Mattias Mandorfer

Background: Compensated advanced chronic liver disease (cACLD) encompasses patients with advanced fibrosis/cirrhosis at risk for liver-related complications. The natural history of cACLD has been extrapolated from compensated cirrhosis and historic cohorts, although major advances in diagnosis and management have impacted the clinical course and understanding of disease trajectories. Methods: From 2015 to 2022, 1140 consecutive patients with cACLD (first-time liver stiffness measurement [LSM] ≥10 kPa) at the Vienna General Hospital were followed for first and further decompensation, and death. Baseline data (age, sex, etiological cure, LSM, MELD, platelet count, and albumin) were incorporated into a multistate modelling framework to investigate transition-specific associations. Results: 42% had steatotic liver disease and 37% viral hepatitis. Median LSM at baseline was 16 kPa, and 93% had Child–Turcotte–Pugh stage A. Median follow-up was 3.9 years. Two and 5-year probabilities were: 89%/74% to remain compensated, 3.7%/3.6% for first decompensation, 0.6%/2.1% for further decompensation, 3.7%/12% for liver-related and 2.8%/7.9% for non-liver-related death. LSM ≥15 kPa and ANTICIPATE±NASH ≥75% identified subgroups at particular risk for hepatic decompensation (5.7% vs. 1.5%/ 9.1% vs. 2.1% at 2 years) and liver-related death, but not for non-liver-related death, which was as frequent as hepatic decompensation in those with LSM <15 kPa. LSM and markers of liver dysfunction predicted hepatic decompensation, whereas etiological cure and platelet count were associated with further decompensation. Conclusion: The risk of hepatic decompensation in contemporary patients with cACLD is lower than in previous reports on compensated cirrhosis. Hepatic decompensation accelerates disease progression.

Background and Aims: The applicability of non‐invasive tests (NITs) for clinically significant portal hypertension (CSPH) in patients with hepatocellular carcinoma (HCC) is controversial. We performed a head‐to‐head comparison of various NITs for CSPH and evaluated rule‐in/‐out criteria. Methods: We conducted a retrospective study including 283 patients with HCC undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna Hepatic Haemodynamic Lab with available, same‐day data on NITs (i.e., liver stiffness measurement [LSM], platelet count [PLT], von Willebrand factor antigen [VWF:Ag], and the ratio of VWF:Ag and PLT [VITRO]). For the subsequent analysis, we focused on patients with compensated advanced chronic liver disease (cACLD). Results: Among 164 patients with cACLD, most were BCLC 0/A (50.6%) and CSPH prevalence was 46.3%, the median LSM was 20.0 kPa (IQR: 13.3–37.9), and mean VWF:Ag/VITRO was 266 ± 119%/2.30 ± 1.81. The VITRO score yielded the highest discriminative ability to detect CSPH (AUROC: 0.834), followed by ANTICIPATE ± NASH (AUROC: 0.822), PLT (AUROC: 0.803), LSM (AUROC: 0.779), and VWF:Ag (AUROC: 0.707). The application of the Baveno VII criterium (LSM ≤ 15 kPa & PLT ≥ 150G/L) and the VITRO score (≤ 1.0) individually showed an excellent performance for ruling‐out CSPH (sensitivities: ≥ 95%, NPV: 100%/87.9%). For ruling‐in CSPH by individual criteria, the VITRO score provided the highest PPV (≥ 2.5, specificity/PPV: 89.8%/83.0%), followed by the Baveno VII criteria (specificity/PPV: 81.8%/74.6%). When sequentially applying Baveno VII criteria and VITRO, the grey zone could be significantly reduced to 16% (sensitivity/NPV: 94.7%/92.2%; specificity/PPV: 73.9%/84.4%). Conclusion: The discriminative ability in patients with cACLD and HCC was comparable to patients without HCC. However, PPVs of established criteria were < 90%, which may be explained by the comparatively low prevalence of CSPH in this context.

Background and Aims: The accuracy of Baveno criteria for avoiding endoscopy in patients with hepatocellular carcinoma (HCC) is uncertain, and systematic upper gastrointestinal endoscopy (UGE) may not be necessary. We evaluated Baveno VI criteria performance in this population and developed an alternative non-invasive rule to exclude esophagogastric varices of any grade, rather than high-risk varices (HRV). Methods: Patients with BCLC 0-C HCC and compensated advanced chronic liver disease (cACLD) from the Italian Liver Cancer (ITA.LI.CA) database, with available liver stiffness measurement (LSM), UGE, and blood tests within 6 months of diagnosis, were included. Independent predictors of varices identified by logistic regression were combined through grid search to derive a rule-out strategy (SAPHE-R), validated by bootstrap resampling and in an independent cohort (Vienna). Results: The derivation cohort comprised 598 patients (age, 69 years; male sex, 75.3%; viral etiology, 69.3%; BCLC 0/A, 77.9%; ALBI 1, 54.2%; varices, 33.4%; HRV, 11.2%). Baveno VI criteria missed 8.5% of varices and 6.0% of HRV, sparing 31.1% of UGE. Independent predictors of varices were incorporated into SAPHE-R (LSM≤16 kPa, platelet count ≥160×10 ⁹ /L, ALBI grade 1), which missed 4.0% of varices (HRV 3.0%, spared UGE 17.6%). In the validation cohort (n=149), SAPHE-R missed 4.8% of varices (HRV 3.1%, spared UGE 14.8%). Results remained consistent in sensitivity analyses. In an exploratory analysis, no HVPG-defined CSPH was observed among SAPHE-R rule-out patients (0/22). Conclusions: Baveno VI criteria showed suboptimal performance in patients with HCC and cACLD, whereas SAPHE-R provided a reliable non-invasive strategy to rule out varices, facilitating variceal risk assessment in patients with HCC.

Introduction: The liver produces angiotensinogen (AGT), the key upstream precursor of the renin-angiotensin system (RAS). We measured AGT levels in patients across distinct advanced chronic liver disease (ACLD) stages and investigated the impact of AGT levels on clinical outcomes. Methods: We included clinically stable ACLD outpatients undergoing hepatic venous pressure gradient (HVPG) measurement between May 2018 and October 2023, as well as healthy controls (HCs) recruited in the prospective Vienna Cirrhosis Study (VICIS; NCT03267615). AGT was assessed by converting it to angiotensin I (Ang I) through incubation with excess recombinant human renin. RAS parameters were measured by liquid chromatography-tandem mass spectrometry. Patients were stratified as compensated (cACLD), single decompensated (sdACLD), or further decompensated ACLD (fdACLD). Results: Overall, 60 individuals (cACLD: n=16; sdACLD: n=22; fdACLD: n=12; HC: n=10) were included. AGT levels decreased significantly compared with HC and with increasing ACLD severity (HC: 943.2 vs. cACLD: 550.4 vs. sdACLD: 476.9 vs. fdACLD: 439.8 nmol/L; p p =0.002) and Ang 1-7 (cACLD: 3.0 vs. sdACLD: 3.2 vs. fdACLD: 8.5 pmol/L; p =0.022) increased significantly with ACLD severity. AGT did not correlate with Ang II (ρ=−0.23; p =0.101), but with Ang 1-7 (ρ=0.32; p =0.022) and MELD-Na (ρ=−0.29; p =0.042). Exploratory survival analyses, limited by the small sample size, showed that lower AGT was associated with all-cause mortality (adjusted for age and MELD-Na: asHR: 1.59; 95% CI: 1.09–2.27; p =0.012/adjusted for age and albumin: asHR: 1.52; 95% CI: 1.05–2.21; p =0.026). Conclusions: AGT levels decreased in ACLD, correlated with hepatic dysfunction, and were linked to all-cause mortality in exploratory survival analyses. Still, classical and alternative RAS parameters increased in parallel to ACLD severity.

Background: While portal hypertension (PH) typically resolves after liver transplantation (LT), persistence of PH may affect post‐transplant outcomes. We assessed the evolution of PH after LT and its impact on adverse outcomes. Methods: We recorded clinical, laboratory, and imaging parameters of LT recipients between 2016 and 2022 in Vienna and Zagreb. Persistent features of CSPH were defined as the presence of portosystemic collaterals, platelet count (PLT) ≤ 110 G/L, and/or splenomegaly (≥ 13 cm). PH‐related clinical events were defined as variceal bleeding, ascites requiring intervention, hepatic hydrothorax, portal vein thrombosis, or liver‐related death within 12 months post‐LT. Post‐LT outcomes were analyzed using landmark Cox regression for 3 months post‐LT. Results: Of 645 LT recipients (76% male, median age 59 years) listed with a median MELD of 15 points and PLT of 99 G/L, features of CSPH were present in 537 (83.3%) at baseline. At year 1 after LT, MELD improved to 9 (IQR 7–12), PLT increased to 160 G/L (IQR 120–207), and features of CSPH persisted in 251/453 classifiable patients (55.4%). PH events occurred in 75 (11.6%) and 84 (13%) deaths. In a landmark analysis from 3 months post‐LT ( n = 521, 29 deaths), persistent thrombocytopenia (< 110 G/L) at M3 independently predicted mortality (aHR 2.31, 95% CI 1.01–5.30, p = 0.048) after adjustment for MELD, age, CRP, and pre‐LT TIPS. Conclusions: While PH improves after LT, features of CSPH persisted in 55% of classifiable patients and PH‐related clinical events occurred in 11.6% within the first year after LT. Persistent thrombocytopenia (< 110 G/L) at 3 months post‐LT independently predicted post‐LT mortality (aHR 2.31, 95% CI 1.01–5.30, p = 0.048).

Portal hypertension (PH) after liver transplantation (LT) is rare but associated with complications and mortality. The VITRO score—combining von Willebrand factor antigen (vWF-Ag) divided by platelet count (PLT)—reflects PH severity in cirrhosis, yet its prognostic value after LT remains unknown. VITRO score dynamics and clinical outcomes were evaluated in 272 consecutive adult patients with available vWF-Ag measurements undergoing LT between 2016 and 2022 at the Medical University of Vienna. Laboratory parameters were assessed at listing, pre-LT, and at 3–6 and 12 months post-LT. Endpoints included overall mortality and a composite endpoint of PH events and/or liver-related death within 12 months post-LT. At listing, 89% of patients presented with clinically significant portal hypertension (CSPH), with markedly elevated vWF levels (median: 369%, IQR: 262–420) and VITRO scores (median: 3.3, IQR: 2.1–4.8). Following LT, PLT normalized in most cases, with vWF levels decreasing to 206% (IQR: 141–296) and VITRO scores improving to 1.1 (IQR: 0.9–1.5) at 3–6 months post-LT. ΔVITRO was significantly associated with both overall mortality (HR: 1.57, 95% CI: 1.28–1.93, p p p p =0.001) and post-LT MELD decrease (aHR 0.36, p =0.026). These findings remained robust in landmark sensitivity analyses from month 3 post-LT and after bootstrap-based internal validation. Post-LT VITRO score dynamics independently predict liver-related mortality and PH-related complications. Integration of ΔVITRO monitoring into post-LT care may facilitate individualized risk stratification after liver transplantation.

Background: The acute hepatic venous pressure gradient (HVPG)‐response to i.v. propranolol predicts outcomes in patients with advanced chronic liver disease (ACLD) and clinically significant portal hypertension (CSPH). While non‐invasive tests (NIT) to monitor non‐selective beta‐blocker (NSBB)‐induced HVPG changes are lacking, spleen stiffness measurement (SSM) has shown promising results as a surrogate for HVPG. This study aimed to assess the correlation between changes in SSM at 100 Hz and HVPG upon acute i.v. propranolol. Methods: ACLD patients with CSPH undergoing paired HVPG and SSM‐100 Hz assessments pre‐ and post‐i.v. propranolol (0.15 mg/kg) at three expert centres between 2019 and 2024 were included. HVPG‐response was defined as a ≥ 10% decrease in HVPG. Results: Ninety‐four patients (63.8% males, median age 57.5 [Q1–Q3: 50.0–65.0] years, BMI 26.6 [22.8–31.1] kg/m ² ) were included. Most had alcohol‐related liver disease (ALD)/metabolic‐associated liver disease (59.6%) or metabolic‐associated steatotic liver disease (11.7%). The median HVPG decreased from 17 (Q1–Q3: 15–20) mmHg to 16 (Q1–Q3: 12–19) mmHg post‐NSBB ( p < 0.001), with 45.7% achieving an acute HVPG‐response. SSM decreased by −8.7 ([Q1–Q3: −19.2; −0.2] kPa, p < 0.001). HVPG‐responders had a significant SSM decrease (−12.4 [Q1–Q3: −26.3; −5.6] kPa, p < 0.001), while non‐responders showed no change. A moderate correlation between relative changes in SSM and HVPG was observed (Spearman's ρ: 0.387; p < 0.001). Relative change in SSM achieved an area under the receiver operating characteristic curve (AUROC) of 0.717 (95% CI: 0.614–0.820, p < 0.001) for diagnosing HVPG‐response. Conclusion: SSM‐100 Hz dynamics are associated with HVPG changes upon i.v. propranolol administration. Although the discriminative ability of changes in SSM was insufficient for clinical use, they may serve as a surrogate of efficacy in clinical trials investigating medical therapies for portal hypertension.