Reduction In Hepatic Venous Pressure Gradient Research Articles

5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial

β-blockers reduce hepatic venous pressure gradient (HVPG) by decreasing portal inflow, with no reduction in intrahepatic vascular resistance. 5-Methyltetrahydrofolate (5-MTHF) can prevent oxidative loss of tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase coupling. It also converts homocysteine (tHcy) into methionine and enables the degradation of asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase. The aim of this study was to evaluate the effects of 5-MTHF in combination with propranolol on HVPG and nitric oxide bioavailability markers in patients with cirrhosis and portal hypertension. Sixty patients with cirrhosis and HVPG ≥12mmHg were randomized 1:1 to receive treatment with 5-MTHF+propranolol or placebo+propranolol for 90 days under double-blind conditions. HVPG and markers of nitric oxide bioavailability (BH4, ADMA and tHcy) were measured again at the end of treatment. Groups were similar in terms of baseline clinical and hemodynamic data and nitric oxide bioavailability markers. HVPG decreased in both groups, but the magnitude of the change was significantly greater in the group treated with 5-MTHF+propranolol compared to placebo+propranolol (percentage decrease, 20 [29-9] vs. 12.5 [22-0], p=0.028), without differences in hepatic blood flow. At the end of treatment, 5-MTHF+propranolol (vs. placebo+propranolol) was associated with higher BH4 (1,101.4 ± 1,413.3 vs. 517.1 ± 242.8pg/ml, p<0.001), lower ADMA (109.3 ± 52.7 vs. 139.9 ± 46.7μmol/L, p=0.027) and lower tHcy (μmol/L, 11.0 ± 4.6 vs. 15.4 ± 7.2μmol/L, p=0.010) plasma levels. In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol. This effect appears to be mediated by improved nitric oxide bioavailability in the hepatic microcirculation. 2014-002018-21. Currently, the pharmacological prevention of cirrhosis complications due to portal hypertension, such as esophageal varices rupture, is based on the use of β-blockers, but some patients still present with acute variceal bleeding, mainly due to an insufficient reduction of portal pressure. In this study, we sought to demonstrate that the addition of folic acid to β-blockers is more effective in reducing portal pressure than β-blockers alone. This finding could represent the basis for validation studies in larger cohorts, which could impact the future prophylactic management of variceal bleeding in cirrhosis. Enhancing the benefit of β-blockers with a safe, accessible, cost-effective drug could improve clinical outcomes in cirrhosis, which in turn could translate into a reduction in the rates and costs of hospitalization, and ultimately into improved survival.

Non-invasive candidate proteinsignature predicts hepatic venous pressure gradient reduction in cirrhotic patients after sustained virologic response.

A reduction in hepatic venous pressure gradient (HVPG) is the most accurate marker for assessing the severity of portal hypertension and the effectiveness of intervention treatments. This study aimed to evaluate the prognostic potential of blood-based proteomic biomarkers in predicting HVPG response amongst cirrhotic patients with portal hypertension due to Hepatitis C virus (HCV) and had achieved sustained virologic response (SVR). The study comprised 59 patients from two cohorts. Patients underwent paired HVPG (pretreatment and after SVR), liver stiffness (LSM), and enhanced liver fibrosis scores (ELF) measurements, as well as proteomics-based profiling on serum samples using SomaScan® at baseline (BL) and after SVR (EOS). Machine learning with feature selection (Caret, Random Forest and RPART) methods were performed to determine the proteins capable of classifying HVPG responders. Model performance was evaluated using AUROC (pROC R package). Patients were stratified by a change in HVPG (EOS vs. BL) into responders (greater than 20% decline in HVPG from BL, or <10 mmHg at EOS with >10 mmHg at BL) and non-responders. LSM and ELF decreased markedly after SVR but did not correlate with HVPG response. SomaScan (SomaLogic, Inc., Boulder, CO) analysis revealed a substantial shift in the peripheral proteome composition, reflected by 82 significantly differentially abundant proteins. Twelve proteins accurately distinguished responders from non-responders, with an AUROC of .86, sensitivity of 83%, specificity of 83%, accuracy of 83%, PPV of 83%, and NPV of 83%. A combined non-invasive soluble protein signature was identified, capable of accurately predicting HVPG response in HCV liver cirrhosis patients after achieving SVR.

The rationale and study design of two phase II trials examining the effects of BI 685509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis

BackgroundClinically significant portal hypertension (CSPH) drives cirrhosis-related complications (i.e. hepatic decompensation). Impaired nitric oxide (NO) bioavailability promotes sinusoidal vasoconstriction, which is the initial pathomechanism of CSPH development. Activation of soluble guanylyl cyclase (sGC), a key downstream effector of NO, facilitates sinusoidal vasodilation, which in turn may improve CSPH. Two phase II studies are being conducted to assess the efficacy of the NO-independent sGC activator BI 685509 in patients with CSPH due to various cirrhosis aetiologies.MethodsThe 1366.0021 trial (NCT05161481) is a randomised, placebo-controlled, exploratory study that will assess BI 685509 (moderate or high dose) for 24 weeks in patients with CSPH due to alcohol-related liver disease. The 1366.0029 trial (NCT05282121) is a randomised, open-label, parallel-group, exploratory study that will assess BI 685509 (high dose) alone in patients with hepatitis B or C virus infection or non-alcoholic steatohepatitis (NASH) and in combination with 10 mg empagliflozin in patients with NASH and type 2 diabetes mellitus for 8 weeks. The 1366.0021 trial will enrol 105 patients, and the 1366.0029 trial will enrol 80 patients. In both studies, the primary endpoint is the change from baseline in hepatic venous pressure gradient (HVPG) until the end of treatment (24 or 8 weeks, respectively). Secondary endpoints include the proportion of patients with an HVPG reduction of >10% from baseline, the development of decompensation events and the change from baseline in HVPG after 8 weeks in the 1366.0021 trial. In addition, the trials will assess changes in liver and spleen stiffness by transient elastography, changes in hepatic and renal function and the tolerability of BI 685509.DiscussionThese trials will enable assessment of the short-term (8 weeks) and longer-term (24 weeks) safety of BI 685509, and the effect of sGC activation by BI 685509 on CSPH due to various cirrhosis aetiologies. The trials will use central readings of the diagnostic gold standard HVPG for the primary endpoint, and changes in established non-invasive biomarkers, such as liver and spleen stiffness. Ultimately, these trials will provide key information for developing future phase III trials.Trial registration1366.0021: EudraCT no. 2021–001285-38; ClinicalTrials.gov NCT05161481. Registered on 17 December 2021, https://www.clinicaltrials.gov/ct2/show/NCT05161481.1366.0029: EudraCT no. 2021–005171-40; ClinicalTrials.gov NCT05282121. Registered on 16 March 2022, https://www.clinicaltrials.gov/ct2/show/NCT05282121.

Antibiotics and probiotics on hepatic venous pressure gradient in cirrhosis: A systematic review and a meta-analysis.

BackgroundModulation of the gut microbiome could favorably alter the hepatic venous pressure gradient (HVPG) in cirrhosis and portal hypertension (PH).AimThis meta-analysis was to evaluate the effects of microbiome-targeted therapies (MTTs) on HVPG in persons with cirrhosis and PH.MethodsPubMed, The Cochrane Library, Embase, Web of Science and Scopus were searched for randomized clinical trials (RCTs) analyzing the effects on HVPG in people with cirrhosis who received MTTs. Clinical outcomes were pooled using RevMan5.3 software. A trial sequential analysis was applied to calculate the required information size and evaluate the credibility of the meta-analysis results.ResultsA total of six studies were included. MTTs were associated with a reduction of 1.22 mm Hg in HVPG (95% CI: -2.31, -0.14 mmHg, P = 0.03). Subgroup analysis showed a greater reduction with longer duration (-1.88 mmHg;95% CI: -3.23, -0.53; P = 0.006). In the trial sequential analysis of HVPG reduction, the cumulative Z curve crossed the traditional significance boundary without the achievement of required information size (330).ConclusionsMTTs may be associated with a reduction in HVPG in patients with cirrhosis and PH. Microbiome-targeted therapies merit additional large-sample studies to define the efficacy of HVPG.Systematic review registrationPROSPERO 2020: CRD4202021609.

Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis

Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective β-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression. Eighty-seven patients (carvedilol/propranolol, n= 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective β-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P= .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P= .034). Cumulative incidences for rebleeding (Gray test, P= .027) and liver-related death (P= .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P= .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P= .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models. Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.

Intragastric Balloon in Obese Compensated Nonalcoholic Steatohepatitis Cirrhosis Patients Is Safe and Achieves Significant Weight Reduction at 6-Months.

Weight reduction is the mainstay treatment for Nonalcoholic steatohepatitis (NASH). intragastric balloon (IGB) placement has proven benefit in terms of weight reduction. The aim of the present study is to assess the safety and efficacy of IGB placement in compensated NASH cirrhosis. Nonalcoholic steatohepatitis cirrhosis patients with CTP ≤ 7, BMI of > 30, and who were unable to achieve weight reduction with lifestyle modification in past 3months were prospectively enrolled. Spatz3™ adjustable gastric balloon was placed endoscopically. Primary objective was to determine efficacy in weight loss at 6months, with secondary objectives of reduction in hepatic venous pressure gradient (HVPG), liver fat (controlled attenuation parameter, CAP), liver stiffness measurement (LSM) and clinical events as well as the tolerability and adverse events due to IGB placement. Altogether 56 cirrhosis patients, with a baseline BMI of 35.24 ± 3.92 and a CTP score of 6.27 ± 1.28 underwent IGB placement. The absolute weight reduction achieved was 15.88kg (- 16.46%) and reduction in BMI was - 10.1% at 6months. The percentage total body weight loss of ≥ 10% was achieved in 31 (55.35%) patients. The reduction in HVPG at 6-months was 11.12% (n = 16, 14.18 ± 2.12 to 12.60 ± 1.67mmHg). The mean reduction in LSM was 28.6% and in CAP was 10.09%. Three (5.36%) patients required removal of IGB before 6-months due to persisting vomiting. No patient developed new-onset decompensation or any serious adverse event. IGB placement is a safe, well tolerated and effective option for reduction in weight and portal pressure in compensated obese cirrhosis patients. Clinicaltrails.gov identifier no: NCT03753438.

Randomised clinical study: acute effects of metformin versus placebo on portal pressure in patients with cirrhosis and portal hypertension.

Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect. To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion. In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90minutes after ingestion of 1000-mg metformin (n=16) or placebo (n=16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow. The mean relative change in HVPG was -16% (95% CI: -28% to -4%) in the metformin group compared with 4% (95% CI: -6% to 14%) in the placebo group (time×group interaction, P=0.008). In patients with baseline HVPG ≥12mm Hg clinically significant improvements in HVPG (HVPG <12mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P=0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O2 uptake or inflammation markers between groups. A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.

Splenic non-infarction volume determines a clinically significant hepatic venous pressure gradient response to partial splenic embolization in patients with cirrhosis and hypersplenism.

This study aimed to investigate changes in the hepatic venous pressure gradient (HVPG) by partial splenic embolization (PSE) and to identify the determinants of a clinically meaningful postoperative HVPG reduction. Sixty-eight patients with cirrhosis and hypersplenism who underwent PSE at our department between September 2007 and June 2020 were included. The HVPG was evaluated pre- and immediately post-PSE. The patients were divided into three groups according to their preprocedural HVPG: low-HVPG (< 10mmHg, n = 22), intermediate-HVPG (10mmHg ≤ HVPG < 16mmHg, n = 33), and high-HVPG (≥ 16mmHg, n = 13). Overall, PSE significantly reduced HVPG from 12.2 ± 4.0 to 9.4 ± 3.6mmHg (p < 0.01) with a relative decrease of 22.2 ± 20.4%. In addition, HVPG reductions were 19.4 ± 28.7%, 24.0 ± 15.9%, and 22.5 ± 13.3% in the low-, intermediate-, and high-HVPG groups, respectively, indicating no significant difference in HVPG reduction between the groups. An HVPG decrease of ≥ 20% from the baseline, defined in this study as a clinically significant HVPG response to PSE, was achieved in 55.9% of all patients. Multivariate logistic regression and receiveroperating characteristic curve analyses identified splenic non-infarction volume as an independent determinant of a 20% decrease in HVPG (p < 0.05), with a cut-off of 139.2cm3 (sensitivity, 76.3%; specificity, 60.0%; p < 0.05). The splenic non-infarction volume, namely the residual functional spleen volume, independently determines a clinically significant HVPG response to PSE in patients with cirrhosis and hypersplenism.

Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites

The safety of non-selective β-blockers (NSBBs) has been questioned in refractory ascites (RA). We studied the effects of NSBBs on cardiac systolic function, systemic hemodynamics, and renal perfusion pressure (RPP) and function in patients with diuretic-responsive ascites (DRA) and RA. We performed a prospective pre-post repeated-measures study in cirrhotic patients, 18 with DRA and 20 with RA on NSBBs for variceal bleeding prophylaxis. Systolic function (by ejection intraventricular pressure difference [EIVPD]), hepatic venous pressure gradient (HVPG), cardiopulmonary pressures, RPP, and sympathetic activation were measured at baseline and after 4 weeks of propranolol. EIVPD was elevated at baseline (RA 4.5 [2.8-5.7] and DRA 4.2 [3.1-5.7] mmHg; normal 2.4-3.6 mmHg) and directly related to the severity of vasodilation and sympathetic activation. NSBBs led to similar reductions in heart rate and HVPG in both groups. NSBBs reduced EIPVD in RA but not in DRA (-20% vs.-2%, p <0.01). In RA, the NSBB-induced reduction in EIPVD correlated with the severity of vasodilation and with higher plasma nitric oxide, norepinephrine and IL-6 (r >0.40, all p<0.05). NSBBs reduced RPP in both groups, but impaired renal function only in patients with RA. Reduced EIPVD correlated with decreases in RPP and estimated glomerular filtration rate (r>0.40, all p <0.01). After NSBB treatment, RPP dropped below the threshold of renal flow autoregulation in 11 of the 20 (55%) patients with RA, including the 4 fulfilling the criteria for HRS-AKI. Renal perfusion and function depend critically on systolic function and sympathetic hyperactivation in RA. NSBBs blunt the sympathetic overdrive, hamper cardiac output, lower RPP below the critical threshold and impair renal function. β-blockade should be used cautiously or even avoided in patients with RA. We have identified the mechanisms by which non-selective beta-blockers could impair survival in patients with refractory ascites. We show that peripheral vasodilation and sympathetic activation lead to increased left ventricle systolic function in patients with cirrhosis and ascites, which acts as an adaptive mechanism to maintain renal perfusion. When ascites becomes refractory, this compensatory cardiac response to vasodilation is critically dependent on sympathetic hyperactivation and is hardly able to maintain renal perfusion. In this setting, β-blockade blunts the sympathetic overdrive of cardiac function, hampers cardiac output, lowers renal perfusion pressure below the critical threshold and impairs renal function.

Hemodynamic Effects of Adding Simvastatin to Carvedilol for Primary Prophylaxis of Variceal Bleeding: A Randomized Controlled Trial.

Beta-blockers are the mainstay agents for portal pressure reduction and to modestly reduce hepatic venous pressure gradient (HVPG). We studied whether addition of simvastatin to carvedilol in cirrhotic patients for primary prophylaxis improves the hemodynamic response. Cirrhotic patients with esophageal varices and with baseline HVPG > 12 mm Hg were prospectively randomized for primary prophylaxis to receive either carvedilol (group A, n = 110) or carvedilol plus simvastatin (group B, n = 110). Primary objective was to compare hemodynamic response (HVPG reduction of ≥20% or <12 mm Hg) at 3 months, and secondary objectives were to compare first bleed episodes, death, and adverse events. The groups were comparable at baseline. The proportion of patients achieving HVPG response at 3 months was comparable between groups (group A-36/62 [58.1%], group B-36/59 [61%], P = 0.85). The degree of mean HVPG reduction (17.3% and 17.8%, respectively, P = 0.98) and hemodynamic response (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.43-1.83, P = 0.74) was also not different between the groups. Patients who achieved target heart rate with no hypotensive episodes in either group showed better hemodynamic response (77.8% vs 59.2%, P = 0.04). Failure to achieve target heart rate (OR: 0.48; 95% CI: 0.22-1.06) and Child C cirrhosis (OR: 4.49; 95% CI: 1.20-16.8) predicted nonresponse. Three (3.7%) patients on simvastatin developed transient transaminitis and elevated creatine phosphokinase and improved with drug withdrawal. Two patients in each group bled (P = 0.99). Three patients and 1 patient, respectively, in group A and B died (P = 0.32), with sepsis being the cause of death. Addition of simvastatin to carvedilol for 3 months for primary prophylaxis of variceal bleeding does not improve hemodynamic response over carvedilol monotherapy. Simvastatin usage should be closely monitored for adverse effects in Child C cirrhotic patients.

Highlights from the literature

The PREDESCI trial,1 published in The Lancet , is the first randomised controlled trial (RCT) to evaluate the efficacy of non-selective beta-blockers in the primary prevention of hepatic decompensation in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH). Two hundred and one patients with compensated cirrhosis and CSPH (baseline hepatic venous pressure gradient (HVPG) ≥10 mm Hg), no previous decompensation and no high-risk oesophageal varices were recruited. Acute HVPG responders to intravenous propranolol were randomised to propranolol or placebo and non-responders to carvedilol or placebo. The primary endpoint was decompensation (ascites, variceal bleeding or overt encephalopathy) or liver-related death. Decompensation or death occurred in 16% (16/100) in the beta-blocker group versus 27% (27/101) in the placebo group (HR 0.51, 95% CI 0.26 to 0.97, p=0.04). This difference was largely attributable to a significant reduction in the incidence of ascites (HR 0.42, 95% CI 0.19 to 0.92, p=0.03). There was a greater reduction in HVPG in the carvedilol group compared to propranolol (16% vs 10%, p=0.036) and no significant reduction in the placebo group. The development …

Observation of immediate and mid-term effects of partial spleen embolization in reducing hepatic venous pressure gradient.

Objective:To observe the immediate and mid-term effects of partial spleen embolization (PSE) in reducing hepatic venous pressure gradient (HVPG) in patients with cirrhotic esophagogastric varices.Methods:Patients diagnosed with cirrhosis and esophagogastric varices in our hospital between July 2016 and March 2018 were consecutively selected. Forty-three patients were selected based on the eligibility criteria to undergo PSE. The change in HVPG 5 minutes before and after embolization, was used to determine the immediate effect of PSE on HVPG reduction. HVPG was retested after 6 months to observe the change in the antihypertensive effect along with time.Results:Forty-three patients successfully underwent PSE and HVPG measurements. The HVPG was 17.7 ± 3.9 mmHg and 13.9 ± 3.1 mmHg before and after PSE, respectively, showing a significant decrease (21.5%, P < .05). Among them, 18 cases were retested for HVPG at 6 months after PSE, and the results showed significant differences in the HVPG levels before, immediately and 6 months after PSE. Compared with preoperative PSE, HVPG was decreased by 22.9% and 17.7% (P < 0.05) immediately and at 6 months after operation, respectively. There was no significant change at 6 months after PSE when compared with immediate postoperative PSE. No serious complications were observed in patients during their postoperative hospital stay.Conclusion:PSE immediately reduced the portal pressure, and HVPG remained stable at 6 months after surgery. PSE is considered as a safe and easy to implement method, and is expected to be one of the treatments for reducing the portal pressure.

Changes in Hepatic Venous Pressure Gradient Predict Hepatic Decompensation in Patients Who Achieved Sustained Virologic Response to Interferon-Free Therapy.

Background and AimsSustained virologic response (SVR) to interferon (IFN)‐free therapies ameliorates portal hypertension (PH); however, it remains unclear whether a decrease in hepatic venous pressure gradient (HVPG) after cure of hepatitis C translates into a clinical benefit. We assessed the impact of pretreatment HVPG, changes in HVPG, and posttreatment HVPG on the development of hepatic decompensation in patients with PH who achieved SVR to IFN‐free therapy. Moreover, we evaluated transient elastography (TE) and von Willebrand factor to platelet count ratio (VITRO) as noninvasive methods for monitoring the evolution of PH.Approach and ResultsThe study comprised 90 patients with HVPG ≥ 6 mm Hg who underwent paired HVPG, TE, and VITRO assessments before (baseline [BL]) and after (follow‐up [FU]) IFN‐free therapy. FU HVPG but not BL HVPG predicted hepatic decompensation (per mm Hg, hazard ratio, 1.18; 95% confidence interval, 1.08‐1.28; P < 0.001). Patients with BL HVPG ≤ 9 mm Hg or patients who resolved clinically significant PH (CSPH) were protected from hepatic decompensation. In patients with CSPH, an HVPG decrease ≥ 10% was similarly protective (36 months, 2.5% vs. 40.5%; P < 0.001) but was observed in a substantially higher proportion of patients (60% vs. 24%; P < 0.001). Importantly, the performance of noninvasive methods such as TE/VITRO for diagnosing an HVPG reduction ≥ 10% was inadequate for clinical use (area under the receiver operating characteristic curve [AUROC], < 0.8), emphasizing the need for HVPG measurements. However, TE/VITRO were able to rule in or rule out FU CSPH (AUROC, 0.86‐0.92) in most patients, especially if assessed in a sequential manner.ConclusionsReassessment of HVPG after SVR improved prognostication in patients with pretreatment CSPH. An “immediate” HVPG decrease ≥ 10% was observed in the majority of these patients and was associated with a clinical benefit, as it prevented hepatic decompensation. These results support the use of HVPG as a surrogate endpoint for interventions that lower portal pressure by decreasing intrahepatic resistance.

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

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. 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. Of the 1113 patients included in the studies, 968 patients (87%) had been treated with nonselective β-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. In a meta-analysis of clinical trials, we found that patients with cirrhosis with and without ascites who respond to treatment with nonselective β-blockers (based on reductions in HVPG) have a reduced risk of events, death, or liver transplantation.

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

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. Sixty-six patients with cirrhosis and HVPG≥10mm 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. 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. 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.

A return to harmful alcohol consumption impacts on portal hemodynamic changes following alcoholic hepatitis.

Increased hepatic venous pressure gradient (HVPG) plays a role in the clinical manifestations of alcoholic hepatitis (AH). The evolution of HVPG and the influence of alcohol use in the intermediate term are unclear. The aim of this study was to explore HVPG modifications following AH taking into consideration alcohol use and clinical manifestations. Patients with AH (n=37; age 52 years; model for end-stage liver disease: 18.5; Maddrey score: 43) and chronic excessive drinkers with compensated cirrhosis (n=19; age: 54 years; model for end-stage liver disease: 9.2) underwent HVPG measurement and liver biopsy. Ten long-standing abstinent alcoholic cirrhotics served as controls. After discharge, patients were monitored for alcohol use and clinical complications, with repeated HVPG after a median duration of 100 days. Inflammation was determined using plasma C-reactive protein. At baseline, compared with chronic excessive drinkers and alcoholic cirrhotics, patients with AH had increased HVPG (18.1±0.6 vs. 13.8±1.4 vs. 15±1.3 mmHg, P<0.05). During follow-up, patients who became abstinent or reported occasional drinking were more likely to achieve a greater than 20% reduction in HVPG compared with those returning to harmful alcohol (45 vs. 0%, P<0.01), and suffered from fewer complications (25 vs. 68%, P<0.03). High baseline C-reactive protein levels correlated to the Maddrey (r=0.38), but no relationship was observed between changes in inflammation and HVPG. Elevated HVPG is a feature of AH, with a clinically significant reduction in values in abstinent or occasional drinkers after weeks of follow-up. A return to harmful alcohol has a negative impact on portal hemodynamics and associated clinical complications.

Physical exercise in cirrhotic patients: Towards prehabilitation on waiting list for liver transplantation. A systematic review and meta-analysis

Early survival after Liver Transplantation (LT) is reduced among sarcopenic patients. Despite, Adapted Physical Activity (APA) before LT is rarely proposed for the risk to impair portal hypertension and its resulting complications. To assess the effects of APA program in adults affected by End Stage Liver Disease (ESLD) on hospital stay, 1-year mortality and morbidity after LT, adverse events (Primary outcomes). Secondary outcomes were changes in VO2 peak, muscle morphology, 6minutes walking distance test (6MWD), Body Mass Index (BMI), MELD, CHILD score and Hepatic Venous Pressure Gradient (HVPG). MEDLINE, EMBASE, Google Scholar and the Cochrane Library database were explored for randomized clinical trials (RCT). Data were collected by one review author on the type of study, participants, treatments used for primary and secondary outcomes. Review Manager 5.2 was used for the analysis. Four RCT with 81 patients were included. Primary outcomes: no severe adverse event was observed, but no published data were available on hospital stay or mortality after LT. CHILD, MELD and BMI were not worsened by physical activity. No significant muscle diameter, 6MWD and VO2 peak changes were observed after exercise. Significant reduction in HVPG in the treatment group was observed in a single study (MD-2.5mmHg; 95%CI [-04.76, -0.24]; P=0.03). Knowledge in this field is still at an early stage. Evidence derived from small trials of medium quality on ESLD patients suggests that APA is safe, without increasing portal hypertension. Further research is very likely to have an important impact on our confidence in the intervention effect.

Propranolol versus carvedilol for the primary prophylaxis of variceal bleeding: a proposed multicenter, randomized, double-blind trial

Background: Bleeding from esophageal varices is one of the most frequent and deadly complications of liver cirrhosis, with six-week mortality rates as high as 30%. The estimation of portal pressure by means of hepatic venous pressure gradient (HVPG) measurement remains the single most accurate predictor of bleeding in individual patients. An increasing number of studies have reported a greater reduction of HVPG using carvedilol compared to the current standard of care, propranolol; however, there are still no clinical trials comparing carvedilol to propranolol head-to-head for the prophylaxis of variceal bleeding. Aims: To compare carvedilol versus propranolol for the prevention of a first variceal bleed (primary prophylaxis) in patients with cirrhosis and esophageal varices. Methods: This is a proposed design and protocol for a multicenter, randomized, active-controlled, double-blind, parallel group, phase III superiority trial, including a total of 452 patients with cirrhosis and esophageal varices that are at high risk of bleeding. Potential impact of the study: In view of the encouraging results obtained with carvedilol in prior studies, we believe a trial comparing propranolol to carvedilol in terms of clinical outcomes is necessary to clearly establish whether carvedilol should become the treatment of choice for the primary prohylaxis of variceal bleeding. If this trial is successfully conducted, results can be expected to have a substantial impact on clinical practice and future research directions.

Randomised clinical study: the effects of oral taurine 6g/day vs placebo on portal hypertension.

The amino sulphonic acid taurine reduces oxidative endoplasmatic reticulum stress and inhibits hepatic stellate cell activation, which might lead to reduction of portal pressure in cirrhosis. To assess the haemodynamic effects of taurine supplementation in patients with cirrhosis and varices. Patients with hepatic venous pressure gradient (HVPG) ≥12mm Hg were included in this prospective proof of concept study. Concomitant nonselective beta-blockers therapy was not allowed. Patients received either 4weeks of oral taurine (6g/day), or placebo, prior to evaluation of HVPG response. Thirty patients were screened and 22 included in the efficacy analysis (12 taurine/10 placebo; 64% male, mean age: 52±11years, Child A: 9%, B:64%, C:27%, ascites:68%). In the taurine group, mean HVPG dropped from 20mm Hg (±4) at baseline to 18mm Hg (±4) on day 28 (mean relative change: -12%, P=.0093). In the placebo group, mean HVPG increased from 20 mm Hg (±5) at baseline to 21mm Hg (±5) on day 28 (mean relative change:+2%, P=.4945). Taurine had no significant effects on systemic haemodynamics. Seven of 12 patients (58%) on taurine achieved a HVPG response >10%, compared to none in the placebo group (P=.0053). In a multivariate linear model, HVPG reduction was significantly larger in the taurine group compared to placebo group (P=.0091 and P=.0109 for absolute and relative change respectively). Treatment-related adverse events included gastrointestinal discomfort and fatigue, and were usually mild and comparable between treatment groups. Taurine is safe and may reduce portal pressure in cirrhotic patients. More studies on the underlying mechanisms of action and long-term effects of taurine supplementation are warranted.

A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.

HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using β-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693-1707).