Portal pressure reductions induced by nonselective beta-blockers improve outcomes and decrease mortality in patients with cirrhosis with and without ascites.
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ABSTRACT:
SUBMITTER: Turco L
PROVIDER: S-EPMC9306434 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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Portal pressure reductions induced by nonselective beta-blockers improve outcomes and decrease mortality in patients with cirrhosis with and without ascites.
Turco Laura L García-Tsao Guadalupe G
Clinical liver disease 20220603 1
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Project description:Background and aimsLittle is known about the effectiveness of nonselective beta blockers (NSBBs) in preventing hepatic decompensation in routine clinical settings. We investigated whether NSBBs are associated with hepatic decompensation or liver-related mortality in a national cohort of veterans with Child-Turcotte-Pugh (CTP) A cirrhosis with no prior decompensations.Approach and resultsIn an active comparator, new user (ACNU) design, we created a cohort of new users of carvedilol ( n = 123) versus new users of selective beta blockers (SBBs) ( n = 561) and followed patients for up to 3 years. An inverse probability treatment weighting (IPTW) approach balanced demographic and clinical confounders. The primary analysis simulated intention-to-treat ("pseudo-ITT") with IPTW-adjusted Cox models; secondary analyses were pseudo-as-treated, and both were adjusted for baseline and time-updating drug confounders. Subgroup analyses evaluated NSBB effects by HCV viremia status, CTP class, platelet count, alcohol-associated liver disease (ALD) etiology, and age. In pseudo-ITT analyses of carvedilol versus SBBs, carvedilol was associated with a lower hazard of any hepatic decompensation (HR 0.59, 95% CI 0.42-0.83) and the composite outcome of hepatic decompensation/liver-related mortality (HR 0.56, 95% CI 0.41-0.76). Results were similar in pseudo-as-treated analyses (hepatic decompensation: HR 0.55, 95% CI 0.33-0.94; composite outcome: HR 0.62, 95% 0.38-1.01). In subgroup analyses, carvedilol was associated with lower hazard of primary outcomes in the absence of HCV viremia, higher CTP class and platelet count, younger age, and ALD etiology.ConclusionsThere is an ongoing need to noninvasively identify patients who may benefit from NSBBs for the prevention of hepatic decompensation.
| S-EPMC9877112 | biostudies-literature
Project description:BackgroundIt has been suggested that beta-blockers may increase mortality in patients with cirrhosis and refractory ascites but the effect of beta-blockers discontinuation or reinitiation has not been examined.AimsTo compare, in hospitalised patients with cirrhosis and ascites, the effect of BB on survival and to examine the effect/predictors of beta-blockers discontinuation and reinitiation.MethodsSub-analysis of NACSELD (North American consortium for the study of end-stage liver disease, database containing prospective data on hospitalised patients with cirrhosis) data from 7 centres enrolling >100 patients with ascites. Data on BB discontinuation and reinitiation were collected by chart review.ResultsSeven hundred and sixteen patients, 307 (43%) on beta-blockers at admission and 366 (51%) with refractory ascites, were followed to death or hospital discharge. Beta-blocker use was associated with a lower white blood cell count at admission. Beta-blocker use in hospitalised patients with ascites was not associated with a higher mortality, even in those with refractory ascites. No significant changes in mean arterial pressure (MAP) were observed between groups. Discontinuation of beta-blockers (49%) was driven by low MAP, infection and acute kidney injury at time of discontinuation but was not associated with a higher mortality. Beta-blocker reinitiation occurred in 40% prior to discharge and was mainly driven by an increase in MAP.ConclusionsBeta-blocker use is safe in patients with cirrhosis and ascites (including those with refractory ascites) provided beta-blockers are discontinued in the presence of a low MAP and reinitiated once MAP reincreases. A potentially beneficial anti-inflammatory effect of beta-blockers is suggested.
| S-EPMC6016372 | biostudies-literature
Project description:Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End-Stage Liver Disease score of 8 (range 6-15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] -1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] -3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase-3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect.
| S-EPMC6587783 | biostudies-literature
Project description:BackgroundMR elastography can determine organ-related stiffness, which reflects the degree of fibrosis. Liver stiffness increases in cirrhosis, and stiffness increases further post-prandially due to increased portal blood in-flow. Non-selective beta-blockers (NSBB) reduce the portal venous inflow, but their effect on liver and spleen stiffness are disputed.AimsTo assess whether MR elastography of the liver or spleen reflects the severity of cirrhosis, whether treatment with NSBB changes liver and spleen stiffness and whether changes in stiffness can predict the effect of NSBB on portal pressure.MethodsFifty-two patients with cirrhosis underwent liver vein catheterization and two-dimensional (2D) MR elastography on separate days. Thirty-six of the patients had a hepatic venous pressure gradient (HVPG) of ≥12 mmHg and were tested prior to, and after, intravenous infusion of NSBB using HVPG measurement and MR elastography.ResultsHVPG showed a strong, positive, linear relationship with liver stiffness (r2 = 0.92; P < .001) and spleen stiffness (r2 = 0.94; P < .001). The cut-off points for identifying patients with a HVPG ≥ 12 mmHg were 7.7 kPa for liver stiffness (sensitivity 0.78, specificity 0.64) and 10.5 kPa for spleen stiffness (sensitivity 0.8, specificity 0.79). Intravenous administration of NSBB significantly decreased spleen stiffness by 6.9% (CI: 3.5-10.4, P < .001), but NSBB had no consistent effect on liver stiffness. However, changes in spleen stiffness were not related to the HVPG response (P = .75).ConclusionsTwo-dimensional MR elastographic estimation of liver or spleen stiffness reflects the degree of portal hypertension in patients with liver cirrhosis, but changes in stiffness after NSBB do not predict the effect on HVPG.
| S-EPMC8373798 | biostudies-literature
Project description:A 60-year-old woman without a history of liver diseases, but with a history of regular alcohol consumption, presented with a right-sided transudative pleural effusion. Neither parenchymal lung lesion nor pleural thickening was seen on a chest computed tomography. On abdominal ultrasonography, the liver size and contour were normal, and ascites was not noted. Despite performing imaging and laboratory studies, we could not find a cause of the pleural effusion. Thus, due to her history of regular alcohol consumption, we decided to measure liver stiffness using a transient elastography (Fibroscan(®), Echosens(TM), Paris, France), which showed a value of 35.3 kPa suggestive of liver cirrhosis. An intraperitoneal injection of a radioisotope demonstrated the transdiaphragmatic flow of fluid from peritoneal cavity to pleural cavity. The diagnosis was confirmed as hepatic hydrothorax. Management consisting of restricted salt and water intake with diuretics resulted in resolution of the hepatic hydrothorax.
| S-EPMC4722098 | biostudies-other
Project description:BackgroundArterial blood pressure (BP) is a reliable marker of circulatory dysfunction in cirrhotic patients. There are no prospective studies evaluating the association between different levels of arterial BP and ascites development in compensated cirrhotic patients. Therefore, we evaluated the relationship between arterial BP and ascites development in compensated cirrhotic patients.Materials and methodsA total of 402 patients with compensated HCV-related cirrhosis were prospectively followed during 6 years to identify ascites development. At baseline, patients underwent systolic, diastolic and mean arterial pressure (MAP) measurements. Any history of arterial hypertension was also recorded. The occurrence of events such as bleeding, hepatocellular carcinoma, death and liver transplantation prior to ascites development were considered as competing risk events.ResultsOver a median of 156 weeks, ascites occurred in 54 patients (13%). At baseline, MAP was significantly lower in patients with ascites development (75.9 mm/Hg [95%CI, 70.3-84.3]) than those without ascites (93.6 mm/Hg [95% CI: 86.6-102.3]). After adjusting for covariates, the 6-year cumulative incidence of ascites was 40% (95%CI, 34%-48%) for patients with MAP<83.32 mm/Hg. In contrast, cumulative incidences of ascites were almost similar among patients with MAP values between 83.32 mm/Hg and 93.32 mm/Hg (7% [95% CI: 4%-12%]), between 93.32 mm/Hg and 100.31 mm/Hg (5% [95% CI: 4%-11%]) or higher than 100.31 mm/Hg (3% [95% CI: 1%-6%]). The MAP was an independent predictor of ascites development.ConclusionsThe MAP is closely related to the development of ascites in compensated HCV-related cirrhosis. The risk of ascites development increases in 4.4 fold for subjects with MAP values <83.32 mm/Hg.
| S-EPMC3995756 | biostudies-literature
Project description:Background: Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model. Methods: Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured in-vivo. Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed. Results: Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model. Conclusion: In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis.
| S-EPMC8418541 | biostudies-literature
Project description:Increased levels of intestinal VEGF are thought to worsen portal hypertension. The cause of the increase in the level of intestinal VEGF found during cirrhosis is not known. The aim of this study is to demonstrate a relationship between portal pressure (PP) and intestinal/ plasma VEGF levels in different stages of fibrosis/cirrhosis. In this experiment, rats were exposed to carbon tetrachloride (CCl(4) ) for 6, 8 and 12 weeks. At the end of exposure, the three groups of rats exhibited three different stages of pathology: non-cirrhotic, early fibrotic and cirrhotic, respectively. For those rats and their age-matched controls, PP and intestinal/plasma VEGF levels were measured. Rats inhaling CCl(4) for 12 weeks developed portal hypertension (18.02 ± 1.07 mmHg), while those exposed for 6 weeks (7.26 ± 0.58 mmHg) and for 8 weeks (8.55 ± 0.53 mmHg) did not. The rats exposed for 12 weeks also showed a 40% increase in the level of intestinal VEGF compared to the controls (P < 0.05), while those rats exposed to CCl(4) inhalation for 6 and 8 weeks did not. There was a significant positive correlation between PP and intestinal VEGF levels (r(2) = 0.4, P < 0.005). Plasma VEGF levels were significantly elevated in those rats exposed to 12 weeks of CCl(4) inhalation (63.7 pg/ml, P < 0.01), compared to the controls (8.5 pg/ml). However, no correlation was observed between PP and plasma VEGF levels. It is concluded that portal pressure modulates intestinal VEGF levels during the development of cirrhosis.
| S-EPMC3213314 | biostudies-literature
Project description:Coronary flow velocity (CFV) is reduced in pathologic cardiac hypertrophy. This functional reduction is linked to adverse cardiac remodeling, hypertension and fibrosis, and angiotensin II (AngII) is a key molecular player. Angiotensin receptor blockers (ARBs) are known to attenuate adverse cardiac remodeling and fibrosis following increased afterload, while the mechanism by which these drugs offer clinical benefits and regulate hemodynamics remains unknown. To establish a direct connection between coronary flow changes and angiotensin-induced hypertension, we used a Doppler echocardiographic method in two distinct disease models. First, we performed serial echocardiography to visualize coronary flow and assess heart function in patients newly diagnosed with hypertension and currently on ARBs or calcium channel blockers (CCBs). CFV improved significantly in the hypertensive patients after 12 weeks of ARB treatment but not in those treated with CCBs. Second, using murine models of pressure overload, including Ang II infusion and aortic banding, we mimicked the clinical conditions of Ang II- and mechanical stress-induced hypertension, respectively. Both Ang II infusion and aortic banding increased the end-systolic pressure-volume relationship and cardiac fibrosis, but interestingly, only Ang II infusion resulted in a significant reduction in CFV and corresponding activation of pressure-sensitive proteins, including connective tissue growth factor, hypoxia-inducible factor 1α and signal transducer and activator of transcription 3. These data support the existence of a molecular and functional link between AngII-induced hemodynamic remodeling and alterations in coronary vasculature, which, in part, can explain the clinical benefit of ARB treatment in hypertensive patients.
| S-EPMC8260442 | biostudies-literature
Project description:Background: Nonselective beta-blockers (NSBBs) can reduce the incidence or mortality of certain types of cancers, and NSBBs exert a protective effect on hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the potential preventive effect of NSBBs has not yet been investigated in patients with chronic hepatitis B (CHB) who have a high HCC risk regardless of the presence of underlying cirrhosis. Aim: This study evaluated the association between NSBB use and HCC incidence in patients with CHB without cirrhosis and decompensation. Methods: From the 2000 Longitudinal Generation Tracking Database, we enrolled patients who were newly diagnosed as having CHB from January 2001 to December 2011 and then followed them up for at least 5 years. To estimate the causal effect of NSBBs on the time-to-event outcomes of HCC, a marginal Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: After adjustment, no significant benefit of HCC risk reduction was observed between the NSBB users and nonusers (adjusted HR, 0.82; 95% CI, 0.52-1.31). The cumulative defined daily dose (cDDD) analysis revealed no significant dose correlation among the three groups [adjusted HR (95% CI): 1.08, (0.56-2.05), 0.54 (0.17-1.77), and 0.76 (0.40-1.42) in the <90 cDDD, 90 to <180 cDDD, and ≥180 cDDD groups, respectively]. Duration-dependent associations were not observed. Multivariable stratified analysis results demonstrated that HCC risk markedly decreased in the patients aged >55 years (adjusted HR, 0.49; 95% CI, 0.25-0.96; p = 0.04). Conclusion: NSBB did not significantly prevent HCC in the patients with CHB infection without cirrhosis and decompensation. This study provided one of valuable results that it is not clinically required to use NSBBs as recommended chemoprevention for HCC in high-risk patients who have CHB.
| S-EPMC8777254 | biostudies-literature