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Background Aims: Carvedilol is a non-selective β-blocker (NSBBs) with anti-α1-adrenergic activity, more effective than traditional NSBBs in reducing portal-pressure (HVPG). However, 35%-45% of patients still have insufficient HVPG-decrease. Statins ameliorate endothelial dysfunction, reduce hepatic vascular resistance, and have pleiotropic effects. We investigated whether the addition of simvastatin improves the efficacy of carvedilol on HVPG in cirrhosis with severe portal-hypertension and suboptimal response to traditional-NSBBs., Methods: Patients with cirrhosis and high-risk varices referred for primary prophylaxis were consecutively included. HVPG was measured at baseline and again after i.v.propranolol. Suboptimal responders (HVPG-decrease <20%) were treated with carvedilol and were randomized to double-blind administration of placebo or simvastatin. Chronic HVPG response was assessed after 4-6-weeks, repeating HVPG-measurements after a standard liquid meal to estimate endothelial dysfunction. Plasma samples were obtained before each study to investigate inflammatory parameters., Results: Of 184 eligible patients, 82 were randomized to carvedilol+simvastatin (N=41) or carvedilol+placebo (N=41). Baseline characteristics were similar. HVPG significantly decreased with both, carvedilol+simvastatin (18.6±4-to-15.7±4 mm Hg, p<0.001) and carvedilol+placebo (18.9±3-to-16.9±3 mm Hg, p<0.001). The decrease was greater with carvedilol+simvastatin (2.97±2.5 vs. 2.05±1.6 mm Hg, p=0.031). An HVPG-decrease ≥20% occurred in 37% versus 15% patients respectively (OR:3.37, 95% CI=1.15-9.85; p=0.021). With test-meal, HVPG increased in both groups (p<0.01), although carvedilol+simvastatin attenuated such increment (12±8% vs. 23±16%, p<0.001). Cytokine levels (IL-6,MCP-1,MDA) decreased significantly more with carvedilol+simvastatin (p<0.01). Incidence of adverse events was similar., Conclusion: In patients with severe portal hypertension (all with high-risk varices) and suboptimal hemodynamic response to traditional NSBBs, combined therapy with carvedilol plus simvastatin significantly enhances the portal-pressure reduction achieved with carvedilol-monotherapy, improves endothelial dysfunction and reduces pro-inflammatory cytokines., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Alcohol consumption is a leading cause of preventable morbidity and mortality worldwide and the primary cause of advanced liver disease. Alcohol use disorder (AUD) is a chronic, frequently relapsing condition characterized by persistent alcohol consumption despite its negative consequences. Alcohol-associated liver disease (ALD) encompasses a series of stages, from fatty liver (steatosis) to inflammation (steatohepatitis), fibrosis, and, ultimately, liver cirrhosis and its complications. The development of ALD is complex, involving both genetic and environmental factors, yet the exact mechanisms at play remain unclear. Alcohol-associated hepatitis (AH), a severe form of ALD, presents with sudden jaundice and liver failure. Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD to stop the progression of the disease, making alcohol abstinence the most effective way to improve prognosis across all stages of ALD. For patients with advanced ALD who do not respond to medical therapy, liver transplantation is the only option that can improve prognosis. Recently, AH has become an early indication for liver transplantation in non-responders to medical treatment, showing promising results in carefully selected patients. This review provides an update on the epidemiology, natural history, pathogenesis, and current treatments for ALD. A deeper insight into novel targeted therapies investigated for AH focusing on new pathophysiologically-based agents is also discussed, including anti-inflammatory and antioxidative stress drugs, gut-liver axis modulators, and hepatocyte regenerative molecules.

Background & Aims: One-third of non-cirrhotic portal vein thrombosis (NCPVT) cases are associated with local factors. The risk of rethrombosis after anticoagulation withdrawal is unknown. We aimed to determine factors associated with new splanchnic or extrasplanchnic thrombotic events in this setting., Methods: We performed a retrospective study including cases of recent NCPVT associated with local factors. High- and low-risk prothrombotic factors, prespecified according to RIPORT study criteria, were assessed. Univariate and multivariate Cox models assessed the influence of different variables on the occurrence of new thrombotic events., Results: At baseline, 83/154 (53.9%) patients had at least one prothrombotic factor including 50 (32.5%) with a high-risk and 33 (21.4%) with a low-risk prothrombotic factor. Oestrogen-containing contraception was discontinued in all patients. During follow-up, 63/140 (45%) patients had at least one prothrombotic factor, including 47 (33.6%) with a high-risk and 16 (11.4%) with a low-risk prothrombotic factor. Seventeen new thrombotic events occurred after a median follow-up of 52 (IQR 14-62) (min-max 3.0-69.0) months. New thromboses were associated with high-risk factors (hazard ratio [HR] 3.817, 95% CI 1.303-11.180, p = 0.015), but were inversely related to recanalization (HR 0.222, 95% CI 0.078-0.635, p = 0.005) and anticoagulation (HR 0.976, 95% CI 0.956-0.995, p = 0.016). When a high-risk factor was present a new thrombotic event occurred in 7.4%, 14.6%, 14.6% and 28.8% of patients at 1, 3, 5 and 7 years under anticoagulants, respectively, compared to 21.2%, 21.2%, 58% and 58% without anticoagulants, respectively., Conclusions: In cases of recent NCPVT associated with local factors, high-risk factors for thrombosis are associated with new thrombotic events. Permanent anticoagulation appears beneficial in this high-risk situation., Impact and Implications: In non-cirrhotic portal vein thrombosis (NCPVT) associated with local factors, systematic screening for prothrombotic factors is recommended, but the prevalence of the latter is not clearly established, and the risk of recurrent intra or extrasplanchnic thromboembolism is poorly described. Thus, interest in permanent anticoagulation remains. NCPVT associated with local factors is a matter of concern for hepatologists, gastroenterologists and digestive surgeons. Due to a lack of knowledge, practices are heterogeneous. Our findings highlight that systematic screening for prothrombotic factors in NCPVT is needed even when associated with local factors, as it may justify long-term anticoagulation for the prevention of new intra or extrasplanchnic thrombotic events in at least one-third of cases. The interest in long-term anticoagulation should be investigated prospectively in the absence of high-risk prothrombotic factors., Clinical Trial Number: NCT0536064., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Patients with vascular liver diseases (VLD) are at higher risk of both severe courses of COVID-19 disease and thromboembolic events. The impact of SARS-CoV-2 vaccination in patients with VLD has not been described and represents the aim of our study., Methods: International, multicenter, prospective observational study in patients with VLD analyzing the incidence of COVID-19 infection after vaccination, severity of side effects, occurrence of thromboembolic events and hepatic decompensation. In a subgroup of patients, the humoral and cellular responses to vaccination were also analyzed., Results: A total of 898 patients from 14 European centers - part of the VALDIG network - were included, 872 (97.1%) patients received two vaccine doses (fully vaccinated), and 674 (75.1%) three doses. Of the total cohort, 151/898 had a COVID-19 infection prior to vaccination, of whom 9/151 (5.9%) were re-infected. Of the 747/898 patients who were not previously infected, 11.2% (84/747) were diagnosed with a COVID-19 infection during the study period. Two infected patients required intensive care unit admission and infection was fatal in two fully vaccinated patients. Adverse effects were reported in around 40% of patients, with local side effects being the most frequent. During the study period, 31 (3.5%) patients had thromboembolic events and 21 (2.3%) hepatic decompensations. No cases of vaccine-induced thrombocytopenia were reported. Vaccine immunogenicity was assessed in 36 patients; seroconversion reached 100% and IFNy T-cell responses significantly increased post two mRNA-1273 vaccine doses., Conclusion: Patients with VLD seem to have a preserved immune response to SARS-CoV-2 vaccination, which appears to be safe and effective in preventing severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, though the contribution of vaccination as a cofactor in VLD remains to be elucidated., Impact and Implications: Patients with vascular liver disease (VLD) are at increased risk of both SARS-CoV-2 infection and severe COVID-19 disease. The potential risks associated with vaccination against this infection need thorough investigation. Our research enhances the understanding of the effects of COVID-19 vaccination in patients with VLD, highlighting its good tolerability. Moreover, patients with VLD appear to have a preserved immune response to SARS-CoV-2 vaccination, providing protection against severe COVID-19 infection. Our study cannot definitively establish a direct link between vaccination and thrombotic events, and no cases of vaccine-induced thrombocytopenia were reported., (© 2024 The Authors.)

Advanced chronic liver disease (ACLD) is associated with a wide spectrum of immune dysfunction. The clinical impact of SARS-CoV-2 on the development of decompensation and immune response in unvaccinated outpatients has not as yet been clearly defined. This study aimed to evaluate the clinical and immunological impact of SARS-CoV-2 on outpatients with ACLD. This is an observational case-control study, in which ACLD outpatients were included prospectively and consecutively and classified into two groups: SARS-CoV-2 infected and non-infected. Patients' baseline characteristics and infection data were collected and analyzed. Immunoglobulin G (IgG) levels against Spike 1 were evaluated. The primary endpoint was risk of liver decompensation during follow-up, assessed after propensity score matching and adjusted by Cox regression. Between October 2020 and July 2021, ACLD outpatients (n = 580) were identified, and 174 patients with clinical follow-up were included. SARS-CoV-2 infection incidence was 7.6% (n = 44). Risk of liver decompensation was significantly higher after infection (HR = 2.43 [1.01-5.86], p = 0.048) vs. non-infection. The time of IgG evaluation was similar in all patients (n = 74); IgG concentrations were significantly higher in compensated vs. decompensated patients (1.02 ± 0.35 pg/mL vs. 0.34 ± 0.16 pg/mL, p < 0.0001) and correlated with hemoglobin levels. The dysregulation of the innate immune response in patients with decompensated liver disease increased the risk of further decompensation following SARS-CoV-2, mainly due to a worsening of ascites.

Background and Aims: Alcohol use disorder has been reported in patients undergoing bariatric procedures, but the pattern of alcohol consumption has not been evaluated. We investigated the prevalence, risk factors, and impact of binge drinking (BD) at the time of surgery and during follow-up., Methods: A prospective, longitudinal study of subjects undergoing bariatric surgery was included in the LABS-2 registry between 2006 and 2009. Participants with AUDIT questionnaire at the time of surgery and a minimum of 12 months follow-up were included. BD was defined as consuming ≥5 drinks on at least 1 occasion in the previous month. Liver biopsies were obtained during bariatric procedures in not all cases. Survival analysis was performed with the adjusted Cox regression model and competing risk., Results: A total of 2257 subjects were included, with a median follow-up of 79 months. The prevalence of BD at time of surgery was 12%, and it raised up to 23% during follow-up. Patients with BD predominantly had a binge eating disorder (OR=1.35 [95% CI: 1.04-1.76]), regularly consumed fast food [OR=1.4 (95% CI: 1.07-1.85)] and used other drugs (OR=2.65 [95% CI: 1.74-4.04]). Within liver biopsies evaluation, BD showed higher hepatic iron deposits (OR=3.00 [95% CI: 1.25-7.21]). BD at the time of surgery was associated with a higher risk of BD during follow-up (OR=10.49 [95% CI: 7.86-14.00]) and long-term mortality (HR: 3.21 [95% CI: 1.67-6.18]). Specific causes of death in these patients with BD were liver disease (p=0.020), suicide (p=0.015), neoplasms (p=0.034), and respiratory (p=0.025)., Conclusions: The prevalence of BD in patients undergoing bariatric surgery is high and increases the risk of postoperative liver disease, suicides, and long-term mortality., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Etiologic factor removal (ER) drives recompensation and improves portal hypertension in cirrhosis. Esophageal varices (EV) and portosystemic shunts (PSS) have been found in patients despite hepatic venous pressure gradient (HVPG) dropping below 10 mmHg after ER, questioning HVPG accuracy in reflecting true portal pressure in the setting of ER. We aim to evaluate the correlation of HVPG with direct portal pressure (DPP) in patients with persistence of EV after ER despite HVPG <10 mmHg., Methods: This is a bicentric 'proof of concept' study evaluating HVPG and ultrasound-guided percutaneous DPP in patients with HCV or alcohol-related cirrhosis with persistent varices and HVPG <10 mmHg after at least 5 years of ER., Results: Seven patients with HCV and three with alcohol-related cirrhosis with persistent varices and HVPG <10 mmHg after at least 5 years of ER were included. At evaluation, all patients had a patent portal vein and were compensated. The median platelet count was 129.5 (IQR 95-145) × 10 9 /ml, and the median liver stiffness measurement was 16.15 (IQR 14.4-22.3) kPa. In five patients, EV remained the same size (two large and three small), and five downsized to small after ER. Wedge hepatic vein pressure (median 19 [IQR 16.5-20] mmHg) and portal pressure (median 18 [IQR 15-19.5] mmHg) had an excellent correlation (R = 0.93, p <0.0001). Portal pressure gradient (PPG) confirmed the absence of clinically significant portal hypertension as identified by HVPG across all the patients., Conclusions: HVPG accurately reflects PPG in the context of HCV and alcohol-related cirrhosis regression. After ER, EV may persist despite HVPG <10 mmHg. The benefit of prophylaxis in patients with EV and HVPG <10 mmHg is unknown. Future studies with clinical endpoints are needed to validate our findings., Impact and Implications: Despite a favorable evolution after the removal of the etiologic factor, varices persist in some patients, and there is a lack of concise guidelines for the evaluation and management of portal hypertension in this population. Our research underscores the persistence of varices in the absence of clinically significant portal hypertension and significantly demonstrates the accuracy of hepatic venous pressure gradient (HVPG) in reflecting portal vein pressure in this specific patient group. These findings emphasize the crucial role of HVPG in the assessment of portal hypertension after etiologic factor removal and lay the groundwork for further investigation into clinical outcomes and the necessity of non-selective beta-blockers in individuals with persistent varices after the removal of etiologic factor., (© 2024 The Authors.)

Infections are a major cause of morbidity and mortality in cirrhosis, especially those caused by multi-drug resistant bacteria. During the COVID-19 pandemic, the incidence and type of infection in these patients may have been influenced by the restrictive measures implemented. We aimed to compare the infections in patients with cirrhosis hospitalized before the COVID-19 pandemic versus those hospitalized during the pandemic. We retrospectively compared infections in patients with cirrhosis hospitalized in the hepatology unit during the pre-pandemic period (3/2019-2/2020) with infections in patients hospitalized during the pandemic (3/2020-2/2021). Baseline characteristics, type of infections, type of bacteria, antimicrobial resistance and mortality were evaluated. There were 251 hospitalizations in 170 patients during the pre-pandemic period and 169 hospitalizations in 114 patients during the pandemic period. One or more infections were identified in 40.6% of hospitalizations during the pre-pandemic period and 43.8% of hospitalizations during the pandemic, P = 0.52. We found 131 infections in the pre-pandemic period and 75 infections during the pandemic. The percentage of nosocomial infections decreased in the pandemic period (25.3% vs. 37.4% in the pre-pandemic period, P = 0.06). We found a non-significant trend to a higher incidence of infections by multi-drug resistant organisms (MDRO) in the pandemic period than in the pre-pandemic period (6.5% vs. 4%). The incidence of infections was similar in both periods. However, during the pandemic, we observed a trend to a lower incidence of nosocomial infections with a higher incidence of MDRO infections., (© 2024. The Author(s).)

Background: The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and clinical impact of AWS in patients hospitalized with AH., Methods: A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR])., Findings: In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3-27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05-2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31-3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36-0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02-4.64) and phenobarbital (HR = 2.99, 95% CI 1.07-8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44-3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38-4.49), and ICU admission (OR = 1.96, 95% CI 1.19-3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40-3.82), 90-day (HR = 1.78, 95% CI 1.18-2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06-2.24)., Interpretation: AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH., Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors., Competing Interests: The authors declare no conflict of interest regarding this manuscript., (© 2023 The Authors.)

Background/aims: Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated., Methods: A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching., Results: The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD., Conclusions: Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency., (© 2023. The Author(s).)

Background & Aims: Vascular liver diseases (VLDs) are represented mainly by portosinusoidal vascular disease (PSVD), noncirrhotic splanchnic vein thrombosis (SVT), and Budd Chiari syndrome (BCS). It is unknown whether patients with VLDs constitute a high-risk population for complications and greater coronavirus disease 2019 (COVID-19)-related mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to assess the prevalence and severity of SARS-CoV-2 infection among patients with VLDs, as well as to assess its impact on hepatic decompensation and survival., Methods: This is an observational international study analyzing the prevalence and severity of SARS-CoV-2 infection in VLDs between March 2020 and March 2021, compared with the general population (GP). Patients from Spain (5 centers; n = 493) and France (1 center; n = 475) were included., Results: Nine hundred sixty-eight patients were included: 274 with PSVD, 539 with SVT, and 155 with BCS. Among them, 138 (14%) were infected with SARS-CoV-2: 53 with PSVD, 77 with SVT, and 8 with BCS. The prevalence of SARS-CoV-2 infection in patients with PSVD (19%) and SVT (14%) was significantly higher than in the GP (6.5%; P < .05), whereas it was very similar in patients with BCS (5%). In terms of infection severity, patients with VLDs also presented a higher need of hospital admission (14% vs 7.3%; P < .01), intensive care unit admission (2% vs 0.7%; P < .01), and mortality (4% vs 1.5%; P < .05) than the GP. Previous history of ascites (50% vs 8%; P < .05) and post-COVID-19 hepatic decompensation (50% vs 4%; P < .05) were associated with COVID-19 mortality., Conclusions: Patients with PSVD and SVT could be at higher risk of infection by SARS-CoV-2 and at higher risk of severe COVID-19 disease., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction., Methods: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days., Results: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC., Discussion: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality., (Copyright © 2021 by The American College of Gastroenterology.)

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH., Methods: We performed a retrospective, international multicenter cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method., Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p <0.001). Steroids only improved survival in patients with MELD scores between 21 (HR 0.61; 0.39-0.95; p = 0.027) and 51 (HR 0.72; 0.52-0.99; p = 0.041). The maximum effect of corticosteroid treatment (21-30% survival benefit) was observed with MELD scores between 25 (HR 0.58; 0.42-0.77; p <0.001) and 39 (HR 0.57; 0.41-0.79; p <0.001). No corticosteroid benefit was seen in patients with MELD >51. The type of corticosteroids used (prednisone, prednisolone, or methylprednisolone) was not associated with survival benefit (p = 0.247)., Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39., Lay Summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90- or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51)., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode., Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient's data for survival including two clinical trials (BETA and ALFAE) was performed., Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo ( p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21-0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02)., Conclusions: Repeated doses of albumin might be beneficial for patient's survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.

The phase angle is a versatile measurement to assess body composition, frailty and prognosis in patients with chronic diseases. In cirrhosis, patients often present alterations in body composition that are related to adverse outcomes. The phase angle could be useful to evaluate prognosis in these patients, but data are scarce. The aim was to analyse the prognostic value of the phase angle to predict clinically relevant events such as hospitalisation, falls, and mortality in patients with cirrhosis. Outpatients with cirrhosis were consecutively included and the phase angle was determined by electrical bioimpedance. Patients were prospectively followed to determine the incidence of hospitalisations, falls, and mortality. One hundred patients were included. Patients with phase angle ≤ 4.6° (n = 31) showed a higher probability of hospitalisation (35% vs 11%, p = 0.003), falls (41% vs 11%, p = 0.001) and mortality (26% vs 3%, p = 0.001) at 2-year follow-up than patients with PA > 4.6° (n = 69). In the multivariable analysis, the phase angle and MELD-Na were independent predictive factors of hospitalisation and mortality. Phase angle was the only predictive factor for falls. In conclusion, the phase angle showed to be a predictive marker for hospitalisation, falls, and mortality in outpatients with cirrhosis., (© 2021. The Author(s).)

Background & Aims: We recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism., Methods: We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells., Results: Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes., Conclusions: Altered metabolite levels and messenger RNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aim: Frailty is increasingly recognized as a major prognostic factor in cirrhosis in addition to conventional liver insufficiency scores. The aim was to compare the prevalence and characteristics of frailty between patients with cirrhosis and controls, and to analyse its prognostic value., Methods: We included outpatients with cirrhosis and age- and gender-matched non-cirrhotic controls. Frailty was defined according to the Fried frailty criteria. In patients with cirrhosis, we analysed the ability of the degree of frailty to predict a composite endpoint, consisting of hospitalization, admission to a long-term care centre, falls or death., Results: We included 135 patients with cirrhosis and 135 controls. The prevalence of frailty was higher among patients with cirrhosis: 35 (25.9%) frail, 74 (54.8%) pre-frail and 26 (19.2%) robust vs 14 (10.4%) frail, 67 (49.6%) pre-frail and 54 (40%) robust (P < .001) in controls. This difference was mainly as a result of decreased muscle strength in patients with cirrhosis. During follow-up, frail patients with cirrhosis showed a higher probability of composite endpoint, hospitalization and falls than pre-frail and robust cirrhotic patients but mortality was similar. MELD-Na score and frailty were independent predictive factors for hospitalization, frailty for falls, and MELD-Na score and albumin for survival. Vitamin D deficiency and increased cystatin C were associated with frailty., Conclusions: Frailty was more frequent in outpatients with cirrhosis than in controls, mainly because of a decrease in muscle strength, and it could be a predictive factor for hospitalization and falls in these patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Clinically significant portal hypertension (CSPH), defined as a hepatic venous pressure gradient (HVPG) ≥10 mmHg, persists 24 weeks after sustained virological response (SVR) in up to 78% of patients with HCV-related cirrhosis treated with direct-acting antivirals. These patients remain at risk of decompensation. However, long-term paired clinical and hemodynamic data are not available for this population., Methods: We conducted a prospective multicenter study in 226 patients with HCV-related cirrhosis and CSPH who achieved SVR after antiviral therapy. Patients with CSPH 24 weeks after end of treatment (SVR24) were offered another hemodynamic assessment 96 weeks after end of treatment (SVR96)., Results: All patients were clinically evaluated. Out of 176 patients with CSPH at SVR24, 117 (66%) underwent an HVPG measurement at SVR96. At SVR96, 55/117 (47%) patients had HVPG <10 mmHg and 53% had CSPH (65% if we assume persistence of CSPH in all 59 non-evaluated patients). The proportion of high-risk patients (HVPG ≥16 mmHg) diminished from 41% to 15%. Liver stiffness decreased markedly after SVR (median decrease 10.5 ± 13 kPa) but did not correlate with HVPG changes (30% of patients with liver stiffness measurement <13.6 kPa still had CSPH). Seventeen (7%) patients presented with de novo/additional clinical decompensation, which was independently associated with baseline HVPG ≥16 mmHg and history of ascites., Conclusions: Patients achieving SVR experienced a progressive reduction in portal pressure during follow-up. However, CSPH may persist in up to 53-65% of patients at SVR96, indicating persistent risk of decompensation. History of ascites and high-risk HVPG values identified patients at higher risk of de novo or further clinical decompensation., Lay Summary: As a major complication of cirrhosis, clinically significant portal hypertension (CSPH) is associated with adverse clinical outcomes. Herein, we show that CSPH persists at 96 weeks in just over half of patients with HCV-related cirrhosis, despite HCV elimination by direct-acting antivirals. Despite viral cure, patients with CSPH at the start of antiviral treatment remain at long-term risk of hepatic complications and should be managed accordingly., Competing Interests: Conflict of interest S. Lens has received speaker and consultant fees from Gilead, Abbvie and Janssen. Z. Mariño has acted as a speaker for Abbvie, Gilead, Janssen and is on the advisory board for Gilead and Abbvie. JL. Calleja is a consultant and lecturer for BMS, Gilead Sciences, Abbvie and MSD. X. Torras has received consultancy fees from Gilead, BMS and is a lecturer for Abbvie, Gilead, Janssen and MSD. Agustín Albillos has served as advisor/lecturer for AbbVie, Gilead Sciences, Gore, Griffols, Intercept Pharmaceuticals, and Merck & Co. and has received research/educational grants from Gilead Sciences. J. Bosch is a consultant/member of advisory boards for Gilead, Conatus, Exallenz, BMS, BioVie, BLB, Brudy, Surrozen and Actelion and has received research grants from Conatus and Gilead. R. Bañares has received consultancy fees from Abbvie and speaker fees from Gilead, Abbvie and Janssen. JC. Garcia-Pagan received consultant fees from Shionogi and research grants from Novartis and Gore. X. Forns has received consultancy fees from Gilead, Abbvie, and unrestricted grant support from Abbvie. The remaining authors have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of β-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis., Methods: Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting β-blockers and again after 1 to 3 months of treatment (short-term)., Results: Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under β-blockers, decompensated patients had lower portal pressure decrease (10 ± 18% vs. 15 ± 12%; p <0.05) and had greater reductions in heart rate (p <0.001) and CO (17 ± 15% vs. 10 ± 21%; p <0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with β-blockers than survivors (21 ± 14% vs. 15 ± 16%; p <0.05) and CO under β-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66-0.83). Death risk was higher in decompensated patients with CO <5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25-0.77; p = 0.004)., Conclusions: In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to β-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of β-blockers on CO might adversely influence survival in decompensated cirrhosis., Lay Summary: β-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of β-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of β-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of β-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background/aims: Despite secondary-prophylaxis with β-blockers and endoscopic-variceal-ligation rebleeding is frequent, particularly within the first-6-weeks. Early-rebleeding may have greater impact on death-risk than late rebleeding, which may affect therapy. We assessed whether the influence of rebleeding on long-term survival of patients on secondary-prophylaxis is greater in patients with early-rebleeding., Methods: 369 patients with cirrhosis were consecutively included once recovered from first variceal-bleeding. The impact of rebleeding on survival was investigated according to whether it occurred within 6-weeks (early-rebleeding) or later (late-rebleeding)., Results: During 46-months of follow-up (IQR: 14-61), 45 patients (12%) had early-rebleeding, 74(20%) had late-rebleeding and 250(68%) had not rebleeding. Mortality risk was higher in early-rebleeding group vs. late-rebleeding (HR = 0.476, 95%CI = 0.318-0.712, p < 0.001) and was similar in late-rebleeding group vs. no-rebleeding (HR = 0.902, 95%CI = 0.749-1.086, p = 0.271). Adjusting for baseline risk-factors, early-rebleeding was independently associated with mortality-risk (HR = 1.58, 95%CI = 1.02-2.45; p = 0.04). Child-Pugh&MELD scores improved at 3rd-4th-week only in patients without early-rebleeding (p < 0.05). Presence of ascites or encephalopathy, MELD-score>12 and HVPG>20 mmHg identified patients at risk of early-rebleeding., Conclusions: Patients with early-rebleeding have higher risk of death than patients without rebleeding and even than those rebleeding later. Our results suggest that patients at risk of early rebleeding might benefit from preemptive therapies such as early-TIPS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Aim: To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites., Methods: We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed., Results: We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group ( P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group ( P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up., Conclusion: Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections., Competing Interests: Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.

Background & Aims: Patients with hepatitis C virus-associated cirrhosis and clinical significant portal hypertension (CSPH, hepatic venous pressure gradient [HVPG] 10 mmHg or greater), despite achieving sustained virological response (SVR) to therapy, remain at risk of liver decompensation. We investigated hemodynamic changes following SVR in patients with CSPH and whether liver stiffness measurements (LSMs) can rule out the presence of CSPH., Methods: We performed a multicenter prospective study of 226 patients with hepatitis C virus-associated cirrhosis and CSPH who had SVR to interferon-free therapy at 6 Liver Units in Spain. The portal pressure gradient was determined based on HVPG at baseline and 24 weeks after therapy; patients also underwent right-heart catheterization and LSM at these time points. Primary outcomes were effects of SVR on the hepatic, pulmonary, and systemic hemodynamics; factors related to HVPG ≥10% reduction and to CSPH persistence; and whether LSMs can rule out the presence of CSPH after SVR., Results: Most patients (75%) had esophageal varices, 21% were Child-B, and 29% had at least 1 previous episode of liver decompensation. Overall, HVPG decreased from 15 (IQR: 12-18) before treatment to 13 (10-16) mmHg after SVR (reduction of 2.1 ± 3.2 mmHg; P < .01). However, CSPH persisted in 78% of patients. HVPG decreased by 10% or more from baseline in 140 patients (62%). Baseline level of albumin below 3.5 g/dL was the only negative factor associated with an HVPG reduction of 10% or more. LSM decreased from 27 (20-37) kPa before treatment to 18 (14-28) kPa after SVR (P < .05). One third of patients with a reduction in LSM to below 13.6 kPa after SVR still had CSPH. A higher baseline HVPG and a lower decrease in LSM after treatment were associated with persistence of CSPH after SVR. Systemic hemodynamics improved after SVR. Interestingly, pulmonary hypertension was present in 13 patients at baseline and 25 after SVR, although only 3 patients had increased pulmonary resistance., Conclusions: In a multicenter prospective study of patients with hepatitis C virus-associated cirrhosis, an SVR to all-oral therapy significantly reduced HVPG, compared with before treatment. Nevertheless, CSPH persists in most patients despite SVR, indicating persistent risk of decompensation. In this population, changes in LSM do not correlate with HVPG and cut-off values are not reliable in ruling out CSPH after SVR., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Ornithine phenylacetate (OP) has been proven effective in lowering ammonia plasma levels in animals, and to be well tolerated in cirrhotic patients. A trial to assess OP efficacy in lowering plasma ammonia levels versus placebo in cirrhotic patients after an upper gastrointestinal bleeding was performed. The primary outcome was a decrease in venous plasma ammonia at 24 hours., Methods: A total of 38 consecutive cirrhotic patients were enrolled within 24 hours of an upper gastrointestinal bleed. Patients were randomized (1:1) to receive OP (10 g/day) or glucosaline for 5 days., Results: The primary outcome was not achieved. A progressive decrease in ammonia was observed in both groups, being slightly greater in the OP group, with significant differences only at 120 hours. The subanalysis according to Child-Pugh score showed a statistically significant ammonia decrease in Child-Pugh C-treated patients at 36 hours, as well as in the time-normalized area under the curve (TN-AUC) 0-120 hours in the OP group [40.16 μmol/l (37.7-42.6); median (interquartile range) (IQR)] versus placebo group [65.5 μmol/l (54-126); p = 0.036]. A decrease in plasma glutamine levels was observed in the treated group compared with the placebo group, and was associated with the appearance of phenylacetylglutamine in urine. Adverse-event frequency was similar in both groups. No differences in hepatic encephalopathy incidence were observed., Conclusions: OP failed to significantly decrease plasma ammonia at the given doses (10 g/day). Higher doses of OP might be required in Child-Pugh A and B patients. OP appeared well tolerated., Competing Interests: Conflict of Interest statement: Potential competing interests: Juan Córdoba (deceased) received consulting fees from Ocera Therapeutics Inc. The remaining authors declare that they have nothing to disclose. Study medication was purchased from Ocera Therapeutics Inc., by the promoters of the study.

Background: Hospital mortality in patients with spontaneous bacterial peritonitis (SBP) is high despite albumin treatment, particularly in those with worse liver and/or renal function., Aim: To determine the independent predictive factors of in-hospital mortality and to create and validate a predictive model of mortality in patients with SBP., Methods: We analysed all cirrhotic patients with high-risk SBP (serum urea ≥11 mmol/L and/or serum bilirubin ≥68 μmol/L) between 2001 and 2011. We developed a predictive model of in-hospital mortality and validated this in a different cohort., Results: We included 118 high-risk SBP episodes treated with antibiotics and albumin. In-hospital mortality was 33/118 (28%). The independent predictive factors of in-hospital mortality at SBP diagnosis were serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure. A predictive model including these four variables showed a discrimination accuracy (AUC) of 0.850, 95% CI 0.777-0.922. A cut-off point of 0.245 showed a sensitivity of 0.85 and specificity of 0.75. The in-hospital mortality was 28/49 (57.1%) in patients with a model value ≥0.245, and 5/69 (7.2%) in patients with a model value <0.245 (P < 0.001). The validation series included 161 patients with an in-hospital mortality of 40/161 (24.8%), 30/77 (39.0%) in patients with a model value ≥0.245, and 10/84 (11.9%) in those with a model value <0.245 (P < 0.001)., Conclusions: We developed and validated a predictive model of mortality that includes serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure in high-risk patients with spontaneous bacterial peritonitis. These findings may help to identify patients who would benefit from additional therapeutic strategies., (© 2016 John Wiley & Sons Ltd.)

The progression of cirrhosis is associated with alterations in the composition of the gut microbiome. To assess microbial translocation, we compared the serum microbial composition of patients with and without ascites and characterized the ascitic fluid microbiome using 16S rDNA high-throughput sequencing data. A complex and specific microbial community was detected in the serum and ascitic fluid of patients with cirrhosis but barely detectable in the serum of healthy controls. The serum microbiome of patients with ascites presented higher levels of lipopolysaccharide binding protein, a marker of microbial translocation, associated with higher diversity and relative abundance of Clostridiales and an unknown genus belonging to the Cyanobacteria phylum compared to patients without ascites. The composition of the fecal microbiome was also more altered in patients with than without ascites, confirming previous studies on fecal microbiome. We propose that alteration of the serum and fecal microbiome composition be considered indicators of cirrhosis progression.

Unlabelled: Patients with cirrhosis often have functional limitations, decreased muscle mass, and a high risk of falls. These variables could improve with exercise. The aim was to study the effects of moderate exercise on functional capacity, body composition and risk of falls in patients with cirrhosis. Twenty-three cirrhotic patients were randomized to an exercise programme (n = 14) or to a relaxation programme (n = 9). Both programmes consisted of a one-hour session 3 days a week for 12 weeks. At the beginning and end of the study, we measured functional capacity using the cardiopulmonary exercise test, evaluated body composition using anthropometry and dual energy X-ray absorptiometry, and estimated risk of falls using the Timed Up&Go test. In the exercise group, cardiopulmonary exercise test showed an increase in total effort time (p<0.001) and ventilatory anaerobic threshold time (p = 0.009). Upper thigh circumference increased and mid-arm and mid-thigh skinfold thickness decreased. Dual energy X-ray absorptiometry showed a decrease in fat body mass (-0.94 kg, 95%CI -0.48 to -1.41, p = 0.003) and an increase in lean body mass (1.05 kg, 95%CI 0.27 to 1.82, p = 0.01), lean appendicular mass (0.38 kg, 95%CI 0.06 to 0.69, p = 0.03) and lean leg mass (0.34 kg, 95%CI 0.10 to 0.57, p = 0.02). The Timed Up&Go test decreased at the end of the study compared to baseline (p = 0.02). No changes were observed in the relaxation group. We conclude that a moderate exercise programme in patients with cirrhosis improves functional capacity, increases muscle mass, and decreases body fat and the Timed Up&Go time., Trial Registration: ClinicalTrials.gov NCT01447537.

Chagas disease is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi (T. cruzi), whose reemergence as oral outbreaks is currently a public health problem in Venezuela. T. cruzi infection induces myocardial damage; which according to the microvascular theory, is derived from parasite-mediated disruption of the endothelium, inducing platelet aggregation and ischemia. In order to determine whether ventricular repolarization disorders observed in human patients are characteristic signs of the disease that can be reproduced in NMRI mice; we studied 12 patients with a well documented diagnosis of acute Chagas disease, based on epidemiological, clinical, parasitological and molecular data. Also, T. cruzi isolates from the blood of human patients from other Venezuelan geographical regions were characterized and inoculated in albino NMRI mice. A standard 12-lead and bipolar electrocardiogram configuration were done in human patients during the acute phase of the disease and in mice, after three weeks of infection. Results in human showed repolarization disorders, characterized by: negative, bimodal or biphasic T waves, ST segment depression or elevation and early repolarization. In mice a significant increase in T wave amplitude, increased QT interval duration and elevation or depression of ST segment were observed. These findings were evidenced in all infected mice, suggesting that electrocardiographic repolarization abnormalities in a well documented clinical and epidemiological context are signs that increase the sensitivity for the diagnosis of acute Chagas' disease.

Adenosine released during ischemia and hypoxia can induce ventricular arrhythmias. This phenomenon is also observed in Chagas disease. This study involved pharmacologic analysis of the arrhythmogenic properties of adenosine in healthy Sprague-Dawley rats (n=14) and in rats with chronic Chagas cardiomyopathy (n=14). Electrocardiographic and pharmacologic studies were performed on isolated hearts prepared using the Langendorff method. Adenosine increased ventricular arrhythmias in both groups of animals in a dose-dependent manner: 50% of chagasic rats developed ventricular fibrillation compared with 7.14% of healthy rats (P< .05). Fibrillation was prevented by A1 (i.e., DPCPX) and A2a (i.e., 8-CSC) receptor antagonists. Arrhythmia was associated with a prolonged QT interval, early depolarization, and the R-on-T and torsade de pointes phenomena. In conclusion, adenosine is a proarrythmic drug that is able to induce ventricular fibrillation in chagasic rat hearts.