Reporting System, 0302 clinical medicine, Retrospective Studie, Odds Ratio, Medicine, Pharmacology (medical), 030212 general & internal medicine, Aged, 80 and over, Middle Aged, Cytokine release syndrome, Female, Chemical and Drug Induced Liver Injury, Cytokine Release Syndrome, liver injury, Human, United State, Adult, medicine.medical_specialty, Pulmonary Fibrosi, Antibodies, Monoclonal, Humanized, tocilizumab, Young Adult, 03 medical and health sciences, Tocilizumab, Internal medicine, Adverse Drug Reaction Reporting Systems, Humans, Adverse effect, Aged, Monitoring, Physiologic, Retrospective Studies, Pharmacology, Pancreatiti, United States Food and Drug Administration, business.industry, COVID-19, Retrospective cohort study, Odds ratio, medicine.disease, United States, COVID-19 Drug Treatment, Clinical trial, Pancreatitis, chemistry, Adverse Drug Reaction Reporting System, business
Abstract

Given its approval for the treatment of cytokine release syndrome, tocilizumab is under investigation in severe coronavirus disease-2019. To characterize serious adverse events (AEs) with tocilizumab, we queried the worldwide FDA Adverse Event Reporting System and performed disproportionality analysis, selecting only designated medical events (DMEs) where tocilizumab was reported as suspect, with a focus on hepatic reactions. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL 95% CI) > 1. A total of 2,433 reports of DMEs were recorded with tocilizumab, mainly in rheumatic diseases. Statistically significant RORs emerged for 13 DMEs, with drug-induced liver injury (n = 91; LL 95% CI 3.07), pancreatitis (151; 1.41), and pulmonary fibrosis (222; 7.21) as unpredictable AEs. A total of 174 cases of liver-related DMEs were retrieved (proportion of deaths = 18.4%), with median onset of 27.5 days. These serious unpredictable reactions occurring in chronic real-world tocilizumab use may support patient care and monitoring of ongoing clinical trials.

Published
2020

34. Albumin: Indications in chronic liver disease

Author

Paolo Caraceni, Manuel Tufoni, Giacomo Zaccherini, Mauro Bernardi, Tufoni M., Zaccherini G., Caraceni P., and Bernardi M.

Subjects
paracentesi, Liver Cirrhosis, medicine.medical_specialty, Hepatorenal Syndrome, Cirrhosis, Serum Albumin, Human, Peritonitis, Chronic liver disease, Severity of Illness Index, Gastroenterology, Drug Administration Schedule, Liver cirrhosi, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, Spontaneous bacterial peritonitis, Hepatorenal syndrome, Internal medicine, Ascites, Paracentesis, medicine, Humans, Diuretics, Infusions, Intravenous, Review Articles, Aged, medicine.diagnostic_test, business.industry, Albumin, Acute kidney injury, Acute Kidney Injury, medicine.disease, spontaneous bacterial peritonitis, ascite, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, human albumin, Chronic Disease, Female, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract

Albumin is currently employed as a plasma expander to prevent and treat specific complications of cirrhosis with ascites, such as the prevention of paracentesis-induced circulatory dysfunction and renal dysfunction induced by spontaneous bacterial peritonitis, as well as the diagnosis and treatment of acute kidney injury and hepatorenal syndrome. Recently, evidence has shown that long-term albumin administration in patients with decompensated cirrhosis reduces mortality and incidence of complications, eases the management of ascites, is cost effective, and has a good safety profile.

Published
2020

35. Characteristics and survival of patients with primary biliary cholangitis and hepatocellular carcinoma

Author

Edoardo G. Giannini, Giulia Pieri, Sara Labanca, Maria Corina Plaz Torres, Antonio Gasbarrini, Elisabetta Biasini, Claudia Campani, Nora Cazzagon, Francesco Giuseppe Foschi, Andrea Mega, Alberto Masotto, Giovanni Raimondo, Gian Ludovico Rapaccini, Rodolfo Sacco, Eugenio Caturelli, Maria Guarino, Francesco Tovoli, Gianpaolo Vidili, Maurizia Rossana Brunetto, Gerardo Nardone, Gianluca Svegliati-Baroni, Donatella Magalotti, Francesco Azzaroli, Giuseppe Cabibbo, Maria Di Marco, Angelo Sangiovanni, Franco Trevisani, Maurizio Biselli, Paolo Caraceni, Annagiulia Gramenzi, Francesca Benevento, Alessandro Granito, Luca Muratori, Fabio Piscaglia, Federica Bertellini, Fabio Farinati, Giorgio Palano, Filippo Pelizzaro, Barbara Penzo, Elisa Pinto, Gloria Allegrini, Calogero Cammà, Ciro Celsa, Paolo Giuffrida, Caterina Stornello, Mauro Grova, Carmelo Marco Giacchetto, Gabriele Rancatore, Maria Vittoria Grassini, Valentina Adotti, Stefano Gitto, Fabio Marra, Martina Rosi, Vittoria Bevilacqua, Alberto Borghi, Andrea Casadei Gardini, Fabio Conti, Lucia Napoli, Marco Domenicali, Maria Teresa Migliano, Nicoletta de Matthaeis, Francesca Romana Ponziani, Andrea Olivani, Gabriele Missale, Valentina Cossiga, Mario Capasso, Filomena Morisco, Ester Marina Cela, Antonio Facciorusso, Valentina Lauria, Giorgia Ghittoni, Giorgio Pelecca, Fabrizio Chegai, Fabio Coratella, Mariano Ortenzi, Serena Dell'Isola, Maria Stella Franzè, Carlo Saitta, Assunta Sauchella, Elton Dajti, Federico Ravaioli, Filippo Oliveri, Gabriele Ricco, Veronica Romagnoli, Alessandro Inno, Fabiana Marchetti, Pietro Coccoli, Antonio Malerba, Alberta Cappelli, Rita Golfieri, Cristina Mosconi, Matteo Renzulli, Giannini, Edoardo G, Pieri, Giulia, Labanca, Sara, Plaz Torres, Maria Corina, Gasbarrini, Antonio, Biasini, Elisabetta, Campani, Claudia, Cazzagon, Nora, Foschi, Francesco Giuseppe, Mega, Andrea, Masotto, Alberto, Raimondo, Giovanni, Rapaccini, Gian Ludovico, Sacco, Rodolfo, Caturelli, Eugenio, Guarino, Maria, Tovoli, Francesco, Vidili, Gianpaolo, Brunetto, Maurizia Rossana, Nardone, Gerardo, Svegliati-Baroni, Gianluca, Magalotti, Donatella, Azzaroli, Francesco, Cabibbo, Giuseppe, Di Marco, Maria, Sangiovanni, Angelo, Trevisani, Franco, Giannini, E. G., Pieri, G., Labanca, S., Plaz Torres, M. C., Gasbarrini, A., Biasini, E., Campani, C., Cazzagon, N., Foschi, F. G., Mega, A., Masotto, A., Raimondo, G., Rapaccini, G. L., Sacco, R., Caturelli, E., Guarino, M., Tovoli, F., Vidili, G., Brunetto, M. R., Nardone, G., Svegliati-Baroni, G., Magalotti, D., Azzaroli, F., Cabibbo, G., Di Marco, M., Sangiovanni, A., Trevisani, F., Biselli, M., Caraceni, P., Gramenzi, A., Benevento, F., Granito, A., Muratori, L., Piscaglia, F., Bertellini, F., Farinati, F., Palano, G., Pelizzaro, F., Penzo, B., Pinto, E., Allegrini, G., Camma, C., Celsa, C., Giuffrida, P., Stornello, C., Grova, M., Giacchetto, C. M., Rancatore, G., Grassini, M. V., Adotti, V., Gitto, S., Marra, F., Rosi, M., Bevilacqua, V., Borghi, A., Gardini, A. C., Conti, F., Napoli, L., Domenicali, M., Migliano, M. T., de Matthaeis, N., Ponziani, F. R., Olivani, A., Missale, G., Cossiga, V., Capasso, M., Morisco, F., Cela, E. M., Facciorusso, A., Lauria, V., Ghittoni, G., Pelecca, G., Chegai, F., Coratella, F., Ortenzi, M., Dell'Isola, S., Franze, M. S., Saitta, C., Sauchella, A., Dajti, E., Ravaioli, F., Oliveri, F., Ricco, G., Romagnoli, V., Inno, A., Marchetti, F., Coccoli, P., Malerba, A., Cappelli, A., Golfieri, R., Mosconi, C., and Renzulli, M.

Subjects
Male, Carcinoma, Hepatocellular, Cholestatic liver disease, Outcome, Surveillance, Survival, Treatment, Hepatology, Prognosi, Liver Cirrhosis, Biliary, Risk Factor, Settore MED/12 - GASTROENTEROLOGIA, Liver Neoplasms, Gastroenterology, Prognosis, Risk Factors, Humans, Female, Human, Aged
Abstract

Background: Comprehensive and contemporary data pertaining large populations of patients with Primary Biliary Cholangitis (PBC) and hepatocellular carcinoma (HCC) are missing. Aim: To describe main characteristics and outcome of PBC patients with HCC diagnosed in the new millennium. Methods: Analysing the Italian Liver Cancer registry we identified 80 PBC patients with HCC diagnosed after the year 2000, and described their clinical characteristics, access to treatment and survival. Results: Median age of patients was 71 years and 50.0% were males. Cirrhosis was present in 86.3% of patients, being well-compensated in 58.0%. Median HCC diameter was smaller in patients under surveillance (2.6vs 4.0cm, P=0.007). Curative treatment, feasible in 50.0% of patients, was associated with improved survival compared to palliative and supportive care (42vs 33vs 6 months, P

Published
2022

36. Surveillance for hepatocellular carcinoma with a 3-months interval in 'extremely high-risk' patients does not further improve survival

Author

Filippo Pelizzaro, Giulia Peserico, Marco D'Elia, Nora Cazzagon, Francesco Paolo Russo, Alessandro Vitale, Edoardo G. Giannini, Manuela Piccinnu, Gian Ludovico Rapaccini, Maria Di Marco, Eugenio Caturelli, Marco Zoli, Rodolfo Sacco, Giuseppe Cabibbo, Fabio Marra, Andrea Mega, Filomena Morisco, Antonio Gasbarrini, Gianluca Svegliati-Baroni, Francesco Giuseppe Foschi, Andrea Olivani, Alberto Masotto, Gerardo Nardone, Giovanni Raimondo, Francesco Azzaroli, Gianpaolo Vidili, Filippo Oliveri, Franco Trevisani, Fabio Farinati, Maurizio Biselli, Paolo Caraceni, Francesca Garuti, Annagiulia Gramenzi, Andrea Neri, Valentina Santi, Fabio Piscaglia, Francesco Tovoli, Alessandro Granito, Luca Muratori, Francesca Benevento, Elton Dajti, Giovanni Marasco, Federico Ravaioli, Alberta Cappelli, Rita Golfieri, Cristina Mosconi, Matteo Renzulli, Angela Imondi, Anna Sartori, Barbara Penzo, Elisa Pinto, Ester Marina Cela, Antonio Facciorusso, Valentina Cacciato, Edoardo Casagrande, Alessandro Moscatelli, Gaia Pellegatta, Nicoletta De Matthaeis, Gloria Allegrini, Valentina Lauria, Giorgia Ghittoni, Giorgio Pelecca, Fabrizio Chegai, Fabio Coratella, Mariano Ortenzi, Gabriele Missale, Alessandro Inno, Fabiana Marchetti, Anita Busacca, Calogero Cammà, Vincenzo Di Martino, Giacomo Emanuele Maria Rizzo, Maria Stella Franzè, Carlo Saitta, Assunta Sauchella, Vittoria Bevilacqua, Alberto Borghi, Andrea Casadei Gardini, Fabio Conti, Anna Chiara Dall'aglio, Giorgio Ercolani, Federica Mirici, Claudia Campani, Chiara Di Bonaventura, Stefano Gitto, Pietro Coccoli, Antonio Malerba, Maria Guarino, Maurizia Brunetto, Veronica Romagnoli, Pelizzaro, F., Peserico, G., D'Elia, M., Cazzagon, N., Russo, F. P., Vitale, A., Giannini, E. G., Piccinnu, M., Rapaccini, G. L., Di Marco, M., Caturelli, E., Zoli, M., Sacco, R., Cabibbo, G., Marra, F., Mega, A., Morisco, F., Gasbarrini, A., Svegliati-Baroni, G., Foschi, F. G., Olivani, A., Masotto, A., Nardone, G., Raimondo, G., Azzaroli, F., Vidili, G., Oliveri, F., Trevisani, F., Farinati, F., Biselli, M., Caraceni, P., Garuti, F., Gramenzi, A., Neri, A., Santi, V., Piscaglia, F., Tovoli, F., Granito, A., Muratori, L., Benevento, F., Dajti, E., Marasco, G., Ravaioli, F., Cappelli, A., Golfieri, R., Mosconi, C., Renzulli, M., Imondi, A., Sartori, A., Penzo, B., Pinto, E., Cela, E. M., Facciorusso, A., Cacciato, V., Casagrande, E., Moscatelli, A., Pellegatta, G., De Matthaeis, N., Allegrini, G., Lauria, V., Ghittoni, G., Pelecca, G., Chegai, F., Coratella, F., Ortenzi, M., Missale, G., Inno, A., Marchetti, F., Busacca, A., Camma, C., Di Martino, V., Rizzo, G. E. M., Franze, M. S., Saitta, C., Sauchella, A., Bevilacqua, V., Borghi, A., Casadei Gardini, A., Conti, F., Dall'Aglio, A. C., Ercolani, G., Mirici, F., Campani, C., Di Bonaventura, C., Gitto, S., Coccoli, P., Malerba, A., Guarino, M., Brunetto, M., Romagnoli, V., Pelizzaro, Filippo, Peserico, Giulia, D'Elia, Marco, Cazzagon, Nora, Russo, Francesco Paolo, Vitale, Alessandro, Giannini, Edoardo G., Piccinnu, Manuela, Rapaccini, Gian Ludovico, Di Marco, Maria, Caturelli, Eugenio, Zoli, Marco, Sacco, Rodolfo, Cabibbo, Giuseppe, Marra, Fabio, Mega, Andrea, Morisco, Filomena, Gasbarrini, Antonio, Svegliati-Baroni, Gianluca, Foschi, Francesco Giuseppe, Olivani, Andrea, Masotto, Alberto, Nardone, Gerardo, Raimondo, Giovanni, Azzaroli, Francesco, Vidili, Gianpaolo, Oliveri, Filippo, Trevisani, Franco, Farinati, Fabio, Biselli, Maurizio, Caraceni, Paolo, Garuti, Francesca, Gramenzi, Annagiulia, Neri, Andrea, Santi, Valentina, Piscaglia, Fabio, Tovoli, Francesco, Granito, Alessandro, Muratori, Luca, Benevento, Francesca, Dajti, Elton, Marasco, Giovanni, Ravaioli, Federico, Cappelli, Alberta, Golfieri, Rita, Mosconi, Cristina, Renzulli, Matteo, Imondi, Angela, Sartori, Anna, Penzo, Barbara, Pinto, Elisa, Cela, Ester Marina, Facciorusso, Antonio, Cacciato, Valentina, Casagrande, Edoardo, Moscatelli, Alessandro, Pellegatta, Gaia, De Matthaeis, Nicoletta, Allegrini, Gloria, Lauria, Valentina, Ghittoni, Giorgia, Pelecca, Giorgio, Chegai, Fabrizio, Coratella, Fabio, Ortenzi, Mariano, Missale, Gabriele, Inno, Alessandro, Marchetti, Fabiana, Busacca, Anita, Cammà, Calogero, Di Martino, Vincenzo, Rizzo, Giacomo Emanuele Maria, Franzè, Maria Stella, Saitta, Carlo, Sauchella, Assunta, Bevilacqua, Vittoria, Borghi, Alberto, Casadei Gardini, Andrea, Conti, Fabio, Dall'aglio, Anna Chiara, Ercolani, Giorgio, Mirici, Federica, Campani, Claudia, Di Bonaventura, Chiara, Gitto, Stefano, Coccoli, Pietro, Malerba, Antonio, Guarino, Maria, Brunetto, Maurizia, and Romagnoli, Veronica

Subjects
medicine.medical_specialty, Carcinoma, Hepatocellular, Survival, Hepatocellular carcinoma, Cancer stage, Surveillance interval, Internal medicine, medicine, Humans, Propensity Score, Survival analysis, High risk patients, Hepatology, business.industry, Liver Neoplasms, Settore MED/09 - MEDICINA INTERNA, Gastroenterology, Patient survival, medicine.disease, Survival Analysis, Propensity score matching, Survival Analysi, Liver cancer, business, Median survival, Human
Abstract

Background An enhanced surveillance schedule has been proposed for cirrhotics with viral etiology, who are considered at extremely high-risk of hepatocellular carcinoma (HCC). Aims We compared the 3- and 6-months surveillance interval, evaluating cancer stage at diagnosis and patient survival. Methods Data of 777 HBV and HCV cirrhotic patients with HCC diagnosed under a 3-months (n = 109, 3MS group) or a 6-months (n = 668, 6MS group) surveillance were retrieved from the Italian Liver Cancer database. Survival in the 3MS group was considered as observed and adjusted for lead-time bias, and survival analysis was repeated after a propensity score matching. Results The 3-months surveillance interval neither reduced the share of patients diagnosed outside the Milano criteria, nor increased their probability to receive curative treatments. The median survival of 6MS patients (55.0 months [45.9–64.0]) was not significantly different from the observed (47.0 months [35.0–58.9]; p = 0.43) and adjusted (44.9 months [33.4–56.4]; p = 0.30) survival of 3MS patients. A propensity score analysis confirmed the absence of a survival advantage for 3MS patients. Conclusions A tightening of surveillance schedule does not increase the diagnosis of early-stage tumors, the feasibility of curative treatments and the survival. Therefore, we should maintain the 6-months interval in the surveillance of viral cirrhotics.

Published
2022

37. Management of Ascites in Patients with Cirrhosis: An Update

Author

Manuel Tufoni, Paolo Caraceni, Giacomo Zaccherini, Giulia Iannone, Zaccherini G., Tufoni M., Iannone G., and Caraceni P.

Subjects
medicine.medical_specialty, Cirrhosis, Anti-mineralocorticoid, Disease, Review, anti-mineralocorticoids, Decompensated cirrhosi, effective hypovolemia, Hypovolemia, Ascites, medicine, Paracentesis, Loop diuretic, Adverse effect, Intensive care medicine, medicine.diagnostic_test, business.industry, loop diuretics, portal hypertension, General Medicine, medicine.disease, human albumin, Portal hypertension, TIPS, Medicine, vaptans, Portosystemic shunt, medicine.symptom, business, decompensated cirrhosis
Abstract

Ascites represents a critical event in the natural history of liver cirrhosis. From a prognostic perspective, its occurrence marks the transition from the compensated to the decompensated stage of the disease, leading to an abrupt worsening of patients’ life expectancy. Moreover, ascites heralds a turbulent clinical course, characterized by acute events and further complications, frequent hospitalizations, and eventually death. The pathophysiology of ascites classically relies on hemodynamic mechanisms, with effective hypovolemia as the pivotal event. Recent discoveries, however, integrated this hypothesis, proposing systemic inflammation and immune system dysregulation as key mechanisms. The mainstays of ascites treatment are represented by anti-mineralocorticoids and loop diuretics, and large volume paracentesis. When ascites reaches the stage of refractoriness, however, diuretics administration should be cautious due to the high risk of adverse events, and patients should be treated with periodic execution of paracentesis or with the placement of a trans-jugular intra-hepatic portosystemic shunt (TIPS). TIPS reduces portal hypertension, eases ascites control, and potentially modify the clinical course of the disease. Further studies are required to expand its indications and improve the management of complications. Long-term human albumin administration has been studied in two RCTs, with contradictory results, and remains a debated issue worldwide, despite a potential effectiveness both in ascites control and long-term survival. Other treatments (vaptans, vasoconstrictors, or implantable drainage systems) present some promising aspects but cannot be currently recommended outside clinical protocols or a case-by-case evaluation.

Published
2021

38. Patients with chronic HCV and decompensated cirrhosis are at risk for MELD purgatory

Author

Lisette Krassenburg, Grishma Hirode, Hooman Farhang Zangneh, Raoel Maan, Alnoor Ramji, Michael P. Manns, Heiner Wedemeyer, Markus Cornberg, Robert De Knegt, Kosh Agarwal, Zillah Cargill, Gonzalo Crespo, Giuseppina Brancaccio, Maria Cristina Morelli, Ilaria Lenci, Chiara Mazzarelli, Paolo Angeli, Patrizia Burra, Gabriella Verucchi, Maria Francesca Donato, Paola Carrai, Silvia Martini, Paolo Caraceni, Francesco Paolo Russo, Robert De Man, Harry Janssen, Bettina Hansen, Adriaan Van der Meer, and Jordan Feld

Subjects
Hepatology
Published
2022

39. Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium

Author

E. Palacio, Koos de Wit, Daniela Campion, Salvatore Piano, Elisa Pose, T. Lanzillotti, Carlos Jiménez, Sara Montagnese, Patrick S. Kamath, Rajeshwar P. Mookerjee, Miquel Gómez i Serra, Ruben Hernaez, M. Aban, Marta Carol, G. Nicolao, Claire Francoz, Giacomo Zaccherini, Hugh Watson, Isabel Graupera, M.T. Chiappa, Jonel Trebicka, Macarena Simón-Talero, Frank Erhard Uschner, Cristina Solé, Alejandro Forner, Ulrich Beuers, F. Durand, Paolo Caraceni, Victor Vargas, Marta Cervera, Carlo Alessandria, Adrià Juanola, V. Esnault, Jeltje Helder, Marko Korenjak, Olivier Roux, Laura Napoleone, Ferran Torres, S. Graf-Dirmeier, Judit Pich, Ann T. Ma, Maria Martha Bernardi, M. Pérez-Guasch, Núria Fabrellas, Pere Ginès, Maricela Quintana López, Elsa Solà, Emma Avitabile, Aleksander Krag, Juan G. Abraldes, Gastroenterology and Hepatology, Graduate School, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Elsa Solà, Elisa Pose, Daniela Campion, Salvatore Piano, Olivier Roux, Macarena Simon-Talero, Frank Uschner, Koos de Wit, Giacomo Zaccherini, Carlo Alessandria, Ulrich Beuers, Paolo Caraceni, Claire Francoz, Rajeshwar P. Mookerjee, Jonel Trebicka, Victor Vargas, Miquel Serra, Ferran Torres, Sara Montagnese, Aleksander Krag, Ruben Hernaez, Marko Korenjak, Hugh Watson, Juan G. Abraldes, Patrick S. Kamath, Pere Ginès, LiverHope Consortium Investigators, Institut Català de la Salut, [Solà E, Pose E] Liver Unit, Hospital Clínic De Barcelona, Barcelona, School of Medicine and Health Sciences University of Barcelona, Spain. Institut d´Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain. [Campion D] Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Turin, Italy. [Piano S] Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine - DIMED, University of Padova, Padova, Italy. [Roux O] Hepatology and Liver Intensive Care Unit, Hospital Beaujon, APHP, Clichy, France. [Simon-Talero M] Unitat del Fetge, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Liver Cirrhosis, 0301 basic medicine, Cirrhosis, administración de los servicios de salud::gestión de la atención al paciente::tratamiento de las enfermedades [ATENCIÓN DE SALUD], enfermedades del sistema digestivo::enfermedades hepáticas::cirrosis hepática [ENFERMEDADES], Digestive System Diseases::Liver Diseases::Liver Cirrhosis [DISEASES], Trasplantament hepàtic, Disease, Severity of Illness Index, 0302 clinical medicine, Clinical trials, Quality of life, ACLF, Ascites, Secondary Prevention, Liver transplant, Otros calificadores::/terapia [Otros calificadores], Hepatic encephalopathy, Clinical Trials as Topic, education.field_of_study, Disease Management, 3. Good health, Clinical trial, Europe, Natural history, Hepatic cirrhosis, Research Design, Qualitat de vida, Ascite, Disease Progression, 030211 gastroenterology & hepatology, AKI, ascites, cirrhosis, clinical trials, endpoints, hepatic encephalopathy, hyponatremia, infections, liver transplant, quality of life, medicine.symptom, Infection, Hyponatremia, técnicas de investigación::métodos::diseño de la investigación [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], medicine.medical_specialty, Consensus, Cirrosi hepàtica, Endpoint Determination, Population, Infections, 03 medical and health sciences, Investigative Techniques::Methods::Research Design [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Hypertension, Portal, medicine, Humans, Intensive care medicine, education, Health Services Administration::Patient Care Management::Disease Management [HEALTH CARE], Cirrosi hepàtica - Tractament, Cirrhosi, Hepatology, business.industry, Other subheadings::/therapy [Other subheadings], Endpoint, medicine.disease, Assaigs clínics - Disseny, 030104 developmental biology, Etiology, Endpoints, business, Hepatic transplantation
Abstract

Clinical trials; Liver transplant; Quality of life Ensayos clínicos; Trasplante de hígado; Calidad de vida Assaigs clínics; Trasplantament de fetge; Qualitat de vida 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.

Published
2021

40. Assessing the role of amino acids in systemic inflammation and organ failure in patients with {ACLF}

Author

Juan José Lozano, Paolo Caraceni, Ferran Aguilar, Anna Curto, Joan Clària, Giacomo Zaccherini, Florence Castelli, Chiara Formentin, Richard Moreau, Paolo Angeli, Vicente Arroyo, François Fenaille, Mauro Bernardi, Christophe Junot, E. Weiss, Rajiv Jalan, Giacomo Zaccherini, Ferran Aguilar, Paolo Caraceni, Joan Cl{`{a}}ria, Juan Jos{'{e}} Lozano, Fran{c{c}}ois Fenaille, Florence Castelli, Christophe Junot, Anna Curto, Chiara Formentin, Emmanuel Wei, Mauro Bernardi, Rajiv Jalan, Paolo Angeli, Richard Moreau, Vicente Arroyo, Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Liver Cirrhosis, Male, Multiple Organ Failure, Transsulfuration pathway, Pharmacology, Systemic inflammation, Severity of Illness Index, Anabolic metabolism, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Bioma, Biomass, Dormancy, Immunity, Multiorgan failure, Small-molecules, Metabolome, medicine, Humans, Amino Acids, chemistry.chemical_classification, Inflammation, Methionine, Hepatology, biology, Catabolism, Acute-On-Chronic Liver Failure, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Metabolism, Middle Aged, Prognosis, Cystathionine beta synthase, Amino acid, 030104 developmental biology, chemistry, Protein Biosynthesis, biology.protein, 030211 gastroenterology & hepatology, Female, medicine.symptom, Biomarkers, Metabolic Networks and Pathways
Abstract

Background & Aims Systemic inflammation and organ failure(s) are the hallmarks of acute-on-chronic liver failure (ACLF), yet their pathogenesis remains uncertain. Herein, we aimed to assess the role of amino acids in these processes in patients with ACLF. Methods The blood metabolomic database of the CANONIC study (comprising 137 metabolites, with 43% related to amino acids) – obtained in 181 patients with ACLF and 650 with acute decompensation without ACLF (AD) – was reanalyzed with a focus on amino acids, in particular 9 modules of co-regulated metabolites. We also compared blood metabolite levels between ACLF and AD. Results The main findings in ACLF were: i) Metabolite modules were increased in parallel with increased levels of markers of systemic inflammation and oxidative stress. ii) Seventy percent of proteinogenic amino acids were present and most were increased. iii) A metabolic network, comprising the amino acids aspartate, glutamate, the serine-glycine one-carbon metabolism (folate cycle), and methionine cycle, was activated, suggesting increased purine and pyrimidine nucleotide synthesis. iv) Cystathionine, L-cystine, glutamate and pyroglutamate, which are involved in the transsulfuration pathway (a methionine cycle branch) were increased, consistent with increased synthesis of the antioxidant glutathione. v) Intermediates of the catabolism of 5 out of the 6 ketogenic amino acids were increased. vi) The levels of spermidine (a polyamine inducer of autophagy with anti-inflammatory effects) were decreased. Conclusions In ACLF, blood amino acids fueled protein and nucleotide synthesis required for the intense systemic inflammatory response. Ketogenic amino acids were extensively catabolized to produce energy substrates in peripheral organs, an effect that was insufficient because organs failed. Finally, the decrease in spermidine levels may cause a defect in autophagy contributing to the proinflammatory phenotype in ACLF. Lay summary Systemic inflammation and organ failures are hallmarks of acute-on-chronic liver failure (ACLF). Herein, we aimed to characterize the role of amino acids in these processes. The blood metabolome of patients with acutely decompensated cirrhosis, and particularly those with ACLF, reveals evidence of intense skeletal muscle catabolism. Importantly, amino acids (along with glucose), are used for intense anabolic, energy-consuming metabolism in patients with ACLF, presumably to support de novo nucleotide and protein synthesis in the activated innate immune system.

Published
2021

42. Author Correction: Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors: First Italian Clinical Trial

Author

Deborah Malvi, Antonietta D'Errico, Federica Odaldi, Massimo Del Gaudio, Lorenzo Maroni, Andrea Angeletti, Maria Cristina Morelli, Giorgia Comai, Maurizio Baldassarre, Vito Marco Ranieri, Giuliana Germinario, Antonio Daniele Pinna, Guido Fallani, Matteo Ravaioli, Gaetano La Manna, Matteo Cescon, Francesco Vasuri, Chiara Donadei, Valentina Rosa Bertuzzo, Paolo Caraceni, Antonio Siniscalchi, Vanessa De Pace, and Gianandrea Pasquinelli

Subjects
Male, medicine.medical_specialty, lcsh:Medicine, Kidney, Extended criteria, Humans, Medicine, Aspartate Aminotransferases, Author Correction, lcsh:Science, Infusion Pumps, Aged, Oxygenators, Membrane, Machine perfusion, Multidisciplinary, business.industry, Liver and kidney, Graft Survival, lcsh:R, Organ Preservation, Middle Aged, Kidney Transplantation, Tissue Donors, Liver Transplantation, Surgery, Cold Temperature, Perfusion, Clinical trial, Transplantation, Liver, Female, lcsh:Q, business
Abstract

With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of liver (LT) and kidney transplantation (KT) from Extended Criteria Donors (ECD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (SCS-L and SCS-K). HOPE and SCS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in SCS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary non-function was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in KT and in LT.

Published
2020

43. Low Adherence To Nutritional Recommendations In Patients With Cirrhosis: A Prospective Observational Study

Author

Manuel Tufoni, Ilaria Bolondi, Francesco Palmese, Sonia Berardi, Ferdinando Giannone, Giacomo Zaccherini, Maurizio Baldassarre, Silvia Boffelli, Paolo Caraceni, and Franco Trevisani

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Gastroenterology, medicine, Observational study, Inadequate food intake, medicine.disease, Intensive care medicine, business
Published
2019

44. Pro: The Role of Albumin in Pre–Liver Transplant Management

Author

Giacomo Zaccherini, Mauro Bernardi, Paolo Caraceni, Bernardi, Mauro, Zaccherini, Giacomo, and Caraceni, Paolo

Subjects
Liver Cirrhosis, medicine.medical_specialty, Cirrhosis, Waiting Lists, medicine.medical_treatment, Serum albumin, Serum Albumin, Human, Disease, 030230 surgery, Liver transplantation, Gastroenterology, Antioxidants, Drug Administration Schedule, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Immunologic Factors, Medicine, Transplantation, Hepatology, biology, business.industry, Incidence (epidemiology), Albumin, medicine.disease, Pathophysiology, Liver Transplantation, Treatment Outcome, Practice Guidelines as Topic, biology.protein, 030211 gastroenterology & hepatology, Surgery, business
Abstract

The wait-list mortality of patients with decompensated cirrhosis awaiting liver transplantation remains elevated due to the occurrence of complications. Etiologic treatments improve patient survival and lower the incidence of complications when applied in compensated cirrhosis, but a decompensated disease does not improve or even progress despite a response to therapy in a substantial number of patients. Thus, disease-modifying treatments that reduce the incidence of complications and improve survival are most needed. Such treatments should be able to counteract one or possibly more pathophysiological mechanisms and thus lead to the proinflammatory and pro-oxidant milieu that characterizes decompensated cirrhosis. In this respect, albumin represents a potentially ideal agent. In fact, besides its ability to expand plasma volume, albumin possesses nononcotic properties, exerting potent antioxidant and immune-modulating effects. Recent studies have assessed the effect of longterm albumin administration in decompensated cirrhosis. Although the results of these studies may appear conflicting, their analyses suggest that albumin, if given in a sufficient amount and for a sufficient duration, can significantly reduce the incidence of life-threatening complications of cirrhosis and patient mortality. For these reasons, we favor albumin administration to patients with decompensated cirrhosis wait-listed for liver transplantation.

Published
2019

47. PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis

Author

William Bernal, Agustín Albillos, Alex Amoros, Wim Laleman, Michael Manns, Javier Martínez, Maximilian J. Brol, Pere Ginès, Alessandra Pohlmann, Joerg Tobiasch Moritz, Francois Smits, Elisabet Garcia-Lopez, Joan Clària, Jennifer Lehmann, Jonel Trebicka, Christoph Welsch, Vicente Arroyo, Richard Moreau, Tony Bruns, Monica Mesquita, Christian Jansen, Peter Jarcuska, Harald Rupprechter, Martin Janicko, Thierry Gustot, Macarena Simón-Talero, Giacomo Zaccherini, Cristina Ripoll, Luise Aamann, Oliviero Riggio, Martina Rizzo, Karen Vagner Danielsen, Javier Romaní Fernández, Jelte J Schaapman, Frank Erhard Uschner, Juan Acevedo, Miguel Á. Rodríguez, David Semela, Carlo Alessandria, Carmine Gambino, Lise Lotte Gluud, Paolo Caraceni, Emanuela Ciraci, István Altorjay, Cristina Solé, Salvatore Piano, Minneke J. Coenraad, Pierre Nahon, Haluk Tarik Kani, Faouzi Saliba, Agnese Antognoli, Andrea De Gottardi, Osman Ozdogan, Henning Grønbæk, Christian J. Steib, Anna Curto, Hans Van Vlierberghe, Manuel Romero-Gómez, T.M. Welzel, Roland Amathieu, Sylvie Tresson, Carla Pitarch, Frederik Nevens, Alexander Zipprich, Christian Trautwein, Ilaria Giovo, Victor Vargas, Laure Elkrief, Giorgio Maria Saracco, Johannes Chang, Mattias Mandorfer, Paul Horn, Thomas Berg, Nesrine Amari, Sara Mareso, Heinz Zoller, Osagie Akpata, Mária Papp, Adam Herber, Thomas Reiberger, Flemming Bendtsen, Elsa Solà, Ferran Aguilar, Jose Presa Ramos, Miriam Maschmeier, Tamas Tornai, Manuela Merli, Rajiv Jalan, Martina Gagliardi, Cornelius Engelmann, Rafael Bañares, Daniela Campion, Antonella Putignano, Natalie Van den Ende, Claire Francoz, Marco Pavesi, Paola Ponzo, Rita Garcia, Sven Francque, Vish Patel, Esau Moreno, Alessandra Brocca, Rudolf E. Stauber, Zsuzsanna Vitális, Rajeshwar P. Mookerjee, Ahmed Elsharkawy, Eleonora Bertoli, Michael Praktiknjo, Stephen D. Ryder, Cristina Sanchez, Boglarka Balogh, Debbie L. Shawcross, Manuel Tufoni, Paolo Angeli, Florian Rainer, Pavel Strnad, István Tornai, Edilmar Alvarado-Tapias, Alexander L. Gerbes, Didier Samuel, Maurizio Baldassarre, Cesar Jimenez, Stefan Zeuzem, Pietro Gatti, Germán Soriano, Robert Schierwagen, Ana Clemente, Mauro Bernardi, Daniel Markwardt, Trebicka, Jonel, Fernandez, Javier, Papp, Maria, Caraceni, Paolo, Laleman, Wim, Gambino, Carmine, Giovo, Ilaria, Uschner, Frank Erhard, Jansen, Christian, Jimenez, Cesar, Mookerjee, Rajeshwar, Gustot, Thierry, Albillos, Agustin, Bañares, Rafael, Jarcuska, Peter, Steib, Christian, Reiberger, Thoma, Acevedo, Juan, Gatti, Pietro, Shawcross, Debbie L, Zeuzem, Stefan, Zipprich, Alexander, Piano, Salvatore, Berg, Thoma, Bruns, Tony, Danielsen, Karen Vagner, Coenraad, Minneke, Merli, Manuela, Stauber, Rudolf, Zoller, Heinz, Ramos, José Presa, Solé, Cristina, Soriano, Germán, de Gottardi, Andrea, Gronbaek, Henning, Saliba, Faouzi, Trautwein, Christian, Kani, Haluk Tarik, Francque, Sven, Ryder, Stephen, Nahon, Pierre, Romero-Gomez, Manuel, Van Vlierberghe, Han, Francoz, Claire, Manns, Michael, Garcia-Lopez, Elisabet, Tufoni, Manuel, Amoros, Alex, Pavesi, Marco, Sanchez, Cristina, Praktiknjo, Michael, Curto, Anna, Pitarch, Carla, Putignano, Antonella, Moreno, Esau, Bernal, William, Aguilar, Ferran, Clària, Joan, Ponzo, Paola, Vitalis, Zsuzsanna, Zaccherini, Giacomo, Balogh, Boglarka, Gerbes, Alexander, Vargas, Victor, Alessandria, Carlo, Bernardi, Mauro, Ginès, Pere, Moreau, Richard, Angeli, Paolo, Jalan, Rajiv, Arroyo, Vicente, Banares, Rafael, Reiberger, Thomas, Shawcross, Debbie L., Berg, Thomas, Ramos, Jose Presa, Sole, Cristina, Soriano, German, Van Vlierberghe, Hans, Claria, Joan, Gines, Pere, Maschmeier, Miriam, Semela, David, Elkrief, Laure, Elsharkawy, Ahmed, Tornai, Tamas, Tornai, Istvan, Altorjay, Istvan, Antognoli, Agnese, Baldassarre, Maurizio, Gagliardi, Martina, Bertoli, Eleonora, Mareso, Sara, Brocca, Alessandra, Campion, Daniela, Saracco, Giorgio Maria, Rizzo, Martina, Lehmann, Jennifer, Pohlmann, Alessandra, Brol, Maximilian J., Chang, Johannes, Schierwagen, Robert, Sola, Elsa, Amari, Nesrine, Rodriguez, Miguel, Nevens, Frederik, Clemente, Ana, Janicko, Martin, Markwardt, Daniel, Mandorfer, Mattias, Welsch, Christoph, Welzel, Tanja M., Ciraci, Emanuela, Patel, Vish, Ripoll, Cristina, Herber, Adam, Horn, Paul, Bendtsen, Flemming, Gluud, Lise Lotte, Schaapman, Jelte, Riggio, Oliviero, Rainer, Florian, Moritz, Joerg Tobiasch, Mesquita, Monica, Alvarado-Tapias, Edilmar, Akpata, Osagie, Aamann, Luise, Samuel, Didier, Tresson, Sylvie, Strnad, Pavel, Amathieu, Roland, Simon-Talero, Macarena, Smits, Francois, van den Ende, Natalie, Martinez, Javier, Garcia, Rita, Rupprechter, Harald, Engelmann, Cornelius, and Ozdogan, Osman Cavit

Subjects
0301 basic medicine, Liver Cirrhosis, Male, Cirrhosis, Organ Dysfunction Scores, acute complication, Chronic liver disease, Acute complications, Non-elective admission, Outcome, Risk factors, 0302 clinical medicine, Preventive Health Services, Medicine and Health Sciences, Gastro-entérologie, risk factors, 610 Medicine & health, Medical History Taking, factors, Toxic encephalopathy, Bacterial Infections, Middle Aged, Prognosis, Europe, Cohort, Disease Progression, outcome, 030211 gastroenterology & hepatology, Female, medicine.symptom, Needs Assessment, Risk, medicine.medical_specialty, Alcoholic hepatitis, 03 medical and health sciences, Internal medicine, medicine, Humans, Decompensation, Medical history, Inflammation, Hepatology, business.industry, Hepatitis, Alcoholic, Organ dysfunction, Acute-On-Chronic Liver Failure, chronic liver disease, medicine.disease, Precipitating Factors, 030104 developmental biology, Human medicine, business, non-elective admission
Abstract

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., info:eu-repo/semantics/published

Published
2021

48. Clinical features and comorbidity pattern of HCV infected migrants compared to native patients in care in Italy: A real-life evaluation of the PITER cohort

Author

Maria Giovanna Quaranta, Luigina Ferrigno, Xhimi Tata, Franca D'Angelo, Marco Massari, Carmine Coppola, Elisa Biliotti, Alessia Giorgini, Diletta Laccabue, Alessia Ciancio, Pier Luigi Blanc, Marzia Margotti, Donatella Ieluzzi, Maurizia Rossana Brunetto, Francesco Barbaro, Francesco Paolo Russo, Ilaria Beretta, Giulia Morsica, Gabriella Verucchi, Annalisa Saracino, Massimo Galli, Loeta A. Kondili, Cesare Mazzaro, Manuela Bertola, Ornella Schioppa, Antonio Benedetti, Laura Schiadà, Monica Cucco, Andrea Giacometti, Laura Brescini, Sefora Castelletti, Alessandro Fiorentini, Gioacchino Angarano, Michele Milella, Alfredo Di Leo, Maria Rendina, Fulvio Salvatore D'abramo, Chiara Lillo, Andrea Iannone, Mariano Piazzolla, Lorenzo Badia, Fabio Piscaglia, Francesca Benevento, Ilaria Serio, Francesco Castelli, Serena Zaltron, Angiola Spinetti, Silvia Odolini, Raffaele Bruno, Mario Mondelli, Luchino Chessa, Martina Loi, Carlo Torti, Chiara Costa, Maria Mazzitelli, Vincenzo Pisani, Vincenzo Scaglione, Enrico Maria Trecarichi, Anna Linda Zignego, Monica Monti, Francesco Madia, Letizia Attala, Piera Pierotti, Elena Salomoni, Elisa Mariabelli, Teresa Antonia Santantonio, Serena Rita Bruno, Ester Marina Cela, Matteo Bassetti, Giovanni Mazzarello, Anna Ida Alessandrini, Antonio Di Biagio, Laura Ambra Nicolini, Giovanni Raimondo, Roberto Filomia, Alessio Aghemo, Rossella Meli, Adriano Lazzarin, Stefania Salpietro, Anna Ludovica Fracanzani, Erika Fatta, Rosa Lombardi, Pietro Lampertico, Marta Borghi, Roberta D'ambrosio, Elisabetta Degasperi, Massimo Puoti, Chiara Baiguera, Federico D'amico, Maria Vinci, Maria Grazia Rumi, Massimo Zuin, Paola Zermiani, Pietro Andreone, Paolo Caraceni, Valeria Guarneri, Erica Villa, Veronica Bernabucci, Laura Bristot, Maria Luisa Paradiso, Guglielmo Migliorino, Alessandra Gambaro, Giuseppe Lapadula, Anna Spolti, Alessandro Soria, Pietro Invernizzi, Antonio Ciaccio, Martina LucÀ, Federica Malinverno, Laura Ratti, Daniela Caterina Amoruso, Federica Pisano, Ferdinando Scarano, Laura Staiano, Filomena Morisco, Valentina Cossiga, Ivan Gentile, Antonio Riccardo Buonomo, Maria Foggia, Emanuela Zappulo, Alessandro Federico, Marcello Dallio, Nicola Coppola, Caterina Sagnelli, Salvatore Martini, Caterina Monari, Gerardo Nardone, Costantino Sgamato, Liliana Chemello, Luisa Cavalletto, Daniela Sterrantino, Alberto Zanetto, Paola Zanaga, Giuseppina Brancaccio, Antonio Craxì, Salvatore Petta, Vincenza Calvaruso, Luciano Crapanzano, Salvatore Madonia, Marco Cannizzaro, Erica Maria Bruno, Anna Licata, Simona Amodeo, Adele Rosaria Capitano, Carlo Ferrari, Elisa Negri, Alessandra Orlandini, Marco Pesci, Roberto Gulminetti, Layla Pagnucco, Giustino Parruti, Paola Di Stefano, Barbara Coco, Romina Corsini, Elisa Garlassi, Massimo Andreoni, Elisabetta Teti, Carlotta Cerva, Lorenzo Baiocchi, Giuseppe Grassi, Antonio Gasbarrini, Maurizio Pompili, Martina De Siena, Gloria Taliani, Martina Spaziante, Marcello Persico, Mario Masarone, Andrea Aglitti, Gemma Calvanese, Marco Anselmo, Pasqualina De Leo, Monica Marturano, Giorgio Maria Saracco, Quaranta M.G., Ferrigno L., Tata X., D'Angelo F., Massari M., Coppola C., Biliotti E., Giorgini A., Laccabue D., Ciancio A., Blanc P.L., Margotti M., Ieluzzi D., Brunetto M.R., Barbaro F., Russo F.P., Beretta I., Morsica G., Verucchi G., Saracino A., Galli M., Kondili L.A., Mazzaro C., Bertola M., Benedetti A., Schiada L., Cucco M., Giacometti A., Brescini L., Castelletti S., Fiorentini A., Angarano G., Milella M., Leo A.D., Rendina M., Salvatore D'ABRAMO F., Lillo C., Iannone A., Piazzolla M., Badia L., Piscaglia F., Benevento F., Serio I., Castelli F., Zaltron S., Spinetti A., Odolini S., Bruno R., Mondelli M., Chessa L., Loi M., Torti C., Costa C., Mazzitelli M., Pisani V., Scaglione V., Trecarichi E.M., Zignego A.L., Monti M., Madia F., Attala L., Pierotti P., Salomoni E., Mariabelli E., Santantonio T.A., Bruno S.R., Cela E.M., Bassetti M., Mazzarello G., Alessandrini A.I., Biagio A.D., Nicolini L.A., Raimondo G., Filomia R., Aghemo A., Meli R., Lazzarin A., Salpietro S., Fracanzani A.L., Fatta E., Lombardi R., Lampertico P., Borghi M., D'ambrosio R., Degasperi E., Puoti M., Baiguera C., D'AMICO F., Vinci M., Rumi M.G., Zuin M., Zermiani P., Andreone P., Caraceni P., Guarneri V., Villa E., Bernabucci V., Bristot L., Paradiso M.L., Migliorino G., Gambaro A., Lapadula G., Spolti A., Soria A., Invernizzi P., Ciaccio A., LucA M., Malinverno F., Ratti L., Amoruso D.C., Pisano F., Scarano F., Staiano L., Morisco F., Cossiga V., Gentile I., Buonomo A.R., Foggia M., Zappulo E., Federico A., Dallio M., Coppola N., Sagnelli C., Martini S., Monari C., Nardone G., Sgamato C., Chemello L., Cavalletto L., Sterrantino D., Zanetto A., Zanaga P., Brancaccio G., Craxi A., Petta S., Calvaruso V., Crapanzano L., Madonia S., Cannizzaro M., Bruno E.M., Licata A., Amodeo S., Capitano A.R., Ferrari C., Negri E., Orlandini A., Pesci M., Gulminetti R., Pagnucco L., Parruti G., Stefano P.D., Coco B., Corsini R., Garlassi E., Andreoni M., Teti E., Cerva C., Baiocchi L., Grassi G., Gasbarrini A., Pompili M., Siena M.D., Taliani G., Spaziante M., Persico M., Masarone M., Aglitti A., Calvanese G., Anselmo M., Leo P.D., Marturano M., Saracco G.M., Quaranta, M, Ferrigno, L, Tata, X, D'Angelo, F, Massari, M, Coppola, C, Biliotti, E, Giorgini, A, Laccabue, D, Ciancio, A, Blanc, P, Margotti, M, Ieluzzi, D, Brunetto, M, Barbaro, F, Russo, F, Beretta, I, Morsica, G, Verucchi, G, Saracino, A, Galli, M, Kondili, L, Mazzaro, C, Bertola, M, Benedetti, A, Schiada, L, Cucco, M, Giacometti, A, Brescini, L, Castelletti, S, Fiorentini, A, Angarano, G, Milella, M, Leo, A, Rendina, M, Salvatore D'ABRAMO, F, Lillo, C, Iannone, A, Piazzolla, M, Badia, L, Piscaglia, F, Benevento, F, Serio, I, Castelli, F, Zaltron, S, Spinetti, A, Odolini, S, Bruno, R, Mondelli, M, Chessa, L, Loi, M, Torti, C, Costa, C, Mazzitelli, M, Pisani, V, Scaglione, V, Trecarichi, E, Zignego, A, Monti, M, Madia, F, Attala, L, Pierotti, P, Salomoni, E, Mariabelli, E, Santantonio, T, Bruno, S, Cela, E, Bassetti, M, Mazzarello, G, Alessandrini, A, Biagio, A, Nicolini, L, Raimondo, G, Filomia, R, Aghemo, A, Meli, R, Lazzarin, A, Salpietro, S, Fracanzani, A, Fatta, E, Lombardi, R, Lampertico, P, Borghi, M, D'Ambrosio, R, Degasperi, E, Puoti, M, Baiguera, C, D'Amico, F, Vinci, M, Rumi, M, Zuin, M, Zermiani, P, Andreone, P, Caraceni, P, Guarneri, V, Villa, E, Bernabucci, V, Bristot, L, Paradiso, M, Migliorino, G, Gambaro, A, Lapadula, G, Spolti, A, Soria, A, Invernizzi, P, Ciaccio, A, Luca, M, Malinverno, F, Ratti, L, Amoruso, D, Pisano, F, Scarano, F, Staiano, L, Morisco, F, Cossiga, V, Gentile, I, Buonomo, A, Foggia, M, Zappulo, E, Federico, A, Dallio, M, Coppola, N, Sagnelli, C, Martini, S, Monari, C, Nardone, G, Sgamato, C, Chemello, L, Cavalletto, L, Sterrantino, D, Zanetto, A, Zanaga, P, Brancaccio, G, Craxi, A, Petta, S, Calvaruso, V, Crapanzano, L, Madonia, S, Cannizzaro, M, Bruno, E, Licata, A, Amodeo, S, Capitano, A, Ferrari, C, Negri, E, Orlandini, A, Pesci, M, Gulminetti, R, Pagnucco, L, Parruti, G, Stefano, P, Coco, B, Corsini, R, Garlassi, E, Andreoni, M, Teti, E, Cerva, C, Baiocchi, L, Grassi, G, Gasbarrini, A, Pompili, M, Siena, M, Taliani, G, Spaziante, M, Persico, M, Masarone, M, Aglitti, A, Calvanese, G, Anselmo, M, Leo, P, Marturano, M, Saracco, G, Quaranta, M. G., Ferrigno, L., Tata, X., D'Angelo, F., Massari, M., Coppola, C., Biliotti, E., Giorgini, A., Laccabue, D., Ciancio, A., Blanc, P. L., Margotti, M., Ieluzzi, D., Brunetto, M. R., Barbaro, F., Russo, F. P., Beretta, I., Morsica, G., Verucchi, G., Saracino, A., Galli, M., Kondili, L. A., Mazzaro, C., Bertola, M., Benedetti, A., Schiada, L., Cucco, M., Giacometti, A., Brescini, L., Castelletti, S., Fiorentini, A., Angarano, G., Milella, M., Leo, A. D., Rendina, M., Salvatore D'ABRAMO, F., Lillo, C., Iannone, A., Piazzolla, M., Badia, L., Piscaglia, F., Benevento, F., Serio, I., Castelli, F., Zaltron, S., Spinetti, A., Odolini, S., Bruno, R., Mondelli, M., Chessa, L., Loi, M., Torti, C., Costa, C., Mazzitelli, M., Pisani, V., Scaglione, V., Trecarichi, E. M., Zignego, A. L., Monti, M., Madia, F., Attala, L., Pierotti, P., Salomoni, E., Mariabelli, E., Santantonio, T. A., Bruno, S. R., Cela, E. M., Bassetti, M., Mazzarello, G., Alessandrini, A. I., Biagio, A. D., Nicolini, L. A., Raimondo, G., Filomia, R., Aghemo, A., Meli, R., Lazzarin, A., Salpietro, S., Fracanzani, A. L., Fatta, E., Lombardi, R., Lampertico, P., Borghi, M., D'Ambrosio, R., Degasperi, E., Puoti, M., Baiguera, C., D'Amico, F., Vinci, M., Rumi, M. G., Zuin, M., Zermiani, P., Andreone, P., Caraceni, P., Guarneri, V., Villa, E., Bernabucci, V., Bristot, L., Paradiso, M. L., Migliorino, G., Gambaro, A., Lapadula, G., Spolti, A., Soria, A., Invernizzi, P., Ciaccio, A., Luca, M., Malinverno, F., Ratti, L., Amoruso, D. C., Pisano, F., Scarano, F., Staiano, L., Morisco, F., Cossiga, V., Gentile, I., Buonomo, A. R., Foggia, M., Zappulo, E., Federico, A., Dallio, M., Coppola, N., Sagnelli, C., Martini, S., Monari, C., Nardone, G., Sgamato, C., Chemello, L., Cavalletto, L., Sterrantino, D., Zanetto, A., Zanaga, P., Brancaccio, G., Craxi, A., Petta, S., Calvaruso, V., Crapanzano, L., Madonia, S., Cannizzaro, M., Bruno, E. M., Licata, A., Amodeo, S., Capitano, A. R., Ferrari, C., Negri, E., Orlandini, A., Pesci, M., Gulminetti, R., Pagnucco, L., Parruti, G., Stefano, P. D., Coco, B., Corsini, R., Garlassi, E., Andreoni, M., Teti, E., Cerva, C., Baiocchi, L., Grassi, G., Gasbarrini, A., Pompili, M., Siena, M. D., Taliani, G., Spaziante, M., Persico, M., Masarone, M., Aglitti, A., Calvanese, G., Anselmo, M., Leo, P. D., Marturano, M., and Saracco, G. M.

Subjects
Male, HCV genotypes, Ethnic group, Linked-to-care patient, Comorbidity, Hepacivirus, Logistic regression, medicine.disease_cause, Comorbidities, Direct acting antivirals, HCV Cohort, Linked-to-care patients, Aged, Antiviral Agents, Coinfection, Female, Hepatitis C, Chronic, Humans, Italy, Middle Aged, Transients and Migrants, 0302 clinical medicine, Medicine, Chronic, Gastroenterology, virus diseases, Hepatitis C, Life evaluation, 030220 oncology & carcinogenesis, Cohort, 030211 gastroenterology & hepatology, Comorbiditie, Human, Hepatitis C virus, Settore MED/12 - GASTROENTEROLOGIA, 03 medical and health sciences, Disease severity, Antiviral Agent, Hepaciviru, Hepatology, business.industry, Settore MED/09 - MEDICINA INTERNA, medicine.disease, digestive system diseases, Direct acting antiviral, business, Demography
Abstract

Background: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. Methods: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. Results: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p < 0.001), females 56.5% vs. 45.3%, (p < 0.001), HBsAg positivity 3.8% vs. 1.4%, (p < 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p < 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p < 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p > 0.05) of migrants and natives who eradicated HCV, respectively. Conclusion: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted.

Published
2021

49. The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis

Author

Paolo Caraceni, Vicente Arroyo, Jonel Trebicka, Mauro Bernardi, Paolo Angeli, Thierry Gustot, Rajiv Jalan, Richard Moreau, Joan Clària, Javier Fernández, Arroyo V., Angeli P., Moreau R., Jalan R., Claria J., Trebicka J., Fernandez J., Gustot T., Caraceni P., and Bernardi M.

Subjects
Liver Cirrhosis, 0301 basic medicine, Cirrhosis, Cirrosi hepàtica, Multiple Organ Failure, Stable decompensated cirrhosis, Vasodilation, Esophageal and Gastric Varices, Systemic inflammation, 03 medical and health sciences, 0302 clinical medicine, Bacterial infections, Immunopathology, ACLF, Hypertension, Portal, Ascites, medicine, Humans, Decompensation, Hepatic encephalopathy, Stable decompensated cirrhosi, Inflammation, Hepatology, business.industry, Unstable decompensated cirrhosis, Pre-ACLF, medicine.disease, Inflamació, Acute-on-chronic liver failure, 030104 developmental biology, Metabolism, Hepatic cirrhosis, Hepatic Encephalopathy, Immunology, 030211 gastroenterology & hepatology, Bacterial infection, medicine.symptom, Gastrointestinal Hemorrhage, business, Vasoconstriction
Abstract

Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequently impaired organ function.

Published
2021

50. Portal Hypertension and Ascites: Patient-and Population-centered Clinical Practice Guidelines by the Italian Association for the Study of the Liver (AISF)

Author

Paolo Caraceni, Gennaro D'Amico, Vincenzo La Mura, Raffaele Bruno, Ignazio Grattagliano, Roberto de Franchis, Calogero Cammà, Paolo Angeli, Marco Senzolo, Filippo Schepis, Oliviero Riggio, Bruno R., Camma C., Caraceni P., D'Amico G., Grattagliano I., La Mura V., Riggio O., Schepis F., Senzolo M., Angeli P., de Franchis R., and Camma' Calogero

Subjects
Liver Cirrhosis, Population, Scopus, Disease, Esophageal varices, Ascites, Hypertension, Portal, Medicine, Humans, education, Portal hypertension, education.field_of_study, Variceal bleeding, Hepatology, Esophageal varice, business.industry, Gastroenterology, medicine.disease, Acute kidney injury, Clinical Practice, Natural history, Italy, Hepatorenal syndrome, Hypertension, Ascite, Portal, Medical emergency, medicine.symptom, business, Resource utilization, Human
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)

Published
2021

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