Search

Over three decades ago, National Council of Teachers of Mathematics (NCTM, 1991) proposed that "for students to develop the ability to formulate problems, to explore, conjecture, and reason logically, to evaluate whether something makes sense, classroom discourse must be founded on mathematical evidence" (p. 34). As math interventionists supporting small groups of Grades K--4 students, the first three authors wondered how they could still provide their students with opportunities to engage in reasoning-based discourse despite the directive to have students who had yet to learn their basic facts work in small groups. All authors were committed to uplifting individual students' thinking through positioning them to think flexibly about various strategies by developing the role of a student referee, whose main responsibility is facilitating small-group conversations grounded in mathematical reasoning. Although the authors support small groups of elementary students in their understanding of number concepts, teachers can adapt their approach to other content and grade levels.

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of advanced chronic liver disease (ACLD). Portal hypertension drives hepatic decompensation and is best diagnosed by hepatic venous pressure gradient (HVPG) measurement. Here, we investigate the prognostic value of HVPG in MASLD-related compensated ACLD (MASLD-cACLD)., Methods: This European multicentre study included patients with MASLD-cACLD characterised by HVPG at baseline. Hepatic decompensation (variceal bleeding/ascites/hepatic encephalopathy) and liver-related mortality were considered the primary events of interest., Results: A total of 340 patients with MASLD-cACLD (56.2% male; median age 62 [55-68] years, median MELD 8 [7-9], 71.2% with diabetes) were included. Clinically significant portal hypertension (CSPH: i.e., HVPG ≥10 mmHg) was found in 209 patients (61.5%). During a median follow-up of 41.5 (27.5-65.8) months, 65 patients developed hepatic decompensation with a cumulative incidence of 10.0% after 2 years (2Y) and 30.7% after 5 years (5Y) in those with MASLD-cACLD with CSPH, compared to 2.4% after 2Y and 9.4% after 5Y in patients without CSPH. Variceal bleeding did not occur without CSPH. CSPH (subdistribution hazard ratio [SHR] 5.13; p <0.001) was associated with an increased decompensation risk and a higher HVPG remained an independent risk factor in the multivariable model (adjusted SHR per mmHg: 1.12, p <0.001). Liver-related mortality occurred in 37 patients at a cumulative incidence of 3.3% after 2Y and 21.4% after 5Y in CSPH. Without CSPH, the incidence after 5Y was 0.8%. Accordingly, a higher HVPG was also independently associated with a higher risk of liver-related death (adjusted SHR per mmHg: 1.20, p <0.001)., Conclusion: HVPG measurement is of high prognostic value in MASLD-cACLD. In patients with MASLD-cACLD without CSPH, the short-term risk of decompensation is very low and liver-related mortality is rare, while the presence of CSPH substantially increases the risk of both., Impact and Implications: While the incidence of compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide, insights into the impact of clinically significant portal hypertension (CSPH) on the risk of liver-related events in MASLD-cACLD remain limited. Based on the findings of this European multicentre study including 340 MASLD-cACLD patients, we could show that increasing HVPG values and the presence of CSPH in particular were associated with a significantly higher risk of first hepatic decompensation and liver-related mortality. In contrast, the short-term incidence of decompensation in patients with MASLD-cACLD without CSPH was low and the risk of liver-mortality remained negligible. Thus, HVPG measurements can provide important prognostic information for individualised risk stratification in MASLD-cACLD and may help facilitate the study of novel and promising treatment possibilities for MASLD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The prognostic performance of von Willebrand factor (VWF) may vary across clinical stages of advanced chronic liver disease (ACLD). Therefore, we investigated the evolution of VWF and other biomarkers throughout the full ACLD spectrum and evaluated their stage-specific prognostic utility., Methods: We retrospectively included Viennese ACLD patients with available information on hepatic venous pressure gradient (HVPG), C-reactive protein (CRP)/VWF levels and outcomes. ACLD stages were defined according to D'Amico et al. We included an external validation cohort from Padua., Results: We observed gradual increases in VWF throughout ACLD stages. In contrast, HVPG levelled off in decompensated ACLD (dACLD), whereas MELD showed only minor changes in the early stages and CRP did not increase until stage 3. VWF was associated with hepatic decompensation/liver-related death in compensated ACLD (cACLD) in a fully adjusted model, while it was not independently predictive of ACLF/liver-related death in dACLD. After backward selection, HVPG/CRP/VWF remained the main predictors of hepatic decompensation/liver-related death in cACLD. Notably, the performance of the non-invasive CRP/VWF-based model was comparable to invasive HVPG-based models (C-index:0.765 ± 0.034 vs. 0.756 ± 0.040). The discriminative ability of the CRP/VWF-based model was confirmed in an external validation cohort using another VWF assay which yielded systematically lower values., Conclusion: VWF is the only biomarker that gradually increases across all ACLD stages. It is of particular prognostic value in cACLD, where a CRP/VWF-based model is equivalent to an invasive HVPG-based model. Systematic differences in VWF underline the importance of interlaboratory surveys. Moreover, our findings reinforce the notion that, already in cACLD, inflammation is a key disease-driving mechanism., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: Endothelial dysfunction and portal hypertension (PH) are reflected by increased von Willebrand factor antigen (VWF-Ag) levels in advanced chronic liver disease (ACLD). This study investigated VWF release and cleavage and their association with PH and clinical outcomes., Methods: Levels of VWF-Ag, VWF-N (VWF-propeptide), and VWF-A (VWF processed by the main VWF-cleaving protease ADAMTS13) were assessed in 229 patients with clinically stable ACLD (hepatic venous pressure gradient [HVPG] ≥ 6 mmHg; absence of bacterial infections or acute decompensation) undergoing HVPG-measurement. Liver-healthy individuals served as controls (n = 24)., Results: VWF-Ag and VWF-N were similarly accurate for the identification of clinically significant PH (CSPH; HVPG ≥ 10 mmHg) in compensated ACLD (AUROC: VWF-Ag 0.748; VWF-N 0.728). ADAMTS13 activity was similar between patients with ACLD and controls and did not correlate with PH and disease severity, whereas VWF cleavage decreased in patients with CSPH (i.e., VWF-Ag/-A-ratio increased). In vitro VWF activity strongly reflected VWF-Ag levels (Spearman's r = 0.874, p < 0.001), but decreased (vs. controls) in patients with CSPH when normalized to VWF-Ag levels (VWF-activity/-Ag-ratio). VWF-Act/-Ag ratio correlated negatively with ADAMTS13 activity (r =- 0.256, p < 0.001). ADAMTS13 activity was independently predictive for (i) portal vein thrombosis (PVT) and (ii) hepatic decompensation or liver-related death., Conclusions: VWF-Ag levels and its propeptide are similarly suitable surrogates of PH in patients with compensated ACLD. ADAMTS13-Act was not linked to disease and PH severity, however, when normalized to VWF-Ag, both VWF cleavage and VWF activity were decreased in patients with CSPH, as compared to liver-healthy individuals. Low ADAMTS13-Act was associated with presumably more procoagulant VWF and adverse outcomes., Clinical Trial Number: NCT03267615., (© 2023. The Author(s).)

Background & Aims: Increased aggregation of individual platelets upon activation, as assessed by whole blood aggregometry standardised to platelet count (PLT), has recently been linked to progression of advanced chronic liver disease (ACLD). Moreover, changes in primary haemostasis have been implicated in bleeding and thrombosis in patients with ACLD.We aimed (i) to identify the determinants of the primary haemostatic capacity - as assessed by Platelet Function Analyzer 100 (PFA-100) (' in vitro bleeding time') - in patients with ACLD and (ii) to investigate its potential association with clinical outcomes., Methods: PFA-100 was performed in 688 patients with ACLD undergoing hepatic venous pressure gradient measurement. Hepatic decompensation and liver-related death as well as bleeding and thrombosis were the outcomes of interest., Results: Sixty-three percent of patients had a PFA-100 collagen/epinephrine closure time (CT) of >150 s ( i.e. prolonged). PLT and haematocrit were the main determinants of CT, whereas it was not impacted by von Willebrand factor antigen. Mirroring the increasing prevalence/severity of thrombocytopaenia and anaemia, we observed a progressive prolongation of CT ( i.e. decreased primary haemostatic capacity) with more advanced disease, as indicated by clinical stage, Child-Turcotte-Pugh score, United Network for Organ Sharing model for end-stage liver disease (2016) score, and hepatic venous pressure gradient. Although increased CT ( i.e . decreased primary haemostatic capacity) was associated with an increased risk of hepatic decompensation/liver-related death, these associations were less consistent after adjusting/correcting for PLT/haematocrit and established prognostic indicators. Finally, CT was not associated with the incidence of major bleedings or thromboses., Conclusions: These findings do not support the hypothesis that increased platelet adhesion - assessed in vitro under shear stress by PFA-100 - promotes ACLD progression., Impact and Implications: The potential of platelets to aggregate in the bloodstream may be increased in patients with advanced chronic liver disease. Platelet Function Analyzer 100 (PFA-100), a blood test reflecting in vitro bleeding time, might be suggestive of an impaired primary clot forming capacity. In our study, we could show that PFA-100 results were not linked to bleeding/thrombotic events. Our findings do not support the hypothesis that an increased adhesion of platelets (assessed by PFA-100) might lead to a disease progression in patients with advanced chronic liver disease., Competing Interests: RP received travel support from AbbVie, Gilead, and Takeda. BSc received travel support from AbbVie, Ipsen, and Gilead. BSi received travel support from AbbVie and Gilead. MP served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche and received travel support from Bayer and Bristol-Myers Squibb. MT served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, and Shire and received travel support from AbbVie, Falk, Gilead, and Intercept as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. TR served as a speaker and/or consultant and/or advisory board member for and received speaking honoraria from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Roche, Siemens, and W. L. Gore & Associates and received travel support from AbbVie, Boehringer-Ingelheim, Gilead, and Roche as well as grants/research support from AbbVie, Boehringer-Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens, and W. L. Gore & Associates. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Echosens, Gilead, Takeda, and W. L. Gore & Associates and received travel support from AbbVie and Gilead. All other authors declared no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background and Aims: Removal/suppression of the primary etiological factor reduces the risk of decompensation and mortality in compensated cirrhosis. However, in decompensated cirrhosis, the impact of etiologic treatment is less predictable. We aimed to evaluate the impact of etiological treatment in patients with cirrhosis who developed ascites as single index decompensating event., Approach and Results: Patients with cirrhosis and ascites as single first decompensation event were included and followed until death, liver transplantation, or Q3/2021. The etiology was considered "cured" (alcohol abstinence, hepatitis C cure, and hepatitis B suppression) versus "controlled" (partial removal of etiologic factors) versus "uncontrolled." A total of 622 patients were included in the study. Etiology was "cured" in 146 patients (24%), "controlled" in 170 (27%), and "uncontrolled" in 306 (49%). During follow-up, 350 patients (56%) developed further decompensation. In multivariable analysis (adjusted for age, sex, varices, etiology, Child-Pugh class, creatinine, sodium, and era of decompensation), etiological cure was independently associated with a lower risk of further decompensation (HR: 0.46; p = 0.001). During follow-up, 250 patients (40.2%) died, while 104 (16.7%) underwent LT. In multivariable analysis, etiological cure was independently associated with a lower mortality risk (HR: 0.35, p < 0.001)., Conclusions: In patients with cirrhosis and ascites as single first decompensating event, the cure of liver disease etiology represents a main treatment goal since this translates into considerably lower risks of further decompensation and mortality., (Copyright © 2023 American Association for the Study of Liver Diseases.)

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., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Non-selective betablockers (NSBBs) reduce the risk of hepatic decompensation in patients with compensated advanced chronic liver disease (cACLD). Metabolic co-morbidities (MetC) are increasingly observed in cACLD patients., Aims: To investigate the impact of MetC on the haemodynamic effects of NSBB and hepatic decompensation in cACLD., Methods: cACLD patients undergoing paired hepatic venous pressure gradient (HVPG) measurements before/under NSBB therapy were retrospectively considered for this study. We recorded baseline characteristics on MetC (obesity, dyslipidaemia and diabetes), as well as hepatic decompensation and liver-related mortality during follow-up., Results: We included 92 patients (Child-A n = 80, 87%; Child-B n = 12, 13%). MetC were found in 34 (37%) patients: 19 (20.7%) with obesity, 14 (15.2%) with dyslipidaemia and 23 (34.8%) with diabetes. The median baseline HVPG of 18 (IQR:15-21) mmHg decreased to 15 (IQR:9-12) mmHg under NSBB. HVPG-response (decrease ≥10% or to ≤12 mmHg) was achieved in 60 (65.2.%) patients. Patients with diabetes (OR: 0.35, p = 0.021) and higher BMI (OR: 0.89 per kg/m 2 , p = 0.031) were less likely to achieve HVPG-response. During a median follow-up of 2.3 (0.5-4.2) years, 18 (19.5%) patients experienced hepatic decompensation. Child-B (adjusted subdistribution hazard ratio, aSHR: 4.3 [95% CI:1.5-12.2], p = 0.006), HVPG-response (aSHR: 0.3 [95% CI:0.1-0.9], p = 0.037) and diabetes (aSHR: 2.8 [95% CI:1.1-7.2], p = 0.036) were independently associated with hepatic decompensation., Conclusions: In patients with cACLD, diabetes and a higher BMI impair the HVPG-response to NSBB. Furthermore, diabetes-independently from Child B and lack of HVPG-response-increases the risk of hepatic decompensation., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Genetic factors such as the transmembrane 6 superfamily 2 (TM6SF2) rs58542926 single nucleotide variant(SNV) modulate the susceptibility for (advanced) chronic liver disease ([A]CLD). However, the impact of this variant in patients who have already progressed to ACLD is unknown., Methods: The association between TM6SF2-rs58542926 genotype and liver-related events was evaluated in 938 ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement., Results: Mean HVPG was 15±7 mmHg and mean UNOS MELD (2016) 11±5 points. Viral hepatitis (n = 495, 53%) was the most common cause of ACLD, followed by alcohol-related (ARLD; n = 342, 37%) and non-alcoholic fatty liver disease (NAFLD; n = 101, 11%). While 754 (80%) patients harboured the TM6SF2 wild-type (C/C), 174 (19%) and 10 (1%) patients had one or two T-alleles. At baseline, patients with at least one TM6SF2 T-allele had more pronounced portal hypertension (HVPG: 16±7 vs. 15±7 mmHg; p = 0.031), higher gamma-glutamyl transferase levels (123 [63-229] vs. 97 [55-174] UxL -1 ; p = 0.002), and more commonly hepatocellular carcinoma (17% vs. 12%; p = 0.049). Harbouring the TM6SF2 T-allele was associated with the composite endpoint hepatic decompensation/liver transplantation/liver-related death (SHR: 1.44 [95%CI: 1.14-1.83]; p = 0.003). This was confirmed in multivariable competing risk regression analyses that were adjusted for severity of portal hypertension and hepatic dysfunction at baseline., Conclusion: The TM6SF2 variant modulates liver disease progression beyond the development of ACLD, as it modifies the risks of hepatic decompensation and liver-related death, independently of baseline liver disease severity., Competing Interests: Conflict of interest The authors have nothing to disclose regarding the work under consideration for publication. Conflicts of interests outside the submitted work: L.B., M.U., P.W., R.P., G.S., C.W., and A.F.S. have nothing to disclose. B.Sc. received travel support from AbbVie, Ipsen, and Gilead. B.Si. received travel support from AbbVie and Gilead. M.P. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche, and received travel support from Bayer and Bristol-Myers Squibb. P.F. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, MYR Pharmaceuticals, and Vivaraxx and received grants/research support from Gilead. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens, and W. L. Gore & Associates as well as travel support from AbbVie, Boehringer Ingelheim, Gilead and Roche. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Gilead, and Takeda., (Copyright © 2023. Published by Elsevier Ltd.)

Background and Aims: Alcohol-related liver disease is a leading cause of liver-related mortality. The effect of alcohol abstinence on the natural history of alcohol-related cirrhosis across distinct stages of portal hypertension has not been thoroughly investigated. In this study, we assessed the clinical implications of abstinence in patients with alcohol-related cirrhosis and clinically significant portal hypertension., Methods: Alcohol abstinence, hepatic decompensation, and mortality were assessed in patients with alcohol-related cirrhosis who underwent a baseline hepatic venous pressure gradient (HVPG) measurement and were diagnosed with clinically significant portal hypertension (HVPG ≥10 mm Hg)., Results: A total of 320 patients with alcohol-related cirrhosis (median age: 57 [interquartile range (IQR), 49.7-63.1] years; 75.6% male; 87.5% decompensated) and a median HVPG of 20 (IQR, 17-23) mm Hg were followed up for a median of 36 (IQR, 14-80) months. Overall, 241 (75.3%) patients remained abstinent, while 79 (24.7%) patients had active alcohol consumption. Alcohol abstinence was linked to a significantly reduced risk of hepatic decompensation (adjusted hazard ratio [aHR], 0.391; P < .001), as well as liver-related (aHR, 0.428; P < .001) and all-cause (aHR, 0.453; P < .001) mortality, after adjusting for baseline HVPG, MELD, and previous decompensation. Importantly, alcohol abstinence significantly reduced the cumulative incidence of hepatic decompensation in both groups with HVPG 10-19 mm Hg (P < .001) and HVPG ≥20 mm Hg (P = .002). The 3-year decompensation probability was 32.4% vs 60.0% in HVPG 10-19 mm Hg and 57.5% vs 82.6% in HVPG ≥20 mm Hg for abstinent patients vs active drinkers, respectively., Conclusions: Alcohol abstinence improves prognosis across all stages of portal hypertension in alcohol-related cirrhosis, including in patients who have already progressed to high-risk portal hypertension. (ClinicalTrials.gov, Number: NCT03267615)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective β-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding., Methods: Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression., Results: Eighty-seven patients (carvedilol/propranolol, n = 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective β-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P = .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P = .034). Cumulative incidences for rebleeding (Gray test, P = .027) and liver-related death (P = .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P = .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P = .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models., Conclusions: Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD., Methods: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <-1·455 vs -1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226., Findings: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression., Interpretation: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases., Funding: Innovative Medicines Initiative 2., Competing Interests: Declaration of interests KS is an employee of Versantis AG. MT received speaker fees from BMS, Falk Foundation, Gilead, Intercept, Janssen, MSD, and Roche; advised for AbbVie, Albireo, BiomX, Boehringer Ingelheim, Falk Pharma, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens, and Shire; received travel grants from AbbVie, Falk, Gilead, Intercept, and Janssen; and received research grants from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. MT is also co-inventor of patents on the medical use of norUDCA filed by the Medical Universities of Graz and Vienna. AGH reports consultancy for Julius Clinical, Novo Nordisk, Echosens, Inventiva, and has received research grants from Novo Nordisk and Gilead. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento, and as a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, and Pfizer. EB has also received a research grant from Gilead Sciences for fatty liver research. VW-SW has served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; and as a speaker for AbbVie, Bristol-Myers Squibb, Echosens, and Gilead Sciences. VW-SW has also received a research grant from Gilead Sciences for fatty liver research. TK and JW received unrestricted research grants from Echosens. TK has served as a speaker for Echosens. GPA has served as a consultant and an advisory board member for Pfizer, Inventiva Pharma, GlaxoSmithKline, and KaNDy Therapeutics; has been a consultant to BerGenBio, Median Technologies, FRACTYL, Amryt Pharmaceuticals, and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. GS has acted as speaker for Merck, Gilead, AbbVie, Novo Nordisk, and Pfizer; served as an advisory board member for Pfizer, Merck, Novo Nordisk, Gilead, and Intercept; and has received unrestricted research funding from Theratechnologies. ETs has served on the advisory boards for Boehringer, Pfizer, NovoNordisk, Orphalan, Univar, and Alexion; and has been a speaker for NovoNordisk and Dr Falk. MY received research support from Kowa Co. HH's institutions have received research grants from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, and Pfizer. W-KC has served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, and Novo Nordisk; and as a speaker for Hisky Medical and Viatris. SM received honorarium fees from Echosens. MV has served as a consultant or a speaker for Gilead Sciences and Intercept Pharmaceuticals. VdL reports consultancy fees for AbbVie, BMS, Echosens, Gilead Sciences, Intercept Pharmaceuticals, MSD, Myr-Pharma, Pfizer, Supersonic Imagine, and Tillotts. MN has been on the advisory board or has been a consultant for 89BIO, Altimmune, BI, Gilead, cohBar, Cytodyn, Pfizer, GSK, Novo Nordisk, EchoSens, Madrigal, NorthSea, Perspectum, Terns, Takeda, Sami-Sabina group, Siemens, and Roche diagnostic; has received research support from Allergan, Akero, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Corcept, Enanta, Madrigal, Novartis, Pfizer, Shire, TERNS, Viking, and Zydus; and is a shareholder or has stocks in Anaetos, Chrownwell, Cytodyn, Ciema, Rivus Pharma, and Viking. CF-P is employed by Echosens. AG has served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; and received research funding from Intercept, Falk, and Novartis. MM is employed by Novartis. TT is employed by Pfizer. QMA is coordinator of the IMI2 LITMUS consortium; has received research grant funding from AbbVie, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer, Vertex; has received consultancy fees on behalf of Newcastle University for Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Blade, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly, Galmed, Genfit, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe, Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk, Pfizer, Poxel, ProSciento, Raptor Pharma, Servier, Viking Therapeutics; and has received speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit, Gilead, Integritas Communications, MedScape. SAH has received research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, and Viking; and has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, Hightide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking. MP is a shareholder of Perspectum. All other authors declared no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Hyponatremia has prognostic implications in patients with cirrhosis, and thus, has been incorporated in the 2016 MELD-UNOS update. Changes in serum chloride are commonly perceived as 'just' parallel to changes in serum sodium. However, these are less well studied in the context of cirrhosis., Aims: To investigate whether serum chloride independently predicts outcomes in patients with advanced chronic liver disease (ACLD) and stable clinical course or with critical illness., Methods: 891 patients with ACLD (defined by hepatic venous pressure gradient [HVPG] ≥6 mm Hg) were followed after HVPG measurement between 2003 and 2020 (ACLD cohort). 181 critically ill patients with cirrhosis admitted to the ICU between 2004 and 2007 were recruited for the ICU cohort. Hypo-/hypernatremia (normal: 136-145 mmol/L) and hypo-/hyperchloremia (normal: 98-107 mmol/L) at baseline were assessed., Results: ACLD cohort: 68% of male patients with a median MELD (adjusted for Na) of 11 (9-17) were included (Child-Pugh-stages-A/B/C: 46%/38%/16%) and followed for a median of 60 months. Lower serum chloride (adjusted average HR per mmol/L: 0.965 [95% confidence interval (95% CI): 0.945-0.986], p = 0.001) showed a significant association with hepatic decompensation/liver-related mortality on multivariable Cox regression analysis adjusted for age, HVPG, albumin and MELD. In line, hypochloremia was significantly associated with hepatic decompensation/liver-related mortality (adjusted average HR: 1.656 [95% CI:1.267-2.163], p < 0.001). ICU cohort: 70% of patients were male, median MELD was 31(22-39) at ICU admission (92% with Child-Pugh-stage-C). After adjusting for hypo-/hypernatremia, MELD, and blood pH, hypochloremia remained independently associated with ICU-mortality (aOR Cl: 3.200 [95%CI: 1.209-8.829], p = 0.021)., Conclusion: Hypochloremia is associated with increased mortality in clinically stable and critically ill patients with cirrhosis independently of MELD including serum sodium., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Baveno VII proposed liver stiffness measurement (LSM)/platelet count (PLT)-based criteria ('ruled out,' LSM ≤15 kPa plus PLT ≥150 G/L; 'ruled in': LSM ≥25 kPa) for clinically significant portal hypertension (CSPH) in compensated advanced chronic liver disease (cACLD). However, a substantial proportion of patients remains 'unclassified.', Methods: Patients with evidence of cACLD (LSM ≥10 kPa) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital 2004 to 2021 (derivation [2004-2016], n = 221; validation [2017-2021], n = 81) were included. The performance of noninvasive tests (NITs) including von Willebrand factor antigen to PLT ratio (VITRO) for the detection of CSPH (HVPG ≥10 mmHg) were evaluated., Results: Overall, viral hepatitis was the predominant (50.7%) etiology, followed by alcoholic liver disease (15.2%) and nonalcoholic steatohepatitis (13.2%); CSPH prevalence was 62.3%. In the derivation cohort, 45.7% were 'unclassified' according to Baveno VII criteria; in this group, VITRO showed an excellent diagnostic performance for the detection of CSPH (area under the receiver operating curve, 0.909; 95% confidence interval, 0.823-0.965). VITRO ≤1.5 and ≥2.5 ruled out (sensitivity, 97.7%; negative predictive value, 97.5%) and ruled in (specificity, 94.7%; positive predictive value, 91.2%), respectively, CSPH in patients who were 'unclassifiable' by Baveno VII criteria. The application of a sequential Baveno VII-VITRO algorithm reallocated 73% and 70% of 'unclassified' patients to the 'ruled in' and 'ruled out' group, respectively, while maintaining high sensitivity and negative predictive value and specificity and positive predictive value in the derivation and validation cohort, respectively. No patient allocated to the 'CSPH ruled out' group by the Baveno VII-VITRO algorithm developed decompensation within 5 years, whereas 5-year decompensation rates were negligible (4%) and substantial (23.9%) among 'unclassified' and 'CSPH ruled in' patients, respectively., Conclusions: The sequential application of VITRO in patients with cACLD who were 'unclassifiable' with regard to CSPH by Baveno VII criteria substantially decreased the number of 'unclassifiable' patients to <15% and refined prognostication., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The environment of the infection site affects bacterial growth and antibiotic activity. When bacterial growth and antibiotic activity are studied in body fluids, samples of multiple subjects are usually pooled, averaging out potentially relevant differences in composition. The ascitic fluid (AF) environment is frequently associated with spontaneous bacterial peritonitis (SBP) in cirrhotic patients. In this study, bacterial growth and ceftriaxone activity were evaluated in individual AF using an in vitro model of SBP, reflecting the environment and pharmacokinetics at the infection site. Methods: AF was obtained from nine cirrhotic patients with non-infected ascites. Growth of nine bacterial strains (three Escherichia coli , four Staphylococcus aureus , one Enterococcus faecalis , and one Klebsiella pneumoniae ) in individual AF was assessed and correlated with biomarkers including potential risk factors for SBP. Ceftriaxone time-kill experiments, in which the pharmacokinetic profile observed in AF following a 1 g intravenous infusion was replicated, were performed with two  E. coli and two S. aureus isolates with minimum inhibitory concentrations around the ceftriaxone resistance breakpoint. Results: Significant correlations were found between bacterial growth and AF levels of protein (Spearman's rank correlation coefficient ρ = -0.35), albumin (ρ = -0.31), and complement C3c (ρ = -0.28), and serum levels of bilirubin (ρ = 0.39) and aspartate aminotransferase (ρ = 0.25). Ceftriaxone was active in AF, even against resistant isolates, generally resulting in ≥2 log reductions in bacterial count within 24 h. Conclusion: Ascites patients may be predisposed to or protected against SBP based on the antimicrobial capacity of their AF. Ceftriaxone at clinical AF concentrations is active in the AF environment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Os, Wulkersdorfer, Eberl, Oesterreicher, Schwabl, Reiberger, Paternostro, Weber, Willinger and Zeitlinger.)

Background & Aims: Ammonia levels predicted hospitalisation in a recent landmark study not accounting for portal hypertension and systemic inflammation severity. We investigated (i) the prognostic value of venous ammonia levels (outcome cohort) for liver-related outcomes while accounting for these factors and (ii) its correlation with key disease-driving mechanisms (biomarker cohort)., Methods: (i) The outcome cohort included 549 clinically stable outpatients with evidence of advanced chronic liver disease. (ii) The partly overlapping biomarker cohort comprised 193 individuals, recruited from the prospective Vienna Cirrhosis Study (VICIS: NCT03267615)., Results: (i) In the outcome cohort, ammonia increased across clinical stages as well as hepatic venous pressure gradient and United Network for Organ Sharing model for end-stage liver disease (2016) strata and were independently linked with diabetes. Ammonia was associated with liver-related death, even after multivariable adjustment (adjusted hazard ratio [aHR]: 1.05 [95% CI: 1.00-1.10]; p  = 0.044). The recently proposed cut-off (≥1.4 × upper limit of normal) was independently predictive of hepatic decompensation (aHR: 2.08 [95% CI: 1.35-3.22]; p <0.001), non-elective liver-related hospitalisation (aHR: 1.86 [95% CI: 1.17-2.95]; p  = 0.008), and - in those with decompensated advanced chronic liver disease - acute-on-chronic liver failure (aHR: 1.71 [95% CI: 1.05-2.80]; p  = 0.031). (ii) Besides hepatic venous pressure gradient, venous ammonia was correlated with markers of endothelial dysfunction and liver fibrogenesis/matrix remodelling in the biomarker cohort., Conclusions: Venous ammonia predicts hepatic decompensation, non-elective liver-related hospitalisation, acute-on-chronic liver failure, and liver-related death, independently of established prognostic indicators including C-reactive protein and hepatic venous pressure gradient. Although venous ammonia is linked with several key disease-driving mechanisms, its prognostic value is not explained by associated hepatic dysfunction, systemic inflammation, or portal hypertension severity, suggesting direct toxicity., Impact and Implications: A recent landmark study linked ammonia levels (a simple blood test) with hospitalisation/death in individuals with clinically stable cirrhosis. Our study extends the prognostic value of venous ammonia to other important liver-related complications. Although venous ammonia is linked with several key disease-driving mechanisms, they do not fully explain its prognostic value. This supports the concept of direct ammonia toxicity and ammonia-lowering drugs as disease-modifying treatment., Competing Interests: The authors have nothing to disclose regarding the work under consideration for publication. LB, JK, GS, MJ, LH, AFS, PS, and TS have nothing to disclose. The following authors disclose conflicts of interests outside the submitted work. RP received travel support from AbbVie, Gilead and Takeda. BSc received travel support from AbbVie, Ipsen and Gilead. BSi received travel support from AbbVie and Gilead. MP served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche, and received travel support from Bayer and Bristol-Myers Squibb. MT served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. TR received grant support from AbbVie, Boehringer-Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens, and W. L. Gore & Associates; speaking honoraria from AbbVie, Gilead, Gore, Intercept, Roche, and MSD; consulting/advisory board fees from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, and Siemens; and travel support from AbbVie, Boehringer-Ingelheim, Gilead, and Roche. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Gilead, Takeda, and W. L. Gore & Associates and received travel support from AbbVie and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation., (© 2023. The Author(s).)

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., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Previous single-cell RNA-sequencing analyses have shown that Trem2-expressing macrophages are present in the liver during obesity, non-alcoholic steatohepatitis (NASH) and cirrhosis. Herein, we aimed to functionally characterize the role of bone marrow-derived TREM2-expressing macrophage populations in NASH., Methods: We used bulk RNA sequencing to assess the hepatic molecular response to lipid-dependent dietary intervention in mice. Spatial mapping, bone marrow transplantation in two complementary murine models and single-cell sequencing were applied to functionally characterize the role of TREM2 + macrophage populations in NASH., Results: We found that the hepatic transcriptomic profile during steatohepatitis mirrors the dynamics of recruited bone marrow-derived monocytes that already acquire increased expression of Trem2 in the circulation. Increased Trem2 expression was reflected by elevated levels of systemic soluble TREM2 in mice and humans with NASH. In addition, soluble TREM2 levels were superior to traditionally used laboratory parameters for distinguishing between different fatty liver disease stages in two separate clinical cohorts. Spatial transcriptomics revealed that TREM2 + macrophages localize to sites of hepatocellular damage, inflammation and fibrosis in the steatotic liver. Finally, using multiple murine models and in vitro experiments, we demonstrate that hematopoietic Trem2 deficiency causes defective lipid handling and extracellular matrix remodeling, resulting in exacerbated steatohepatitis, cell death and fibrosis., Conclusions: Our study highlights the functional properties of bone marrow-derived TREM2 + macrophages and implies the clinical relevance of systemic soluble TREM2 levels in the context of NASH., Lay Summary: Our study defines the origin and function of macrophages (a type of immune cell) that are present in the liver and express a specific protein called TREM2. We find that these cells have an important role in protecting against non-alcoholic steatohepatitis (a progressive form of fatty liver disease). We also show that the levels of soluble TREM2 in the blood could serve as a circulating marker of non-alcoholic fatty liver disease., Competing Interests: Conflict of interest The authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Von Willebrand factor antigen (VWF) is a non-invasive marker for clinically significant portal hypertension (HVPG≥10 mmHg) and confers HVPG-independent prognostic information. While quantification of increased VWF-levels is not relevant in the context of von Willebrand disease, highly elevated VWF may be of clinical significance in ACLD. Thus, we have modified our analytical approach to quantify very high VWF-levels (i.e.,>420%) and investigated their prognostic value., Methods: Patients undergoing HVPG-measurement at the Vienna Hepatic Hemodynamic Lab with evidence of ACLD and information on VWF were considered. Clinical stages (CS) were defined as follows: Probable compensated ACLD (cACLD): LSM≥10kPa&HVPG<6 mmHg; 0: cACLD&6-9 mmHg; 1: cACLD&HVPG≥10 mmHg; 2: bleeding; 3: non-bleeding decompensation; 4: ≥2 decompensations., Results: 124 (16%) of 793 patients had VWF>420%. The proportion of VWF>420% increased with disease severity (probable cACLD-0: 5(4%) vs. 1: 22(10%) vs. 2-4: 97(23%),p ≤ 0.001) as well as across HVPG (<6mmHg: 1(2%) vs. 6-9: 6(6%) vs. 10-15: 17(9%) vs. ≥16: 100(22%),p ≤ 0.001) and MELD (<10: 17(6%) vs. 10-14: 27(10%) vs. ≥15: 79(32%),p ≤ 0.001) strata. In patients with VWF>420%, median VWF was 533 (IQR:466-611)% and VWF was unrelated to HVPG (Spearman's ρ=0.139,p = 0.123), but showed direct correlations of weak/moderate strength with MELD (ρ=0.336,p < 0.001) and CRP (ρ=0.286,p = 0.001). In the subgroup with VWF>420%, VWF was predictive of decompensation/liver-related mortality (VWF per 10%; hazard ratio (HR): 1.02(95% confidence interval (95%CI): 1.01-1.04),p = 0.008, even after adjusting for other factors (VWF per 10%; adjusted HR: 1.02(95%CI: 1.00-1.05),p = 0.031)., Conclusion: The proportion of patients with substantially elevated VWF values steadily increases with disease progression. While VWF is not reflective of HVPG in these patients, it is correlated with hepatic dysfunction and systemic inflammation. Importantly, quantification of high values provides prognostic information., Competing Interests: Declaration of Competing Interest K.P., L.B., R.J.N., J.W., R.P., D.P., P.S., A.F.S., and P.Q. have nothing to declare., (Copyright © 2022. Published by Elsevier Ltd.)

Background & Aims: Portal hypertension is the strongest predictor of hepatic decompensation and death in patients with cirrhosis. However, its discriminatory accuracy in patients with nonalcoholic fatty liver disease (NAFLD) has been challenged because hepatic vein catheterization may not reflect the real portal vein pressure as accurately as in patients with other etiologies. We aimed to evaluate the relationship between hepatic venous pressure gradient (HVPG) and presence of portal hypertension-related decompensation in patients with advanced NAFLD (aNAFLD)., Methods: Multicenter cross-sectional study included 548 patients with aNAFLD and 444 with advanced RNA-positive hepatitis C (aHCV) who had detailed portal hypertension evaluation (HVPG measurement, gastroscopy, and abdominal imaging). We examined the relationship between etiology, HVPG, and decompensation by logistic regression models. We also compared the proportions of compensated/decompensated patients at different HVPG levels., Results: Both cohorts, aNAFLD and aHVC, had similar baseline age, gender, Child-Pugh score, and Model for End-Stage Liver Disease score. Median HVPG was lower in the aNAFLD cohort (13 vs 15 mmHg) despite similar liver function and higher rates of decompensation in aNAFLD group (32% vs 25%; P = .019) than in the aHCV group. For any of the HVPG cutoff analyzed (&lt;10, 10-12, or 12 mmHg) the prevalence of decompensation was higher in the aNAFLD group than in the aHCV group., Conclusions: Patients with aNAFLD have higher prevalence of portal hypertension-related decompensation at any value of HVPG as compared with aHCV patients. Longitudinal studies aiming to identify HVPG thresholds able to predict decompensation and long-term outcomes in aNAFLD population are strongly needed., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Nonselective beta-blockers are used as prophylaxis for variceal bleeding in patients with advanced chronic liver disease (ACLD). The acute hemodynamic response to intravenous propranolol (i.e., ≥10% reduction in hepatic venous pressure gradient [HVPG]) is linked to a decreased risk of variceal bleeding. In this study, we aimed to investigate the overall prognostic value of an acute response in compensated and decompensated ACLD. We analyzed the long-term outcome of prospectively recruited patients with ACLD following a baseline HVPG measurement with an intraprocedural assessment of the acute hemodynamic response to propranolol. Overall, we included 98 patients with ACLD (mean ± SD age, 56.4 ± 11.5 years; 72.4% decompensated; 88.8% varices; mean ± SD HVPG, 19.9 ± 4.4 mm Hg) who were followed for a median of 9.6 (interquartile range, 6.5-18.2) months. Fifty-seven patients (58.2%) demonstrated an acute hemodynamic response to propranolol that was associated with a decreased risk of variceal bleeding (at 12 months, 3.6% vs. 15% in nonresponder; log-rank, p = 0.038) and hepatic decompensation (at 12 months, 23% vs. 33% in nonresponder; log-rank, p = 0.096). On multivariate analysis, the acute response was an independent predictor of first/further hepatic decompensation (adjusted hazards ratio, 0.31; 95% confidence interval [CI], 0.13-0.70; p = 0.005). Importantly, there was a tendency toward a prolonged transplant-free survival in acute responders compared to nonresponders (34.2; 95% CI, 29.2-39.2 vs. 25.2; 95% CI, 19.8-30.6 months; log-rank, p = 0.191). Conclusions: Patients with ACLD who achieve an acute hemodynamic response to intravenous propranolol experience a lower risk of variceal bleeding and nonbleeding hepatic decompensation events compared to nonresponders. An assessment of the acute hemodynamic response to intravenous propranolol provides important prognostic information in ACLD., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background & Aims: Alpha-1 antitrypsin (AAT) deficiency causes/predisposes individuals to advanced chronic liver disease (ACLD). However, the role of the SERPINA1 Pi∗Z allele in patients who have already progressed to ACLD is unclear. Thus, we aimed to evaluate the impact of the Pi∗Z allele on the risk of liver transplantation/liver-related death in patients with ACLD, while adjusting for the severity of liver disease at inclusion., Methods: A total of 1,118 patients with ACLD who underwent hepatic venous pressure gradient (HVPG) measurement and genotyping for the Pi∗Z/Pi∗S allele at the Vienna Hepatic Hemodynamic Lab were included in this retrospective analysis. The outcome of interest was liver transplantation/liver-related death, while non-liver-related death and removal/suppression of the primary etiological factor were considered as competing risks., Results: Viral hepatitis was the most common etiology (44%), followed by alcohol-related (31%) and non-alcoholic fatty liver disease (11%). Forty-two (4%) and forty-six (4%) patients harboured the Pi∗Z and Pi∗S variants, respectively. Pi∗Z carriers had more severe portal hypertension (HVPG: 19±6 vs. 15±7 mmHg; p < 0.001) and hepatic dysfunction (Child-Turcotte-Pugh: 7.1±1.9 vs. 6.5±1.9 points; p = 0.050) at inclusion, compared to non-carriers. Contrarily, the Pi∗S allele was unrelated to liver disease severity. In competing risk regression analysis, harbouring the Pi∗Z allele was significantly associated with an increased probability of liver transplantation/liver-related death, even after adjusting for liver disease severity at inclusion. The detrimental impact of the common Pi∗MZ genotype (adjusted subdistribution hazard ratio: ≈1.56 vs. Pi∗MM) was confirmed in a fully adjusted subgroup analysis. In contrast, Pi∗S carriers had no increased risk of events., Conclusion: Genotyping for the Pi∗Z allele identifies patients with ACLD at increased risk of adverse liver-related outcomes, thereby improving prognostication. Therapies targeting the accumulation of abnormal AAT should be evaluated as disease-modifying treatments in Pi∗Z allele carriers with ACLD., Lay Summary: Alpha-1 antitrypsin deficiency is a genetic disease that affects the lung and the liver. Carrying two dysfunctional copies of the gene causes advanced liver disease. Harbouring one dysfunctional copy increases disease severity in patients with other liver illness. However, the significance of this genetic defect in patients who already suffer from advanced liver disease is unclear. Our study found that harbouring at least one dysfunctional copy of the alpha-1 antitrypsin gene increases the risk of requiring a liver transplantation or dying from a liver disease. This indicates the need for medical therapies aimed at treating the hepatic consequences of this genetic defect., Competing Interests: The authors have nothing to disclose regarding the work under consideration for publication. Conflicts of interests outside the submitted work: L.B., M.U., P.W., R.P., L.H., M.J., G.S., C.W., P.F., and A.F.S. have nothing to disclose. B.Sc. Received travel support from AbbVie, Ipsen, and Gilead. B.Si. Received travel support from AbbVie and Gilead. D.B. received speaker fees from AbbVie and Siemens, as well as grant support form Gilead and Siemens, as well as travel support from AbbVie and Gilead. M.P. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche, and received travel support from Bayer and Bristol-Myers Squibb. P.F. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, MYR Pharmaceuticals, and Vivaraxx and received grants/research support from Gilead. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept, as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens, and W. L. Gore & Associates as well as travel support from AbbVie, Boehringer Ingelheim, Gilead and Roche. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and W. L. Gore & Associates and received travel support from AbbVie and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Authors.)

Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of pathologies ranging from non-alcoholic fatty liver (NAFL), characterized by simple steatosis without inflammation, to non-alcoholic steatohepatitis (NASH), characterized by steatosis of the liver accompanied by inflammation and hepatocyte ballooning, which can lead to advanced fibrosis, cirrhosis and hepatocellular carcinoma. Apart from lifestyle modifications such as weight loss, a Mediterranean diet and physical activity, only a few NAFLD-specific pharmacological treatment options such as Vitamin E and Pioglitazone are considered by current international guidelines. However, recently randomized controlled trials with GLP-1 agonists, FXR and PPAR ligands as well as other agents have been published and may expand the therapeutic armamentarium for NAFLD in the near future. Finally, knowledge about treating complications of end-stage liver disease due to NASH becomes an increasingly important cornerstone in the treatment of the broad disease spectrum of NAFLD. In this review, we summarize currently available and future treatment options for patients with NAFLD that may help internal medicine specialists treat the complete clinical spectrum of this highly prevalent liver disease., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background & Aims: 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., Methods: 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.', Results: 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., Conclusions: 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: It has been suggested that the ratio of procoagulant factor VIII to anticoagulant protein C (FVIII/PC) reflects the hemostatic equilibrium. Moreover, FVIII/PC predicted decompensation/death in a small study not accounting for portal hypertension severity. We investigated (i) the prognostic value of FVIII/PC (outcome-cohort) and (ii) whether FVIII/PC reflects the hypercoagulable state (assessed by thrombomodulin-modified thrombin generation assay [TM-TGA]) or the risk of bleeding/thrombotic events in patients undergoing hepatic venous pressure gradient (HVPG) measurement during follow-up., Methods: (i) The outcome-cohort comprised 576 patients with evidence of advanced chronic liver disease (liver stiffness measurement ≥10 kPa and/or HVPG ≥6 mmHg). (ii) TM-TGA-cohort patients (n = 142) were recruited from the prospective VIenna CIrrhosis Study (VICIS: NCT03267615)., Results: (i) FVIII/PC significantly increased across clinical stages (p <0.001) as well as HVPG (p <0.001) and MELD score (p <0.001) strata and remained independently associated with decompensation/liver-related death (adjusted hazard ratio 1.06; 95% CI 1.01-1.11; p = 0.013), even after multivariable adjustment. It was also associated with acute-on-chronic liver failure (ACLF) development (adjusted hazard ratio 1.10; 95% CI 1.02-1.19; p = 0.015) in patients with decompensated cirrhosis. (ii) FVIII/PC showed a weak positive correlation with endogenous thrombin potential (Spearman's ρ = 0.255; p = 0.002), but this association disappeared after adjusting for the severity of liver disease. FVIII/PC was not associated with the development of bleeding (p = 0.272) or thrombotic events (p = 0.269). However, FVIII/PC correlated with biomarkers of different pathophysiological mechanisms that promote liver disease progression., Conclusion: FVIII/PC provides prognostic information regarding hepatic decompensation/death and ACLF, independently of established prognostic indicators. However, this is not evidence that hypercoagulability drives disease progression, as the correlation between FVIII/PC and thrombin generation is confounded by liver disease severity and FVIII/PC was not associated with thrombosis. Therefore, FVIII/PC does not reflect coagulation and results from previous studies on FVIII/PC require re-interpretation., Clinical Trial Number: NCT03267615 (in part)., Lay Summary: A balanced coagulation system is essential for preventing bleeding episodes and blood clot formation (thrombosis). Blood of patients with advanced liver disease may have increased coagulation potential, possibly promoting the worsening of liver disease via thrombosis in the blood vessels of the liver. The ratio between the results of 2 blood tests (procoagulant factor VIII to anticoagulant protein C) has been suggested to reflect these increases in coagulation potential. Our study demonstrates, on the one hand, that this ratio is a versatile predictor of the development of complications of cirrhosis, yet on the other hand, that it is unrelated to coagulation., Competing Interests: Conflicts of interest The authors have nothing to disclose regarding the work under consideration for publication. Conflicts of interests outside the submitted work: L.B., R.J.N., J.W., R.P., L.H., M.J., A.F.S., G.S., P.Q., and T.L. have nothing to disclose. Be.Sc. received travel support from AbbVie, Ipsen and Gilead. Be.Si. received travel support from AbbVie and Gilead. D.B. received travel support from AbbVie and Gilead and speaker fees from AbbVie. M.P. served as a speaker and/or consultant and/or advisory board member for Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche and received travel support from Bayer and Bristol-Myers Squibb. C.A. received honoraria for lectures and advisory boards from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer. M.T. received grant support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx, honoraria for consulting from Albireo, Boehringer-Ingelheim, BiomX, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus, and Shire, speaker fees from Bristol-Myers Squibb, Falk, Gilead, Intercept, and MSD, as well as travel support from AbbVie, Falk, Gilead, and Intercept. T.R. received grant support from AbbVie, Boehringer-Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens, and W. L. Gore & Associates; speaking honoraria from AbbVie, Gilead, Gore, Intercept, Roche, and MSD; consulting/advisory board fees from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, and Siemens; and travel support from AbbVie, Boehringer-Ingelheim, Gilead, and Roche. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of Competing Interest The authors report no real or potential conflict of interest related to this study. The following conflicts of interests outside of this study exist R.P.: no conflict of interests. J.B., B.H., V.P. and H.S.: no conflict of interests. B.SIM.: received travel support from AbbVie and Gilead. G.S.: no conflict of interests. P.S.: received speaking honoraria from Bristol-Myers Squibb and Boehringer-Ingelheim, consulting fees from PharmaIN, and travel support from Falk. B.SCH.: no conflict of interests. T.BU.: Speaker honoraria from Bristol-Myers Squibb. Travel support from Gilead, Abbvie, and Bristol-Myers Squibb. D.B.: Has received travel support from AbbVie and Gilead and served as speaker for AbbVie. T.BI.: no conflict of interests. M.M.: Speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Collective Acumen, Gilead, and W. L. Gore & Associates. Travel support from AbbVie, Bristol-Myers Squibb, and Gilead. M.T.: Speaker for BMS, Falk, Gilead, Intercept, and MSD; advisory boards for Albireo, BiomX, Boehringer Ingelheim, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, and Regulus. He further received travel grants from Abbvie, Falk, Gilead and Intercept and unrestricted research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. He is also co-inventor of patents on the medical use of norUDCA filed by the Medical University of Graz. T.R.: grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche., (Copyright © 2021. Published by Elsevier Ltd.)

Background & Aims: Porto-sinusoidal vascular disease (PSVD) was recently proposed as novel clinical entity characterized by typical histological changes with or without portal hypertension (PH) in the absence of cirrhosis. Thus, we aimed to describe clinical characteristics and the outcome of PSVD patients and to compare these to patients meeting traditional idiopathic non-cirrhotic portal hypertension (INCPH) criteria., Methods: Patients undergoing liver biopsy (baseline) ±hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 2000-2019 were screened for PSVD and INCPH criteria., Results: 91 patients were diagnosed with PSVD of which 28 (30.8%) also fulfilled INCPH criteria (INCPH+/PSVD+). Specific histological and specific clinical PH signs were found in 72 (79.1%) and 54 (59.3%) patients, respectively. INCPH+/PSVD+ showed higher Child-Pugh-scores (7±2 vs 6±1 points; P = .002) and a higher prevalence of decompensation (57.1% vs 28.6%; P = .009) than INCPH-/PSVD+ patients. Importantly, hepatic decompensation after three years (3Y) occurred in 11.2% of PSVD patients with specific clinical signs of PH, while no decompensation occurred in patients with only specific histological or with unspecific clinical/histological signs (P = .002). When categorizing by INCPH definition, 3Y decompensation was 13.4% in INCPH+/PSVD+ and 3.8% in INCPH-/PSVD+ (P = .120). While overall mortality was similar in INCPH+/PSVD+ (n = 6; 21.4%) and INCPH-/PSVD+ (n = 10; 15.9%) patients (P = .558), liver-related mortality tended to be higher in INCPH+/PSVD+ (6.9%) than in INCPH-/PSVD+ (0%; P = .078)., Conclusion: Novel PSVD criteria facilitate diagnosis. Compared to INCPH, clinical course of PSVD patients is more favorable. Importantly, specific signs of PH including varices and collaterals are associated with hepatic decompensation and mortality., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes., Methods: Plasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A-C), HVPG (6-9 mmHg, 10-15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD., Results: With increasing PH, hyperdynamic state was indicated by higher heart rates (6-9 mmHg: median 71.0 [IQR 18.0] bpm, 10-15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p < 0.001), lower mean arterial pressure (6-9 mmHg: 103.0 [13.5] mmHg, 10-15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p = 0.032) and lower serum sodium (6-9 mmHg: 139.0 [3.0] mmol/L, 10-15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p < 0.001). Across HVPG strata (6-9 mmHg vs. 10-15 mmHg vs ≥ 16 mmHg), median plasma levels of renin (21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL; p < 0.001), proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07-2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70-5.84; p < 0.001) and the overall cohort aHR: 1.42; 95% CI 1.01-2.01; p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27-26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36-7.95; p = 0.008). ProBNP levels did not predict clinical outcomes., Conclusions: The cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients., (© 2021. The Author(s).)

Objective: Systemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment initiation impacts biomarkers of systemic inflammation and (2) whether these changes in systemic inflammation predict complications and mortality., Design: Biomarkers of systemic inflammation, that is, white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) were determined at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB and under stable NSBB intake. The influence of NSBB-related changes in systemic inflammation on the risk of decompensation and liver-related death was analysed using competing risk regression., Results: Our study comprised 307 stable patients with ACLD (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17-24) mm Hg) including 231 (75.2%) with decompensated disease.WBC significantly decreased upon NSBB therapy initiation (median: -2 (IQR -19;+13)%, p=0.011) in the overall cohort. NSBB-related reductions of WBC (Child-C: -16 (-30;+3)% vs Child-B: -2 (-16;+16)% vs Child-A: +3 (-7;+13)%, p<0.001) and of CRP (Child-C: -26 (-56,+8)% vs Child-B: -16 (-46;+13)% vs Child-A: ±0 (-33;+33)%, p<0.001) were more pronounced in advanced stages of cirrhosis. The NSBB-associated changes in WBC correlated with changes in CRP (Spearman's ρ=0.228, p<0.001), PCT (ρ=0.470, p=0.002) and IL-6 (ρ=0.501, p=0.001), but not with changes in HVPG (ρ=0.097, p=0.088).An NSBB-related decrease in systemic inflammation (ie, WBC reduction ≥15%) was achieved by n=91 (29.6%) patients and was found to be an independent protective factor of further decompensation (subdistribution HR, sHR: 0.694 (0.49-0.98), p=0.038) in decompensated patients and of liver-related mortality in the overall patient cohort (sHR: 0.561 (0.356-0.883), p=0.013)., Conclusion: NSBB therapy seems to exert systemic anti-inflammatory activity as evidenced by reductions of WBC and CRP levels. Interestingly, this effect was most pronounced in Child-C and independent of HVPG response. An NSBB-related WBC reduction by ≥15% was associated with a decreased risk of further decompensation and death., Competing Interests: Competing interests: BSim received travel support from AbbVie and Gilead, DJMB has received travel support from AbbVie and Gilead, PS received speaking honoraria from Bristol-Myers Squibb and Boehringer-Ingelheim, consulting fees from PharmaIN and travel support from Falk. BSch received travel support from Gilead, AbbVie and Ipsen. TB received travel support from AbbVie, Bristol-Myers Squibb and Medis, as well as speaker fees from Bristol-Myers Squibb. AFS has served as a speaker and/or consultant and/or advisory board member for Boehringer Ingelheim, Gilead and MSD. MP is an investigator for Bayer, BMS, Lilly and Roche; served as a speaker and/or consultant for Bayer, BMS, Ipsen, Eisai, Lilly, MSD and Roche; and received travel support from Bayer and BMS. MT received grant support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda; honoraria for consulting from Albireo, Boehringer-Ingelheim, BiomX, Falk, Genfit, Gilead, Intercept, MSD, Novartis, Phenex and Regulus; speaker fees from Bristol-Myers Squibb, Falk, Gilead, Intercept and MSD; as well as travel support from AbbVie, FalkGilead and Intercept. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb and Gilead. TR received grant support from AbbVie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare and Gore; speaking honoraria from AbbVie, Gilead, Gore, Intercept, Roche and MSD; consulting/advisory board fee from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD and Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and increasing liver disease, which encompasses a variety of liver diseases of different severity. NAFLD can lead to liver cirrhosis with all its complications as well as hepatocellular carcinoma (HCC). Steatosis of the liver is not only related to obesity and other metabolic risk factors, but can also be caused by several drugs, including certain cytotoxic chemotherapeutic agents. In patients undergoing liver surgery, hepatic steatosis is associated with an increased risk of post-operative morbidity and mortality. This review paper summarizes implications of hepatic steatosis on the management of patients with cancer. Specifically, we discuss the epidemiological trends, pathophysiological mechanisms, and management of NAFLD, and its role as a leading cause of liver cancer. We elaborate on factors promoting immunosuppression in patients with NAFLD-related HCC and how this may affect the efficacy of immunotherapy. We also summarize the mechanisms and clinical course of chemotherapy-induced acute steatohepatitis (CASH) and its implications on cancer treatment, especially in patients undergoing liver resection., Competing Interests: Disclosure MT received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept, and Merck Sharp & Dohme (MSD); advisory board fees from Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, Genfitt, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also co-inventor of patents on the medical use of norUDCA filed by the Medical University of Graz. MP is an investigator for Bayer, BMS, Lilly, and Roche; he received speaker honoraria from Bayer, BMS, Eisai, Lilly, and MSD; he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, MSD, and Roche; he received travel support from Bayer and BMS. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors., Design: Patients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0-F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study., Results: 703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3-4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added., Conclusion: In biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy., (© 2021. The Author(s).)

Introduction: Recently, based on data from the PREDICT study, the European Foundation for the Study of Chronic Liver Failure (EF-CLIF) consortium proposed pathophysiological/prognostic groups in hospitalized patients with cirrhosis: stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC), pre-acute-on-chronic liver failure (pre-ACLF), and ACLF. We evaluated the outcomes of these subgroups in a real-life cohort of hospitalized patients with cirrhosis., Methods: Patients with cirrhosis developing first AD between 09/2010 and 12/2017 at the Vienna General Hospital were evaluated for this retrospective analysis., Results: Two hundred and ten patients with cirrhosis (aged 57.6 ± 11.8 years) including n = 45 (21.4%) SDC, n = 100 (47.6%) UDC, n = 28 (13.3%) pre-ACLF, and n = 37 (17.6%) with ACLF were considered. The proposed AD subgroups discriminated between patients with favorable (1-year mortality: SDC: 6.7% and UDC: 19.6%) and dismal prognosis (90-day mortality: pre-ACLF: 42.9%). Interestingly, systemic inflammation gradually increased (e.g., C-reactive protein, SDC: 0.9 mg/dl, vs. UDC: 2.0 mg/dl vs. pre-ACLF: 3.2 mg/dl, p < 0.001) while renal function was progressively deteriorating (creatinine levels, SDC: 0.8 mg/dl vs. UDC: 0.9 mg/dl vs. pre-ACLF: 1.2 mg/dl, p < 0.001) across prognostic subgroups in patients with cirrhosis., Discussion: The recently proposed pathophysiological/prognostic EF-CLIF subgroups are also reproduceable in a real-life cohort of cirrhotic patients. As ACLF is a common and important complication, patients at risk of pre-ACLF at index AD should be evaluated and if disease proceeds, been treated early and aggressively to avoid excessive mortality., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background & Aims: 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., Methods: 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., Results: 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)., Conclusion: 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., Lay Summary: 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., Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT03267615)., Competing Interests: Conflict of interest DC, MJ, LH, RP, PS, AFS declare no conflicts of interest. BeSi has received travel support from AbbVie and Gilead. DB has received travel support from AbbVie and Gilead, as well as speaker fees from AbbVie. BeSc received travel support from Abbvie, Gilead and Ipsen. MP is an investigator for Bayer, BMS, Lilly, and Roche; he received speaker honoraria from Bayer, BMS, Eisai, Lilly, and MSD; he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, MSD, and Roche; he received travel support from Bayer and BMS. MT received grant support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda, honoraria for consulting from BiomX, Boehringer Ingelheim, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, and Regulus, speaker fees from BMS, Falk, Gilead, Intercept and MSD, as well as travel support from Abbvie, Falk, Gilead and Intercept. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. TR received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Siemens; and travel support from Abbvie, Boehringer-Ingelheim, Gilead and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Experimental data indicates that placental growth factor (PLGF) is involved in the pathophysiology of portal hypertension (PH) due to advanced chronic liver disease (ACLD). We investigated serum levels of PLGF and its "scavenger", the receptor soluble fms-like tyrosine kinase-1 (sFLT1, or sVEGFR1), in ACLD patients with different severity of PH and portal-hypertensive gastropathy (PHG)., Methods: PLGF and sVEGFR1 were measured in ACLD patients with hepatic venous pressure gradient (HVPG) ≥6 mmHg (n = 241) and endoscopic evaluation of PHG (n = 216). Patients with pre-/posthepatic PH, TIPS, liver transplantation and hepatocellular carcinoma were excluded., Results: Thirty-two (13%) patients had HVPG 6-9 mmHg, 128 (53%) 10-19 mmHg and 81 (34%) ≥20 mmHg; 141 (59%) had decompensated ACLD (dACLD). PLGF (median 17.2 vs. 20.8 vs. 22.4 pg/mL; p = 0.002), sVEGFR1 (median 96.0 vs. 104.8 vs. 119.3 pg/mL; p < 0.001) levels increased across HVPG strata, while PLGF/sVEGFR1 ratios remained similar (0.19 vs. 0.20 vs. 0.18 pg/mL; p = 0.140). The correlation between PLGF and HVPG was weak (Rho = 0.190,95%CI 0.06-0.31; p = 0.003), and the PLGF/sVEGFR1 ratio did not correlate with HVPG (p = 0.331). The area-under-the-receiver operating characteristics (AUROC) for PLGF to detect clinically significant PH (CSPH;i.e. HVPG ≥ 10 mmHg) yielded only 0.688 (0.60-0.78; p < 0.001). When compared to ACLD patients without PHG, PLGF levels (20 without vs. 21.4 with mild vs. 17.1 pg/mL with severe PHG, respectively; p = 0.005) and PLGF/sVEGFR1 ratios (0.20 vs. 0.19 vs. 0.17; p = 0.076) did not increase with mild and severe PHG., Conclusion: While PLGF levels tended to increase with severity of PH, the PLGF/sVEGFR1 ratio remained stable across HVPG strata. Neither PLGF nor the PLGF/sVEGFR1 ratio had diagnostic value for prediction of CSPH. The severity of PHG was also not associated with stepwise increases in PLGF levels or PLGF/sVEGFR1 ratio., Competing Interests: Declaration of Competing Interest BeSi received travel support from AbbVie and Gilead. PS received speaking honoraria from Bristol-Myers Squibb and Boehringer-Ingelheim, consulting fees from PharmaIN, and travel support from Falk and Phenex Pharmaceuticals. DB received travel support from AbbVie and Gilead. TB received speaker honoraria from BMS, travel support from Abbvie, BMS, and Gilead; travel grant, financial award/grant from Medis. BeSc received travel support from Abbvie and Gilead. MP is an investigator for Bayer, BMS, Lilly, and Roche; he received speaker honoraria from Bayer, BMS, Eisai, Lilly, and MSD; he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, MSD, and Roche; he received travel support from Bayer and BMS. MT received speaker fees from BMS, Falk Foundation, Gilead, Intercept and MSD; advisory board fees from Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, MSD, Novartis, Phenex and Regulus. He further received travel grants from Abbvie, Falk, Gilead and Intercept and unrestricted research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. MM served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. TR received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche. AFS, AS, EE, KW, AB, TS, KL and RP declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: In most immune-competent individuals, hepatitis E (HEV) infections appear silent. It is unclear whether past HEV infections deteriorate disease severity in patients with non-alcoholic fatty liver disease (NAFLD)., Methods: Patients with biopsy-proven NAFLD and data on anti-HEV immunoglobulin M (HEV-IgM) and anti-HEV IgG antibodies (HEV-IgG) were included. The NAFLD activity score (NAS) was used to grade and stage all liver biopsy samples. The HEV-IgG prevalence was compared to a healthy cohort of 997 subjects., Results: One hundred sixty-seven patients with NAFLD were included with the following characteristics: age, 50 ± 13 years; NAS ≤4, 89 (53.3%); NAS 5-8, 78 (46.7%); cirrhosis, 16 (9.6%). Two patients (1.2%) were HEV-IgM-positive, however HEV polymerase chain reaction remained negative and no signs of acute hepatitis were seen. Forty-four patients (26.3%) were HEV-IgG-positive and they were significantly older (55 ± 10 years vs. 48 ± 13 years, P < 0.001) and predominantly men (31 [70.5%] vs.13 [29.5%], P = 0.022). Distribution across NAS (P = 0.610) was not different. However, HEV-IgG-positive patients were significantly more often found with cirrhosis (8 [18.2%] vs. 8 [6.5%], P = 0.024) and liver stiffness values >10 kPa (14 [58.2%] vs. 29 [43.3%], P = 0.026). Multivariable analyses revealed age (odds ratio [OR], 1.054 [1.022-1.086]) and male sex (OR 2.77 [1.27-6.04]) associated with HEV-IgG positivity. Presence of diabetes (OR 3.86 [1.18-12.59]), higher aspartate aminotransferase levels (OR, 1.02 [1.006-1.033]), and HEV-IgG seropositivity (OR 3.52 [1.11-11.13]) were independently linked to cirrhosis. Finally, HEV-IgG positivity was not independently associated with NAFLD patients in a case-control study including healthy subjects., Conclusions: Prevalence of anti-HEV-IgG antibodies in patients with NAFLD is linked to age and male sex. Furthermore, previous HEV infection was an independent risk factor for cirrhosis. Whether this finding is causal or solely associative is unclear and should be elucidated in future studies., (© 2020 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background and Aims: The liver plays a key role in the storage, metabolism and homeostasis of fat-soluble vitamins. We investigated the relation of Vitamin(Vit)A/D/E serum levels with severity of liver disease and portal hypertension (PHT)., Methods: VitA/D/E serum levels were assessed in 234 patients with advanced chronic liver disease (ACLD, i.e. hepatic venous pressure gradient [HVPG] ≥ 6 mmHg). Patients with hepatocellular carcinoma, pre-/post-hepatic PHT, TIPS or liver transplantation were excluded., Results: Most patients were male (n = 153; 65%) with a median age of 57.6 (49.7-64.5) years. Thirty-two (14%) patients had HVPG 6-9 mmHg, 66 (28%) 10-15 mmHg, and 136 (58%) ≥ 16 mmHg, respectively. VitD deficiency (25-OH-vitamin-D <50 nmol/L) was found in 133 (57%) with higher prevalence in Child-Turcotte-Pugh (CTP)-C: 85% vs. B: 66% vs. A: 47% (p < 0.001). VitD levels displayed significant but weak correlations with hepatic dysfunction and PHT. VitE levels were normal in 227 (97%) patients and displayed no relevant association with hepatic dysfunction or PHT. Only 63 (27%) patients had normal (>1.05 µmol/L) VitA levels, while 58 (25%) had mild (0.70-1.04 µmol/L), 71 (30%) moderate (0.35-0.69 µmol/L), and 42(18%) severe(<0.35 µmol/L) VitA deficiency. VitA correlated with HVPG (Rho = -0.409), CTP score (Rho = -0.646), and serum bile acid levels (Rho = -0.531; all p < 0.001). The prevalence of decompensated ACLD (dACLD) continuously increased with severity of VitA deficiency (no: 40% vs. mild: 51% vs. moderate: 67% vs. severe: 91% had dACLD; p < 0.001). CTP score (per point; OR 2.46; 95%CI 1.80-3.37; p <0.001), age (per year; OR 0.95; 95%CI 0.92-0.98; p = 0.001) and elevated bile acid levels(>10 µmol/L; OR 3.62; 95%CI 1.61-8.14; p = 0.002) were independently associated with VitA deficiency., Conclusion: VitA and VitD but not VitE deficiencies are highly prevalent in ACLD. VitA deficiency strongly correlates with hepatic dysfunction, PHT and bile acid levels and is associated with decompensated ACLD., Trial Registration Number: NCT03267615.

Background: Liver biopsy remains essential for the diagnostic work-up of patients with liver disease., Aims: To evaluate aspiration vs. core-biopsy needles for transjugular liver biopsy (TJLB) in patients undergoing hepatic venous pressure gradient (HVPG) measurements., Methods: 84 patients undergoing TJLB between 06/2017 and 12/2018 were prospectively included. Liver biopsy specimens were systematically evaluated for quantitative and qualitative criteria such as number of portal tracts, sample length and fragmentation., Results: In direct comparison of paired TJLB specimens (n=35), core-biopsy samples were significantly longer (median 12 vs. 9mm, p=0.012), tended to contain more portal tracts (median 8 vs. 6, p=0.064) and were less fragmented (p<0.001), which resulted in better confidence for liver fibrosis assessment (p=0.035). However, a superior quality in terms of less fragmentation of core-biopsy specimens (p<0.05) was only confirmed in patients with HVPG ≥10mmHg or liver stiffness measurement >40kPa. In contrast, the aspiration needle provided significantly longer samples in patients with HVPG <10mmHg (median 21 vs. 12mm, p=0.007) or with liver stiffness measurement <20kPa (median 21 vs. 11mm, p=0.025)., Conclusion: In patients with HVPG ≥10mmHg, we recommend to performed TJLB using core-biopsy needles, while the aspiration needle provides high quality liver biopsy specimens in patients with HVPG <10mmHg., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose regarding the work under consideration for publication. The following authors disclose conflicts of interests outside the submitted work: J.S. received grant support from Eli Lilly and Company, and Gilead. B.Si. received travel support from AbbVie. B.Sch. received travel support from AbbVie and Gilead. P.S. received travel support from Boehringer Ingelheim and Gilead as well as speaker fees from Boehringer Ingelheim. M.P. received travel support from Bayer and served as advisory board member for Bayer, Bristol-Myers Squibb, and Eisai. M.T. received travel support from AbbVie, Falk, Gilead and Intercept, grant support from Albireo, Cymabay, Falk, Gilead, Intercept, MSD, and Takeda, honoraria for consulting from AbbVie, BiomX, Boehringer Ingelheim, Falk, Gilead, Genfit, Intercept, MSD, Novartis, Phenex and Regulus, as well as speaker fees from Falk, Gilead, Intercept and MSD. M.M. received travel support from AbbVie, Bristol-Myers Squibb, and Gilead, and served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, and W. L. Gore & Associates. T.R. received travel support from Boehringer Ingelheim, Gilead, and Roche, served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Roche, Siemens, and W. L. Gore & Associates, and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, MSD, Philips, and W. L. Gore & Associates. G.S., K.W., R.P., A.F.S., T.M. and A.B. have nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aim: Iron deficiency anemia (IDA)is the leading cause of anemia worldwide. Data on prevalence and clinical impact of anemia in cirrhosis are scarce. Aim was to report on the following:(i) prevalence of anemia and IDA in cirrhosis and (ii) its possible impact on clinical outcomes., Methods: Consecutive cirrhotic patients from a prospective registry study were included. Anemia was defined as hemoglobin concentration ≤ 12 g/dL. IDA was defined as Hb ≤ 12 g/dL + transferrin-saturation < 20%. Follow up for hepatic decompensation and mortality started with study inclusion and terminated in December 2017. A retrospective validation cohort of 1244 patients was used to validate our findings., Results: Two hundred forty-two patients with compensated (n = 53 [21.9%]) and decompensated (n = 189 [78.1%]) cirrhosis were included. Anemia was present in 128 patients (52.9%); of those, 63 (49.2%) had IDA. Prevalence of anemia increased with Child-Pugh Score (CPS; A: 26.5%, B: 59.2%, C: 69%; P < 0.001) and with decompensated cirrhosis(62.4% vs 18.8%, P < 0.001). Within anemic patients, a higher proportion of patients in CPS A/B vs C (73% vs 35%; P = 0.025) and in compensated cirrhosis (80% vs 46.6%; P = 0.043) were found with IDA. Model for End-Stage Liver Disease (MELD) scores were significantly lower in patients with IDA (14.4 vs 17.9 non-ID-anemia; P = 0.005). Similar results were found in the validation cohort: median MELD (16[8-28]non-IDA vs 12 [7-23] IDA; P < 0.001) and within anemic patients IDA was more common in patients with MELD <15 (58%) versus >15 (24%, P < 0.001). Anemia was associated with a significant risk for hepatic decompensation and/or mortality both in the validation (aSHR: 1.65, P = 0.008) and in the derivation cohort (aSHR: 2.11, P < 0.001) and an independent risk factor for hepatic decompensation and/or mortality in compensated patients (aHR: 4.91, P = 0.004)., Conclusion: Anemia is highly prevalent in cirrhosis. In compensated cirrhosis, CPS A/B, and low MELD, IDA seems to be the most likely reason for anemia. Furthermore, anemia is associated with a significant risk for hepatic decompensation or mortality during long-term follow up., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: The prognostic impact of liver steatosis in obese patients is well established. Limited data on the risk factors for and impact of hepatic steatosis in lean patients are available., Aims: Assess risk factors for liver steatosis in lean patients and investigate its impact on survival., Methods: Patients without viral hepatitis and with a BMI ≤ 25 kg/m 2 undergoing liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) by transient elastography were retrospectively identified. Clinical characteristics and laboratory test results were obtained at the time of LSM/CAP measurement. National death registry data were obtained in order to assess survival., Results: Among n = 218 lean patients, n = 97 (34.5%) showed significant liver steatosis (CAP ≥ 268 dB/m), while n = 184 (65.5%) had no or just mild steatosis (CAP < 268 dB/m). Patients with steatosis had higher GGT (238.0(± 450.3) vs. 112.1(± 180.0) IU/mL; p = 0.013), AST (63(± 67.4) vs. 38.5(± 32.9) IU/mL; p = 0.001), ALT (59.1(± 58.8) vs. 44.3(± 52.7) IU/mL; p = 0.048) and triglyceride levels (120.1(± 80.3) vs. 96.1(± 58.2) mg/dL; p = 0.014), and showed a trend toward more severe fibrosis (LSM 15.6(± 19.5) vs. 12.0(± 15.7) kPa; p = 0.115). In multivariate binary logistic regression analysis, only serum uric acid levels were independently associated with liver steatosis (odds ratio 1.43 per unit mg/dL; 95% CI 1.001-2.054; p = 0.049). During a mean follow-up of 38.9(± 10.6) months, n = 14 patients (5.0%) died. In the absence of advanced fibrosis, survival after 1 year was similar in patients without (98.7%) and with (98.6%) significant steatosis. Patients with advanced fibrosis had worse 1-year survival without concomitant significant steatosis (84.8%) than patients with steatosis (95.8%; log-rank p < 0.001)., Conclusions: High serum uric acid levels increase the risk of liver steatosis in lean patients. Liver fibrosis but not hepatic steatosis is a risk factor for impaired survival in lean patients.

Background & Aims: Phosphodiesterase-5 inhibitors (PDE-5-I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side-effects have been reported. Non-selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE-5-I with NSBB and its impact on PH and ED in experimental cirrhosis., Methods: ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile-duct-ligation or carbon-tetrachloride intoxication in rats. Corpus cavernosum pressure - a surrogate of ED -, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE-5 signalling were analysed using PCR and western Blot., Results: ED in humans was related to severity of liver disease and to NSBB treatment. PDE-5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side-effects., Conclusions: ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE-5-I and NSBB improves ED and PH in experimental cirrhosis., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease., Methods: HDL-related biomarkers were studied in 508 patients with compensated or decompensated cirrhosis (including acute-on-chronic liver failure [ACLF]) and 40 age- and gender-matched controls. Specifically, we studied levels of HDL-C, its subclasses HDL2-C and HDL3-C, and apolipoprotein A1 (apoA-I), as well as HDL cholesterol efflux capacity as a metric of HDL functionality., Results: Baseline levels of HDL-C and apoA-I were significantly lower in patients with stable cirrhosis compared to controls and were further decreased in patients with acute decompensation (AD) and ACLF. In stable cirrhosis (n = 228), both HDL-C and apoA-I predicted the development of liver-related complications independently of model for end-stage liver disease (MELD) score. In patients with AD, with or without ACLF (n = 280), both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, both HDL-C and apoA-I had high diagnostic accuracy for 90-day mortality in patients with AD (AUROCs of 0.79 and 0.80, respectively, similar to that of MELD 0.81). On Kaplan-Meier analysis, HDL-C <17 mg/dl and apoA-I <50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to advanced chronic liver disease (AUROCs HDL-C: 0.81 vs. MELD: 0.77)., Conclusion: HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure., Lay Summary: People who suffer from cirrhosis (scarring of the liver) have low levels of cholesterol carried by high-density lipoproteins (HDL-C). These alterations are connected to inflammation, which is a problem in severe liver disease. Herein, we show that reduced levels of HDL-C and apolipoprotein A-I (apoA-I, the main protein carried by HDL) are closely linked to the severity of liver failure, its complications and survival. Both HDL-C and apoA-I can be easily measured in clinical laboratories and are as good as currently used prognostic scores calculated from several laboratory values by complex formulas., Competing Interests: Conflicts of interest Alexander Gerbes received personal fees from CSL Behring, GRIFOLS, and Falk. All other authors declare that they have no conflicts of interest related to the study. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: The ratio of von Willebrand Factor to platelets (VITRO) reflects the severity of fibrosis and portal hypertension and might thus hold prognostic value., Methods: Patients with compensated cirrhosis were recruited. VITRO, Child-Pugh score (CPS) and MELD were determined at study entry. Hepatic decompensation was defined as variceal bleeding, ascites or hepatic encephalopathy. Liver transplantation and death were recorded., Results: One hundred and ninety-four patients with compensated cirrhosis (CPS-A 89%, B 11%; 56% male; median age 56 years; 50% with varices) were included. During a median follow-up of 45 months (IQR 29-61), decompensation occurred in 35 (18%) patients and 14 (7%) patients deceased. The risk of hepatic decompensation was significantly increased in the n = 88 (45%) patients with a VITRO ≥ 2.5 (p < 0.001). Patients with a VITRO ≥ 2.5 had a higher probability of decompensation at 1-year 9% (95% CI 3-16) vs. 0% (95% CI 0-0) and at 2-years 18% (95% CI 10-27%), vs. 4% (95% CI 0-8%) as compared to patients with VITRO < 2.5. Patients with VITRO ≥ 2.5, the estimated 1-year/2-year survival rates were at 98% (95% CI 95-100%) and 94% (95% CI 88-99%) as compared to 100% (95% CI 100-100%) both in the patients with a VITRO < 2.5 (p < 0.001). After adjusting for age, albumin and MELD, VITRO ≥ 2.5 remained as significant predictor of transplant-free mortality (HR 1.38, CI 1.09-1.76; p = 0.007). Patients with compensated cirrhosis and VITRO > 2.1 after hepatitis C eradication remained at significantly increased risk for decompensation (p = 0.033)., Conclusions: VITRO is a valuable prognostic tool for estimating the risk of decompensation and mortality in patients with compensated cirrhosis-including the setting after hepatitis C eradication.

Background: There is conflicting evidence regarding reliability criteria for the controlled attenuation parameter (CAP; a marker for hepatic steatosis [HS]). Thus, we assessed the diagnostic performance of CAP according to different reliability criteria based on real-world data from an academic centre., Methods: Patients undergoing measurement of CAP and liver biopsy (±6 months) at the Medical University of Vienna were included. HS was assessed according to SAF score., Results: In total 319 patients were included. The main aetiologies were non-alcoholic fatty liver disease (NAFLD, n  = 177, 55.5%), viral hepatitis ( n  = 49, 15.4%), and alcoholic liver disease (ALD, n  = 29, 9.1%). Histological steatosis and fibrosis stages were: S0: 93 (29.2%), S1: 100 (31.3%), S2: 67 (21.0%), and S3: 59 (18.5%); F0/F1: 150 (47.0%), F2: 47 (14.7%), and F3/F4: 122 (48.3%). In the overall cohort, the area under the receiver operating characteristic curve (AUC) of CAP was 0.843 (95% confidence interval [CI]: 0.798-0.887) for diagnosing HS ≥ S1), 0.789 (95%CI: 0.740-0.839) for ≥S2, and 0.767 (95%CI: 0.712-0.823) for S3. CAP corrections as suggested by Karlas et al. did not improve the diagnostic performance. Importantly, the AUC of CAP for HS ≥ S1 was numerically highest in patients with CAP-IQR/median<0.10 or <0.20 (obtained in 37.9% and 74.9%), in whom CAP also had better diagnostic performance, as compared with patients not meeting these criteria. Moreover, it was substantially higher in 288 (90.3%) patients with CAP-IQR/median<0.3: 0.856 (95%CI: 0.809-0.903) vs. patients not meeting this criterion (0.530 [95%CI: 0.309-0.751]). In contrast, the previously suggested reliability criterion of CAP-IQR<40 dB/m was not associated with an improved diagnostic performance for HS≥S1 (0.866 [95%CI: 0.812-0.920] vs. 0.799 [95%CI: 0.717-0.881]) and was only obtained in 199 (62.4%) patients., Conclusion: CAP-IQR/median<0.1, <0.2, and <0.3 identify reliable measurements for diagnosing any hepatic steatosis (≥S1). Importantly, CAP-IQR/median<0.3 has a considerably higher applicability in clinical practice, as compared with the previously suggested CAP-IQR<40 dB/m criterion.