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

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.

Although ascites is the most frequent first decompensating event in cirrhosis, the clinical course after ascites as the single index decompensation is not well defined. The aim of this multicentre study was thus to systematically investigate the incidence and type of further decompensation after ascites as the first decompensating event and to assess risk factors for mortality. A total of 622 patients with cirrhosis presenting with grade 2/3 ascites as the single index decompensating event at 2 university hospitals (Padova and Vienna) between 2003 and 2021 were included. Events of further decompensation, liver transplantation, and death were recorded. The mean age was 57 ± 11 years, and most patients were male (n = 423, 68%) with alcohol-related (n = 366, 59%) and viral (n = 200,32%) liver disease as the main aetiologies. In total, 323 (52%) patients presented with grade 2 and 299 (48%) with grade 3 ascites. The median Child–Pugh score at presentation was 8 (IQR 7–9), and the mean model for end-stage liver disease (MELD) was 15 ± 6. During a median follow-up period of 49 months, 350 (56%) patients experienced further decompensation: refractory ascites (n = 130, 21%), hepatic encephalopathy (n = 112, 18%), spontaneous bacterial peritonitis (n = 32, 5%), hepatorenal syndrome–acute kidney injury (n = 29, 5%). Variceal bleeding as an isolated further decompensation event was rare (n = 18, 3%), whereas non-bleeding further decompensation (n = 161, 26%) and ≥2 concomitant further decompensation events (n = 171, 27%) were frequent. Transjugular intrahepatic portosystemic shunt was used in only 81 (13%) patients. In patients presenting with grade 2 ascites, MELD ≥15 indicated a considerable risk for further decompensation (subdistribution hazard ratio [SHR] 2.18; p <0.001; 1-year incidences: <10: 10% vs. 10–14: 13% vs. ≥15: 28%) and of mortality (SHR 1.89; p = 0.004; 1-year incidences: <10: 3% vs. 10–14: 6% vs. ≥15: 14%). Importantly, mortality was similarly high throughout MELD strata in grade 3 ascites (p = n.s. for different MELD strata; 1-year incidences: <10: 14% vs. 10–14: 15% vs. ≥15: 20%). Further decompensation is frequent in patients with ascites as a single index decompensation event and only rarely owing to bleeding. Although patients with grade 2 ascites and MELD <15 seem to have a favourable prognosis, those with grade 3 ascites are at a high risk of mortality across all MELD strata. Decompensation (the development of symptoms as a result of worsening liver function) marks a turning point in the disease course for patients with cirrhosis. Ascites (i.e. , the accumulation of fluid in the abdomen) is the most common first decompensating event, yet little is known about the clinical course of patients who develop ascites as a single first decompensating event. Herein, we show that the severity of ascites is associated with mortality and that in patients with moderate ascites, the widely used prognostic MELD score can predict patient outcomes.

Background & Aims: While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited.Methods: Liver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low‐molecular‐weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti‐Xa peak levels and thrombomodulin‐modified thrombin generation assays (TM‐TGAs) were measured in a subgroup of 35/28 DOAC patients.Results: Among patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child‐Pugh‐stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure‐related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow‐up of 10.5 (IQR: 4.0‐27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS‐B/C (at 12 months: 36.9% vs CPS‐A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59‐6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00‐16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82‐9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti‐Xa peak levels were higher in patients with CPS‐B/C (345 [95% CI: 169‐395] vs CPS‐A: 137 [95% CI: 96‐248] ng/mL, P = .048) and were associated with lower TM‐TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients.Conclusions: Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.

Non-invasive tests to assess the probability of clinically significant portal hypertension (CSPH) - including the ANTICIPATE±NASH models based on liver stiffness measurement and platelet count±BMI, and the von Willebrand factor antigen to platelet count ratio (VITRO) - have fundamentally changed the management of compensated advanced chronic liver disease (cACLD). However, their prognostic utility has not been compared head-to-head to the gold standard for prognostication in cACLD, i.e. the hepatic venous pressure gradient (HVPG). Patients with cACLD (liver stiffness measurement ≥10 kPa) who underwent advanced characterization via same-day HVPG/non-invasive test assessment from 2007-2022 were retrospectively included. Long-term follow-up data on hepatic decompensation was recorded. Four hundred and twenty patients with cACLD of varying etiologies, with a CSPH prevalence of 67.6%, were included. The cumulative incidence of hepatic decompensation at 1 and 2 years was 4.7% and 8.0%, respectively. HVPG, VITRO, and ANTICIPATE±NASH-CSPH-probability showed similar time-dependent prognostic value (AUROCs 0.683-0.811 at 1 year and 0.699-0.801 at 2 years). In competing risk analyses adjusted for MELD score and albumin, HVPG (adjusted subdistribution hazard ratio [aSHR] 1.099 [95% CI 1.054-1.150] per mmHg; p <0.001), or VITRO (aSHR 1.134 [95% CI 1.062-1.211] per unit; p <0.001), or ANTICIPATE±NASH-CSPH-probability (aSHR 1.232 [95% CI 1.094-1.387] per 10%; p <0.001) all predicted first decompensation during follow-up. Previously proposed cut-offs (HVPG ≥10 mmHg vs. <10 mmHg, VITRO ≥2.5 vs. <2.5, and ANTICIPATE-CSPH probability ≥60% vs. <60%) all accurately discriminated between patients at negligible risk and those at substantial risk of hepatic decompensation. The prognostic performance of ANTICIPATE±NASH-CSPH-probability and VITRO is comparable to that of HVPG, supporting their utility for identifying patients who may benefit from medical therapies to prevent first hepatic decompensation. Non-invasive tests have revolutionized the diagnosis and management of clinically significant portal hypertension in patients with compensated advanced chronic liver disease (cACLD). However, limited data exists regarding the prognostic utility of non-invasive tests in direct comparison to the gold standard for prognostication in cACLD, i.e. the hepatic venous pressure gradient. In our study including 420 patients with cACLD, the ANTICIPATE±NASH model and VITRO yielded similar AUROCs to hepatic venous pressure gradient for hepatic decompensation within 1 to 2 years. Thus, non-invasive tests should be applied and updated in yearly intervals in clinical routine to identify patients at short-term risk, thereby identifying patients who may benefit from treatment aimed at preventing hepatic decompensation.

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.