Evolving portal hypertension through Baveno VII recommendations.

The Baveno VII consensus workshop has provided several novel recommendations regarding the management of patients with clinically significant portal hypertension (CSPH). The expert panel summarized the existing data into simple clinical rules to aid clinicians in their clinical practice. The use of non-invasive tests (NITs), especially liver stiffness measurement (LSM), have gain an important role in daily practice. The use of LSM alone or in combination with platelet count can be used to rule-in and rule-out compensated advanced chronic liver disease (cACLD) and CSPH. Further decompensation events were defined as a prognostic stage associated with an even higher mortality than that associated with first decompensation. Moreover, the term hepatic recompensation was introduced in Baveno VII consensus implying a partial or complete regression of the functional and structural changes of cirrhosis after the removal of the underlying etiology. This review will summarize the reader main aspects of Baveno VII consensus regarding the use of NITs in cACLD, analyze further decompensation events, and evaluate recent recommendations for prophylaxis and management of liver decompensation events.

Beta-blockers in the era of precision medicine in patients with cirrhosis.

For decades, non-selective beta-blockers (NSBBs) have been the standard of care for the primary and secondary prevention of bleeding from oesophageal varices. However, several questions regarding the best clinical use of NSBBs remain unanswered and new data continue to emerge. Herein, we aim to delineate the therapeutic window of NSBBs in cirrhosis from a more individualised perspective. We address the current controversy of widening the therapeutic window and prescribing NSBBs to all patients with clinically significant portal hypertension. Although transient elastography is useful to rule-in clinically significant portal hypertension, we lack robust data supporting the use of NSBBs in patients without varices. While most data are based on propranolol, accumulating evidence suggests that carvedilol is superior and should be the first-line treatment until the decompensated stage. The clinical risk-to-benefit ratio appears to deteriorate in advanced decompensated stages and the risk of harm is high in patients with refractory ascites, low blood pressure and renal impairment, which clinically define closure of the therapeutic window. We also critically review non-invasive surrogates and biomarkers for predicting the haemodynamic response to NSBBs and confirm that the absence of reliable non-invasive methods is one of the main challenges facing the field.

Non-selective beta-blockers in patients with ascites: The complex interplay among the liver, kidney and heart.

Non-selective beta-blockers (NSBBs) are the cornerstone of the primary and secondary prophylaxis of variceal bleeding in cirrhotic patients. They additionally prevent ascites development and death in compensated patients with clinically significant portal hypertension. After ascites onset, NSBBs remain beneficial for preventing further decompensations. However, as the cirrhosis progresses, the inflammation increases, systemic vasodilatation worsens, ascites turns refractory and cardiodynamic equilibrium becomes extremely fragile. In this scenario, NSBBs can critically impair the cardiac reserve and facilitate a haemodynamic breakdown, imperilling renal perfusion. Consequently, NSBB treatment should be carefully monitored or even avoided in such patients, and other options for portal hypertension management should be considered. In the present review, we explore the effects of NSBBs in patients with ascites and discuss the complex interplay among their hepatic, systemic and renal haemodynamic effects in this scenario.

Risk Factors for Hepatic Hydrothorax in Cirrhosis Patients with Ascites - A Clinical Cohort Study.

BACKGROUND: The risk factors for hepatic hydrothorax are unknown. METHODS: We used data from three randomized trials of satavaptan treatment in patients with cirrhosis and ascites followed for up to 1 year. We excluded patients with previous hepatic hydrothorax or other causes for pleural effusion. The candidate risk factors were age, sex, heart rate, mean arterial pressure, diuretic-resistant ascites, a recurrent need for paracentesis, diabetes, hepatic encephalopathy, International Normalized Ratio, creatinine, bilirubin, albumin, sodium, platelet count, use of non-selective beta-blockers (NSBBs), spironolactone, furosemide, proton pump inhibitors, and insulin. We identified risk factors using a Fine and Gray regression model and backward selection. We reported subdistribution hazard ratios (sHR) for hepatic hydrothorax. Death without hepatic hydrothorax was a competing risk. RESULTS: Our study included 942 patients, of whom 41 developed hepatic hydrothorax and 65 died without having developed it. A recurrent need for paracentesis (sHR: 2.55, 95% CI: 1.28-5.08), bilirubin (sHR: 1.18 per 10 µmol/l increase, 95% CI: 1.09-1.28), diabetes (sHR: 2.49, 95% CI: 1.30-4.77) and non-use of non-selective beta-blockers (sHR: 2.27, 95% CI: 1.13-4.53) were risk factors for hepatic hydrothorax. Development of hepatic hydrothorax was associated with a high mortality-hazard ratio of 4.35 (95% CI: 2.76-6.97). CONCLUSIONS: In patients with cirrhosis and ascites, risk factors for hepatic hydrothorax were a recurrent need for paracentesis, a high bilirubin, diabetes and non-use of NSBBs. Among these patients with cirrhosis and ascites, development of hepatic hydrothorax increased mortality fourfold.

Precision medicine in variceal bleeding: Are we there yet?

Variceal bleeding is one of the most feared complications of portal hypertension in patients with cirrhosis because of its deleterious impact on prognosis. Adequate management of patients at risk of developing variceal bleeding includes the prevention of the first episode of variceal bleeding and rebleeding, and is crucial in modifying prognosis. The presence of clinically significant portal hypertension is the main factor determining the risk of development of varices and other liver-related decompensations; therefore, it should be carefully screened for and monitored. Treating patients with clinically significant portal hypertension based on their individual risk of portal hypertension-related bleeding undoubtedly improves prognosis. The evaluation of liver haemodynamics and liver function can stratify patients according to their risk of bleeding and are no question useful tools to guide therapy in an individualised manner. That said, recent data support the idea that tailoring therapy to patient characteristics may effectively impact on prognosis and increase survival in all clinical scenarios. This review will focus on evaluating the available evidence supporting the use of individual risk characteristics for clinical decision-making and their impact on clinical outcome and survival. In primary prophylaxis, identification and treatment of patients with clinically significant portal hypertension improves decompensation-free survival. In the setting of acute variceal bleeding, the risk of failure and rebleeding can be easily predicted, allowing for early escalation of treatment (i.e. pre-emptive transjugular intrahepatic portosystemic shunt) which can improve survival in appropriate candidates. Stratifying the risk of recurrent variceal bleeding based on liver function and haemodynamic response to non-selective beta-blockers allows for tailored treatment, thereby increasing survival and avoiding adverse events.

Beta-adrenergic receptor blockers and liver cancer mortality in a national cohort of hepatocellular carcinoma patients.

Background: ß-adrenergic signaling has been implicated in the pathology of hepatocellular carcinoma (HCC), but the evidence from clinical studies is limited. In this national population-based cohort study, we investigated the possible association of ß-adrenergic receptor blockers and cancer-specific mortality among patients with primary HCC diagnosed in Sweden between 2006 and 2014.Methods: Patients were identified from the Swedish Cancer Register (n = 2104) and followed until 31 December 2015. We used Cox regression to evaluate the association of ß-blockers dispensed within 90 days prior to cancer diagnosis, ascertained from the national Prescribed Drug Register, with liver cancer mortality identified from the Cause of Death Register, while controlling for socio-demographic factors, tumor characteristics, comorbidity, other medications and treatment procedures.Results: Over a median follow-up of 9.9 months, 1601 patients died (of whom 1309 from liver cancer). Compared with non-use, ß-blocker use at cancer diagnosis [n = 714 (predominantly prevalent use, 93%)] was associated with lower liver cancer mortality [0.82 (0.72-0.94); p = .005]. Statistically significant associations were observed for non-selective [0.71 (0.55-0.91); p = .006], ß1-receptor selective [0.86 [0.75-1.00); p = .049] and lipophilic [0.78 (0.67-0.90); p = .001] ß-blockers. No association was observed for hydrophilic ß-blockers [1.01 (0.80-1.28); p = .906] or other antihypertensive medications. Further analysis suggested that the observed lower liver cancer mortality rate was limited to patients with localized disease at diagnosis [0.82 (0.67-1.01); p = .062].Conclusion: ß-blocker use was associated with lower liver cancer mortality rate in this national cohort of patients with HCC. A higher-magnitude inverse association was observed in relation to non-selective ß-blocker use.

Metabolomics discloses potential biomarkers to predict the acute HVPG response to propranolol in patients with cirrhosis.

BACKGROUND: In cirrhosis, a decrease in hepatic venous pressure gradient (HVPG) > 10% after acute iv propranolol (HVPG response) is associated with a lower risk of decompensation and death. Only a part of patients are HVPG responders and there are no accurate non-invasive markers to identify them. We aimed at discovering metabolomic biomarkers of HVPG responders to propranolol. METHODS: Sixty-six patients with cirrhosis and HVPG ≥ 10 mm Hg in whom the acute HVPG response to propranolol was assessed, were prospectively included. A targeted metabolomic serum analysis using ultrahigh-performance liquid chromatography coupled to mass spectrometry was performed. Different combinations of 2-3 metabolites identifying HVPG responders (HVPG reduction > 10%) were obtained by stepwise logistic regression. The best of these model (AUROC, Akaike criterion) underwent internal cross-validation and cut-offs to classify responders/non-responders was proposed. RESULTS: A total of 41/66 (62%) patients were HVPG responders. Three hundred and eighty-nine metabolites were detected and 177 were finally eligible. Eighteen metabolites were associated to the HVPG response at univariate analysis; at multivariable analysis, a model including a phosphatidylcholine (PC(P-16:0/22:6)) and a free fatty acid (20:2(n-6), eicosadienoic acid) performed well for HVPG response, with an AUROC of 0.801 (0.761 at internal validation). The cut-off 0.629 was the most efficient for overall classification (49/66 patients correctly classified). Two cut-off values allowed identifying responders (0.688, PPV 84%) and non-responders (0.384, NPV 82%) with undetermined values for 17/66 patients. Clinical variables did not add to the model. CONCLUSIONS: The combination of two metabolites helps at identifying HVPG responders to acute propranolol. It could be a useful non-invasive test to classify the HVPG response to propranolol.

Treatment with non-selective beta-blockers affects the systemic inflammatory response to bacterial DNA in patients with cirrhosis.

BACKGROUND & AIMS: The use of non-selective beta-blockers has been associated with lower rates of infection and reduced infection-associated morbidity in patients with cirrhosis. However, it is unknown if these drugs modify the systemic inflammatory response to circulating bacterial DNA. METHODS: Sixty-three patients with cirrhosis were included during an episode of decompensation by ascites. Thirty of those patients were on beta-blockers. Blood samples were obtained after each patient had been in the supine position for at least 30 minutes in a quiet atmosphere. Bacterial DNA, serum cytokines, nitric oxide, and LPS were determined. Phagocytic and oxidative burst activities were determined in polymorphonuclear cells from the patients. RESULTS: The detection rate of bacterial DNA in the blood was the same (33%) for patients not treated and treated with non-selective beta-blockers. Patients naive to non-selective beta-blockers showed significantly higher serum levels of IL6, IFN-gamma and IL10 in response to the presence of bacterial DNA. Patients treated with non-selective beta-blockers showed higher basal inflammatory activity that did not change with the presence of bacterial DNA. Monocytes and granulocytes from patients treated with non-selective beta-blockers showed a significantly increased phagocytic capacity in the presence of bacterial DNA. CONCLUSIONS: In patients with cirrhosis, chronic treatment with beta-blockers is associated with a higher unstimulated production of serum cytokines and an increased phagocytic activity in the presence of bacterial DNA.

Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites.

BACKGROUND & AIMS: Carvedilol, a non-selective beta-blocker (NSBB) with additional anti-alpha 1 receptor activity, is a potent portal hypotensive agent and has been used as prophylaxis against variceal bleeding. However, its safety in patients with decompensated liver cirrhosis and ascites is still disputed. In this study, we examined whether long-term use of carvedilol in patients with ascites is a risk factor for mortality. METHODS: A single-centre retrospective analysis of 325 consecutive patients with liver cirrhosis and ascites presenting to our Liver Unit between 1st of January 2009 to 31st August 2012 was carried out. The primary outcome was all-cause and liver-specific mortality in patients receiving or not receiving carvedilol as prophylaxis against variceal bleeding. RESULTS: The final cohort after propensity score matching comprised 264 patients. Baseline ascites severity and UK end-stage liver disease (UKELD) score between carvedilol (n=132) and non-carvedilol (n=132) treated patient groups were comparable. Median follow-up time was 2.3years. Survival at the end of the follow-up was 24% and 2% for the carvedilol and the non-carvedilol groups respectively (log-rank p<0.0001). The long-term survival was significantly better in carvedilol than non-carvedilol group (log-rank p<0.001). The survival difference remained significant after adjusting for age, gender, ascites severity, aetiology of cirrhosis, previous variceal bleed, spontaneous bacterial peritonitis prophylaxis, serum albumin and UKELD with hazard ratio of 0.59 (95% confidence interval [CI]: 0.44, 0.80; p=0.001), suggesting a 41% reduction in mortality risk. When stratified by the severity of ascites, carvedilol therapy resulted in hazard ratio of 0.47 (95% CI: 0.29, 0.77; p=0.003) in those with mild ascites. Even with moderate or severe ascites, carvedilol use was not associated with increased mortality risk. CONCLUSION: Long-term carvedilol therapy is not harmful in patients with decompensated cirrhosis and ascites. LAY SUMMARY: The safety of carvedilol and other non-selective beta-blocker drugs in patients with liver cirrhosis and ascites is still debated. In this study, we have shown that carvedilol therapy in these patients was associated with reduced risk of mortality, particularly in those with mild ascites. We concluded that low dose, chronic treatment with carvedilol in patients with liver cirrhosis and ascites is not detrimental.

Novel Approaches to Reducing the Risk of Variceal Hemorrhage.

BACKGROUND: Complications of advanced liver disease occur at the moment of clinical significant portal hypertension. Nitric oxide (NO) dysfunction and fibrosis play an important role in the pathophysiology of PH, but other mechanisms are also involved. Non-selective beta blockers (NSBB) stay the cornerstone in the primary and secondary prevention of variceal bleeding, but their safety in advanced cirrhosis has been recently debated and new drugs are under investigation. Transjugular intrahepatic portosystemic shunt and balloon tamponade are the standard therapy in case of refractory variceal bleeding, but both interventions have drawbacks. Key Message: Transelastography under certain conditions and the presence of collateral circulation on imaging allow to rule-in CSPH, which makes patients open at risk for variceal hemorrhage. FXR agonists are intrahepatic NO donors; they reduce fibrosis and prevent bacterial translocation, which make them promising drugs for the treatment of PH. NSBB should be used with caution in patients with refractory ascites and certainly in those with hepatorenal syndrome. Preliminary clinical data suggest that simvastatin and enoxaparin improve the prognosis of patients with cirrhosis. Finally, covered esophageal metallic stents are safer and more effective than balloon tamponade in the case of refactory variceal bleeding. CONCLUSIONS: Liver stiffness measurements enable the selection of patients for endoscopic screening for esophageal varices. In the case of tense ascites, the dose of NSBB should be adapted to the hemodynamic condition of the patient. Self-expanding, covered esophageal metallic stents replace balloon tamponade in the treatment of massive variceal hemorrhage.

Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: Non-selective beta blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute-on-chronic liver failure (ACLF) is characterized by systemic inflammation and high mortality. As NSBBs may have beneficial effects on gut motility and permeability and, systemic inflammation, the aims of this prospective, observational study were to determine whether ongoing use of NSBBs reduced 28-day mortality in ACLF patients. METHODS: The study was performed in 349 patients with ACLF included in the CANONIC study, which is a prospective observational investigation in hospitalized cirrhotic patients with acute deterioration. The data about the use of NSBBs, its type and dosage was specifically recorded. Patient characteristics at enrollment significantly associated with treatment and mortality were taken into account as potential confounders to adjust for treatment effect. A logistic regression model was fitted. RESULTS: 164 (47%) ACLF patients received NSBBs whereas 185 patients did not. Although the CLIF-C ACLF scores were similar at presentation, more patients in the NSBB treated group had lower grades of ACLF (p=0.047) at presentation and significantly more patients improved. Forty patients (24.4%) died in NSBB treated group compared with 63 patients (34.1%) (p=0.048) [estimated risk-reduction 0.596 (95%CI: 0.361-0.985; p=0.0436)]. This improvement in survival was associated with a significantly lower white cell count (NSBB: 8.5 (5.8); no NSBB: 10.8 (6.6); p=0.002). No long-term improvement in survival was observed. CONCLUSIONS: This study shows for the first time that ongoing treatment with NSBBs in cirrhosis is safe and reduces the mortality if they develop ACLF. Careful thought should be given before stopping NSBBs in cirrhotic patients.

The renal effects of droxidopa are maintained in propranolol treated cirrhotic rats.

BACKGROUND & AIMS: Droxidopa improves hemodynamic and renal alterations of cirrhotic rats without changing portal pressure. We aimed to evaluate the effects of a combined treatment with droxidopa and non-selective beta-blockers or statins in order to decrease portal pressure, while maintaining droxidopa beneficial effects. METHODS: Acute studies combining droxidopa with carvedilol, propranolol or atorvastatin in four-week bile-duct ligated (BDL) rats and a chronic study combining propranolol and droxidopa for 5 days in CCl4 -cirrhotic rats were performed. Hemodynamic values were registered and biochemical parameters from blood and urine samples analyzed. RESULTS: Bile-duct ligated rats treated with carvedilol + droxidopa showed no changes in mean arterial pressure (MAP) and portal pressure (PP) compared to vehicles. Atorvastatin + droxidopa combination also failed to reduce PP, but maintained the beneficial increase in MAP and superior mesenteric artery resistance (SMAR) and decrease in blood flow (SMABF) caused by droxidopa. In contrast, the acute administration of propranolol + droxidopa significantly reduced PP maintaining a mild increase in MAP and improving, in an additive way, the decrease in SMABF and increase in SMAR caused by droxidopa. This combination also preserved droxidopa diuretic effect. When chronically administered to CCl4 -cirrhotic rats, propranolol + droxidopa caused a decrease in PP, a significant reduction in SMABF and an increase in SMAR. The combination did not alter liver function and droxidopa diuretic and natriuretic effect, and even improved free water clearance. CONCLUSION: Droxidopa could be effective for the renal alterations of cirrhotic patients on propranolol therapy and the combination of both drugs may balance the adverse effects of each treatment.

Carvedilol to prevent hepatic decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by new non-invasive model (CHESS2306).

Background & Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvedilol-treating cohort. Results: In the meta-analysis with six studies (n = 819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new "CSPH risk" model. In the HVPG cohort (n = 151), the new model accurately predicted CSPH with cutoff values of 0 and -0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n = 1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <-0.68 (low-risk), -0.68 to 0 (medium-risk), and >0 (high-risk). In the carvedilol-treated cohort, patients with high-risk CSPH treated with carvedilol (n = 81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n = 613 before propensity score matching [PSM], n = 162 after PSM). Conclusions: Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Management of liver disease and portal hypertension in cystic fibrosis: a review.

INTRODUCTION: Cystic fibrosis (CF)-associated liver disease can significantly affect the quality of life and survival of people with CF. The hepatobiliary manifestations in CF are various, with focal/multilobular biliary cirrhosis more common in children and porto-sinusoidal vascular disease (PSVD) in young adults. Portal hypertensive complications, particularly bleeding from esophagogastric varices and hypersplenism are common, while liver failure is rarer and mainly linked to biliary disease. AREAS COVERED: This review explores current therapeutic options for CF-associated liver disease, presenting ongoing studies and new insights into parthenogenesis for potential future therapies. EXPERT OPINION: Monitoring for signs of portal hypertension is essential. Limited evidence supports ursodeoxycholic acid (UDCA) efficacy in halting CF liver disease progression. The effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on liver outcomes lacks definitive data, since patients with CF-related liver disease were excluded from trials due to potential hepatotoxicity. A proposed approach involves using UDCA and modulators in early stages, along with anti-inflammatory agents, with further therapeutic strategies awaiting randomized trials. Prevention of portal hypertensive bleeding includes endoscopic sclerotherapy or ligation of esophageal varices. Nonselective beta-blockers may also prevent bleeding and could be cautiously implemented. Other non-etiological treatments require investigation.

Predicting response to non-selective beta-blockers with liver-spleen stiffness and heart rate in patients with liver cirrhosis and high-risk varices.

INTRODUCTION: Non-selective beta-blockers (NSBB) are used for primary prophylaxis in patients with liver cirrhosis and high-risk varices (HRVs). Assessing therapeutic response is challenging due to the invasive nature of hepatic venous pressure gradient (HVPG) measurement. This study aims to define a noninvasive machine-learning based approach to determine response to NSBB in patients with liver cirrhosis and HRVs. METHODS: We conducted a prospective study on a cohort of cirrhotic patients with documented HRVs receiving NSBB treatment. Patients were followed-up with clinical and elastography appointments at 3, 6, and 12 months after NSBB treatment initiation. NSBB response was defined as stationary or downstaging variceal grading at the 12-month esophagogastroduodenoscopy (EGD). In contrast, non-response was defined as upstaging variceal grading at the 12-month EGD or at least one variceal hemorrhage episode during the 12-month follow-up. We chose cut-off values for univariate and multivariate model with 100% specificity. RESULTS: According to least absolute shrinkage and selection operator (LASSO) regression, spleen stiffness (SS) and liver stiffness (LS) percentual decrease, along with changes in heart rate (HR) at 3 months were the most significant predictors of NSBB response. A decrease > 11.5% in SS, > 16.8% in LS, and > 25.3% in HR was associated with better prediction of clinical response to NSBB. SS percentual decrease showed the highest accuracy (86.4%) with high sensitivity (78.8%) when compared to LS and HR. The multivariate model incorporating SS, LS, and HR showed the highest discrimination and calibration metrics (AUROC = 0.96), with the optimal cut-off of 0.90 (sensitivity 94.2%, specificity 100%, PPV 95.7%, NPV 100%, accuracy 97.5%).

Immune changes over time and survival in patients with cirrhosis treated with non-selective beta-blockers: A prospective longitudinal study.

BACKGROUND: Treatment with non-selective beta-blockers (NSBB) has been associated with anti-inflammatory and anti-cancer effects in patients with cirrhosis. This study aims to analyze the impact of chronic NSBB treatment on immune activation and disease progression in stable outpatients with cirrhosis. METHODS: In this prospective follow-up of 150 patients with cirrhosis, 39 received treatment with NSBB. Blood samples were taken every 6-9 months, and immune and adrenergic variables were measured. Mixed linear models were used to assess the effect of NSBB on these variables over time. Multivariate Cox regression was used to study associations with adverse clinical events (hepatocellular carcinoma, death, or liver transplant). RESULTS: Median follow-up was 1635 days. NSBB treatment was associated with significantly lower levels of IL-6 (ß - 4.7; 95% confidence interval [CI] -6.9, -2.6) throughout the study. During follow-up, 11 patients developed hepatocellular carcinoma, 32 died, and 4 underwent liver transplant. Patients with higher concentrations of IL-10, IL-6 and IFN-γ developed more clinical events. Event-free survival was significantly better in patients treated with NSBB (hazard ratio 0.36, 95% CI 0.18, 0.71) in a multivariate Cox regression adjusted for Child-Pugh-Score, esophageal varices, and platelets. CONCLUSION: Chronic treatment with NSBB in patients with stable cirrhosis gives rise to a different state of immune activation, characterized by lower concentrations of IL-6 over time, and it is associated with a reduced risk of adverse event (death, hepatocellular carcinoma, or transplant), after controlling for disease severity.

Non-Selective Beta-Blockers and Risk of Sepsis in Patients with Cirrhosis and Ascites: Results from a Large Observational Study.

Background and Aims: Previous studies have not been able to determine whether non-selective beta-blockers (NSBB) reduce the risk of sepsis in cirrhosis. We aimed to examine this question with data from 1198 patients with cirrhosis and ascites included in clinical studies of satavaptan, a vasopressin receptor antagonist with no effect on infection risk. Methods: Risk of sepsis was estimated for NSBB users vs nonusers. Patients were examined every four weeks, or in relation to hospitalization, for the one-year duration of the trials. We computed the cumulative risk of sepsis for patients who did vs did not use NSBB at baseline. We used Cox regression to compare hazard rates of sepsis between current users and nonusers, accounting for changes in NSBB use over time. We adjusted for patient sex and age, MELD-Na score, albumin, use of antibiotics, use of proton pump inhibitors, cirrhosis etiology, history of variceal bleeding or SBP, severity of ascites and HE, HCC, other cancers, and diabetes, while stratifying on geographical region. Results: Of the 1198 patients, 54% used NSBB at some time. There were 56 sepsis episodes. The 1-year risk of sepsis was reduced to 5.7% (95% confidence interval [CI] 2.8-8.6) in baseline NSBB users vs 11.6% (95% CI 7.0-15.9) in baseline nonusers. The hazard ratio of sepsis for current NSBB users vs current nonusers was reduced to 0.5 (95% CI 0.3-0.8) and after adjustment to 0.7 (95% CI 0.4-1.3). Conclusion: NSBB use may reduce the risk of sepsis in patients with cirrhosis and ascites, but the precision of the estimate was limited by the number of episodes of sepsis.

Pre-emptive TIPS for the treatment of bleeding from gastric fundal varices: Results of a randomised controlled trial.

Background & Aims: Bleeding from gastric fundal varices (isolated gastric varices type 1/gastroesophageal varices type 2) represents a major problem because of a high incidence of rebleeding and death with standard-of-care therapy (endoscopic obliteration with tissue adhesives plus pharmacological therapy). Transjugular intrahepatic portosystemic shunts (TIPSs) are recommended as a rescue therapy. Pre-emptive 'early' TIPS (pTIPS) significantly improves control of bleeding and survival in patients at high-risk of dying or rebleeding from esophageal varices. Methods: This randomised controlled trial investigate whether the use of pTIPS improves rebleeding-free survival in patients with gastric fundal varices (isolated gastric varices type 1 and/or gastroesophageal varices type 2) compared with standard therapy. Results: The study did not achieve the predefined sample size because of low recruitment. Nevertheless, pTIPS (n = 11) was more effective compared with combined endoscopic and pharmacological therapy (n = 10) in improving rebleeding-free survival (per protocol analysis: 100 vs. 28%; p = 0.017). This was mainly because of a better outcome in patients with Child-Pugh B or C scores. There were no differences in serious adverse events or in the incidence of hepatic encephalopathy among the different cohorts. Conclusion: The use of pTIPS should be considered in patients with Child-Pugh B or C scores bleeding from gastric fundal varices. Impact and implications: The first-line treatment of gastric fundal varices (GOV2 and/or IGV1) is the combination of pharmacological therapy and endoscopic obliteration with glue. TIPS is considered the main rescue therapy. Recent data suggest that, in patients at high-risk of dying or rebleeding (Child-Pugh C or B scores + active bleeding at endoscopy) from esophageal varices, the use of pTIPS, performed during the first 72 h from admission, results in an increased rate of control of bleeding and survival compared with combined endoscopic and pharmacological therapy. Herein, we present a randomised controlled trial comparing pTIPS with combined endoscopic (injection of glue) and pharmacological therapy (first, somatostatin or terlipressin; carvedilol after discharge) in the treatment of patients bleeding from GOV2 and/or IGV1. Although we were not able to include the calculated sample size because of the scarcity of these patients, our results show that the use of pTIPS is associated with a significantly higher actuarial rebleeding-free survival when analysed as per protocol. This is because of the greater efficacy of this treatment in patients with Child-Pugh B or C scores.

Innovative approaches to the management of ascites in cirrhosis.

Standard of care for the treatment of ascites in cirrhosis is to administer a sodium-restricted diet and diuretic therapy. The progression of cirrhosis will eventually lead to the development of refractory ascites, at which point diuretics will no longer be able to control the ascites. Second-line therapies such as a transjugular intrahepatic portosystemic shunt (TIPS) placement or repeat large volume paracentesis are then required. There is some evidence that regular infusions of albumin may delay the onset of refractoriness and improve survival, especially if given at an early stage in the natural history of ascites and for a long enough duration. The use of TIPS can eliminate ascites, but its insertion is associated with complications, especially cardiac decompensation and worsening of hepatic encephalopathy. New information is now available regarding how to best select patients for TIPS, what type of cardiac investigations are needed and how under-dilating the TIPS at the time of insertion may help. The use of a non-absorbable antibiotics, such as rifaximin, starting in the pre-TIPS period may also reduce the likelihood of post-TIPS hepatic encephalopathy. In patients who are not suitable for TIPS, the use of an alfapump to remove the ascites via the bladder can improve quality of life without significantly altering survival. In the future it may be possible to use metabolomics to help refine the management of patients with ascites, e.g. to assess their response to non-selective beta-blockers or to predict the development of other complications such as acute kidney injury.

Repurposing beta-blockers for combinatory cancer treatment: effects on conventional and immune therapies.

Beta-adrenergic receptor signaling regulates cellular processes associated with facilitating tumor cell proliferation and dampening anti-tumor immune response. These cellular processes may lead to compromised tumor control and cancer progression. Based on this ramification, Beta-blockers (BBs) have emerged as a potential treatment by inhibiting beta-adrenergic receptor signaling. This review aimed to investigate the relationship between the use of BBs and tumor progression and treatment response. Therefore, the authors explored several aspects: the potential synergistic relationship of BBs with chemotherapy and immunotherapy in enhancing the effectiveness of chemotherapeutic and immunotherapeutic treatments and their role in boosting endogenous immunity. Further, this review explores the distinctions between the major types of BBs: Non-selective Beta Blockers (NSBBs) and Selective Beta Blockers (SBBs), and their contributions to combinatory cancer treatment. In this review, we presented a perspective interpretation of research findings and future directions. Overall, this review discusses the potential and challenge that BBs present in improving the effectiveness and outcome of cancer treatment.