Decrease In Hepatic Venous Pressure Gradient Research Articles

Blood microbiome is associated with changes in portal hypertension after successful direct-acting antiviral therapy in patients with HCV-related cirrhosis

Patients with a significant decrease in hepatic venous pressure gradient (HVPG) have a considerable reduction of liver complications and higher survival after HCV eradication. To evaluate the association between the baseline blood microbiome and the changes in HVPG after successful direct-acting antiviral (DAA) therapy in patients with HCV-related cirrhosis. We performed a prospective study in 32 cirrhotic patients (21 HIV positive) with clinically significant portal hypertension (HVPG ≥10 mmHg). Patients were assessed at baseline and 48 weeks after HCV treatment completion. The clinical endpoint was a decrease in HVPG of ≥20% or HVPG <12 mmHg at the end of follow-up. Bacterial 16S ribosomal DNA was sequenced using MiSeq Illumina technology, inflammatory plasma biomarkers were investigated using ProcartaPlex immunoassays and the metabolome was investigated using GC-MS. During the follow-up, 47% of patients reached the clinical endpoint. At baseline, those patients had a higher relative abundance of Corynebacteriales and Diplorickettsiales order, Diplorickettsiaceae family, Corynebacterium and Aquicella genus and Undibacterium parvum species organisms and a lower relative abundance of Oceanospirillales and Rhodospirillales order, Halomonadaceae family and Massilia genus organisms compared with those who did not achieve the clinical endpoint according to the LEfSe algorithm. Corynebacteriales and Massilia were consistently found within the 10 bacterial taxa with the highest differential abundance between groups. Additionally, the relative abundance of the Corynebacteriales order was inversely correlated with IFN-γ, IL-17A and TNF-α levels and the Massilia genus with glycerol and lauric acid. Baseline-specific bacterial taxa are related to an HVPG decrease in patients with HCV-related cirrhosis after successful DAA therapy.

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.

Partial splenic embolization is superior to intravenous somatostatin for decreasing portal pressure in cirrhotic patients: a dynamic self-controlled cohort study

Aims The efficacy of somatostatin in altering splanchnic hemodynamics in cirrhotic portal hypertension is still controversial. We aimed to establish the dynamic effect of somatostatin on portal pressure in cirrhotic patients and compared its effect with Partial Splenic Embolization (PSE). Methods Eighteen patients with cirrhotic portal hypertension were prospectively recruited. The wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) were repeatedly measured at baseline, 1-, 5-, 10- and 20-min after initiating somatostatin infusion. After somatostatin infusion cessation and washout, WHVP and FHVP were measured before and after PSE. The change in all the variables between time points was analyzed. Results Decreased hepatic venous pressure gradient (HVPG) 5-min after initiation of infusion was identified compared with baseline level (19.6%; p-value: .042), which was achieved through elevated FHVP (37.5%; p-value: 9.26e − 04). There was no significant decrease in WHVP at any time point during somatostatin infusion. The HVPG (17.4%; p-value: 1.27e − 04) and WHVP (10.4%; p-value: 3.00e − 03) post-PSE significantly decreased compared to the washout level. No significant distribution differences in the number of patients with HVPG decrease by a percentage relative to the baseline level were identified between the 5-min time point and post-PSE. Conclusion Our study indicates that somatostatin administration does not decrease WHVP within 20 min at clinically recommended doses. While somatostatin did decrease HVPG, this effect was achieved through increased FHVP, providing a possible explanation for its unclear efficacy. In contrast, PSE decreases both the WHVP and the HVPG.

Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension

Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21,-0.45,-0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n= 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p= 0.06), the decrease being greater in those with higher baseline HVPG (p= 0.018), with a significant interaction between baseline HVPG (continuous, p= 0.024; dichotomous at 16 mmHg [median], p= 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. Clinical Trials.gov #NCT02960204.

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.

HVPG Measurements as a Surrogate of Clinical Events in Cirrhosis: Experience from Clinical Trials

Update current knowledge of the use of hepatic venous pressure gradient (HVPG) as a predictor of clinical events and of efficacy of therapy for portal hypertension. HVPG is a good predictor of clinical events. Decrease in HVPG during therapy is accompanied by a decreased incidence of complications from portal hypertension and improved survival. HVPG measurements are a valuable tool in the management of portal hypertension in cirrhosis. In addition of detecting and grading the severity of portal hypertension, HVPG measurements provide robust prognostic information on the risk of complications, disease progression/regression, and survival. Changes in HVPG in response to therapy predict the effects on clinical outcomes, both during treatment with beta-blockers and when treating HCV-related cirrhosis with specific antivirals. This has led to suggest that HVPG can be used as a surrogate for clinical events when developing new therapies for portal hypertension. Limitations of this approach are discussed.

Shear wave elastography prior to transjugular intrahepatic portosystemic shunt may predict the decrease in hepatic vein pressure gradient.

Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure used to treat portal hypertension complications. Our aim was to evaluate liver and spleen stiffness measurement (LSM and SSM, respectively) changes using acoustic radiation force impulse imaging (ARFI) in comparison to Child-Pugh scores for predicting hepatic venous pressure gradient (HVPG) decreases after TIPS implantation. This prospective study included 31 consecutive clinically significant portal hypertension patients with TIPS indication. All patients received LSM and SSM before TIPS, at baseline, 2days (follow-up 1) and 6weeks (follow-up 2) post-implantation. HVPG was performed during the TIPS procedure. The mean decrease in HVPG after TIPS was 63%. LSM and SSM decreased significantly between baseline and follow-up 2 (p < 0.001 and p < 0.001, respectively). At baseline, follow-up 1 and follow-up 2, significant correlations were detected between mean SSM and mean HVPG (p = 0.026; p = 0.018; p = 0.002, respectively). HVPG decreased to ≤ 10mmHg in 61% of patients for which LSM, SSM, and Child-Pugh score were predictors (p = 0.033, p = 0.002 and p = 0.030, respectively). The area under the curve (AUC) for LSM, SSM, and Child-Pugh was 0.88, 0.90, and 0.84, respectively, with close sensitivity and specificity. SSM had the highest diagnostic accuracy for predicting an HVPG decrease to ≤ 10mmHg in comparison to LSM and Child-Pugh score. Spleen stiffness is superior to liver stiffness and Child-Pugh score as a non-invasive surveillance tool for evaluating patients with clinically significant portal hypertension (HVPG ≥ 10mmHg) prior to TIPS.

Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study.

Sequential measurements of hepatic venous pressure gradient (HVPG) are used to assess the haemodynamic response to nonselective betablockers (NSBBs) in patients with portal hypertension. To assess the rates of HVPG response to different doses of carvedilol. Consecutive patients with cirrhosis undergoing HVPG-guided carvedilol therapy for primary prophylaxis of variceal bleeding between 08/2010 and 05/2015 were retrospectively included. After baseline HVPG measurement, carvedilol 6.25mg/d was administered and HVPG response (HVPG-decrease ≥20% or to ≤12mm Hg) was assessed after 3-4weeks. In case of nonresponse, carvedilol dose was increased to 12.5mg/d and a third HVPG-measurement was performed after 3-4weeks. We also assessed HVPG-response rates according to the Baveno VI consensus (HVPG decrease ≥10% or to ≤12mm Hg) and changes in systolic arterial pressure (SAP). Seventy-two patients (Child A, 37%; B, 35%; C, 28%) were included. 28 (39%) patients achieved a HVPG-decrease≥20% with carvedilol 6.25mg/d and another 10 (14%) with carvedilol 12.5mg/d. Forty (56%) patients had a HVPG decrease ≥10% with carvedilol 6.25mg/d and 24 (33%) with carvedilol 12.5mg/d. Thus, in total, a HVPG-response of ≥20% and ≥10% and was achieved in 38 (53%) and 55 (76%) and of patients respectively. Notably, 6 patients (n=4 with ascites) did not tolerate an increase to 12.5mg/d due to hypotension/bradycardia. However, none of the other patients had a SAP<90mm Hg at the final HVPG measurement. Carvedilol 12.5mg/d was more effective than 6.25mg/d in decreasing HVPG in primary prophylaxis. A total of 76% of patients achieved a HVPG-response of≥10% to carvedilol 12.5mg/d, however, arterial hypotension might occur, especially in patients with ascites.

Pharmacologic prevention of variceal bleeding and rebleeding.

Variceal bleeding is a major complication of portal hypertension, which is associated with significant mortality. Moreover, patients surviving a variceal bleeding episode have very high risk of rebleeding, which is associated with mortality as high as that of the first bleed. Because of this, prevention of bleeding from gastroesophageal varices has been one of the main therapeutic goals since the advent of the first effective therapies for portal hypertension. This review deals with the present day state-of-the-art pharmacological prevention of variceal bleeding in primary and secondary prophylaxis. Pharmacological therapy aims to decrease portal pressure (PP) by acting on the pathophysiological mechanisms of portal hypertension such as increased hepatic vascular tone and splanchnic vasodilatation. Propranolol and nadolol block the beta-1 in the heart and the peripheral beta-2 adrenergic receptors. Beta-1 blockade of cardiac receptors reduces heart rate and cardiac output and subsequently decreases flow into splanchnic circulation. Beta-2 blockade leads to unopposed alpha-1 adrenergic activity that causes splanchnic vasoconstriction and reduction of portal inflow. Both effects contribute to reduction in PP. Carvedilol is more powerful in reducing hepatic venous pressure gradient (HVPG) than traditional nonselective beta-blockers (NSBBs) and achieves good hemodynamic response in nearly 75% of cases. Simvastatin and atorvastatin improve endothelial dysfunction mainly by enhancing endothelial nitric oxide synthase (eNOS) expression and phosphorylation and NO production. In addition, statins deactivate hepatic stellate cells and ameliorate hepatic fibrogenesis. These effects cause a decrease in HVPG and improve liver microcirculation and hepatocyte perfusion in patients with cirrhosis. In addition, several promising drugs under development may change the management of portal hypertension in the coming years. This review provides a background on the most important aspects of the treatment of portal hypertension in patients with compensated and decompensated liver cirrhosis. However, despite the great improvement in the prevention of variceal bleeding over the last years, further therapeutic options are needed.

Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with advanced liver disease.

HIV/HCV co-infected patients show accelerated fibrosis progression and higher risk for complications of portal hypertension (PHT). To assess the effects of interferon-free therapy on portal pressure, liver histology and plasma biomarkers in HIV/HCV-coinfected patients with PHT. Twenty-two patients with paired hepatic venous pressure gradient (HVPG) measurements prior and after successful treatment (SVR) with interferon-free regimens were included. Liver stiffness was assessed by transient elastography and biopsies were scored according to METAVIR. Plasma biomarkers were determined by ELISA. Overall, HVPG decreased from 10.7 ± 4.1 mmHg at baseline to 7.4 ± 4.2 mmHg after HCV treatment (Δ:-3.3 ± 2.7 mmHg; p < 0.001). In patients with clinically significant PHT (HVPG≥10 mmHg, n = 11), HVPG decreased from 14.1 ± 2.9 to 10.4 ± 3.9 mmHg (Δ:-3.7 ± 3.3 mmHg; p = 0.004) and a haemodynamic response (HVPG decrease ≥10%) was observed in 73%. In 64% of patients with subclinical PHT (HVPG 6-9 mmHg, n = 11), portal pressure normalised at SVR. Mean liver stiffness decreased from 20.8 kPa to 11.5 kPa (Δ:-8.8 ± 7.4 kPa; p < 0.001). Fifty percent (7/14) of patients with cirrhosis were re-classified as METAVIR ≤F3 and all patients with decompensated cirrhosis improved their Child-Pugh stage. After successful HCV treatment, 39% still had persistent histological necroinflammatory activity (METAVIR A1), which correlated with less HVPG response and more steatosis. While most biomarkers improved with SVR, METAVIR A1 patients had significantly higher plasma levels of fibrogenic (PDGF, TGF-β) and angiogenic (VEGF, Angiopoietin1) biomarkers. Interferon-free therapy reduces PHT and halts histological necroinflammatory activity in the majority of HIV/HCV-coinfected patients after SVR, which may lead to re-compensation of liver function in cirrhosis. Biomarkers could identify patients with persisting hepatic necroinflammation.

Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension

We aimed to investigate the impact of sustained virologic response (SVR) to interferon (IFN)-free therapies on portal hypertension in patients with paired hepatic venous pressure gradient (HVPG) measurements. One hundred and four patients with portal hypertension (HVPG ⩾6mmHg) who underwent HVPG and liver stiffness measurement before IFN-free therapy (baseline [BL]) were retrospectively studied. Among 100 patients who achieved SVR, 60 patients underwent HVPG and transient elastography (TE) after antiviral therapy (follow-up [FU]). SVR to IFN-free therapies significantly decreased HVPG across all BL HVPG strata: 6-9mmHg (BL: 7.37±0.28 vs. FU: 5.11±0.38mmHg; -2.26±0.42mmHg; p<0.001), 10-15mmHg (BL: 12.2±0.4 vs. FU: 8.91±0.62mmHg; -3.29±0.59mmHg; p<0.001) and ⩾16mmHg (BL: 19.4±0.73 vs. FU: 17.1±1.21mmHg; -2.3±0.89mmHg; p=0.018). In the subgroup of patients with BL HVPG of 6-9mmHg, HVPG normalized (<6mmHg) in 63% (12/19) of patients, while no patient progressed to ⩾10mmHg. Among patients with BL HVPG ⩾10mmHg, a clinically relevant HVPG decrease ⩾10% was observed in 63% (26/41); 24% (10/41) had a FU HVPG <10mmHg. Patients with Child-Pugh stage B were less likely to have a HVPG decrease (hazard ratio [HR]: 0.103; 95% confidence interval [CI]: 0.02-0.514; p=0.006), when compared to Child-Pugh A patients. In the subgroup of patients with BL CSPH, the relative change in liver stiffness (per %; HR: 0.972; 95% CI: 0.945-0.999; p=0.044) was a predictor of a HVPG decrease ⩾10%. The area under the receiver operating characteristic curve for the diagnosis of FU CSPH by FU liver stiffness was 0.931 (95% CI: 0.865-0.997). SVR to IFN-free therapies might ameliorate portal hypertension across all BL HVPG strata. However, changes in HVPG seemed to be more heterogeneous among patients with BL HVPG of ⩾16mmHg and a HVPG decrease was less likely in patients with more advanced liver dysfunction. TE might be useful for the non-invasive evaluation of portal hypertension after SVR. We investigated the impact of curing hepatitis C using novel interferon-free treatments on portal hypertension, which drives the development of liver-related complications and mortality. Cure of hepatitis C decreased portal pressure, but a decrease was less likely among patients with more pronounced hepatic dysfunction. Transient elastography, which is commonly used for the non-invasive staging of liver disease, might identify patients without clinically significant portal hypertension after successful treatment.

Virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension

Background & aims: Portal pressure, assessed by hepatic venous pressure gradient (HVPG)-measurement, drives the development of liver-related complications and mortality in patients with advanced liver disease. Since a decrease in HVPG translates into a clinically meaningful benefit, it is considered an acceptable surrogate endpoint for etiologic therapies.

Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients

Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (βArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of βArr2 in antrum mucosa. This study shows for the first time that the expression of βArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.

VSL#3® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis

In patients with decompensated cirrhosis, bacterial translocation can contribute to splanchnic vasodilatation, decreased effective circulating volume, and portal hypertension. The primary objective of this randomized, double blind placebo controlled trial was to evaluate the effect of the probiotic VSL#3(®) on the hepatic venous pressure gradient (HVPG). Seventeen patients with decompensated cirrhosis and an HVPG of ≥ 10 mmHg were randomized to receive 2 months of VSL#3(®) or an identical placebo. HVPG, endotoxin, interleukin (IL)-6, IL-8, IL-10, renin, aldosterone, nitric oxide and stool microbiota were measured at baseline and study end. Two of the 17 patients were taken off the trial before completion (one for alcohol abuse and the second for SBP - both in placebo arm). Data were analysed on the remaining 15 patients. The median model for end-stage liver disease score was 12, and 80% of patients had Child Pugh B disease. The treatment arm had a greater decrease in HVPG from baseline to study end than the placebo arm (median change from baseline -11.6% vs +2.8%), although this reduction was not statistically significant in either group. There was a significant reduction in the plasma aldosterone level in the VSL#3(®) group, but no significant changes in the other measured parameters, including the stool microflora analysis. Within the limitations of our sample size, VSL#3(®) therapy does not appear to have a significant impact on portal pressure reduction in patients with decompensated cirrhosis.

Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol

ObjectiveNon-selective β-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number...

A Prospective Evaluation of Pulmonary, Systemic and Hepatic Haemodynamics in HIV–HCV-Coinfected Patients before and after Antiviral Therapy with Pegylated Interferon and Ribavirin

Patients coinfected with HIV and HCV are at risk for developing portal hypertension (PHT), hyperdynamic circulation and pulmonary arterial hypertension (PAH). Data on the influence of antiviral therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV) are limited. Haemodynamic parameters, including hepatic venous pressure gradient (HVPG), pulmonary arterial pressure (PAP(mean)), cardiac output (CO) and systemic vascular resistance (SysVR), were prospectively evaluated before and after PEG-IFN-α+RBV therapy in 80 HIV-HCV-coinfected patients. Baseline evaluation showed a mean HVPG of 4.7 mmHg, CO of 6.15 l/min and PAP(mean) of 14.8 mmHg. PHT was present in 26% of patients, hyperdynamic circulation in 5% and PAH in 4%. Patients with advanced fibrosis (METAVIR stage F3/F4; n=32) had significantly higher CO (P=0.008), lower SysVR (P=0.035), higher PAP(mean) (P=0.018) and higher pulmonary vascular resistance (P=0.022) than patients with stage F0-F2 fibrosis (n=48). Both hyperdynamic circulation and PAH were significantly associated with liver stiffness, fibrosis stage and portal pressure; a non-significant trend was found for CD4(+) T-cell counts and HIV RNA levels. No significant changes in PAP(mean), CO and SysVR were observed after PEG-IFN-α+RBV treatment, although a significant decrease in HVPG was noted in patients with HCV eradication (P=0.013). The overall prevalence of hyperdynamic circulation and PAH in HIV-HCV coinfection is low. Advanced fibrosis, increased liver stiffness, elevated portal pressure and probably CD4(+) T-cell count and HIV viraemia represent risk factors for hyperdynamic circulation and PAH. PHT is present in 26% of HIV-HCV-coinfected patients evaluated for antiviral therapy. Successful HCV eradication significantly decreases HVPG.

Carvedilol or propranolol in portal hypertension? A randomized comparison

Objectives. Carvedilol is a non-selective β-blocker with intrinsic anti-α1-adrenergic activity, potentially more effective than propranolol in reducing hepatic venous pressure gradient (HVPG). We compared the long-term effect of carvedilol and propranolol on HVPG and assessed whether the acute response to oral propranolol predicted the long-term HVPG response on either drug. Material and methods. HVPG was measured in 38 patients with cirrhosis and HVPG ≥ 12 mm Hg at baseline and then again 90 min after an oral dose of 80 mg propranolol. Patients were double-blinded randomized to either carvedilol (21 patients) or propranolol (17 patients) and after 90 days of treatment HVPG measurements were repeated. Results. HVPG decreased by 19.3 ± 16.1% (p < 0.01) and by 12.5 ± 16.7% (p < 0.01) in the carvedilol and propranolol groups, respectively, with no significant difference between treatment regimens (p = 0.21). Although insignificant, an acute decrease in HVPG of ≥12% was the best cut-off value to predict long-term HVPG response to propranolol when using ROC curve analysis. Conclusions. This randomized study showed that carvedilol is at least as effective as propranolol on HVPG after long-term administration. Furthermore, a predictive value of an acute propranolol test on HVPG could not be confirmed.

Development of Ascites in Compensated Cirrhosis With Severe Portal Hypertension Treated With β-Blockers

In compensated cirrhosis, a threshold value of hepatic venous pressure gradient (HVPG) ≥10 mm Hg is required for the development of decompensation. However, whether the treatment of portal hypertension (PHT) can prevent the transition into development of ascites once this level has been reached is unclear. Our aim was to assess the relationship between changes in HVPG induced by β-blockers and development of ascites in compensated cirrhosis with severe PHT. Eighty-three patients without any previous decompensation of cirrhosis, with large esophageal varices and HVPG ≥12 mm Hg were included. After baseline hemodynamic measurements nadolol was administered and a second hemodynamic study was repeated 1-3 months later. During 53±30 months of follow-up, decompensation occurred in 52 patients (62%) and in 81% of them ascites was the first manifestation. Using receiver operating characteristic curve analysis a decrease in HVPG ≥10% was the best cutoff to predict ascites. As compared with nonresponders, patients with an HVPG decrease ≥10% had a lower probability of developing ascites (19% vs. 57% at 3 years, P<0.001), refractory ascites (P=0.007), and hepatorenal syndrome (P=0.027). By Cox regression analysis hemodynamic nonresponse was the best predictor of ascites. By stepwise logistic regression, development of ascites was independently associated with nonresponse, whereas refractory ascites, hepatorenal syndrome, and spontaneous bacterial peritonitis were not. In patients with compensated cirrhosis and large varices treated with β-blockers, an HVPG decrease ≥10% significantly reduces the risk of developing ascitic decompensation and other related complications such as refractory ascites or hepatorenal syndrome.

The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma – a pilot study

Increased intrahepatic vascular resistance and hyperperfusion in the splanchnic circulation are the principal mechanisms leading to portal hypertension in cirrhosis. Several preclinical studies have demonstrated a beneficial effect of the multikinase inhibitor sorafenib on the portal hypertensive syndrome. To investigate the effect of sorafenib on hepatic venous pressure gradient (HVPG), systemic hemodynamics and intrahepatic mRNA expression of proangiogenic, profibrogenic and proinflammatory genes. Patients with liver fibrosis/cirrhosis and hepatocellular carcinoma were treated with sorafenib 400 mg b.d. HVPG measurement and transjugular liver biopsy were performed at baseline and at week 2. Changes in HVPG and intrahepatic mRNA expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), RhoA, tumour necrosis factor-alpha (TNF-α) and placental growth factor (PlGF) were evaluated. Thirteen patients (m/f = 12/1; Child-Pugh class A/B = 10/3) were included. The most common aetiology of liver disease was alcohol consumption (n = 7). Eleven patients had an elevated portal pressure, including eight patients with clinically significant portal hypertension. A significant decrease of HVPG (≥ 20% from baseline) was observed in four subjects. In HVPG responders, we observed mRNA downregulation of VEGF, PDGF, PlGF, RhoA kinase and TNF-α, while no substantial mRNA decrease was found in nonresponders in any of the five genes. In two of the four HVPG responders we observed a dramatic (43-85%) mRNA decrease of all five investigated genes. Larger controlled clinical trials are needed to demonstrate any potential beneficial effect of sorafenib on portal hypertension in patients with cirrhosis.

Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension

Cirrhotic patients chronically treated with beta-blockers who achieve a decrease of hepatic venous pressure gradient (HVPG) > or =20% from baseline or to < or =12 mmHg have a marked reduction of first bleeding or re-bleeding. However, two HVPG measurements are needed to evaluate response. This study was aimed at investigating the predictive role of acute HVPG response to i.v. propranolol for bleeding and survival. We retrospectively studied 166 cirrhotic patients with varices with HVPG response to i.v. propranolol (0.15 mg/kg). All patients subsequently received non-selective beta-blockers to prevent first bleeding (n=78) or re-bleeding (n=88). Thirty-seven patients developed a portal hypertension-related bleeding over 2 years of follow-up. Decrease (12%) in HVPG was the best cut-off for bleeding risk discrimination. This parameter was used to classify patients in responders (n=95) and non-responders (n=71). In primary prophylaxis (54 responders vs. 24 non-responders) the actuarial probability of bleeding was half in responders than in non-responders (12% vs. 23% at 2 years; ns). In secondary prophylaxis (41 responders vs. 47 non-responders) a good hemodynamic response was also significantly and independently associated with a 50% decrease in the probability of re-bleeding (23% at 2 years vs. 46% in non-responders; p=0.032) and a better survival (95% vs. 65%; p=0.003). The evaluation of acute HVPG response to i.v. propranolol before initiating secondary prophylaxis for variceal bleeding is a useful tool in predicting the efficacy of non-selective beta-blockers. If adequately validated, this might be a more cost-effective strategy than the chronic evaluation of HVPG response and might be useful to guide therapeutic decisions in these patients.