Lowering Portal Pressure Improves Outcomes of Patients With Cirrhosis, With or Without Ascites: A Meta-Analysis.

BACKGROUND & AIMS: In unselected patients with cirrhosis, those with reductions in hepatic venous pressure gradient (HVPG) to below a defined threshold (responders) have a reduced risk of variceal hemorrhage (VH) and death. We performed a meta-analysis to compare this effect in patients with vs without ascites. METHODS: We collected data from 15 studies of primary or secondary prophylaxis of VH that reported data on VH and death in responders vs nonresponders. We included studies in which data on ascites at baseline and on other relevant outcomes during follow-up evaluation were available. We performed separate meta-analyses for patients with vs without ascites. RESULTS: Of the 1113 patients included in the studies, 968 patients (87%) had been treated with nonselective ß-blockers. In 993 patients (89%), HVPG response was defined as a decrease of more than 20% from baseline (>10% in 11% of patients) or to less than 12 mm Hg. In the 661 patients without ascites, responders (n = 329; 50%) had significantly lower odds of events (ascites, VH, or encephalopathy) than nonresponders (odds ratio [OR], 0.35; 95% CI, 0.22-0.56). Odds of death or liver transplantation were also significantly lower among responders than nonresponders (OR, 0.50, 95% CI, 0.32-0.78). In the 452 patients with ascites, responders (n = 188; 42%) had significantly lower odds of events (VH, refractory ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome) than nonresponders (OR, 0.27; 95% CI, 0.16-0.43). Overall, odds of death or liver transplantation were lower among responders (OR, 0.47; 95% CI, 0.29-0.75). No heterogeneity was observed among studies. CONCLUSIONS: In a meta-analysis of clinical trials, we found that patients with cirrhosis with and without ascites who respond to treatment with nonselective ß-blockers (based on reductions in HVPG) have a reduced risk of events, death, or liver transplantation.

Nonselective Beta-Blockers Do Not Affect Survival in Cirrhotic Patients with Ascites.

BACKGROUND: The role of nonselective beta-blockers in cirrhotic patients with ascites has been recently questioned; however, definitive evidence in this regard is still lacking. AIMS: To analyze published data on the influence of nonselective beta-blockers as compared to control group on survival of cirrhotic patients with ascites. METHODS: Computerized bibliographic search on the main databases was performed. Hazard ratios from Kaplan-Meier curves were extracted in order to perform an unbiased comparison of survival estimates. Secondary outcomes were mortality in patients with refractory ascites, pooled rate of nonselective beta-blockers interruption, spontaneous bacterial peritonitis and hepato-renal syndrome incidence. RESULTS: Three randomized controlled trials and 13 observational studies with 8279 patients were included. Overall survival was comparable between the two groups (hazard ratio = 0.86, 0.71-1.03, p = 0.11). Study design resulted as the main source of heterogeneity in sensitivity analysis and meta-regression. Mortality in refractory ascites patients was similar in the two groups (odds ratio = 0.90, 0.45-1.79; p = 0.76). No difference in spontaneous bacterial peritonitis (odds ratio = 0.78, 0.47-1.29, p = 0.33) and hepato-renal syndrome incidence (odds ratio = 1.22, 0.48-3.09; p = 0.67) was observed. Pooled rate of nonselective beta-blockers interruption was 18.6% (5.2-32.1%). CONCLUSIONS: Based on our findings, nonselective beta-blockers should not be routinely withheld in patients with cirrhosis and ascites, even if refractory.

Non-selective beta-blocker treatment does not impact on kidney function in cirrhotic patients with varices.

GOALS AND BACKGROUND: Non-selective beta-blockers (NSBBs) are used for bleeding prophylaxis in cirrhotic patients with gastroesophageal varices (GEVs). Recent data suggested that NSBB treatment might increase the risk of renal dysfunction in patients with refractory ascites due to an impaired response to acute haemodynamic stress. STUDY: Retrospective longitudinal assessment of kidney function in a cohort of cirrhotic patients with GEVs with vs. without NSBB therapy. Serum creatinine (SCre), estimated glomerular filtration rate (eGFR), incidence of acute kidney injury (AKI), new onset of large volume ascites and TIPS-/transplant-free survival were compared. RESULTS: Among 176 patients, 93 patients received NSBBs, while 83 did not. Most patients were male (77.8%), had alcoholic aetiology (52.3%) and compensated cirrhosis (51.1% Child-A, MELD: 12.1 ± 3.8). Over a 3-year follow-up, renal function was comparable between patients with and without NSBB treatment. Incidence of AKI was similar in NSBB vs. no-NSBB patients (p = .323). Even in potential risk groups (ascites, MAP <90 mmHg, baseline creatinine > ULN, hyponatraemia, MELD score ≥15 points, Child-Pugh B/C), there was no difference in SCre or eGFR with vs. without NSBBs (p = n.s. at 74/78 and 76/78 of analysed time points). However, multivariate analysis revealed that the presence of ascites (HR: 3.901, 95%CI: 1.352-11.251; p = .012) and pre-existing renal impairment (HR: 4.315, 95%CI: 1.054-17.672; p = .042) were independent risk factors for AKI. Importantly, NSBB use (HR: 0.319, 95%CI: 0.120-0.848; p = .022) was independently associated with improved TIPS-/transplant-free survival. CONCLUSIONS: In our cohort of unselected, mostly compensated cirrhotic patients with GEVs, NSBB treatment was neither associated with worsening of kidney function nor with increased incidence of AKI. On the contrary, NSBB treatment improved TIPS-/transplant-free survival.

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%).

Carvedilol Versus Other Nonselective Beta Blockers for Variceal Bleeding Prophylaxis and Death: A Network Meta-analysis.

Background and Aims: We aimed to perform a network meta-analysis (NWM) to examine comparative effectiveness of non-selective beta blockers (NSBBs) on prophylaxis of gastroesophageal variceal bleeding (GVB) and mortality benefit. Methods: MEDLINE (OVID) and EMBASE databases were searched for eligible randomized clinical trials (RCTs) from inception to July 3, 2021. Outcomes of interest included primary/secondary prophylaxis of GVB, failure to achieve hepatic venous pressure gradient (HVPG) decremental response, liver-related and all-cause mortality. A Bayesian NWM was performed to derive relative risk (RR) with 95% credible intervals (CrIs). The ranking probability of each NSBB was assessed by surface under cumulative ranking curve (SUCRA). Results: Thirty-three RCTs including 3,188 cirrhosis patients with gastroesophageal varices were included. Compared with placebo, nadolol ranked first for reducing variceal bleeding [RR:0.25, (95% CrI:0.11-0.51); SUCRA:0.898], followed by carvedilol [RR:0.33, (95% CrI: 0.11-0.88); SUCRA:0.692] and propranolol [RR:0.52, (95% CrI:0.37-0.75); SUCRA:0.405]. Carvedilol was more effective than propranolol in achieving HVPG decremental response [RR:0.43, (95% CrI: 0.26-0.69)]. Carvedilol ranked first for reducing all-cause mortality [RR: 0.32, (95% CrI:0.17-0.57); SUCRA:0.963), followed by nadolol [RR:0.48, (95% CI:0.29-0.77); SUCRA:0.688], and propranolol [RR:0.77, (95% CI:0.58-1.02); SUCRA: 0.337]. Similar findings were observed for liver-related mortality. Carvedilol ranked the safest. The RR of adverse events was 4.38, (95% CrI:0.33-161.4); SUCRA:0.530, followed by propranolol [RR: 7.54, (95% CrI:1.90-47.89); SUCRA:0.360], and nadolol [RR: 18.24, (95% CrI:91.51-390.90); SUCRA:0.158]. Conclusions: Carvedilol is the preferred NSBB with better survival benefit and lower occurrence of adverse events among patients with gastroesophageal varices.

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.

Acute Variceal Bleed in Cirrhosis is Associated With Reversible Changes in Tight Junction Protein Expression in the Intestine: A Proof-of-Concept Study.

BACKGROUND: Tight junction proteins (TJPs) play an important role in gut-barrier dysfunction in cirrhosis and its complications such as acute variceal bleed (AVB). However, the dynamics of TJPs expression after AVB, its relation to bacterial translocation, and impact on clinical outcome is largely unknown. AIMS: The aim of this study was to study the expression of TJPs in cirrhosis and assess its dynamic changes in AVB. In addition, the relation of TJP expression to endotoxemia and clinical outcomes was assessed. METHODS: In this prospective pilot study, 17 patients of cirrhosis with AVB, 59 patients of cirrhosis without AVB (non-AVB cirrhosis), and 20 controls were assessed for claudin-2 and claudin-4 expression in the duodenal biopsy. In the AVB-cirrhosis group, additional biopsies were obtained after 3 weeks. Endotoxemia was assessed by measuring IgG anti-endotoxin antibody levels. Claudin expression was correlated with a 6-month survival. RESULTS: Claudin-2 expression was downregulated in patients with AVB and non-AVB cirrhosis in villi (P < 0.001 and 0.013) and crypts (P < 0.001 and 0.012), respectively, compared with the controls. Claudin-4 expression was similar in villi (P = 0.079), but lower in crypts (P = 0.007) in patients with cirrhosis. Claudin-2 expression was upregulated on serial biopsies in both villi and crypts (P = 0.003 and 0.001, respectively) in AVB-cirrhosis with postbleed expression comparable with those with non-AVB cirrhosis. IgG anti-endotoxin antibody levels were elevated in cirrhosis with no correlation with claudin-2/4 expression. Claudin-2 expression independently predicted survival at 6 months. CONCLUSION: Both claudin-2 and claudin-4 expression are downregulated in cirrhosis. AVB is associated with dynamic changes in TJPs expression. Gut-barrier dysfunction might predict outcomes independent of bacterial endotoxemia in cirrhosis.

Application of Noninvasive Tools to Decide the Need for Beta-Blockers for Variceal Bleeding Prophylaxis in Compensated Advanced Liver Disease: A Decision Curve Analysis.

Background and aims: Noninvasive tools (NITs) reliably categorise patients with compensated advanced chronic liver disease (cACLD) into high-risk and low-risk group for harbouring varices needing treatment. Here, we assess the ability of these NITs to predict the need for nonselective beta-blockers at baseline based on risk of variceal bleeding (VB) on follow-up. Methods: This was a retrospective multicentre analysis of patients with cACLD categorised at baseline into different risk groups by NITs (Baveno-VI, expanded Baveno-VI, platelet-albumin, platelet-model for end-stage liver disease (MELD) and anticipate study platelet criteria) and by endoscopy (high risk vs low risk/no varices). VB event rates on follow-up were estimated in different risk strata. Decision curve analysis (DCA) was used to estimate the benefit of administering nonselective beta-blockers (NSBB) using NITs over endoscopic classification at different threshold probabilities of VB event rates and estimating the number needed to treat (NNT) to identify one additional bleeder over endoscopy. Results: A total of 1284 patients (mean age: 44.7 ± 13.5 years, 72.4% males) of hepatitis B (29.2%), nonalcoholic fatty liver disease (24.9%), hepatitis C (20.1%), and alcohol (17.5%)-related cACLD were included with 323 (25.2%) having high-risk varices. Ninety-eight (7.6%) patients developed VB over a median follow-up of 20 (9-35) months. The 1-year and 3-year rate of VB with all NITs was 5.7-7.4% and 13.2-16.4% among high-risk and 0-2.3% and 0-5% among low-risk subgroups, respectively (P < 0.001) in both viral and nonviral aetiologies. Among patients classified as low risk on Baveno-VI criteria, none developed VB on follow-up. At thresholds of <3% event rate of VB, Baveno-VI (NNT-176), platelet-albumin (NNT-576) and anticipate platelet (NNT-233) criteria were superior, whereas endoscopic stratification was superior above this event rate on DCA. Conclusions: The use of both elastography and blood-based NITs at baseline can accurately identify the need for NSBB for VB prophylaxis in patients of cACLD on follow-up.

Overview of Complications in Cirrhosis.

Background: Cirrhosis is the outcome of chronic liver disease of any etiology due to progressive liver injury and fibrosis. Consequently, cirrhosis leads to portal hypertension and liver dysfunction, progressing to complications like ascites, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, cirrhotic cardiomyopathy, sarcopenia, hepatocellular carcinoma, and coagulation disorders. End-stage liver disease leads to an impaired quality of life, loss of social and economic productivity, and reduced survival. Methods: This narrative review explains the pathophysiology of complications of cirrhosis, the diagnostic approach and innovative management, with focus on data from India. A comprehensive literature search of the published data was performed in regard with the spectrum, diagnosis, and management of cirrhosis and its complications. Results: There is a change in the epidemiology of metabolic syndrome, lifestyle diseases, alcohol consumption and the spectrum of etiological diagnosis in patients with cirrhosis. With the advent of universal vaccination and efficacious long-term viral suppression agents for chronic hepatitis B, availability of direct-acting antiviral agents for chronic hepatitis C, and a booming liver transplantation programme across the country, the management of complications is essential. There are several updates in the standard of care in the management of complications of cirrhosis, such as hepatorenal syndrome, hepatocellular carcinoma, and hepatic encephalopathy, and new therapies that address supportive and palliative care in advanced cirrhosis. Conclusion: Prevention, early diagnosis, appropriate management of complications, timely transplantation are cornerstones in the management protocol of cirrhosis and portal hypertension. India needs improved access to care, outreach of public health programmes for viral hepatitis care, health infrastructure, and disease registries for improved healthcare outcomes. Low-cost initiatives like immunization, alcohol cessation, awareness about liver diseases, viral hepatitis elimination, and patient focused decision-making algorithms are essential to manage liver disease in India.

Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis.

Hyponatremia is the most common electrolyte abnormality in patients with decompensated cirrhosis on Liver Transplantation (LT) waiting list. Most of these patients have dilutional or hypervolemic hyponatremia secondary to splanchnic vasodilatation. Excessive secretion of the antidiuretic hormone also plays an important role. Hypervolemic hyponatremia is commonly associated with refractory ascites, spontaneous bacterial peritonitis, and hepatic encephalopathy. Although uncommon, the use of diuretics and laxatives can cause hypovolemic hyponatremia that is characterized by the striking absence of ascites or pedal edema. Clinical features are often nonspecific and depend on the acuity of onset rather than the absolute value of serum sodium. Symptoms may be subtle, including nausea, lethargy, weakness, or anorexia. However, rarely patients may present with confusion, seizures, psychosis, or coma. Treatment includes discontinuation of diuretics, beta-blockers, and albumin infusion. Hypertonic saline (3%) infusion may be used in patients with very low serum sodium (<110 mmol/L) or when patients present with seizures or coma. Short-term use of Vasopressin (V2) receptor antagonists may also be used to normalize sodium levels prior to LT. However, all these measures may be futile, and LT remains the definite treatment in these patients to improve survival. In this review, we describe the classification, pathogenesis of hyponatremia, and its clinical implications in patients with cirrhosis. Approach to these patients along with management will also be discussed briefly.

Outcomes of Portal Pressure-Guided Therapy in Decompensated Cirrhosis With Index Variceal Bleed in Asian Cohort.

BACKGROUND AND AIMS: Hemodynamic response to pharmacotherapy improves survival in patients with cirrhosis post variceal bleeding, but long-term outcomes remain unexplored especially in this part of the world. We aimed to study the long-term impact of portal pressure reduction on liver-related outcomes after index variceal bleed. METHODS: Patients with hepatic venous pressure gradient (HVPG) more than 12 mm Hg after index variceal bleed were given non-selective beta-blockers in combination with variceal band ligation. HVPG response was assessed after 4 weeks. Patients were followed up for rebleed events, survival, additional decompensation events and safety outcomes. Rebleed and other decompensations were compared using competing risks analysis, taking death as competing event, and survival was compared using Kaplan-Meier analysis. RESULTS: Forty-eight patients (29 responders and 19 non-responders) were followed up for a median duration of 45 (24-56) months. Rebleeding rates at 1, 3 and 5 years were 10.3%, 20.7% and 20.7% in responders and 15.8%, 44.7% and 51.1% in non-responders, respectively (Gray's test, P = 0.044). Survival rates at 1, 3 and 5 years were 89.7%, 72.1% and 51.9% in responders and 89.5%, 44% and 37.7% in non-responders, respectively (log-rank test, P = 0.1). Both severity of liver disease (MELD score, multivariate sub-distributional hazards ratio: 1.166 [1.014-1.341], P = 0.030) and HVPG non-response (multivariate sub-distributional hazards ratio: 2.476 [1.87-7.030], P = 0.045) predicted rebleeding risk while survival was dependent only on severity of liver disease (MELD > 12, multivariate hazards ratio: 2.36 [1.04-5.38], P = 0.041). CONCLUSION: Baseline severity of liver disease predicted survival and rebleed in these patients. Hemodynamic response, although associated with lower rebleeding rate, had limited impact on survival.

Long-term Outcomes with Carvedilol versus Propranolol in Patients with Index Variceal Bleed: 6-year Follow-up Study.

AIMS AND BACKGROUND: There is limited information on comparison of clinical outcomes with carvedilol for secondary prophylaxis following acute variceal bleed (AVB) when compared with propranolol. We report long-term clinical and safety outcomes of a randomised controlled trial comparing carvedilol with propranolol with respect to reduction in hepatic venous pressure gradient (HVPG) in patients after AVB. METHODS: We conducted a post-hoc analysis of patients recruited in an open-label randomized controlled trial comparing carvedilol and propranolol following AVB, and estimated long-term rates of rebleed, survival, additional decompensation events and safety outcomes. Rebleed and other decompensations were compared using competing risks analysis, taking death as competing event, and survival was compared using Kaplan-Meier analysis. RESULTS: Forty-eight patients (25 taking carvedilol; 23 propranolol) were followed up for 6 years from randomization. More number of patients on carvedilol had HVPG response when compared with those taking propranolol (72%- carvedilol versus 47.8% propranolol, p = 0.047). Comparable 1-year and 3-year rates of rebleed (16.0% and 24.0% for carvedilol versus 8.9% and 36.7% for propranolol; p = 0.457) and survival (94.7% and 89.0% for carvedilol versus 100.0% and 79.8% for propranolol; p = 0.76) were obtained. New/worsening ascites was more common in those receiving propranolol (69.5% vs 40%; p = 0.04). Other clinical decompensations and complications of liver disease occurred at comparable rates between two groups. Drug-related adverse-events were similar in both groups. CONCLUSION: Despite higher degree of HVPG response, long-term clinical, survival and safety outcomes in carvedilol are similar to those of propranolol in patients with decompensated cirrhosis after index variceal bleed with the exception of ascites that developed less frequently in patients with carvedilol.

Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy.

Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.

Fibrosis index predicts variceal bleeding and reduces need for nonselective beta-blocker in compensated cirrhosis with initial small esophageal varices without red-color sign.

BACKGROUND: Various non-invasive markers predicting hepatic fibrosis are poor predictors of esophageal variceal bleeding (EVB). Elastography performs well but resource-limited. Controversy for small EV prevention also exists. We aim to investigate if a non-invasive marker could predict subsequent EVB within 1 and 2 years in patients with compensated liver cirrhosis (CLC), initial small EV without red-color sign (RCS), without use of non-selective beta-blockers (NSBB) and endoscopic variceal ligation (EVL). This marker would also be tested if it could help reduce use of NSBB, thereby avoiding potential side effects and saving medical costs. METHODS: In this retrospective cohort study, 6,803 CLC patients fulfilling the inclusion-exclusion criteria were enrolled between 2001 and 2018, and were followed-up for 1 year, 2 years. The primary outcomes were subsequent EVB within 1 and 2 years of enrollment. Another 281 CLC patients with NSBB use were compared for additional outcome analysis. RESULTS: In total, 539 patients and 710 patients experienced EVB within 1 year and 2 years, respectively. The fibrosis index (FI) with cut-off value of 3.95 showed a negative predictive value (NPV) of 94.3% and an area under receiver operating characteristic (AUROC) of 62.95% for predicting subsequent EVB within 1 year. The EVB and mortality of patients with FI <3.95 and not taking NSBB were significantly lower than those of the other 3 groups. Similar results were demonstrated within 2 years. CONCLUSIONS: In CLC patients with initial small EV and no RCS, low FI scores showed a high NPV and moderate AUROC in predicting subsequent EVB and mortalities, signifying clinically non-significant portal hypertension. Patients with low FI scores and not taking NSBB had significantly lowest EVB and mortality. The medical cost savings for cutting NSBB in these patients would be estimated at least $3 million per year in the U.S. Further randomized control trial study needed to validate this screening tool.

Where does TIPS fit in the management of patients with cirrhosis?

In this review, we summarise the current knowledge on the indications and contraindications of transjugular intrahepatic portosystemic shunt (TIPS) placement for the treatment of the complications of portal hypertension in cirrhosis, specifically variceal haemorrhage and ascites. Moreover, we discuss the role of TIPS for the treatment of portal vein thrombosis (PVT) and the prevention of complications after extrahepatic surgery ('preoperative TIPS') in patients with cirrhosis. The position of TIPS in the treatment hierarchy depends on the clinical setting and on patient characteristics. In acute variceal haemorrhage, preemptive TIPS is indicated in patients at a high risk of failing standard therapy, that is those with a Child-Pugh score of 10-13 points or Child-Pugh B with active bleeding at endoscopy, although the survival benefit in the latter group still remains to be established. Non-preemptive TIPS is a second-line therapy for the prevention of recurrent variceal haemorrhage and for the treatment of ascites. Of note, TIPS may also improve sarcopenia. Contraindications to TIPS placement, independent of clinical setting, include very advanced disease (Child-Pugh >13 points), episodes of recurrent overt hepatic encephalopathy without an identifiable precipitating factor, heart failure, and pulmonary hypertension. In patients with PVT, TIPS placement not only controls complications of portal hypertension, but also promotes portal vein recanalisation. Although the severity of portal hypertension correlates with poor outcomes after extrahepatic surgery, there is no evidence to recommend preoperative TIPS placement.

Can Non-Selective Beta-Blockers (NSBBs) Prevent Enlargement of Small Esophageal Varices in Patients with Cirrhosis? A Meta-analysis.

BACKGROUND: Non-selective beta-blockers (NSBBs) are recommended for prophylaxis of first variceal bleeding in patients of cirrhosis with large esophageal varices. However, the data is conflicting whether NSBBs can also prevent growth of small esophageal varices to large size. AIM: To perform a meta-analysis of the randomized clinical trials comparing NSBBs with placebo for prevention of development of large esophageal varices in patients of cirrhosis with small esophageal varices. METHODS: The PubMed, EMBASE, Science Direct, and Cochrane library databases were searched for relevant papers. A meta-analysis was performed using risk ratios (RRs) with 95% confidence interval (CI) as the effect sizes. RESULTS: Overall, 314 trials were initially retrieved from the database searches, of which five randomized controlled trials were included in the meta-analysis. The incidence of development of large varices (RR = 0.91, 95%CI: 0.29-2.86; P = 0.87) was similar between NSBB and placebo groups. However, the heterogeneity among studies was significant (P < 0.01) with an I2 of 93%. The incidences of first variceal bleeding (RR = 0.72, 95%CI: 0.25-2.12; P = 0.55) and death (RR = 0.76, 95%CI: 0.50-1.15; P = 0.19) were also similar between NSBB and placebo groups; with no heterogeneity. The incidence of adverse events was significantly higher in the NSBB group compared with the placebo group (RR = 4.66, 95%CI: 1.36-15.91; P = 0.01). CONCLUSION: The results of this meta-analysis indicate that NSBBs are not effective in preventing growth of small varices and may lead to significant adverse effects. Hence, NSBBs should not be recommended for cirrhotic patients with small varices.

Hemodynamic Response to Carvedilol is Maintained for Long Periods and Leads to Better Clinical Outcome in Cirrhosis: A Prospective Study.

BACKGROUND: Non-selective beta-blockers (NSBBs), e.g. propranolol, are recommended for prophylaxis of variceal bleeding in cirrhosis. Carvedilol, a newer NSBB with additional anti-α1-adrenergic activity, is superior to propranolol in reducing portal pressure. Repeated HVPG measurements are required to identify responders to NSBB. We aimed to determine whether a single-time HVPG measurement, using acute-hemodynamic-response-testing, is sufficient to predict long-term response to carvedilol, and whether these responders have better clinical outcome. METHODS: Consecutive patients with cirrhosis, aged 18-70 years, in whom NSBB was indicated for primary/secondary prophylaxis of variceal bleeding, and who underwent HVPG were included. Acute-hemodynamic-response was defined as a decrease in HVPG ≥10% from baseline or absolute HVPG value declining to <12 mm Hg, 1 h after 25 mg oral carvedilol. The aims of the study were to determine: the proportion of patients who achieved acute-hemodynamic-response to carvedilol; whether HVPG-response is maintained for 6 months; and clinical outcome of acute-responders to carvedilol therapy for 6 months. RESULTS: The study included 69 patients (median age 51, males 93%). Alcohol was the most common etiology; 59% patients belonged to Child-Pugh class B. NSBB was indicated for primary prophylaxis in 36% and secondary prophylaxis in 64% patients. According to the response criteria, 67% patients were found to be acute-hemodynamic-responders. At 6 months, 92% patients were found to be still maintaining their hemodynamic response to carvedilol. Using intention-to-treat analysis, 76% patients maintained their response. These acute responders, on chronic treatment with carvedilol during the 6-month period, had lesser episodes of variceal bleeding, better ascites control, and improved MELD and CTP scores, than non-carvedilol treated non-responders. However, survival remained similar in both the groups. CONCLUSIONS: A single-time HVPG measurement with acute-hemodynamic-response-testing is simple and reliable method for identifying patients who are more likely to respond to carvedilol therapy. The HVPG-response is maintained over a long period in majority of these patients and carvedilol therapy leads to better clinical outcome in these patients.

Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of ß-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of ß-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient.