Thomas Reiberger

Background: Portal vein thrombosis (PVT) in cirrhosis has a quite unpredictable natural history. Spontaneous recanalization may occur, but predictors and prognostic impact remain uncertain. We performed an individual patient data (IPD) meta-analysis to evaluate survival according to spontaneous recanalization and to identify predictors of recanalization. Methods: We included cohort studies of patients with cirrhosis and PVT not receiving anticoagulation and obtained de-identified IPD. All-cause mortality was analyzed using a competing-risk model (competing event: liver transplantation) adjusted for prespecified baseline covariates. Predictors of recanalization were assessed with mixed-effects ordinal logistic regression including a random study intercept. Results: Eight studies contributed 586 patients. Spontaneous recanalization occurred in 264 (47.7%). Overall recanalization was independently associated with lower mortality (aSHR 0.51; 95% CI 0.28–0.90), with the benefit driven by complete recanalization (aSHR 0.45; 95% CI 0.21–0.94). Recanalization of PVT localized in the main portal vein trunk was linked to a strong survival benefit (interaction SHR 0.39; 95% CI 0.16–0.91; p =0.02), whereas no benefit was observed after recanalization of isolated intrahepatic branch thrombosis. PVT recanalization was more likely to occur in Child–Pugh A (aOR 2.63; 95% CI 1.18–5.88), partial thrombosis (aOR 1.69; 95% CI 1.09–2.56), and isolated intrahepatic location (aOR 2.04; 95% CI 1.23–3.33). Conclusions: Spontaneous recanalization occurs in approximately half of patients with cirrhosis and PVT and is associated with improved survival, particularly when complete and involving the main portal vein trunk. These findings underscore its prognostic relevance and indirectly support anticoagulation to promote recanalization.

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 and Aims: Autoimmune hepatitis is an immune‐mediated liver disease characterized by chronic inflammation and progressive fibrosis. Tissue‐resident memory T cells mediate organ‐specific immunity, but their role in autoimmune hepatitis remains poorly understood. We characterized tissue‐residency‐associated T‐cell populations and their cytokine profiles, assessed associations with disease severity and determined whether these signatures were reflected in peripheral blood. Methods: Paired blood and liver samples were obtained from 19 patients with autoimmune hepatitis. Comparator cohorts included 20 patients with metabolic dysfunction‐associated steatotic liver disease and 20 surgical patients providing non‐inflamed adjacent non‐tumorous liver tissue. Multiparameter flow cytometry assessed tissue‐residency markers, T‐cell differentiation and cytokine production after polyclonal stimulation. Immune phenotypes were correlated with histological and clinical parameters. Results: Autoimmune hepatitis was associated with compartment‐specific remodelling of T‐cell differentiation states and intrahepatic enrichment of CD8 ⁺ T cells expressing CD69, CD103 and CXCR6 relative to paired blood and comparator liver tissues. Intrahepatic CD8 ⁺ T cells exhibited an interferon‐γ‐dominant cytokine profile, whereas CD4 ⁺ T cells showed broader interferon‐γ‐, interleukin‐17A‐ and interleukin‐4‐associated responses. Despite the enrichment of tissue‐residency‐associated CD8 ⁺ T cells, cytokine‐producing CD8 ⁺ T‐cell populations with and without a tissue‐resident memory phenotype contributed comparably to the hepatic T‐cell compartment. Tissue‐residency‐associated phenotypes correlated positively with Ishak fibrosis stage, whereas the frequency of interferon‐γ‐positive intrahepatic CD8 ⁺ T cells correlated inversely with fibrosis. Conclusions: Autoimmune hepatitis was characterized by intrahepatic accumulation of phenotypically distinct and functionally active CD8 ⁺ tissue‐resident memory T cells associated with fibrosis. This immune profile was not reflected in paired blood, indicating compartmentalized hepatic immune remodelling.

Background and aims: Fibronectin is a multifunctional matrix glycoprotein involved in tissue remodeling and hemostasis; however, its clinical relevance in cirrhosis remains unclear. This study characterized circulating fibronectin across stages of advanced chronic liver disease (ACLD) and assessed its correlation to pathophysiological biomarkers and predictive value for liver-related complications. Methods: Patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement were prospectively enrolled with circulating fibronectin measured simultaneously. Associations were assessed using correlation analyses and systems modeling. Competing-risk regression was used to evaluate clinical outcomes. Results: Among 298 patients (median HVPG 17 [12–21] mmHg; MELD 3.0 12 [9–17]), fibronectin levels were lower in decompensated than compensated ACLD (30.3 vs. 38.8 mg/dL; p < 0.001). Fibronectin correlated with hepatic synthesis (cholinesterase: Spearman’s r = 0.64) and MELD 3.0 ( r = − 0.47; both p < 0.001) while showing an independent positive association with ELF ( β = 0.19; p < 0.001). In systems modeling, hepatic synthesis explained most of fibronectin variance (cholinesterase: 37%), followed by fibrinolysis (antiplasmin: 14%) and matrix remodeling (ELF: 12%). In exploratory analyses, higher fibronectin levels were independently associated with variceal bleeding (aSHR 1.04, p = 0.017), and lower fibronectin levels with portal vein thrombosis (aSHR 0.95, p = 0.031), when adjusted for HVPG, MELD 3.0, or IL-6. Fibronectin was not associated with other hepatic decompensation events, hepatocellular carcinoma, or liver-related mortality. Conclusion: Circulating fibronectin reflects hepatic synthetic capacity and matrix remodeling. Its divergent exploratory associations with variceal bleeding and portal vein thrombosis suggest that fibronectin may capture aspects of hemostatic vulnerability. Clinical trial number: NCT03267615.