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An introduction to the journal is presented in which the editor discusses various reports within the issue on topics including probiotics, cirrhosis, and hepatic venous pressure gradient (HVPG).

Background and Aims: Decompensated‐cirrhosis encompasses several stages with different prognosis, such as bleeding, ascites and bleeding‐plus‐ascites. Development of further‐decompensation worsens survival, while non‐selective β‐blockers (NSBBs) can modify the risk. However, how this applies to each stage is uncertain. We aimed to investigate, in each stage of decompensated‐cirrhosis, the influence of further‐decompensation on mortality and whether changes in portal‐pressure (HVPG) under NSBBs influence these outcomes. Methods: Patients with variceal bleeding were consecutively included differentiating those with bleeding‐alone from those who also had ascites. Patients with ascites and high‐risk varices referred for primary‐prophylaxis were also investigated. A baseline haemodynamic study was performed and was repeated after 1‐3‐months under NSBBs. Outcomes were investigated by competing‐risk. Results: Totally 103 patients had bleeding‐alone, 186 bleeding‐plus‐ascites and 187 ascites‐alone. Mean follow‐up was 32‐months (IQR, 12–60). Patients with bleeding‐plus‐ascites had higher HVPG and were more hyperdynamic than patients with ascites‐alone and these than those with bleeding‐alone. At each stage, the mortality risk was more than twice in patients developing further‐decompensation vs. those without (p <.001). In each stage, HVPG‐decrease under NSBBs showed better discrimination to predict further‐decompensation than the baseline MELD, Child–Pugh or HVPG, by time‐dependent ROC‐curves (c‐statistic >70%). At each stage, patients without HVPG‐decreases, either ≥10% or ≥20% from the baseline, had higher risk of further‐decompensation (sHR from 2.43 to 6.73, p <.01) and worse survival. Conclusions: In each stage of decompensated cirrhosis, mortality risk significantly and very markedly increase with further‐decompensation. HVPG‐non‐response to NSBBs may adequately stratify the risk of further decompensation and death, in each stage. This suggests potential benefit with pre‐emptive therapies in HVPG‐non‐responders at each‐stage. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alterations in intestinal microbiota and inflammatory response play a key role in disease progression and development of complications in liver diseases, mainly in cirrhosis and non-alcoholic steatohepatitis. Probiotics can be useful to delay disease progression and to prevent development of complications due to their ability to modulate intestinal flora, intestinal permeability and inflammatory response. Several studies have shown the efficacy of probiotics in the treatment of minimal hepatic encephalopathy and the prevention of episodes of overt hepatic encephalopathy. Probiotics have also been observed to prevent postoperative bacterial infections and to improve liver damage in non-alcoholic steatohepatitis. However, more studies are needed in order to confirm the efficacy and safety of probiotics in patients with liver diseases, and to better understanding of the mechanisms implicated in their effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Delayed bleeding (DB) is the most common major complication of endoscopic mucosal resection (EMR). Two randomized clinical trials recently demonstrated that clip closure after EMR of large nonpedunculated colorectal polyps (LNPCPs) reduces the risk of DB. We analyzed the cost-effectiveness of this prophylactic measure. METHODS: EMRs of LNCPCPs were consecutively registered in the ongoing prospective multicenter database of the Spanish EMR Group from May 2013 until July 2017. Patients were classified according to the Spanish Endoscopy Society EMR group (GSEED-RE2) DB risk score. Cost-effectiveness analysis was performed for both Spanish and US economic contexts. The average incremental cost-effectiveness ratio (ICER) thresholds were set at 54,000 € or $100,000 per quality-adjusted life year, respectively. RESULTS: Weregistered 2,263 EMRs in 2,130 patients. Applying their respective DB relative risk reductions after clip closure (51% and 59%), the DB rate decreased from 4.5% to 2.2% in the total cohort and from 13.7% to 5.7% in the high risk of the DB GSEED-RE2 subgroup. The ICERs for the universal clipping strategy in Spain and the United States, 469,706 € and $1,258,641, respectively, were not cost effective. By contrast, selective clipping in the high-risk of DB GSEED-RE2 subgroup was cost saving, with a negative ICER of -2,194 € in the Spanish context and cost effective with an ICER of $87,796 in the United States. DISCUSSION: Clip closure afterEMR of large colorectal lesions is cost effective in patients with a high risk of bleeding. The GSEED-RE2 DB risk score may be a useful tool to identify that high-risk population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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). 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). 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. 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. • Patients with decompensated cirrhosis have different hemodynamic responses to beta blockers than patients with compensated cirrhosis. • Patients with decompensated cirrhosis have greater reductions in CO and smaller reductions in portal pressure. • The effect of beta blockers on CO may reduce survival times of patients with decompensated cirrhosis. • Careful dose titration of beta blockers using non-invasive CO-monitoring may help in patients with decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Data on the outcome of adverse events (AEs) and the risk of developing acute-on-chronic liver failure (ACLF) after ERCP in patients with cirrhosis are unknown. We examined the incidence and risk factors of post-ERCP AEs in patients with cirrhosis and the appearance of ACLF after ERCP. METHODS: In this multicenter, retrospective, matched-cohort study, we evaluated ERCPs performed from January 2002 to 2015. A group of patients with cirrhosis with non-ERCP interventions and one without interventions was also analyzed for the development of ACLF. RESULTS: A total of 441 ERCPs were analyzed; 158 in patients with cirrhosis (cases) and 283 in patients without cirrhosis (controls). The overall rate of AEs after all ERCPs was significantly higher in cases compared to controls (17% vs 9.5, p = 0.02). Cholangitis developed more in cases compared to controls (6.3% vs 1.8%; p = 0.01). In a subanalysis of those with sphincterotomy, the rate of bleeding was higher in those with cirrhosis (9.4% vs 3.4%; p = 0.03). Logistic regression identified cirrhosis (OR, 2.48; 95% CI, 1.36–4.53; p = 0.003) and sphincterotomy (OR, 2.66; 95% CI, 1.23–5.72; p = 0.01) as risk factors of AEs. A total of 18/158 (11.4%) cases developed ACLF after ERCP. ACLF occurred in 7/27 cases with post-ERCP AEs and in 11/131 without post-ERCP AEs (25.9% vs 8.3%; p = 0.01). A total of 3.2% (13/406) patients without interventions developed ACLF compared to 17.5% (102/580) who developed ACLF after non-ERCP interventions. Patients with decompensated cirrhosis at ERCP had a higher risk of developing ACLF (17% vs 6.8%; p = 0.04). Patients with a MELD score ≥ 15 were 3.1 times more likely (95% CI: 1.14–8.6; p = 0.027) to develop ACLF after ERCP. CONCLUSIONS: The rate of AEs after ERCP is higher in patients with cirrhosis compared to the non-cirrhotic population. The incidence of ACLF is higher in those with AEs after ERCP compared to those without AEs, especially cholangitis. The development of ACLF is common after ERCP and other invasive procedures. ACLF can be precipitated by numerous factors which include preceding events before the procedure, including manipulation of the bile duct, and AEs after an ERCP. [ABSTRACT FROM AUTHOR]

Background and Study Aims: Precut sphincterotomy increases the success of deep biliary cannulation, but the method fails at the initial ERCP in 5-12% of cases. Although other invasive strategies are often used to access the bile duct, a second ERCP may be effective and safe. We evaluated the efficacy, safety, and factors related to a second ERCP after failed cannulation using a precut sphincterotomy.Patients and Methods: We reviewed all patients that underwent an ERCP with native papilla from 2006 to 2014 at two tertiary institutions. Efficacy was based on the cannulation rate of the second ERCP, and safety was assessed in terms of adverse events.Results: We identified 112 patients with failed cannulation after precut, and a second ERCP was performed in 72 (64.3%). Median time between procedures was 7 days (IQR 5-11). Deep cannulation was achieved in 54 cases (75%). The only factor associated with cannulation failure was an ERCP within 4 days after the initial precut (cannulation success 44.4 vs. 79.4% after 4 days, p = 0.026). Adverse events were recorded after the first ERCP in 13 of 112 patients (11.8%): delayed bleeding in four, pancreatitis in five, and perforation in four. After the second ERCP, three of 72 patients (4.2%) presented adverse events: two delayed bleeding and one pancreatitis.Conclusions: A second ERCP after failure of initial biliary cannulation following precut appears to be safe and effective. A second ERCP should be delayed at least 4 days if feasible. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Background & Aim: Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls. Patients and methods: Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson’s Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson’s Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients. Results: The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson’s Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05). Conclusions: With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment. [ABSTRACT FROM AUTHOR]

Background & Aims Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis. Methods Forty-six Sprague-Dawley rats with CCl4-induced cirrhosis were randomized into two groups: VSL#3 group ( n = 22) that received VSL#3 in drinking water, and water group ( n = 24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed 1 week after development of ascites or at week 20. A control group included 11 healthy rats. At this study end, we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin-2 and 4, β-defensin-1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines. Results Mortality during this study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) ( P = 1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group ( P = 0.03 vs. VSL#3 group) and 0/11 in the control group ( P = 0.008 vs. water group). The concentration of ileal and caecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF-α were lower in the VSL#3 group than in the water group ( P < 0.05). Conclusions VSL#3 decreases bacterial translocation, the pro-inflammatory state and ileal oxidative damage and increases ileal occludin expression in rats with experimental cirrhosis. [ABSTRACT FROM AUTHOR]

Background and study aims: Meta-analyses suggest that an intravenous bolus or a high dose continuous infusion of somatostatin reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Clinical guidelines, however, do not recommend this prophylaxis. The aim of this randomized, double-blind clinical trial was to evaluate the effect of somatostatin on the incidence of post- ERCP pancreatitis. Patients and methods: Patients undergoing ERCP at a single center were randomized to either intravenous bolus of somatostatin followed by a short (4-hour) continuous infusion, or to a similar placebo regimen. The primary outcome was post- ERCP pancreatitis, defined as abdominal pain with an amylase level at least three times higher than the upper limit of normality 24 hours after the ERCP and requiring admission for at least 2 days. Results: A total of 510 patientswere enrolled (255 patients per group) and all completed follow-up. The main indications for ERCP were choledocholithiasis (62 %), and biliary malignant stricture (31 %). Post-ERCP pancreatitis occurred in 19 patients (7.5 %) in the somatostatin group and 17 patients (6.7 %) in the placebo group (relative risk [RR] 1.12, 95% confidence interval [95%CI] 0.59-2.1; P=0.73). The number of cases of moderate or severe acute pancreatitis was similar in the somatostatin (2.4 %) and the placebo (3.5 %) groups (RR 0.67, 95%CI 0.24-1.85, P=0.43). No side effects were observed related to the use of somatostatin. Conclusions: Administration of an intravenous bolus of somatostatin followed by a short continuous infusion does not reduce the incidence of post-ERCP pancreatitis. [ABSTRACT FROM AUTHOR]

Background: Physical exercise could improve functional limitations, muscle mass, and health-related quality of life (HRQoL) in patients with cirrhosis. Aim: The purpose of this study was to evaluate the efficacy and safety of an exercise programme and leucine supplementation to increase exercise capacity, muscle mass, and HRQoL in patients with cirrhosis. Patients and Methods: Seventeen outpatients with cirrhosis were randomized to an exercise group ( n = 8) or a control group ( n = 9) in a pilot study. The programme of moderate exercise was performed for 12 weeks under supervision of a physiotherapist. All patients received oral leucine (10 g/day) during the study. At baseline and at the end of the study, we determined exercise capacity (6-min walk and 2-min step tests), anthropometric measurements, and HRQoL by Short Form-36 (SF-36) questionnaire. We also analyzed safety regarding complications of cirrhosis, liver and renal function, inflammatory response and oxidative stress. Results: In the exercise group, exercise capacity improved, as shown by the increase in the 6-min walk test from 365 (160-420) to 445 m (250-500) ( p = 0.01), and in the 2-min step test ( p = 0.02). Lower thigh circumference also increased, from 41 (34-53) to 46 cm (36-56) ( p = 0.02), and the domains of SF-36 general health ( p = 0.03), vitality ( p = 0.01) and social function ( p = 0.04) improved significantly. In the control group, no statistically significant changes were observed in any of the parameters. We did not observe complications of cirrhosis in either group during the study. Conclusions: A programme of moderate physical exercise together with leucine supplements in patients with cirrhosis is safe and improves exercise capacity, leg muscle mass and HRQoL. [ABSTRACT FROM AUTHOR]

Background & Aims Combined therapy with endoscopic variceal ligation ( EVL) and β-blockers ± isosorbide mononitrate ( ISMN) is currently recommended to prevent variceal rebleeding. However, the role of this combined therapy has been challenged by some studies. We performed a systematic review to assess the value of combined therapy with EVL and β-blockers ± ISMN as compared with each treatment alone to prevent rebleeding. Methods Databases, references and meeting abstracts were searched to retrieve randomized trials comparing combined therapy with EVL and β-blockers ± ISMN vs either treatment alone, to prevent variceal rebleeding in cirrhosis. Random-effects model was used for meta-analysis. Results We identified five studies comparing EVL alone or combined with drugs, including a total of 476 patients. Combination therapy reduced overall rebleeding [risk ratios (RR) = 0.44, 95% confidence interval (CI) = 0.28-0.69], and showed a trend towards lower mortality (RR = 0.58, 95% CI = 0.33-1.03), without increasing complications. We identified four trials comparing drugs alone or associated with EVL, including 409 patients. All used β-blockers plus ISMN. Variceal rebleeding decreased with combined therapy ( P < 0.01) but rebleeding from oesophageal ulcers increased ( P = 0.01). Overall, there was a trend towards lower rebleeding (RR = 0.76, 95% CI = 0.58-1.00) without effect on mortality (RR = 1.24, 95% CI = 0.90-1.70). Conclusions The addition of drug therapy to EVL improves the efficacy of EVL alone. However, the addition of EVL to β-blockers and ISMN achieves a non-significant decrease of rebleeding with no effect on mortality. Although combination therapy with EVL plus β-blockers ± ISMN is adequate to prevent rebleeding, β-blockers + ISMN alone may be a valid alternative. [ABSTRACT FROM AUTHOR]

Background & Aims: Refractory ascites (RA) affects 10% of patients with advanced cirrhosis and ascites. Usual therapy includes large volume paracentesis, and in selected patients, a transjugular portosystemic shunt (TIPS). These therapies may be associated with increased morbidity: paracentesis may induce circulatory dysfunction and impair quality of life and TIPS may induce encephalopathy and is associated with increased mortality in patients with severe liver dysfunction. We present the results of a multicenter, non-randomized trial to assess the safety and efficacy of a new automated pump system for treatment of RA. Methods: Forty patients at 9 centers (February 2010–June 2011) received an implanted pump for the automated removal of ascites from the peritoneal cavity into the bladder, from where it was eliminated through normal urination. Patients were followed-up for 6months. The primary study outcome was safety. Secondary outcomes included recurrence of tense ascites and pump performance. Results: Surgical complications occurred early in the study and became less frequent. The pump system removed 90% of the ascites and significantly reduced the median number of large volume paracentesis per month [3.4 (range 1–6) vs. 0.2 (range 0–4); p <0.01]. Cirrhosis-related adverse events decreased along follow-up. Conclusions: The automated pump seems an efficacious tool to move out ascites from the peritoneal cavity to the bladder. Its safety is still moderate, but a broad use in different countries will improve the surgical technique as well as the medical surveillance. A prospective randomized clinical trial vs. large volume paracentesis is underway to confirm these preliminary results. [Copyright &y& Elsevier]

Bacterial peritonitis is a severe complication in patients with cirrhosis and ascites and despite antibiotic treatment, the inflammatory response to infection may induce renal dysfunction leading to death. This investigation evaluated the effect of TNF-α blockade on the inflammatory response and mortality in cirrhotic rats with induced bacterial peritonitis treated or not with antibiotics. Sprague-Dawley rats with carbon-tetrachloride-induced cirrhosis were treated with an intraperitoneal injection of 109 CFU of Escherichia coli diluted in 20 mL of sterile water to induce bacterial peritonitis and randomized to receive subcutaneously-administered placebo, ceftriaxone, anti-TNF-α mAb and ceftriaxone, or anti-TNF-α mAb alone. No differences were observed between groups at baseline in respect to renal function, liver hepatic tests, serum levels of nitrite/nitrate and TNF-α. Treatment with ceftriaxone reduced mortality (73.3%) but differences did not reach statistical significance as compared to placebo. Mortality in rats treated with ceftriaxone and anti-TNF-α mAb was significantly lower than in animals receiving placebo (53% vs. 100%, p<0.01). Serum TNF-α decreased significantly in surviving rats treated with ceftriaxone plus anti-TNF-α mAb but not in treated with antibiotics alone. Additional studies including more animals are required to assess if the association of antibiotic therapy and TNF-α blockade might be a possible approach to reduce mortality in cirrhotic patients with bacterial peritonitis. [ABSTRACT FROM AUTHOR]

The article presents the study which evaluated whether a restrictive threshold for red-cell transfusion in patients with acute gastrointestinal bleeding is safer and more effective than a liberal transfusion strategy. The study was conducted at the Hospital de la Santa Creu i Sant Pau in Barcelona, Spain on June 2003-December 2009. Based on the results, the restrictive strategy substantially improved results in patients with acute upper gastrointestinal bleeding.

OBJECTIVES:In compensated cirrhosis, a threshold value of hepatic venous pressure gradient (HVPG) ≥10 mm Hg is required for the development of decompensation. However, whether the treatment of portal hypertension (PHT) can prevent the transition into development of ascites once this level has been reached is unclear. Our aim was to assess the relationship between changes in HVPG induced by β-blockers and development of ascites in compensated cirrhosis with severe PHT.METHODS:Eighty-three patients without any previous decompensation of cirrhosis, with large esophageal varices and HVPG ≥12 mm Hg were included. After baseline hemodynamic measurements nadolol was administered and a second hemodynamic study was repeated 1-3 months later.RESULTS:During 53±30 months of follow-up, decompensation occurred in 52 patients (62%) and in 81% of them ascites was the first manifestation. Using receiver operating characteristic curve analysis a decrease in HVPG ≥10% was the best cutoff to predict ascites. As compared with nonresponders, patients with an HVPG decrease ≥10% had a lower probability of developing ascites (19% vs. 57% at 3 years, P<0.001), refractory ascites (P=0.007), and hepatorenal syndrome (P=0.027). By Cox regression analysis hemodynamic nonresponse was the best predictor of ascites. By stepwise logistic regression, development of ascites was independently associated with nonresponse, whereas refractory ascites, hepatorenal syndrome, and spontaneous bacterial peritonitis were not.CONCLUSIONS:In patients with compensated cirrhosis and large varices treated with β-blockers, an HVPG decrease ≥10% significantly reduces the risk of developing ascitic decompensation and other related complications such as refractory ascites or hepatorenal syndrome. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Minimal hepatic encephalopathy (MHE) reduces quality of life and impacts daily functioning. It is known to impair fitness to drive, but deficits in attention and reaction may also be associated with falls. Falls may have important consequences in patients with cirrhosis due to coagulopathy, osteoporosis, and operative risk. However, the relationship between MHE and falls has not yet been evaluated. The objective of this study is to retrospectively investigate whether MHE is associated with falls in patients with cirrhosis.METHODS:We included 130 cirrhotic outpatients and 43 controls. MHE was diagnosed according to the results of the psychometric hepatic encephalopathy score (PHES). We recorded the reported incidence and number of falls in the 12 months before the study, the severity of injuries, and the need for healthcare services.RESULTS:Forty-five (34.6%) patients with cirrhosis exhibited MHE. The proportion of patients with MHE that reported falls (40%) was higher than those without MHE (12.9%, P<0.001), which was similar to controls (11.6%). In patients with MHE, there was a higher need for primary healthcare services (8.8 vs. 0%, P=0.004) and hospitalization (6.6 vs. 2.3%, P=0.34) due to falls than in patients without MHE. Patients on psychoactive drugs (n=21) showed a stronger association between MHE and falls: 6/8 (75%) patients with MHE presented falls vs. 2/13 (15.3%) patients without MHE (P=0.01). In patients not receiving psychoactive drugs (n=109), the incidence of falls was 12/37 (32.4%) in patients with MHE vs. 9/72 (12.5%) in those without MHE (P=0.01). Multivariate analysis showed that MHE (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.13-7.48, P=0.02), previous encephalopathy (OR: 2.87, 95% CI: 1.10-7.50, P=0.03), and antidepressant therapy (OR: 3.91, 95% CI: 0.96-15.9, P=0.05) were independent factors associated to previous falls.CONCLUSIONS:Falls are more frequent in cirrhotic patients with MHE, particularly in those on treatment with psychoactive drugs, and are a significant cause for healthcare and hospitalization requirements. [ABSTRACT FROM AUTHOR]

Background: Advances in intensive care support such as therapeutic hypothermia or new liver assist devices have been the mainstay of treatment attempting to bridge the gap from acute liver failure to liver transplantation, but the efficacy of the available devices in reducing mortality has been questioned. To address this issue, the present animal study was aimed to analyze the pure clinical effects of a simple extracorporeal dummy device in an anhepatic porcine model of acute liver failure. Methods: Total hepatectomy was performed in ten female pigs followed by standardized intensive care support until death. Five animals (dummy group, n = 5) underwent additional cyclic connection to an extracorporeal dummy device which consisted of a plasma separation unit. The separated undetoxified plasma was completely returned to the pigs circulation without any plasma substitution or exchange in contrast to animals receiving intensive care support alone (control group, n = 5). All physiological parameters such as vital and ventilation parameters were monitored electronically; laboratory values and endotoxin levels were measured every 8 hours. Results: Survival of the dummy device group was 74 ± 6 hours in contrast to 53 ± 5 hours of the control group which was statistically significant (p < 0.05). Body temperature 24 hours after hepatectomy was significantly lower (36.5 ± 0.5°C vs. 38.2 ± 0.7°C) in the dummy device group. Significant lower values were measured for blood lactate (1.9 ± 0.2 vs. 2.5 ± 0.5 mM/L) from 16 hours, creatinine (1.5 ± 0.2 vs. 2.0 ± 0.3 mg/dL) from 40 hours and ammonia (273 ± 122 vs. 1345 ± 700 μg/dL) from 48 hours after hepatectomy until death. A significant rise of endotoxin levels indicated the onset of sepsis at time of death in 60% (3/5) of the dummy device group animals surviving beyond 60 hours from hepatectomy. Conclusions: Episodes of slight hypothermia induced by cyclic connection to the extracorporeal dummy device produced a significant survival benefit of more than 20 hours through organ protection and hemodynamic stabilisation. Animal studies which focus on a survival benefit generated by liver assist devices should especially address the aspect of slight transient hypothermia by extracorporeal cooling. [ABSTRACT FROM AUTHOR]

Hyponatraemia is common in patients with advanced cirrhosis and is associated with remarkable changes in brain cells, particularly a reduction in myoinositol and other intracellular organic osmolytes related to the hypo-osmolality of the extracellular fluid. It has been recently suggested that hyponatraemia may be an important factor associated with the development of overt hepatic encephalopathy (HE). To test this hypothesis, we retrospectively analysed the incidence and predictive factors of overt HE using a database of 70 patients with cirrhosis included in a prospective study comparing transjugular intrahepatic portosystemic shunts (TIPS) vs large-volume paracentesis in the management of refractory of ascites. Variables used in the analysis included age, sex, previous history of HE, treatment assignment (TIPS vs large volume paracentesis plus albumin), treatment with diuretics, serum bilirubin, serum creatinine and serum sodium concentration. Laboratory parameters were measured at entry, at 1 month and every 3 months during follow-up and at the time of development of HE in patients who developed this complication. During a mean follow-up of 10 months, 50 patients (71%) developed 117 episodes of HE. In the whole population of patients, the occurrence of HE was independently associated with serum hyponatraemia, serum bilirubin and serum creatinine. In conclusion, in patients with refractory ascites, the occurrence of HE is related to the impairment of liver and renal function and presence of hyponatraemia. [ABSTRACT FROM AUTHOR]

Background & Aims: Secondary bacterial peritonitis in cirrhotic patients is an uncommon entity that has been little reported. Our aim is to analyse the frequency, clinical characteristics, treatment and prognosis of patients with secondary peritonitis in comparison to those of patients with spontaneous bacterial peritonitis (SBP). Methods: Retrospective analysis of 24 cirrhotic patients with secondary peritonitis compared with 106 SBP episodes. Results: Secondary peritonitis represented 4.5% of all peritonitis in cirrhotic patients. Patients with secondary peritonitis showed a significantly more severe local inflammatory response than patients with SBP. Considering diagnosis of secondary peritonitis, the sensitivity of Runyon’s criteria was 66.6% and specificity 89.7%, Runyon’s criteria and/or polymicrobial ascitic fluid culture were present in 95.6%, and abdominal computed tomography was diagnostic in 85% of patients in whom diagnosis was confirmed by surgery or autopsy. Mortality during hospitalization was higher in patients with secondary peritonitis than in those with SBP (16/24, 66.6% vs. 28/106, 26.4%) (p <0.001). There was a trend to lower mortality in secondary peritonitis patients who underwent surgery (7/13, 53.8%) than in those who received medical treatment only (9/11, 81.8%) (p =0.21). Considering surgically treated patients, the time between diagnostic paracentesis and surgery was shorter in survivors than in non-survivors (3.2±2.4 vs. 7.2±6.1days, p =0.31). Conclusions: Secondary peritonitis is an infrequent complication in cirrhotic patients but mortality is high. A low threshold of suspicion on the basis of Runyon’s criteria and microbiological data, together with an aggressive approach that includes prompt abdominal computed tomography and early surgical evaluation, could improve prognosis in these patients. [Copyright &y& Elsevier]

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a severe complication of cirrhotic patients associated with a high mortality. AIM: To develop an available experimental model of induced bacterial peritonitis in cirrhosis. MATERIAL Sprague-Dawley rats with carbon-tetrachloride-induced cirrhosis with (N = 22) or without (N = 101) AND METHODS: ascites were randomized to receive an intraperitoneal administration of different concentrations of Escherichia coli ( E. coli) diluted in 1 mL of sterile water in ascitic rats and in different volumes in nonascitic rats. A subgroup of nonascitic animals received ceftriaxone 4 h after E. coli inoculation. Mortality of rats was evaluated 24 h after bacterial inoculation. RESULTS: None of the rats receiving sterile water alone and only one infected with 107 cfu of E. coli died. Ascitic rats showed a lower mortality rate than nonascitic rats infected with 108 or 109 cfu of E. coli ( P < 0.05). Mortality was higher with 109 cfu than with 108 cfu of E. coli in ascitic ( P NS) and nonascitic ( P < 0.01) rats. A trend was noted to ward higher mortality in nonascitic rats inoculated with 108 cfu with increasing water volumes. A marked peritoneal polymorphonuclear cell response was observed 4 h after E. coli injection in both ascitic and nonascitic rats. Antibiotic therapy significantly reduced the mortality rate of rats infected with 108 cfu ( P < 0.01). CONCLUSIONS: This experimental model of induced bacterial peritonitis in cirrhosis with or without ascites may represent a useful tool for the study of pathogenic events postinfection and for the design of new therapeutic strategies to treat patients with SBP. [ABSTRACT FROM AUTHOR]

Background/Aims: TNF-α is involved in the development of bacterial translocation in rats with cirrhosis. The aim of the current study was to evaluate the effect of anti-TNF-α mAb treatment on the incidence of bacterial translocation and systemic infections in rats with cirrhosis and ascites. Methods: Thirty rats with cirrhosis and ascites were randomly assigned to receive two intraperitoneal doses of anti-TNF-α mAb, distilled water or immunoglobulin on days 0 and 4. On day 10, a laparotomy was performed. Results: One out of 11 animals receiving anti-TNF-α mAb treatment, 7 out of 10 of the placebo group (p <0.01), and 5 out of 9 of the IgG group developed bacterial translocation (p <0.05). A significantly reduced number of systemic infections were observed in animals receiving anti TNF-α mAb treatment vs animals receiving placebo (p <0.01). TNF-α in serum at laparotomy in animals receiving anti-TNF-α mAb was higher than that in the rest of groups and was also higher in the overall series of animals showing bacterial translocation. Conclusions: In the experimental model of CCl4-induced rat with cirrhosis and ascitic fluid, anti-TNF-α mAb administration decreases the incidence of bacterial translocation, in a TNF-α/sTNF-α receptor-independent manner, without increasing the risk of systemic infections. [Copyright &y& Elsevier]

: Background/AimsFollowing treatment with beta blockers in patients with cirrhosis and portal hypertension, reduction of hepatic venous pressure gradient (HVPG) to <12 mmHg or by >20% of baseline induces an extremely low risk of variceal bleeding. However, several factors such as compliance to therapy or alcohol abstinence may change the initial response after a long follow-up, and the effect of response on other complications of cirrhosis is less clear. The aim of this study was to assess the long-term maintenance of hemodynamic response and its influence on complications of cirrhosis.: MethodsOne hundred and thirty two cirrhotic patients received nadolol and isosorbide mononitrate to prevent variceal rebleeding. HVPG was measured at baseline, after 1 to 3 months under treatment and again 12 to 18 months later.: ResultsSixty four patients were responders. After a longer follow-up, earlier response did not change in 81% of cases. Changes of response were mainly related to modifications in medication dose or in alcohol intake. As compared with poor-responders, responders had a lower probability of developing ascites (P<0.001) and related conditions, a greater improvement of Child-Pugh score (P=0.03), and a lower likelihood of developing encephalopathy (P=0.001) and of requiring liver transplantation (P=0.002). Eleven responders and 22 poor-responders died (P=0.029).: ConclusionsHemodynamic response to treatment of portal hypertension is usually sustained after a long-term follow-up. Response decreases the probability of developing complications of cirrhosis and the need for liver transplantation, and significantly improves survival. [Copyright &y& Elsevier]

Background/Aims: Probiotics and antioxidants could be alternatives to antibiotics in the prevention of bacterial infections in cirrhosis. The aim of the present study was to determine the effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora, endotoxemia, and bacterial translocation in cirrhotic rats.Methods: Twenty-nine Sprague–Dawley rats with cirrhosis induced by CCl4 and ascites received Lactobacillus johnsonii La1 109 cfu/day in vehicle (antioxidants: vitamin C+glutamate) (n=10), vehicle alone (n=11), or water (n=8) by gavage. Another eight non-cirrhotic rats formed the control group. After 10 days of treatment, a laparotomy was performed to determine microbiological study of ileal and cecal feces, bacterial translocation, endotoxemia, and intestinal malondialdehyde (MDA) levels as index of intestinal oxidative damage.Results: Intestinal enterobacteria and enterococci, bacterial translocation (0/11 and 0/10 vs. 5/8, P<0.01), and ileal MDA levels (P<0.01) were lower in cirrhotic rats treated with antioxidants alone or in combination with Lactobacillus johnsonii La1 compared to cirrhotic rats receiving water. Only rats treated with antioxidants and Lactobacillus johnsonii La1 showed a decrease in endotoxemia with respect to cirrhotic rats receiving water (P<0.05).Conclusions: Antioxidants alone or in combination with Lactobacillus johnsonii La1 can be useful in preventing bacterial translocation in cirrhosis. [Copyright &y& Elsevier]

Background: After an episode of acute bleeding from esophageal varices, patients are at high risk for recurrent bleeding and death. We compared two treatments to prevent recurrent bleeding--endoscopic ligation and combined medical therapy with nadolol and isosorbide mononitrate.Methods: We randomly assigned 144 patients with cirrhosis who were hospitalized with esophageal variceal bleeding to receive treatment with endoscopic ligation (72 patients) or the combined medical therapy (72 patients). Sessions of ligation were repeated every two to three weeks until the varices were eradicated. The initial dose of nadolol was 80 mg orally once daily, with adjustment according to the resting heart rate; isosorbide mononitrate was given in increasing doses, beginning at 20 mg once a day at bed time and rising over the course of one week to 40 mg orally twice a day, unless side effects occurred. The primary end points were recurrent bleeding, complications, and death.Results: The median follow-up period was 21 months. A total of 35 patients in the ligation group and 24 in the medication group had recurrent bleeding. The probability of recurrence was lower in the medication group, both for all episodes related to portal hypertension (P=0.04) and for recurrent variceal bleeding (P=0.04). There were major complications in nine patients treated with ligation (seven had bleeding esophageal ulcers and two had aspiration pneumonia) and two treated with medication (both had bradycardia and dyspnea) (P=0.05). Thirty patients in the ligation group died, as did 23 patients in the medication group (P=0.52). The probability of recurrent bleeding was lower for patients with a hemodynamic response to therapy, defined as a decrease in the hepatic venous pressure gradient of more than 20 percent from the base-line value or to less than 12 mm Hg (18 percent, vs. 54 percent in patients with no hemodynamic response at one year; P<0.001), and the probability of survival was higher (94 percent vs. 78 percent at one year, P=0.02).Conclusions: Combined therapy with nadolol and isosorbide mononitrate is more effective than endoscopic ligation for the prevention of recurrent bleeding and is associated with a lower rate of major complications. A hemodynamic response to treatment is associated with a better long-term prognosis. [ABSTRACT FROM AUTHOR]

Background: Patients who have bleeding from esophageal varices are at high risk for rebleeding and death. We compared the efficacy and safety of endoscopic sclerotherapy with the efficacy and safety of nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding.Methods: Eighty-six hospitalized patients with cirrhosis and bleeding from esophageal varices diagnosed by endoscopy were randomly assigned to treatment with repeated sclerotherapy (43 patients) or nadolol plus isosorbide-5-mononitrate (43 patients). The primary outcomes were rebleeding, death, and complications. The hepatic venous pressure gradient was measured at base line and after three months.Results: Base-line data were similar in the two groups, and the median follow-up was 18 months in both. Eleven patients in the medication group and 23 in the sclerotherapy group had rebleeding. The actuarial probability of remaining free of rebleeding was higher in the medication group for all episodes related to portal hypertension (P = 0.001) and variceal rebleeding (P = 0.002). Four patients in the medication group and nine in the sclerotherapy group died (P = 0.07 for the difference in the actuarial probability of survival). Seven patients in the medication group and 16 in the sclerotherapy group had treatment-related complications (P = 0.03). Thirty-one patients in the medication group underwent two hemodynamic studies; 1 of the 13 patients with more than a 20 percent decrease in the hepatic venous pressure gradient had rebleeding, as compared with 8 of the 18 with smaller decreases in the pressure gradient (P = 0.04) for the actuarial probability of rebleeding at two years).Conclusions: As compared with sclerotherapy, nadolol plus isosorbide mononitrate significantly decreased the risk of rebleeding from esophageal varices. [ABSTRACT FROM AUTHOR]

A letter to the editor about genotype-phenotype correlation in a Spanish population homozygous for the H63D mutation of the HFE gene is presented.

The article discusses the feasibility of lumen-apposing metal stent removal and replacement in the middle of necrosectomy sessions. Topics included are the possibility of stent displacement while extracting or fragmentating necrotic material, the presentation of a video of the stent removal and replacement maneuver performed during gastroscopic surgery on an alcoholic acute pancreatitis patient, and the justification for reusing the metal piece. [ABSTRACT FROM AUTHOR]

Probiotics can prevent pathological bacterial translocation by modulating intestinal microbiota and improving the gut barrier. The aim was to evaluate the effect of a fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 on bacterial translocation in rats with carbon tetrachloride (CCl4)-induced cirrhosis. Sprague-Dawley rats treated with CCl4 were randomized into a probiotic group that received fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 in drinking water or a water group that received water only. Laparotomy was performed one week after ascites development. We evaluated bacterial translocation, intestinal microbiota, the intestinal barrier and cytokines in mesenteric lymph nodes and serum. Bacterial translocation decreased and gut dysbiosis improved in the probiotic group compared to the water group. The ileal β-defensin-1 concentration was higher and ileal malondialdehyde levels were lower in the probiotic group than in water group. There were no differences between groups in serum cytokines but TNF-α levels in mesenteric lymph nodes were lower in the probiotic group than in the water group. Fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 decreases bacterial translocation, gut dysbiosis and ileal oxidative damage and increases ileal β-defensin-1 expression in rats treated with CCl4, suggesting an improvement in the intestinal barrier integrity. [ABSTRACT FROM AUTHOR]

Background: Acute liver injury (ALI) induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug.The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case.Methods: Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol.Results: In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8) and of 10 per million paracetamol users-year (95% CI 4.3-19.4).Conclusions: Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low. [ABSTRACT FROM AUTHOR]