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Background & Aims: Removing the primary aetiological factor in decompensated cirrhosis may lead to a restoration of hepatic function. In this study, we investigated the clinical implications of recompensation and the subsequent survival in patients with decompensated alcohol‐related cirrhosis. Methods: The rate of recompensation was evaluated in patients with decompensated alcohol‐related cirrhosis and persistent alcohol abstinence undergoing a hepatic venous pressure gradient (HVPG) measurement. Recompensation was defined according to Baveno VII criteria as resolution of ascites and hepatic encephalopathy, absence of variceal bleeding and improvement in liver function. Results: Two hundred and four abstinent patients with decompensated alcohol‐related cirrhosis (age: 57.2 [IQR:50.1–63.7] years; 75.0% male; median MELD: 15 [IQR:11–19]) and a median HVPG of 20 (IQR:18–24) mmHg were included. During a median follow‐up of 24.4 (IQR:10.9–50.4) months, 37 patients (18.1%) achieved abstinence‐induced recompensation. Lower baseline HVPG, lower Child‐Pugh score, lower BMI, higher albumin and higher mean arterial pressure were linked to a higher probability of recompensation. After adjusting for age, disease severity, portal hypertension and systemic inflammation, achieving recompensation resulted in a significant and considerable reduction in liver‐related mortality (adjusted HR: 0.091 [95% CI: 0.012–0.677]; p =.019). Only 13 patients (6.4%) developed hepatocellular carcinoma, with a tendency towards a lower risk upon recompensation (HR: 0.398 [95% CI: 0.084–1.878]; p =.245), yet this finding did not reach statistical significance and requires further investigation. Conclusions: Alcohol abstinence led to recompensation in 18.1% of our cohort of HVPG‐characterised patients with decompensated alcohol‐related cirrhosis. Achieving hepatic recompensation resulted in a >90% risk reduction in liver‐related mortality. [ABSTRACT FROM AUTHOR]

Background & Aims: Experimental evidence indicates that systemic inflammation (SI) promotes liver fibrogenesis. This study investigated the potential link between SI and fibrogenesis in patients with advanced chronic liver disease (ACLD). Methods: Serum biomarkers of SI (CRP, IL‐6, procalcitonin [PCT]) and extracellular matrix (ECM) turnover (i.e., fibrogenesis/fibrolysis) were analysed in 215 prospectively recruited patients with ACLD (hepatic venous pressure gradient [HVPG] ≥6 mm Hg) undergoing hepatic vein catheterization. Patients with non‐elective hospitalization or bacterial infection were excluded. Histological alpha‐smooth muscle actin (α‐SMA) area was quantified on full biopsy scans by automated morphometric quantification in a subset of 34 patients who underwent concomitant transjugular liver biopsy. Results: Histological α‐SMA proportionate area correlated with enhanced liver fibrosis (ELF) score (Spearman's ρ = 0.660, p <.001), markers of collagen formation (PRO‐C3, ρ = 0.717, p <.001; PRO‐C6, ρ = 0.526, p =.002) and tissue inhibitor of metalloproteinases‐1 (TIMP1; ρ = 0.547, p <.001), indicating that these blood biomarkers are capable of reflecting the dynamic process of ECM turnover. CRP, IL‐6 and PCT levels correlated with ELF, biomarkers of collagen synthesis/degradation and TIMP1, both in compensated and decompensated patients. Multivariate linear regression models (adjusted for HVPG) confirmed that CRP, IL‐6 and PCT were independently linked to markers of liver fibrogenesis and ECM turnover. Conclusion: Systemic inflammation is linked to both liver fibrogenesis and ECM turnover in ACLD and this association is not confounded by the severity of liver disease, as evaluated by HVPG. Our study confirms experimental data on the detrimental impact of SI on ECM deposition and fibrosis progression in a thoroughly characterized cohort of patients with ACLD. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis has become a leading cause of cirrhosis. The prognostic value of (HVPG)-guided NSBB prophylaxis remains to be investigated in the setting of NASH cirrhosis. Patients with NASH cirrhosis and varices undergoing HVPG-guided NSBB therapy were included. HVPG-response to NSBBs was evaluated within a median 52 (IQR:28–71) days after baseline measurement. HVPG-Response was defined as a decrease of ≥10% from baseline or below <12 mmHg. The composite endpoint was defined as variceal bleeding, decompensation, and liver-related death. Thirtyeight patients were included: Child-A/B:33(87%), Child-C:5(13%) median HVPG:19.7 ± 4.7 mmHg. 21(55.3%) patients achieved HVPG-response to NSBB. Presence of diabetes(aOR:0.16, p = 0.038) and arterial blood pressure (aOR:1.07, p = 0.044) were independently associated with NSBB-response. While NSBB-HVPG-responders showed fewer decompensations within 90 days (n = 1(5%) vs. n = 3(29%), p = 0.172), only Child-Pugh stage B/C (p = 0.001), MELD ≥ 15(p = 0.021) and HVPG ≥ 20 mmHg(p = 0.011) predicted the composite endpoint at 90 days. Similarly, after 2years of follow-up, only Child-Pugh stage (B: p = 0.001, C: p < 0.001), MELD ≥ 15 (p = 0.021), HVPG≥20 mmHg (p = 0.011) predicted the composite endpoint. Importantly, all bleeding events occurred in HVPG-NSBB non-responders. HVPG-response to NSBB was achieved in 55.3% of NASH patients with varices and this seemed to protect from variceal bleeding. However, only baseline HVPG ≥ 20 mmHg, Child-Pugh stage B/C and MELD ≥ 15 were predictors of decompensation/death in patients with NASH cirrhosis and varices. [ABSTRACT FROM AUTHOR]

Portal hypertension (PH)-associated splenomegaly is caused by portal venous congestion and splanchnic hyperemia. This can trigger hypersplenism, which favors the development of cytopenia. We investigated the time-dependent impact of splenectomy on portal pressure and blood cell counts in animal models of non-cirrhotic and cirrhotic PH. Ninety-six rats underwent either partial portal vein ligation (PPVL), bile duct ligation (BDL), or sham operation (SO), with subgroups undergoing additional splenectomy. Portal pressure, mean arterial pressure, heart rate, blood cell counts and hemoglobin concentrations were evaluated throughout 5 weeks following surgery. Following PPVL or BDL surgery, the animals presented a progressive rise in portal pressure, paralleled by decreased mean arterial pressure and accelerated heart rate. Splenectomy curbed the development of PH in both models (PPVL: 16.25 vs. 17.93 ​mmHg, p ​= ​0.083; BDL: 13.55 vs. 15.23 ​mmHg, p ​= ​0.028), increased mean arterial pressure (PPVL: +7%; BDL: +9%), and reduced heart rate (PPVL: −10%; BDL: −13%). Accordingly, splenectomized rats had lower von Willebrand factor plasma levels (PPVL: −22%; BDL: −25%). Splenectomy resulted in higher hemoglobin levels in PPVL (14.15 vs. 13.08 ​g/dL, p ​< ​0.001) and BDL (13.20 vs. 12.39 ​g/dL, p ​= ​0.097) animals, and significantly increased mean corpuscular hemoglobin concentrations (PPVL: +9%; BDL: +15%). Thrombocytopenia only developed in the PPVL model and was alleviated in the splenectomized subgroup. Conversely, BDL rats presented with thrombocytosis, which was not affected by splenectomy. Splenectomy improves both cirrhotic and non-cirrhotic PH, and ameliorates the hyperdynamic circulation. Hypersplenism related anemia and thrombocytopenia were only significantly improved in the non-cirrhotic PH model. [ABSTRACT FROM AUTHOR]

Background and Aims: Portal hypertension (PH) and sarcopenia are common in patients with advanced chronic liver disease (ACLD). However, the interaction between PH and sarcopenia and their specific and independent impact on prognosis and mortality has yet to be systematically investigated in patients with ACLD. Methods: Consecutive patients with ACLD and hepatic venous pressure gradient (HVPG) ≥10 mm Hg with available CT/MRI imaging were included. Sarcopenia was defined by transversal psoas muscle thickness (TPMT) at <12 mm/m in men and <8 mm/m in women at the level of the third lumbar vertebrae. Hepatic decompensation and mortality was recorded during follow‐up. Results: Among 203 patients (68% male, age: 55 ± 11, model for end‐stage liver disease [MELD]: 12 [9‐15]), sarcopenia was observed in 77 (37.9%) and HVPG was ≥20 mm Hg in 98 (48.3%). There was no correlation between TPMT and HVPG (r =.031, P =.66), median HVPG was not different between patients with vs without sarcopenia (P =.211). Sarcopenia was significantly associated with first/further decompensation both in compensated (SHR: 3.05, P =.041) and in decompensated patients (SHR: 1.86, P =.021). Furthermore, sarcopenia (SARC) was a significant predictor of mortality irrespective of HVPG (HVPG < 20‐SARC: SHR: 2.25, P =.021; HVPG ≥ 20‐SARC: SHR: 3.33, P =.001). On multivariate analysis adjusted for age, HVPG and MELD, sarcopenia was an independent risk factor for mortality (aHR: 1.99, 95% confidence interval: 1.2‐3.3, P =.007). Conclusion: Sarcopenia has a major impact on clinical outcomes both in compensated and in decompensated ACLD patients. The presence of sarcopenia doubled the risk for mortality independently from the severity of PH. [ABSTRACT FROM AUTHOR]

Background and Aims: The enhanced liver fibrosis (ELF) score comprises serum markers of fibrogenesis and matrix remodelling and was developed to detect liver fibrosis, however, it may also be useful for the non‐invasive detection of portal hypertension (PHT). Methods: ELF score and its single components (TIMP1/PIIINP/HA) were analysed in 201 patients with advanced chronic liver disease (ACLD; ie hepatic venous pressure gradient (HVPG) ≥6 mm Hg). Patients with pre‐/post‐hepatic PHT, hepatocellular carcinoma beyond Milan criteria, and history of TIPS implantation or liver transplantation were excluded. Results: ELF and its single components correlated with HVPG in the overall cohort: ELF: r =.443, TIMP1: r =.368, PIIINP:r =.332, and HA:r =.419 (all P <.001). The strength of the correlation between ELF and HVPG decreased in higher HVPG strata: 6‐9 mm Hg:r =.569(P =.004), 10‐19 mm Hg:r =.304 (P =.001) and ≥20 mm Hg:r = −.023(P =.853). Area under the receiver operating characteristics (AUROC) of ELF score to detect clinically significant PHT (CSPH; HVPG ≥ 10 mm Hg) was 0.833. Importantly, HA alone yielded an AUROC of 0.828. Detection of CSPH in strictly compensated ACLD (cACLD) patients was less accurate: AUROC: 0.759 (P <.001). CSPH was ruled‐in by ELF ≥ 11.1 with a PPV of 98% (sensitivity: 61%/specificity: 92%/NPV:24%), but CSPH could not be ruled‐out. ELF score had a low AUROC of 0.677 (0.60‐0.75; P <.001) for the diagnosis of high‐risk PHT (HRPH; HVPG ≥ 20mm Hg) and, thus, HRPH could not be ruled‐in by ELF. However, ELF < 10.1 ruled‐out HRPH with a NPV of 95% (sensitivity: 97%/specificity: 26%/PPV: 39%). Conclusion: The ELF score correlates with HVPG at values <20 mm Hg. An ELF ≥ 11.1 identifies patients with a high probability of CSPH, while an ELF < 10.1 may be used to rule‐out HRPH. [ABSTRACT FROM AUTHOR]

Background & Aims: The loss‐of‐function rs72613567 T > TA‐variant in the 17β‐hydroxysteroid dehydrogenase 13 (HSD17B13) gene might protect from alcoholic and non‐alcoholic fatty liver disease (ALD/NAFLD) and associated fibrosis/cirrhosis. We investigated the impact of the T > TA‐variant on hepatic decompensation and mortality and investigated its implications on retinol and sex steroid metabolism in patients who had already developed advanced chronic liver disease (ACLD). Methods: Retrospective analysis in prospectively characterized patients with viral hepatitis‐ and ALD/NAFLD‐induced portal hypertension (hepatic venous pressure gradient (HVPG) ≥ 6 mmHg) diagnosed at the Medical University of Vienna. Results: Among 487 patients who were followed longitudinally, 166 (34%) were heterozygous and 24 (5%) were homozygous for the 'protective' TA‐allele. Patients harbouring at least one TA‐allele had a lower MELD (9 (8‐12) vs 10 (8‐13) points; P =.003) and showed a trend towards lower HVPG (16 ± 6 vs 17 ± 7 mmHg; P =.067). Interestingly, in competing risk analyses adjusted for age, HVPG and MELD, harbouring the TA‐allele was associated with numerically increased risks for mortality (adjusted subdistribution hazard ratio (aSHR): 1.3 (95% confidence interval (95% CI): 0.888‐1.91); P =.18), liver‐related death (aSHR: 1.34 (95% CI: 0.9‐1.98); P =.15) and hepatic decompensation (aSHR: 1.29 (95% CI: 0.945‐1.77); P =.11). This might be explained by trends towards worse outcomes (eg liver‐related death: aSHR: 1.64 (95% CI: 0.95‐2.84); P =.076) in patients with viral hepatitis‐induced ACLD. In a cross‐sectional analysis of 211 additional patients, serum retinol levels were comparable between HSD17B13 genotypes, but in males, serum testosterone levels numerically decreased with an increasing number of TA‐alleles. Conclusion: In patients with viral hepatitis‐ and ALD‐induced portal hypertension, the T > TA‐variant was not protective of hepatic decompensation and mortality. Further studies should investigate the pathophysiological mechanisms underlying the effects of HSD17B13 genotype at different stages of liver disease. [ABSTRACT FROM AUTHOR]

Background: Anaemia is common in advanced chronic liver disease (ACLD) as a result of various risk factors. Aims & Methods: We evaluated the prevalence and severity of anaemia as well as the impact of anaemia on clinical outcomes in consecutive patients with ACLD and portal hypertension. Results: Among 494 patients, 324 (66%) patients had anaemia. Anaemic patients showed higher MELD (12 ± 4 vs 9 ± 3; P <.001), lower albumin (34 ± 6 vs 39 ± 5 g/dL; P <.001) and more often Child‐Pugh B/C stage (56% vs 17%; P <.001). The prevalence of moderate‐severe anaemia (haemoglobin <10 g/dL) increased with the degree of portal hypertension (HVPG: 6‐9 mm Hg: 22% vs HVPG: 10‐19 mm Hg: 24% vs HVPG ≥ 20 mm Hg: 36%; P =.031). The most common aetiologies of anaemia were gastrointestinal bleeding (25%) and iron deficiency (9%), while reason for anaemia remained unclear in 53% of cases. Male gender (odds ratio [OR]: 1.94 [95% CI: 1.09‐3.47]; P =.025), MELD (OR: 1.20 [95% CI: 1.09‐1.32]; P <.001), hepatic decompensation (OR: 4.40 [95% CI: 2.48‐7.82]; P <.001) and HVPG (OR per mm Hg: 1.07 [95% CI: 1.02‐1.13]; P =.004) were independent risk factors for anaemia. Anaemia was associated with hepatic decompensation (1 year: 25.1% vs 8.1%; 5 years: 60.3% vs 32.9%; P <.0001), hospitalization (73% vs 57%; P <.001) and a higher incidence rate of acute‐on‐chronic liver failure (0.05 [95% CI: 0.04‐0.07] vs 0.03 [95% CI: 0.01‐0.04]). Anaemic patients had worse overall survival (1 year: 87.1% vs 93.7%, 5 year survival: 50.5% vs 68.6%; P <.0001) and increased liver‐related mortality (1 year mortality: 9.7% vs 5.7%, 5 year mortality: 38.0% vs 26.9%; P =.003). Conclusion: Two‐thirds of patients with ACLD suffer from anaemia. The degree of hepatic dysfunction and of portal hypertension correlate with severity of anaemia. Anaemia is associated with decompensation, ACLF and increased mortality in patients with ACLD. [ABSTRACT FROM AUTHOR]

Background and Aim: The nuclear farnesoid X receptor (FXR) regulates critical pathways of hepatic metabolism, inflammation, and gut mucosal barrier. Thus, we investigated the association of FXR‐single nucleotide polymorphism (SNPs) with hepatic decompensation and liver‐related mortality in patients with advanced chronic liver disease. Methods: Two FXR‐SNPs (rs56163822 G > T and rs35724 G > C) were genotyped in a cohort of 402 prospectively characterized patients with hepatic venous pressure gradient (HVPG) ≥ 6 mmHg. Results: Only 19 patients (4.7%) harbored a rs56163822 T‐allele and had less pronounced liver disease as indicated by lower Child–Pugh score (CPS, 6 ± 1 vs 7 ± 2 points, P = 0.034) and higher albumin levels (38.9 ± 4.9 vs 35.9 ± 5.9 g/L, P = 0.026). In contrast, n = 267 (66.4%) patients harbored minor rs35724 allele (G/C or C/C) and had more advanced liver disease, as indicated by a higher model of end‐stage liver disease (11 ± 4 vs 10 ± 3, P = 0.016), while other baseline characteristics were similar across FXR‐SNP genotypes. In compensated CPS‐A patients, the rs35724 minor allele was independently protective for the development of ascites (adjusted hazard ratio [aHR] = 0.411, 95% confidence interval (95% CI): 0.191–0.885; P = 0.023) and tended to reduce the risk of hepatic decompensation (aHR = 0.625, 95% CI: 0.374–1.044, P = 0.072) in multivariate analyses. Of note, transplant‐free survival was longer in patients with rs35724 minor allele and HVPG ≥ 10 mmHg (at 5 years: 68.2% vs 55.8%, P = 0.047) and those with HVPG ≥ 16 mmHg (63.3% vs 44.0%, P = 0.021). After adjusting for established risk factors, the rs35724 minor allele was independently associated with reduced liver‐related mortality in the overall cohort (aHR = 0.658, 95% CI: 0.434–0.998, P = 0.049), in compensated CPS‐A patients (aHR = 0.488, 95% CI: 0.252–0.946, P = 0.034), in patients with HVPG ≥ 10 mmHg (aHR = 0.547, 95% CI: 0.346–0.864, P = 0.010), and in patients with HVPG ≥ 16 mmHg (aHR = 0.519, 95% CI: 0.307–0.878, P = 0.014). Conclusion: The FXR‐SNP rs35724 was associated with a reduced risk for development of ascites and liver‐related mortality in patients with advanced chronic liver disease. [ABSTRACT FROM AUTHOR]

Background and aims: Studies in animal models have suggested that hepatic steatosis impacts on portal pressure, potentially by inducing liver sinusoidal endothelial dysfunction and thereby increasing intrahepatic resistance. Thus, we aimed to evaluate the impact of hepatic steatosis on hepatic venous pressure gradient (HVPG) in patients with chronic liver disease. Method: 261 patients undergoing simultaneous HVPG measurements and controlled attenuation parameter (CAP)-based steatosis assessment were included in this retrospective study. Results: The majority of patients had cirrhosis (n = 205; 78.5%) and n = 191 (73.2%) had clinically significant portal hypertension (CSPH; HVPG≥10mmHg). Hepatic steatosis (S1/2/3; CAP ≥248dB/m) was present in n = 102 (39.1%). Overall, HVPG was comparable between patients with vs. without hepatic steatosis (15.5±7.5 vs. 14.8±7.7mmHg; p = 0.465). Neither in patients with HVPG (<6mmHg; p = 0.371) nor in patients with mild portal hypertension (HVPG 6–9mmHg; p = 0.716) or CSPH (HVPG≥10mmHg; p = 0.311) any correlation between CAP and HVPG was found. Interestingly, in patients with liver fibrosis F2/3, there was a negative correlation between CAP and HVPG (Pearson's ρ:-0.522; p≤0.001). In multivariate analysis, higher CAP was an independent 'protective' factor for the presence of CSPH (odds ratio [OR] per 10dB/m: 0.92, 95% confidence interval [CI]:0.85–1.00; p = 0.045), while liver stiffness was associated with the presence of CSPH (OR per kPa: 1.26, 95%CI: 1.17–1.36; p≤0.001). In 78 patients, in whom liver biopsy was performed, HVPG was neither correlated with percentage of histological steatosis (p = 0.714) nor with histological steatosis grade (p = 0.957). Conclusion: Hepatic steatosis, as assessed by CAP and liver histology, did not impact on HVPG in our cohort comprising a high proportion of patients with advanced chronic liver disease. However, high CAP values (i.e. pronounced hepatic steatosis) might lead to overestimation of liver fibrosis by 'artificially' increasing transient elastography-based liver stiffness measurements. [ABSTRACT FROM AUTHOR]

Portal hypertension is the main driver for severe complications in patients with liver cirrhosis. With improved understanding of molecular pathways that promote hepatic vascular remodeling, vasoconstriction, and sinusoidal capillarization potential vascular targets for the treatment of portal hypertension have been identified. Inhibition of vascular endothelial and platelet-derived growth factors–driven angiogenesis has been shown to reduce portal pressure and decrease hepatic inflammation. Angiopoietin/Tie signaling represents additional promising vascular targets in liver disease. The eNOS-NO-sGC-cGMP pathway modulates sinusoidal vasoconstriction and capillarization. Nuclear farnesoid X receptor (FXR) agonists decrease intrahepatic vascular resistance by inhibition of fibrogenesis and sinusoidal remodeling. Statins ameliorate endothelial dysfunction, decrease portal pressure, and reduce fibrogenesis. Anticoagulation with low-molecular heparin or anti-Xa inhibitors improved portal hypertension by deactivation of hepatic stellate cells and potentially via reduction of sinusoidal microthrombosis. This review summarizes important vascular targets for treatment of portal hypertension that have shown promising results in experimental studies. [ABSTRACT FROM AUTHOR]

Transjugular liver biopsy (TJLB) represents an alternative to percutaneous liver biopsy especially in patients with impaired coagulation and ascites. To describe safety and diagnostic yield of aspiration TJLB performed by hepatologists experienced in hepatic venous pressure gradient (HVPG) measurements. 445 TJLB of 399 patients between 01/2007–12/2016 were retrospectively assessed. Histological diagnosis was obtained in 423 (95.1%) biopsies — including 11 (100%) patients with acute liver failure and 34 (97.1%) patients after liver transplantation. A median number of 5 portal tracts (interquartile range:2–9) was obtained. HVPG negatively correlated with sample length (Spearman ρ = −0.310; p < 0.001) and number of portal tracts (ρ = −0.212; p < 0.001). Among n = 151 patients with unknown etiology of liver disease, etiology was successfully identified on liver histology in 126 patients (83.4%). Complications occurred in 28 biopsies (6.3%) including 25 (5.6%) minor and 3 (0.7%) major complications. No deaths due to TJLB were observed. Neither the presence of ascites (6.6% complications) nor of coagulopathy (platelets<50G/L and/or prothrombin time<50%; 4.8% complications) increased the risk for complications. TJLB performed by hepatologists experienced in HVPG measurements is safe - even in patients with ascites or coagulopathy. TJLB has good diagnostic value for histological evaluation of liver disease and acute liver failure. [ABSTRACT FROM AUTHOR]

Background: Transient elastography-based liver stiffness value (TE-LSV) has been investigated for assessing clinically significant portal hypertension (CSPH). The aetiology of CSPH is an important factor determining TE-LSV. There is insufficient evidence for selecting cut-off values.Aims: This study performed a meta-analysis to compare the three most widely used cut-off values (around 13.6 kPa, 18 kPa and 22kPa) of TE-LSV for the diagnosis of CSPH in patients with chronic viral liver disease.Methods: The PubMed, Ovid, Web of Science and Cochrane Library databases were searched. Diagnostic data for cut-off values around 13.6 kPa, 18 kPa and 22 kPa in each included study were extracted. The bivariate model was performed to estimate pooled sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-).Results: Eleven studies assessing 910 patients were included in this meta-analysis. Pooled sensitivities of cut-off values around 13.6 kPa, 18 kPa and 22 kPa were 0.96 (95% CI 0.93-0.97), 0.85 (0.81-0.89) and 0.74 (0.66-0.80), respectively; pooled specificities were 0.60 (0.47-0.75), 0.80 (0.71-0.87) and 0.94 (0.86-0.97), respectively. Pooled LR+ values were 2.4 (1.6-3.7), 4.4 (2.9-6.8) and 11.5 (5.5-23.5) for cut-off values around 13.6 kPa, 18 kPa and 22 kPa, respectively, for pooled LR- values of 0.07 (0.04-0.13), 0.17 (0.12-0.25) and 0.28 (0.22-0.36), respectively.Conclusion: Cut-off values around 13.6 kPa (high sensitivity) and 22 kPa (high specificity) could be used as screening and confirmation tools, respectively, in the diagnosis of CSPH. Overall, the cut-off value around 22 kPa showed the best performance.Key Points: Transient elastography-based liver stiffness could be used to diagnose portal hypertension.Comparison of certain cut-off values would provide more information for clinical decision-making.Cut-off around 13.6 kPa was able to exclude clinically significant portal hypertension (CSPH) effectively.Cut-off around 22 kPa was able to confirm CSPH effectively. [ABSTRACT FROM AUTHOR]

Background Early implantation (<72 h) of a transjugular intrahepatic portosystemic shunt (TIPS) after acute variceal bleeding (AVB) improves survival in highly selected patients. Methods We retrospectively assessed bleeding control and survival of unselected cirrhotic patients undergoing early TIPS implantation within 72 h. We compared the outcomes to patients meeting early TIPS criteria but receiving late TIPS within 3–28 days after AVB and endoscopic/medical treatment. Results Forty-nine patients were included. Mean MELD was 14.4 (±4.4). Thirteen patients (26.5%) presented characteristics that were exclusion criteria in previous early TIPS trials (age > 75, CPS > 13, HCC > Milan, previous beta-blocker/band-ligation, renal insufficiency). Bare metal and PTFE-covered stents were used in n = 32 (65.3%) and n = 17 (34.7%) patients, respectively, and showed similar early re-bleeding rates (9.9% vs. 7.1%; p = 0.6905) and bleeding-related mortality (25.0% vs. 23.5%; p = 0.9906). However, overall re-bleeding rate was lower with PTFE-TIPS (7.7% vs. 64.2%; p = 0.0044) over a median follow-up of 18.5 months with a tendency towards improved survival (median 70.5 vs. 13.8 months; p = 0.204). Additional 68 patients meeting stringent criteria but receiving late TIPS also showed a favorable bleeding-related mortality (8.8%), which was not achieved in similar n = 34 patients by a medical/endoscopic strategy with bleeding-related mortality of 35.7%. Conclusions An early TIPS strategy using covered stents and implementation of ‘stringent criteria’ results in a favorable outcome in patients with acute variceal bleeding. [ABSTRACT FROM AUTHOR]

Background & Aims Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. Methods In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7 days) and cirrhotic (carbon tetrachloride, CCl 4 , 14 weeks) portal hypertension, PX20606 (PX,10 mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10 mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. Results PX decreased portal pressure in non-cirrhotic PPVL (12.6 ± 1.7 vs. 10.4 ± 1.1 mmHg; p = 0.020) and cirrhotic CCl 4 (15.2 ± 0.5 vs. 11.8 ± 0.4 mmHg; p = 0.001) rats. In PPVL animals, we observed less bacterial translocation (−36%; p = 0.041), a decrease in lipopolysaccharide binding protein (−30%; p = 0.024) and splanchnic tumour necrosis factor α levels (−39%; p = 0.044) after PX treatment. In CCl 4 rats, PX decreased fibrotic Sirius Red area (−43%; p = 0.005), hepatic hydroxyproline (−66%; p < 0.001), and expression of profibrogenic proteins (Col1a1, α smooth muscle actin, transforming growth factor β). CCl 4 -PX rats had significantly lower transaminase levels and reduced hepatic macrophage infiltration. Moreover, PX induced sinusoidal vasodilation (upregulation of cystathionase, dimethylaminohydrolase (DDAH)1, endothelial nitric oxide synthase (eNOS), GTP-cyclohydrolase1) and reduced intrahepatic vasoconstriction (downregulation of endothelin-1, p-Moesin). In cirrhosis, PX improved endothelial dysfunction (decreased von-Willebrand factor) and normalized overexpression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietins. While short-term 3-day PX treatment reduced portal pressure (−14%; p = 0.041) by restoring endothelial function, 14 week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (−22%; p = 0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. Conclusions The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. Lay summary The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut. [ABSTRACT FROM AUTHOR]

Background and Aim Plasma renin concentration (PRC) is increased in patients with cirrhosis. The aims of this study were to evaluate the relation of PRC to (i) portal hypertension, (ii) degree of liver dysfunction, and (iii) survival. Methods Plasma renin concentration (range 2.8-39.9 μU/mL) was measured after 30 min in supine position. Also, hepatic venous pressure gradient (HVPG), Child-Pugh (CPS), model for end-stage liver disease scores and transient elastography values (TE, Fibroscan) were evaluated at this time. Mortality was recorded during follow-up. Results One hundred fifty cirrhotic patients (age 55 ± 11 years; 73% male; CPS A 41.3%/B 41.3%/C 17.3%) were included. Mean HVPG was 16.6 ± 6.5 mmHg. Median PRC according to CPS was A 15.45 μU/mL (95%CI 1.56-261.5), B 37.3 μU/mL (95%CI 4.29-1317.65), and C 175.3 μU/mL (95%CI 5.3-5684; P < 0.001). In patients with clinical significant portal hypertension (HVPG ≥ 10 mmHg, n = 123) median PRC was 31.2 μU/mL (95%CI 2.76-1345.4), in those without was 13.7 μU/mL (95%CI 2.7-428.2; P = 0.009). Significantly higher TE values (33.2 [13-75] vs 59.65 kPa [14.5-75]; P = 0.014) were found in patients with elevated PRC. Median follow up was 711 days (95%CI 24-1152). Twenty-two (36.1%) of the 61 patients with elevated PRC and 11 of the 89 (12.4%) with normal PRC died ( P = 0.001). Median PRC was significantly higher in patients that died (83.6 μU/mL [3.39-4451.9] vs 21.5 μU/mL [2.6-1197.9]; P = 0.001). Elevated PRC ( P = 0.005; HR 3.36; 95%CI 1.46-7.85), hepatocellular carcinoma ( P < 0.001; HR 10.68; 95%CI 3.64-31.3), CPS B ( P = 0.013; HR 3.69; 95%CI 1.31-10.4) and CPS C ( P = 0.008; HR 5.36; 95%CI 1.54-18.62) emerged as independent risk factors for mortality. Conclusions In cirrhotic patients PRC correlates with the severity of portal hypertension and liver dysfunction. Moreover, elevated PRC represents an independent risk factor for mortality. [ABSTRACT FROM AUTHOR]

Background & Aims To perform a comprehensive study on independent modulators of liver fibrosis progression and determinants of portal pressure considering immune status, insulin resistance ( IR), serum 25-hydroxyvitamin D (25(OH)D) levels, genetic variants of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and interleukin 28B (IL28B) in a thoroughly documented cohort of HIV/hepatitis C-coinfected (HIV/HCV) patients. Patients & Methods 25(OH)D deficiency (25(OH)DDEF), IR and low CD4+ T-lymphocyte nadir (lowCD4NAD) were defined as 25(OH)D <20 ng × ml−1, HOMA-IR >2 and CD4nadir <200 cells × μl−1 respectively. Liver fibrosis progression rate ( FPR) was calculated as METAVIR F units divided by the number of years since HCV infection. Patients with a FPR > median FPR were assigned to the highFPR group. Results Among 86 HIV/HCV, the median FPR was 0.167 units × years−1. While the prevalence of prior alcohol abuse, lowCD4NAD and 25(OH)DDEF was higher among highFPR patients, the prevalence of IR was comparable. The association between 25(OH)DDEF and FPR was confirmed in a subgroup of patients with METAVIR stage F0/F1/F2 in which 25(OH)D levels are not affected by the severity of liver disease. The distribution of IL28B C/C and PNPLA3 non-C/C was similar, while PNPLA3 G/G was exclusively observed in highFPR patients. LowCD4NAD (OR: 2.95; 95% CI: 1.05-8.24; P = 0.039) and 25(OH)DDEF (OR: 5.62; 95% CI: 2.05-15.38; P = 0.001) were independently associated with highFPR and showed an additive effect. Portal pressure correlated with prior alcohol abuse, HCV-genotype 3, CD4+ nadir and 25(OH)D levels. Conclusions Two potentially modifiable factors, CD4+ nadir and 25(OH)D levels, were both independent modulators of liver fibrosis progression and determinants of portal pressure. Further studies are warranted to assess the relevance of PNPLA3 for FPR in HIV/HCV. [ABSTRACT FROM AUTHOR]

Background & Aims Transient elastography ( TE) can non-invasively diagnose cirrhosis and portal hypertension ( PHT). New TE reliability criteria suggest classifying measurements as very reliable ( IQR/M < 0.1), reliable ( IQR<0.3 or >0.3, if TE < 7.1 kPa) and poorly reliable ( IQR/M > 0.3, if TE > 7.1 kPa). Compare traditional (reliable: success rate >60% + IQR/M ≤ 0.30) and new TE quality criteria (accurate: very reliable + reliable) regarding their diagnostic accuracy for cirrhosis and PHT and to identify potential confounders (age, aetiology, necroinflammatory activity, steatosis, siderosis, cholestasis, aminotransferases) of TE performance. Methods Patients undergoing simultaneous measurements of TE, portal pressure (hepatic venous pressure gradient, HVPG) and liver biopsy were analysed. Results Among 226 patients (48.7 ± 13.1 years, 74.7% male, 75.7% viral aetiology, 57% F3/F4), traditional TE quality criteria identified 71.6% reliable measurements, while new criteria yielded in 83.2% accurate results. Reliable TE values according to both criteria significantly correlated with fibrosis stage ( r = 0.648 vs. r = 0.636) and HVPG ( r = 0.836 vs. r = 0.846). Diagnostic accuracy for cirrhosis (cut-off >14.5 kPa) was 76.5% ( AUC: 0.863) and 75.0% ( AUC: 0.852) for traditional and new TE criteria, respectively, while for predicting HVPG ≥ 10 mmHg (>16.1 kPa), the accuracies were 88.9% ( AUC: 0.957) and 89.8% ( AUC: 0.962). New TE criteria allowed a better discrimination of reliable and non-reliable results for prediction of fibrosis and CSPH. Only aetiology and aminotransferases were independent confounders of the correlation of TE and fibrosis stage, while no confounder affected the correlation of TE and HVPG. Conclusions New reliability criteria for TE measurements increase the number of patients with accurate measurements without affecting diagnostic performance for detecting cirrhosis and portal hypertension. Aetiology of liver disease and aminotransferases should be considered when assessing liver fibrosis by TE. [ABSTRACT FROM AUTHOR]

Background: Introduction of combined antiretroviral therapy (cART) has improved survival of HIV infected individuals, while the relative contribution of liver-related mortality increased. Especially in HIV/HCV-coinfected patients hepatic fibrosis and portal hypertension represent the main causes of liver-related morbidity and mortality. Circulating miRNA-122 levels are elevated in HIV patients and have been shown to correlate with severity of liver injury. However, the association of miRNA-122 levels and hepatic fibrosis and portal hypertension remains to be explored in HIV/HCV coinfection. Methods: From a total of 74 (31% female) patients with HIV/HCV coinfection were included. Serum levels of miRNA-122 were analyzed by quantitative polymerase chain reaction (PCR) and normalized to SV-40 spike-in RNA. Hepatic venous pressure gradient (HVPG) was measured in 52 (70%) patients and the fibrosis stage was determined in 63 (85%) patients using transient elastography. Results: The levels of circulating miRNA-122 were increased in HIV/HCV coinfected patients and significantly correlated with the alanine aminotransferase (ALT) (rs = 0.438; p<0.001) and aspartate transaminase AST values (rs = 0.336; p = 0.003), but not with fibrosis stage (p = n.s.). Interestingly, miRNA-122 levels showed an inverse correlation with hepatic venous pressure gradient (HVPG) (rs = −0.302; p = 0.03). Conclusion: Elevated miRNA-122 levels are associated with liver injury, and with low HVPG. Though, miRNA-122 levels are not suitable to predict the degree of fibrosis, they might function as indicators for portal hypertension in HIV/HCV coinfected patients. [ABSTRACT FROM AUTHOR]

Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects. In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as 'VWF-responders' (as defined by a ≥5% decrease in VWF) versus 'VWF-non-responders.' There were no major differences in baseline characteristics between VWF-responders (61%) and VWF-non-responders. VWF-responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG-response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF-responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF-response was associated with decreased risks of further decompensation (adjusted hazard ratio [aHR], 0.555; 95% confidence interval [CI], 0.337-0.912; P =.020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P =.007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P <.001) in Cox regression models adjusted for prognostic factors including changes in HVPG. Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aim: The aim of this study was to assess the impact of proton pump inhibitor (PPI) intake on the development of spontaneous bacterial peritonitis (SBP) or other infections, as well as on mortality, in a thoroughly documented cohort of patients with cirrhosis and ascites. Patients and Methods: We performed a retrospective analysis of follow-up data from 607 consecutive patients with cirrhosis undergoing their first paracentesis at a tertiary center. A binary logistic regression model investigating the association between PPI intake and SBP at the first paracentesis was calculated. Competing risk analyses and Cox models were used to investigate the effect of PPIs on the cumulative incidence of SBP or other infections and transplant-free survival, respectively. Adjustments were made for age, hepatocellular carcinoma, history of variceal bleeding, varices and model of end-stage liver disease score. Results: Eighty-six percent of patients were receiving PPIs. After adjusting for potential confounding factors, PPI intake was neither associated with increased SBP prevalence at the first paracentesis (odds ratio (OR):1.11,95% confidence interval (95%CI):0.6–2.06; P = 0.731) nor cumulative incidence of SBP (subdistribution hazard ratio (SHR): 1.38; 95%CI:0.63–3.01; P = 0.42) and SBP or other infections (SHR:1.71; 95%CI:0.85–3.44; P = 0.13) during follow-up. Moreover, PPI intake had no impact on transplant-free survival in both the overall cohort (hazard ratio (HR):0.973,95%CI:0.719–1.317; P = 0.859) as well as in the subgroups of patients without SBP (HR:1.01,95%CI:0.72–1.42; P = 0.971) and without SBP or other infections at the first paracentesis (HR:0.944,95%CI:0.668–1.334; P = 0.742). Conclusions: The proportion of cirrhotic patients with PPI intake was higher than in previous reports, suggesting that PPI indications were interpreted liberally. In our cohort with a particularly high prevalence of PPI intake, we observed no association between PPIs and SBP or other infections, as well as mortality. Thus, the severity of liver disease and other factors, rather than PPI treatment per se may predispose for infectious complications. [ABSTRACT FROM AUTHOR]

Background: Liver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) derived degradation fragments in peripheral blood as biomarkers for fibrosis and portal hypertension in patients with HIV/HCV co-infection. Methods: Fifty-eight patients (67% male, mean age: 36.5 years) with HIV/HCV-co-infection were included in the study. Hepatic venous pressure gradient (HVPG) was measured in forty-three patients. The fibrosis stage was determined using FIB4 -Score. ECM degraded products in peripheral blood were measured using specific ELISAs (C4M, MMP-2/9 degraded type IV collagen; C5M, MMP-2/9 degraded type V collagen; PRO-C3, MMP degraded n-terminal propeptide of type III collagen). Results: As expected, HVPG showed strong and significant correlations with FIB4-index (rs = 0.628; p = 7*10−7). Interestingly, PRO-C3 significantly correlated with HVPG (rs = 0.354; p = 0.02), alanine aminotransferase (rs = 0.30; p = 0.038), as well as with FIB4-index (rs = 0.3230; p = 0.035). C4M and C5M levels were higher in patients with portal hypertension (HVPG>5 mmHg). Conclusion: PRO-C3 levels reflect liver injury, stage of liver fibrosis and degree of portal hypertension in HIV/HCV-co-infected patients. Furthermore, C4M and C5M were associated with increased portal pressure. Circulating markers of hepatic ECM remodeling might be helpful in the diagnosis and management of liver disease and portal hypertension in patients with HIV/HCV coinfection. [ABSTRACT FROM AUTHOR]

Background & Aims: Development of the portal-hypertensive syndrome is mediated by splanchnic inflammation and neoangiogenesis. Since peroxisome proliferator-activated receptor gamma (PPARγ) agonists like pioglitazone (PIO) regulate inflammatory response and inhibit angiogenesis in endothelial cells, we evaluated PIO as treatment for experimental portal hypertension. Methods: PIO (10mg/kg) or vehicle (VEH) was administered from day 21–28 after bile duct ligation (BDL), from day 0–7 after partial portal vein ligation (PPVL) or sham-operation (SO), respectively. After treatment, systemic hemodynamics, splanchnic blood flow (SMABF), portal pressure (PP), and portosystemic shunting (PSS) were assessed. Splanchnic and hepatic tissues were analyzed for angiogenic and inflammatory markers. Results: BDL and PPVL showed significantly increased PP, SMABF, and PSS compared to SO-VEH rats. While PIO treatment did not decrease PP or SMABF, PSS was significantly reduced both in cirrhotic (BDL-VEH: 71% to BDL-PIO: 41%; p <0.001) and non-cirrhotic (PPVL-VEH: 62% to PPVL-PIO: 40%; p =0.041) rats. PIO (10μM, in vitro) inhibited endothelial cell migration and significantly increased PPARγ activity in vivo. In BDL rats, PIO decreased hepatic mRNA levels of PPARγ (p =0.01) and PlGF (p =0.071), and splanchnic mRNA expression of PPARγ (p =0.017), PDGFβ (p =0.053) and TNFα (p =0.075). Accordingly, splanchnic protein expression of PPARγ (p =0.032), VEGFR2 (p =0.035), CD31 (p =0.060) and PDGFβ (p =0.066) were lower in BDL-PIO vs. BDL-VEH animals. In PPVL rats, PIO treatment decreased splanchnic gene expression of Ang2 (−12.4 fold), eNOS (−9.3 fold), PDGF (−7.0 fold), PlGF (−11.9 fold), TGFb (−8.3 fold), VEGF-A (−11.3 fold), VEGFR1 (−5.9 fold), IL1b (−14.4 fold), and IL6 (−9.6 fold). Conclusions: Pioglitazone treatment decreases portosystemic shunting via modulation of splanchnic inflammation and neoangiogenesis. Pioglitazone should be assessed for potential beneficial effects in patients with portosystemic collaterals due to portal hypertension. [Copyright &y& Elsevier]

Background We evaluated the effects of nebivolol, a third generation beta-blocker capable of increasing NO-bioavailability on portal pressure, and on splachnic and systemic haemodynamics in a cirrhotic portal hypertensive rat model. Methods Male Sprague-Dawley rats underwent sham operation ( SO) or bile duct ligation ( BDL). When cirrhosis was fully developed, the animals were orally treated with low-dose (5 mg/kg) or high-dose (10 mg/kg) nebivolol ( NEBI) or vehicle ( VEH) for 7 days. Heart rate ( HR), mean arterial pressure ( MAP), portal pressure ( PP) and superior mesenteric artery blood flow ( SMABF) were measured. Portosystemic collateral blood flow ( PSCBF) was quantified using radioactive microspheres. Hepatic and splanchnic NOx levels and GSH/ GSSG ratios (RedOx state) were determined using commercially available kits. Results BDL-VEH rats showed increased HR, PP and PSCBF, whereas MAP was decreased compared to SO-VEH rats. Nebivolol significantly reduced HR both in SO ( P < 0.001) and BDL ( P < 0.001) rats. BDL-NEBI animals had significantly higher PP (15.5 vs. 12.6 mmHg; P = 0.006) and SMABF (5.3 vs. 3.7 ml/min/100g; P = 0.016) than BDL-VEH animals. The increase in PP and SMABF was noted both in low-dose and high-dose BDL-NEBI rats. While no beneficial effects on hepatic RedOx state were observed, splanchnic NOx levels were significantly increased by NEBI treatment in a dose-dependent manner. Nebivolol treatment did not affect PSCBF in SO and BDL animals. Conclusion Nebivolol increases portal pressure in cirrhotic animals by increasing splanchnic blood flow via modulation of NO signalling. Porto-systemic collateral blood flow remained unchanged. These data do not support the use of Nebivolol for treatment of cirrhotic patients with portal hypertension. [ABSTRACT FROM AUTHOR]

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion. [ABSTRACT FROM AUTHOR]

Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting. A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort). HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843–0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%). NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment. Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden. [Display omitted] • Post-treatment LSM/platelet count can be used to estimate the probability of CSPH and predict clinical outcomes in cACLD. • Patients with cACLD and LSM <12 kPa & PLT >150 G/L (CSPH-excluded; no decompensation risk) may not require portal hypertension surveillance. • Patients with cACLD and LSM ≥25 kPa require surveillance/treatment (CSPH-ruled-in; increased decompensation risk). [ABSTRACT FROM AUTHOR]

Background & Aims 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. Methods One hundred and four patients with portal hypertension (HVPG ⩾6 mmHg) 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]). Results SVR to IFN-free therapies significantly decreased HVPG across all BL HVPG strata: 6–9 mmHg (BL: 7.37 ± 0.28 vs. FU: 5.11 ± 0.38 mmHg; −2.26 ± 0.42 mmHg; p <0.001), 10–15 mmHg (BL: 12.2 ± 0.4 vs. FU: 8.91 ± 0.62 mmHg; −3.29 ± 0.59 mmHg; p <0.001) and ⩾16 mmHg (BL: 19.4 ± 0.73 vs. FU: 17.1 ± 1.21 mmHg; −2.3 ± 0.89 mmHg; p = 0.018). In the subgroup of patients with BL HVPG of 6–9 mmHg, HVPG normalized (<6 mmHg) in 63% (12/19) of patients, while no patient progressed to ⩾10 mmHg. Among patients with BL HVPG ⩾10 mmHg, a clinically relevant HVPG decrease ⩾10% was observed in 63% (26/41); 24% (10/41) had a FU HVPG <10 mmHg. 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). Conclusions 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 ⩾16 mmHg 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. Lay summary 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. [ABSTRACT FROM AUTHOR]

Background/Aims: Angiogenesis plays a key role in development of portal hypertension (PHT) and represents a potential therapeutic target. We aimed to evaluate the molecular effects of sorafenib, a multiple tyrosine kinase inhibitor, on splanchnic hemodynamics in rats with partial portal vein ligation (PPVL). Methods: The following four groups of rats were treated orally with sorafenib (10mg/kg per day; SORA group) or placebo (PLAC group) for 7 days, beginning at the day of PPVL or sham operation (SO): (1) PPVL-SORA, (2) PPVL-PLAC, (3) SO-SORA and (4) SO-PLAC. Measurements of mean arterial pressure (MAP), portal pressure (PP), and superior mesenterial artery blood flow (SMABF) were performed. Portosystemic collateral blood flow (PSCBF) was determined by radioactive microspheres. Splanchnic protein expression of CD31, α-smooth muscle actin (αSMA), phospho-extracellular signal-regulated kinase (pERK), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), tumor necrosis factor α (TNFα), and endothelial nitric oxide synthetase (eNOS) was assessed by Western blot. Gene expression was studied by angiogenesis-focused real-time reverse transcription polymerase chain reaction microarray. Results: PP, SMABF, and PSCBF were significantly higher in PPVL rats than in SO rats. MAP and heart rate were similar in all groups. Treatment with sorafenib resulted in a significant decrease of PP (p <0.001) and SMABF (p <0.05) in PPVL-SORA rats compared to PPVL-PLAC rats. PPVL-SORA rats had markedly less PSCBF than PPVL-PLAC rats (p <0.001). Superior mesenteric artery resistance (SMAR) was significantly lower in both PPVL groups compared to both SO groups, but PPVL-SORA rats showed significantly higher SMAR than PPVL-PLAC rats (p <0.05). The increased protein expression of CD31, αSMA, pERK, VEGF, PDGF, TNFα, and eNOS in rats with PHT was markedly decreased by sorafenib treatment. Sorafenib decreased mRNA levels of TNFα, VEGF receptor 2, VEGF receptor 1, transforming growth factor β, cyclooxygenase 1, and expression of various genes that are involved in pathways of cellular proliferation, fibrogenesis, tissue remodeling, inflammation, and angiogenesis. Conclusions: Treatment with sorafenib reduced PP, SMABF, and PSCBF in noncirrhotic rats with prehepatic PHT, without affecting systemic hemodynamics. Additional antiproliferative, anti-inflammatory, and antiangiogenic effects of sorafenib were identified. [Copyright &y& Elsevier]

INTRODUCTION: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice. METHODS: This is an international cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10 kPa, and no previous decompensation. Portal hypertension was defined by an HVPG >5 mm Hg. A positive predictive value ≥90% was considered to validate LSM cutoffs for CSPH (HVPG ≥10 mm Hg), whereas a negative predictive value ≥90% ruled out CSPH. RESULTS: A total of 836 patients with hepatitis C (n = 358), nonalcoholic steatohepatitis (NASH, n = 248), alcohol use (n = 203), and hepatitis B (n = 27) were evaluated. Portal hypertension prevalence was >90% in all cACLD etiologies, except for patients with NASH (60.9%), being even lower in obese patients with NASH (53.3%); these lower prevalences of portal hypertension in patients with NASH were maintained across different strata of LSM values. LSM ≥25 kPa was the best cutoff to rule in CSPH in alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, and nonobese patients with NASH, whereas in obese NASH patients, the positive predictive value was only 62.8%. A new model for patients with NASH (ANTICIPATE-NASH model) to predict CSPH considering body mass index, LSM, and platelet count was developed, and a nomogram was constructed. LSM ≤15 kPa plus platelets ≥150 x 109/L ruled out CSPH in most etiologies. DISCUSSION: Patients with cACLD of NASH etiology, especially obese patients with NASH, present lower prevalences of portal hypertension compared with other cACLD etiologies. LSM ≥25 kPa is sufficient to rule in CSPH in most etiologies, including nonobese patients with NASH, but not in obese patients with NASH. [ABSTRACT FROM AUTHOR]

Distinct prognostic stages of advanced chronic liver disease (ACLD) are defined by severity of portal hypertension (PH) and the presence/absence of clinical complications. We characterised the degree of liver dysfunction, PH, and systemic inflammation across the distinct prognostic stages and assessed their relative impact on decompensation and mortality. A single-centre, prospective cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement between 01/2017 and 08/2019 were classified into 6 prognostic stages: mild PH (HVPG 6–9 mmHg, S0), clinically significant PH (HVPG ≥10 mmHg without varices, S1), presence of varices (S2), history of variceal bleeding (S3), first non-bleeding decompensation (S4), and further decompensation (S5). The model for end-stage liver disease (MELD), C-reactive protein (CRP), and IL-6 levels were assessed in relation to their predictive value for decompensation and death. Among 168 ACLD patients 78 had compensated (cACLD, S0 = 13; S1 = 21; S2 = 44) and 90 had decompensated (dACLD, S3 = 10; S4 = 58; S5 = 22) disease. MELD increased across all stages (p <0.001), whereas HVPG mostly increased within cACLD substages. Significant increases in CRP and IL-6 levels were only noted across dACLD substages. IL-6 was an independent predictor of decompensation at 1-year follow-up in cACLD (hazard ratio [HR] 1.06, 95% CI 1.01–1.10; p = 0.013). In dACLD patients, IL-6 levels predicted death/transplantation after 1-year of follow-up (HR 1.02, 95% CI 1.01–1.03; p = 0.004). HVPG progression occurs mostly in cACLD patients, whereas systemic inflammation, as reflected by IL-6 levels, only increases substantially across dACLD stages. IL-6 levels correlate with the risk of first decompensation in cACLD and of death/transplantation in dACLD patients. Patients with advanced chronic liver disease (ACLD; i.e. liver cirrhosis) have a certain risk of mortality according to their stage of disease. Progression of disease is greatly influenced by increased pressure in the portal venous system (i.e. portal hypertension) and occurrence of clinical complications (i.e. decompensation). Our study demonstrates that systemic inflammation markedly increases across highest disease stages, and the inflammation biomarker IL-6 in blood may specifically indicate risk of disease progression in patients with ACLD. The study is registered at ClinicalTrials.gov (NCT03267615). [Display omitted] • Progression of portal hypertension severity (reflected by HVPG) occurs mostly across compensated ACLD stages. • Systemic inflammation (reflected by CRP and IL-6 levels) substantially increases only across decompensated ACLD. • IL-6 levels are independent predictors of first decompensation in compensated ACLD and death/liver transplantation in decompensated ACLD. [ABSTRACT FROM AUTHOR]

Cirrhosis is a liver disease that leads to increased intrahepatic resistance, portal hypertension (PH), and splanchnic hyperemia resulting in ascites, variceal bleeding, and hepatorenal syndrome. Terlipressin, a prodrug that converts to a short half-life vasopressin receptor 1 A (V1a) full agonist [8-Lys]-Vasopressin (LVP), is an intravenous treatment for PH complications, but hyponatremia and ischemic side effects require close monitoring. We developed PHIN-214 which converts into PHIN-156, a more biologically stable V1a partial agonist. PHIN-214 enables once-daily subcutaneous administration without causing ischemia or tissue necrosis and has a 10-fold higher therapeutic index than terlipressin in healthy rats. As V1a partial agonists, PHIN-214 and PHIN-156 exhibited maximum activities of 28 % and 42 % of Arginine vasopressin (AVP), respectively. The potency of PHIN-156 and LVP relative to AVP is comparable for V1a (5.20 and 1.65 nM, respectively) and V1b (102 and 115 nM, respectively) receptors. However, the EC 50 of PHIN-156 to the V2 receptor was 26-fold higher than that of LVP, indicating reduced potential for dilutional hyponatremia via V2 agonism compared to terlipressin/LVP. No significant off-target binding to 87 toxicologically relevant receptors were observed when evaluated in vitro at 10 µM concentration. In bile duct ligated rats with PH, subcutaneous PHIN-214 reduced portal pressure by 13.4 % ± 3.4 in 4 h. These collective findings suggest that PHIN-214 could be a novel pharmacological treatment for patients with PH, potentially administered outside of hospital settings, providing a safe and convenient alternative for managing PH and its complications. • PHIN-214 is a prodrug of a long acting partial V1a agonist (PHIN-156). • PHIN-214 is a SC drug with 10-fold higher therapeutic index than terlipressin. • PHIN-214 was effective in portal hypertensive bile duct ligated rat model. • PHIN-156 and Lys-Vasopressin (LVP) have comparable affinity to V1a receptor. • PHIN-156 has 26-fold lower affinity to V2 receptor than LVP. [ABSTRACT FROM AUTHOR]