BACKGROUND:Proton pump inhibitors (PPIs) are widely used for upper gastrointestinal symptoms but are frequently prescribed inappropriately and often continued without clear indications. Deprescribing PPIs can be challenging due to symptom recurrence or rebound acid hypersecretion. The mucosal protective agent Poliprotect, a natural formulation with barrier, antioxidant, and anti-inflammatory properties, has shown non-inferiority to omeprazole in non-erosive heartburn and epigastric pain syndrome (EPS) without affecting intestinal microbiota. AIM:To evaluate the role of Poliprotect formulation (neoBianacid) in maintaining symptom control after PPI withdrawal in patients with endoscopy-negative heartburn (HRTB) and EPS. METHODS:This post hoc analysis used data from a multicenter, double-blind RCT including 125 endoscopy-negative patients (80 with HRTB, 45 with EPS) treated with omeprazole 20 mg/day for 4 weeks, followed by 4 weeks of on-demand Poliprotect after PPI discontinuation. Outcomes included symptom severity (VAS), responder rate (≥ 50% VAS reduction), use of rescue medication, quality of life (GIQLI), gastrointestinal symptoms (GSRS), treatment satisfaction, and safety. RESULTS:At the end of deprescription, mean VAS scores remained stable, and 69.5% of PPI responders (65.8%, HRTB, and 76.2%, EPS) maintained symptom control. Additionally, 31% of PPI non-responders (33.3%, HRTB, and 27.3%, EPS) became responders with Poliprotect. Rescue antacid use and quality of life scores were not significantly changed. No adverse events were reported during the deprescribing phase. CONCLUSIONS:On-demand Poliprotect was associated with maintenance of symptom control after PPI withdrawal and outcome improvement in approximately one-third of PPI non-responders. Poliprotect appears to be a safe, well-tolerated, and promising strategy to support PPI discontinuation in endoscopy-negative heartburn and EPS patients. TRIAL REGISTRATION:Clinicaltrial.gov (NCT03238534) and EudraCT Database (2015-005216-15).

BACKGROUND & AIMS:Under-dilated trans-jugular intra-hepatic porto-systemic shunt (U-TIPS, ≤ 7 mm) effectively controls portal hypertension (PH) complications that placed the indication to TIPS while reducing the incidence of hepatic encephalopathy. However, TIPS efficacy in preventing additional PH-complications is reported only for standard endoprosthesis dilation (≥ 8 mm, S-TIPS). This study evaluated whether U-TIPS provides protection comparable to S-TIPS against PH-complications beyond the initial indication, independent of achieving guideline-defined hemodynamic targets. METHODS:Patients treated for refractory ascites (RA) or secondary prophylaxis of PH-related bleeding (PHRB) were included. Adequate hemodynamic response (AHR) was defined as post-TIPS PCPG < 12 mm Hg in RA, and < 12 mm Hg or reduction ≥ 50% in PHRB. Porto-caval pressure gradient (PCPG) values outside these criteria were deemed an inadequate response (IHR). Post-TIPS spontaneous bacterial peritonitis, acute renal injury hepatorenal syndrome-related, hepatic hydrothorax, need for paracentesis, and bleeding, were assessed individually and as a composite endpoint over one year. RESULTS:Of 358 patients, 257 (72%) received U-TIPS and 101 (28%) S-TIPS. The incidence of at least one post-TIPS event was higher in S-TIPS vs. U-TIPS (14% vs. 6%, p = 0.022), with no significant difference between AHR and IHR groups (9% vs. 7%, p = 0.543). On multivariable analysis, S-TIPS (OR 3.13, 95% CI 1.38, 7.21, p = 0.006), Child-Pugh class B (OR 11.6, 95% CI 2.14, 217, p = 0.021) and C (OR 14.4, 95% CI 1.17, 343, p = 0.042), higher MELD score (OR 1.20, 95% CI 1.09, 1.32, p < 0.001) were independently associated with post-TIPS events. CONCLUSIONS:U-TIPS provides non-inferior protection against other PH-complications irrespective of achieving hemodynamic efficacy targets.

BACKGROUND AND AIMS:The benefit of long-term albumin (LTA) in improving survival and reducing complications in patients with cirrhosis and ascites is not consistently observed across studies, possibly reflecting differences in patient populations and treatment regimens. This study aimed to determine whether baseline serum albumin (SA) levels can predict which patients are most likely to benefit from LTA therapy. METHODS:A post hoc analysis of the ANSWER trial was performed in 431 patients randomized to receive standard medical treatment (SMT) alone or SMT plus human albumin (SMT + HA). The interaction between baseline SA and LTA was investigated using competing-risk survival analysis. The primary endpoint was 18-month survival. Secondary endpoints included the incidence of cirrhosis-related complications and hospitalizations. RESULTS:A significant treatment-by-albumin non-linear interaction was found (p = 0.010), indicating heterogeneity of treatment effect across baseline SA levels with the upper bound of the region of statistically demonstrable benefit occurring at approximately 3.2 g/dL (sHR 0.53, 95% CI 0.28-0.99). In patients with SA ≤ 3.2 g/dL, 18-month survival was significantly higher in the SMT + HA group compared with SMT alone (HR 0.47, 95% CI 0.29-0.77; p = 0.0021). No significant survival difference could be demonstrated in patients with SA > 3.2 g/dL (HR 1.04, 95% CI 0.41-2.63; p = 0.93). Regardless of baseline SA levels, LTA was associated with improved ascites control and reduced rates of complications and hospitalizations. CONCLUSIONS:LTA provides survival and morbidity benefits in patients with mild-to-moderate hypoalbuminemia, whereas in patients with normal SA levels, its benefit appears mainly limited to morbidity reduction. Baseline SA may therefore help in prioritizing LTA therapy when resources are constrained.

Background: Refractory hepatic hydrothorax (RHH) develops in up to 15% of patients with cirrhosis and significantly impairs quality of life and clinical outcome of these patients. Transjugular intrahepatic portosystemic shunt (TIPS) has been suggested as a potential treatment. Still, its impact on both clinical efficacy and transplant-free survival (TFS) is uncertain, with data based on small and relatively old studies. Methods. We conducted a multicenter retrospective study including all consecutive patients with cirrhosis who underwent TIPS for RHH in a 16-year period (2008-2023) across 18 European centers. Efficacy and survival were assessed at the last available evaluation during a 1-year follow-up: after 12 months from TIPS, at the date of liver transplant (LT) or death, at the date of the last available visit for patients lost to follow-up. Clinical response was classified as: 1- complete (CR) in case of disappearance of symptoms and no further need for thoracenteses; 2- partial (PR) as decrease of at least 50% of symptoms and/or of need for thoracenteses; 3- null (NR) as no relief in symptoms and/or same or increased need for thoracenteses. Results. A total of 155 patients were included in the analysis. Alcohol was the prevalent etiology (47%), with moderately impaired liver and renal function (Child-Pugh class B 78%, median MELD-Na 15), prevalent right unilateral HH (85%). TIPS improved HH in the majority of patients (88% overall), with 61% of CR. Inter-center variability in clinical CR was modest and not significant with an Intraclass Correlation Coefficient of 0.06 (95% CI -0.19–0.18, p = 0.08). At 12 months after TIPS, 76 patients (49%) were alive, 36 (23%) were deceased, 23 (15%) underwent LT and 20 (13%) were lost to follow-up. Mean TFS was 9.9 ± 0.3 months. TFS was 11.0 ± 0.3 months for CR patients vs 8.4 ± 0.8 months vs 6.9 ± 1.2 months, for PR and NR patients respectively (Log-rank test: p < 0.001; Cox regression: HR = 0.22, 95% CI 0.11–0.43; p < 0.001). Significantly improved survival for CR patients was also confirmed when considering CR to TIPS as a time-varying covariate (HR = 0.25; 95% CI 0.13–0.48; p < 0.001). At multivariable analysis, considering LT as competitive event, clinical CR was the only variable independently associated with improved survival (sHR = 0.28, 95% CI 0.15–0.55, p < 0.001); conversely, bilateral HH and MELD-Na score were independently associated with poorer survival (sHR = 2.55, 95% CI 1.34–4.85, p = 0.004 and sHR = 1.10, 95% CI 1.05–1.15, p < 0.001, respectively). Conclusions. Our study supports the use of TIPS in patients with cirrhosis and RHH, showing that a clinical CR is achieved in a relevant proportion of patients and is associated with improved medium-term TFS.

Background & Aims: Portal hypertension (PH) is a major determinant of poor prognosis in cirrhosis. An under-dilated transjugular intrahepatic portosystemic shunt (U-TIPS) effectively controls PH-related complications that constitute the indication for the procedure, while reducing the incidence of post-TIPS overt hepatic encephalopathy. However, the benefits of TIPS in preventing additional PH-related complications beyond the initial indication have been reported only for standard-diameter stents (≥8 mm, S-TIPS). This study evaluated whether U-TIPS provides protection comparable to S-TIPS against further PH-related complications beyond the initial indication, independently of achieving guideline-defined hemodynamic targets for TIPS success.Methods: Patients treated for refractory ascites (RA) or for secondary prophylaxis of PH-related bleeding (PHRB) were included. Adequate hemodynamic response (AHR) was defined as a post-TIPS porto-caval pressure gradient (PCPG) <12 mmHg in RA, and <12 mmHg or a reduction ≥50% in PHRB. PCPG values outside these thresholds were considered an inadequate hemodynamic response (IHR). S-TIPS was defined as endoprosthesis dilation >7 mm. Post-TIPS PH-related complications beyond the initial indication—spontaneous bacterial peritonitis, acute kidney injury due to hepatorenal syndrome, hepatic hydrothorax, need for paracentesis, and variceal bleeding—were assessed individually and as a composite endpoint over one year. Results: A total of 358 patients were included, of whom 257 (72%) received U-TIPS and 101 (28%) S-TIPS. The incidence of at least one post-TIPS complication was significantly higher in S-TIPS compared with U-TIPS (14% vs. 6%, p=0.022), while no significant difference was observed between AHR and IHR groups (8.7% vs. 6.7%, p=0.543). On multivariable analysis, S-TIPS (OR 3.13, 95% CI 1.38–7.21, p=0.006), Child-Pugh class B (OR 11.6, 95% CI 2.1–217, p=0.021) and C (OR 14.4, 95% CI 1.2–343, p=0.042), and higher MELD score (OR 1.20, 95% CI 1.09–1.32, p<0.001) were independently associated with post-TIPS complications. Conclusions: U-TIPS provides non-inferior protection against additional PH-related complications compared with S-TIPS, irrespective of the achievement of guideline-defined hemodynamic efficacy targets.

Background and Aims: Preliminary results from the PRECIOSA trial (AASLD congress 2025) suggested that patients with normal serum albumin (SA) concentrations may not have a survival benefit from long-term albumin (LTA). We investigated whether baseline SA influences survival and other clinical outcomes in patients receiving LTA.Methods: This is a post-hoc analysis of the ANSWER randomized clinical trial including 431 patients with cirrhosis and uncomplicated grade 2 or 3 ascites randomized to receive standard medical treatment (SMT) alone or SMT + human albumin (HA) (40 g twice weekly for two weeks, then 40 g weekly) for up to 18 months. To identify the most discriminatory baseline SA threshold, candidate cut-offs between 2.5 and 4.2 g/dL (0.1 g/dL increments) were tested. For each value, 18-month survival was compared between treatment arms using the log-rank test, and the cut-off with the lowest p value was selected. The primary endpoint was 18-month survival; secondary endpoints included the incidence rates (IR) of cirrhosis-related complications. Comparisons were conducted within subgroups stratified by baseline SA concentration.Results: At baseline, patients randomized to the two arms did not differ in SA concentration (SMT 3.1±0.5 vs. SMT+HA 3.1±0.6 g/dL, p=0.86). The baseline SA cut-off associated with the greatest survival benefit was 3.2 g/dL. Overall, 275 patients (64%) had baseline SA ≤3.2 g/dL (132 SMT, 143 SMT+HA). The 18-month survival was significantly higher in SMT+HA than SMT in patients with baseline SA ≤3.2 g/dL (HR 0.47, 95%CI 0.29-0.77, p=0.002), while it was similar in patients with SA >3.2 g/dL (HR 1.04, 95%CI 0.41-2.63, p=0.93). In contrast, the cumulative incidence of paracentesis was lower in the SMT+HA group compared to SMT either in patients with SA ≤3.2 g/dL (HR 0.45 95% CI 0.31-0.65, p<0.001) and in those with SA >3.2 g/dL (HR 0.52 95% CI 0.32-0.87, p=0.010). Similarly, the reduction of complications (i.e., spontaneous bacterial peritonitis, non-SBP infections, grade III/IV hepatic encephalopathy) observed in patients receiving LTA was similar in those presenting at baseline either SA ≤3.2 g/dL or SA >3.2 g/dL).Conclusion: Baseline SA concentration can be used to identify those patients with uncomplicated grade 2-3 ascites who receive the greatest survival benefit from LTA, while the advantage associated with LTA in managing ascites and other complications appears to be independent of baseline SA. This finding suggests that patients with at least mild to moderate hypoalbuminemia are the best candidates to receive LTA and could be prioritized in healthcare settings with limited resources.

BACKGROUND AND AIMS:The role of transjugular intrahepatic portosystemic shunt (TIPS) in older adults remains controversial because of limited risk-stratification tools. We aimed to assess whether sarcopenia and myosteatosis are independently associated with post-TIPS mortality and overt hepatic encephalopathy (OHE) in patients aged ≥ 70 years, and whether adding sarcopenia to established prognostic scores improves discrimination for post-TIPS mortality. METHODS:This multicenter retrospective study included 115 consecutive patients with cirrhosis aged ≥ 70 years undergoing TIPS for refractory ascites or secondary prophylaxis of variceal bleeding. Sarcopenia and myosteatosis were assessed by computed tomography at L3. Post-TIPS mortality and time to first OHE episode were analysed using Kaplan-Meier and Cox regression. Sarcopenia was integrated into established prognostic scores, and predictive performance was evaluated using time-dependent ROC analyses. RESULTS:Sarcopenia and myosteatosis were present in 60% and 80% of patients, respectively. During follow-up, 49% died and 45% developed OHE. Sarcopenia was independently associated with both mortality and OHE, whereas myosteatosis and adipose-tissue indices were not. Incorporating sarcopenia improved the discriminative performance of all scores, with MELD 3.0-sarcopenia showing the highest accuracy (AUC 0.845). Predicted survival probabilities clearly separated patients across MELD 3.0 categories according to sarcopenia status. For OHE, sarcopenia increased the risk while underdilated TIPS was protective, defining four distinct risk profiles. CONCLUSIONS:Sarcopenia is highly prevalent and independently predicts both mortality and OHE after TIPS in older adults. Its integration into prognostic tools enhances risk stratification and supports individualised decision-making in this vulnerable population.

The concept of "rebalanced hemostasis" has improved our understanding of the coexistence of bleeding and thrombosis in cirrhosis. This balance, including changes of platelet function, is easily disrupted by inflammation, through bacterial gut translocation. The modulation of platelet activation through non-absorbable antibiotics remains unexplored. A cross-sectional analysis between patients with decompensated cirrhosis (Child–Pugh, CP, classes B and C) versus age-matched controls without cirrhosis and cardiometabolic diseases was performed to characterize the platelet phenotype and assessed short-term rifaximin effects. Platelet phenotyping, soluble myeloid cells TREM-like transcript-1 (sTLT-1), serum lipopolysaccharides (LPS), inflammatory cytokines, and neutrophil extracellular traps (NETs) markers were quantified. Decompensated cirrhosis patients were randomized to either rifaximin 550 mg BID or placebo for 14 days. Primary outcome was the post-treatment LPS change. Twenty-one patients with decompensated cirrhosis (mean age 59 ± 9 years; 65

Background & Aims: Current knowledge of the natural history of patients with porto-sinusoidal vascular disorder (PSVD) is derived from small studies. The aim of the present study was to determine the natural history of PSVD and prognostic factors in a large multicenter cohort of patients. Methods: We performed a retrospective study on patients with PSVD and signs of portal hypertension (PH) prospectively registered in 27 centers. Results: A total of 587 patients were included, median age of 47 years and 38% were women. Four-hundred and one patients had an associated condition, which was graded as severe in 157. Median follow-up was 68 months. At diagnosis, 64% of patients were asymptomatic while 36% had a PH-related complication: PH-related bleeding in 112 patients, ascites in 117, and hepatic encephalopathy in 11. In those not presenting with bleeding, the incidence of first bleeding was 15% at 5 years, with a 5-year rebleeding rate of 18%. The 5-year cumulative incidence of new or worsening ascites was 18% and of developing portal vein thrombosis was 16%. Fifty (8.5%) patients received a liver transplantation and 109 (19%) died, including 55 non-liver-related deaths. Transplant-free survival was 97% and 83% at 1 and 5 years, respectively. Variables independently associated with transplant-free survival were age, ascites, serum bilirubin, albumin and creatinine levels at diagnosis and severe associated conditions. This allowed for the creation of a nomogram that accurately predicted prognosis. Conclusions: The prognosis of PSVD is strongly determined by the severity of the associated underlying conditions and parameters of liver and renal function. (c) 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:Etiopathogenesis of porto-sinusoidal vascular disorder (PSVD) is poorly known. The present study aimed to investigate alterations in gut barrier, bacterial translocation, and pro-aggregating/pro-coagulant state and their relationship with liver injury in patients with PSVD without portal hypertension (PH-) in comparison with PSVD with PH (PH+) and healthy controls. METHODS:34 patients with PSVD (17 PH+ and 17 PH-) and 17 healthy subjects were submitted to measurement of zonulin and lipopolysaccharides (LPS), markers of intestinal permeability, of s-Glycoprotein VI, sP-selectin, ADAMTS13 and von Willebrand factor (vWF), markers of platelet aggregation and vascular dysfunction, factor VIII and F1 + 2, markers of hypercoagulability. In 30 PSVD patients, a histomorphological/immunohistochemical study on liver biopsies was performed. RESULTS:PSVD PH- patients had higher serum levels of LPS, zonulin, vWF, factor VIII, sP-selectin, F1 + 2 and lower levels of ADAMTS13 compared to healthy controls. These alterations were even more pronounced in PSVD PH+. At histological analysis, compared to those of healthy subjects, livers of patients with PSVD PH- showed a higher number of TLR4+ macrophages and of platelets within sinusoids with signs of aggregation. Perivascular fibrosis and sinusoid capillarisation were higher too. PSVD PH- had a lower degree of obliterative portal venopathy and portal inflammation compared to patients PH+. CONCLUSIONS:Even before the development of PH, patients with PSVD exhibit increased intestinal permeability and bacterial translocation, related platelet aggregation, and hypercoagulability, suggesting that endotoxemia may play a pivotal role in the pathogenesis of vascular alterations underlying PSVD. Moreover, this study indicates that PSVD without and with PH represent different stages of the same disease.

Background and aims: In clinical practice, the reduction of portocaval pressure gradient (PCPG) following TIPS does not always meet the recommendation of current guidance. We evaluated the impact of different degrees of PCPG reduction, measured at the end of an elective TIPS, on ascites control, recurrence of portal hypertension-related bleeding (PHRB), and survival. Approach and results: Patients with cirrhosis receiving TIPS for refractory ascites (RA) or for the secondary prophylaxis of PHRB were consecutively enrolled. Reduction in PCPG was defined as inadequate hemodynamic response (IHR) in patients not achieving a PCPG <12 mm Hg for both secondary prophylaxis of PHRB and RA, or a reduction of at least 50% only for PHRB. Four hundred fifteen patients were analyzed. An adequate hemodynamic response (AHR) was achieved in 66%. Fifty percent of patients received an under-dilated (<= 7 mm) endoprosthesis. No significant differences between patients with IHR and AHR were observed in rebleeding rate and ascites control, while overt HE was higher in AHR. Regardless of TIPS indication, survival was not significantly different between IHR and AHR, while advanced age and liver function before TIPS were significantly associated with a higher cumulative incidence of liver-related death. Notably, in patients with RA the cumulative incidence of liver-related mortality was higher when AHR was defined as a post-TIPS PCPG <12 mm Hg or a reduction >= 50%. Conclusions: AHR measured at the end of an elective TIPS may not be essential to define the eventual outcome, while a marked drop in PCPG could negatively affect the prognosis of patients with RA.