BACKGROUND:Clinically significant portal hypertension (CSPH) drives decompensation and mortality in advanced chronic liver disease (ACLD). Although non-selective β-blockers (NSBB) reduce risk, accurate identification of patients with CSPH requires invasive hepatic venous pressure gradient (HVPG) measurement. The non-invasive Baveno-VII CSPH criteria based on liver stiffness measurement (LSM) and platelet count (PLT)-yield 40-50% indeterminate ("gray-zone") results and vary across etiologies and elastography techniques. Spleen stiffness measurement (SSM) has been proposed to improve the accuracy of the Baveno-VII CSPH criteria. We developed and validated a machine-learning (ML) model integrating pan-elastographic LSM and SSM results with clinical variables to improve CSPH rule-out and rule-in accuracy while minimizing indeterminate cases. METHODS:We analyzed 1,435 compensated ACLD patients with paired HVPG, LSM, SSM, and clinical parameters. LSM and SSM were obtained by vibration-controlled transient elastography (VCTE), two-dimensional shear-wave elastography (2D-SWE), or point-SWE (p-SWE). Models were trained (n=943) and internally validated (n=150) using harmonized LSM/SSM from different technologies and clinical variables (PLT, Child-Pugh, age, gender, etiology). Cut-offs were selected for 100% negative predictive value (NPV) to rule-out and 100% positive predictive value (PPV) to rule-in CSPH. External validation was conducted in 342 patients across seven centers, comparing ML performance against Baveno VII, Baveno-SSM single- and dual-cut-off criteria, and, in the VCTE subgroup, ANTICIPATE and NICER scores. RESULTS:A Random Forest-based model based achieved the highest performance (external validation: AUC=0.91, Brier Score=0.13), with cut-offs≤0.45 (rule-out) and ≥0.60 (rule-in) yielding NPV=0.90 (95%C.I.0.84-0.94) and PPV=0.96 (95%C.I.0.92-0.98). The ML gray-zone was 12.3%, versus 47.9% (Baveno VII;p<0.001), 38.6% (Baveno-SSM-dual;p<0.001), and 19.6% (Baveno-SSM-single;p<0.05). In the VCTE external-validation subgroup (n=275), ELM achieved comparable rule-in performance to ANTICIPATE and NICER, while reducing the gray zone to 12.0% versus 41.1% and 41.8%, respectively. CONCLUSIONS:The ELM Score outperformed current Baveno criteria and markedly reduced gray zones across elastography modalities, supporting broader, safer, and non-invasive identification of ACLD patients with HVPG-defined CSPH who may be candidates for NSBB therapy.

BACKGROUND & AIMS:Steatotic liver disease encompasses metabolic dysfunction-associated steatotic liver disease, alcohol-related liver disease, and a mixed type (metabolic dysfunction-associated and alcohol-related liver disease). We investigated the course of compensated advanced chronic liver disease across steatotic liver disease subtypes, the impact of clinically significant portal hypertension, and the role of noninvasive tests. METHODS:This study included patients with steatotic liver disease and compensated advanced chronic liver disease from 17 centers undergoing hepatic venous pressure gradient and noninvasive test assessment through December 2023. Primary outcomes were first hepatic decompensation and liver-related mortality. RESULTS:Among 696 patients (alcohol-related liver disease, 22%; metabolic dysfunction-associated and alcohol-related liver disease, 20%; metabolic dysfunction-associated steatotic liver disease, 58%), 94% had Child-Pugh A, and 60% had clinically significant portal hypertension. Over a median follow-up of 3.8 years, 170 patients decompensated, and 137 died (58% liver-related). The 3-year cumulative decompensation incidence was highest in alcohol-related liver disease (26%), followed by metabolic dysfunction-associated and alcohol-related liver disease (21%) and metabolic dysfunction-associated steatotic liver disease (15%); yet differences were no longer significant after adjusting for age, sex, Model for End-stage Liver Disease, albumin, and hepatic venous pressure gradient. Similarly, liver-related mortality did not differ by steatotic liver disease subtype in adjusted models. Clinically significant portal hypertension independently predicted decompensation across all subtypes. The ANTICIPATE-NASH model showed high and comparable diagnostic accuracy for clinically significant portal hypertension across alcohol-related liver disease, metabolic dysfunction-associated and alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease (area under the receiver operating characteristic curve = 0.831-0.894). An ANTICIPATE-NASH probability ≥60% for ruling-in clinically significant portal hypertension outperformed the original ANTICIPATE model in all subtypes and independently predicted decompensation with similar effect sizes (adjusted subdistribution hazard ratio, 2.57-2.71). CONCLUSIONS:Higher crude decompensation rates in alcohol-related liver disease and metabolic dysfunction-associated and alcohol-related liver disease reflect more severe liver disease at presentation, yet outcomes are comparable across the steatotic liver disease spectrum after accounting for disease severity. ANTICIPATE-NASH accurately identifies clinically significant portal hypertension across steatotic liver disease subtypes, and both invasive and noninvasive measures of portal hypertension predict decompensation and liver-related death.

BACKGROUND & AIMS:Portopulmonary hypertension (PoPH) is a severe complication of cirrhosis and portal hypertension. In 2022, a European task force revised the diagnostic criteria for pulmonary arterial hypertension (PAH), defining early stages as a mean pulmonary arterial pressure (mPAP) of 20.5-24.5 mmHg and pulmonary vascular resistance (PVR) >2 Wood units. We evaluated the prognostic value of these revised criteria in patients with cirrhosis. METHODS:In this longitudinal, multicenter, observational cohort, 428 adults with cirrhosis and portal hypertension underwent right-heart catheterization between 2015 and 2023 and were stratified into five groups: normal, early PoPH, classic PoPH, post-capillary pulmonary hypertension, and unclassified profiles. All-cause mortality was analyzed by multivariable Cox regression and competing-risk models, with liver transplantation as an intercurrent event. RESULTS:Over a median follow-up time of 20.0 months (IQR 8.0-36.0), 3-year survival rates were 76.7%, 49.5%, and 42.0% in the normal mPAP, early PoPH, and classic PoPH groups, respectively. After adjustment for age, sex, liver function, and portal hypertension severity, both early PoPH (hazard ratio 3.5; 95% CI 1.9-6.3; p <0.01) and classic PoPH (hazard ratio 4.5; 2.6-7.6; p <0.01) remained independent predictors of mortality vs. normal mPAP; these associations persisted in competing-risk analysis, whereas post-capillary pulmonary hypertension and unclassified groups did not differ from the normal mPAP cohort. CONCLUSION:Applying the 2022 ESC/ERC definitions of PAH identifies a subset of patients with cirrhosis with early-stage PoPH, characterized by mild pulmonary vascular resistance elevation, who nevertheless face a markedly increased risk of death, emphasizing the need for systematic screening and early targeted intervention. IMPACT AND IMPLICATIONS:Portopulmonary hypertension (PoPH) is a severe and often overlooked complication of cirrhosis. Using the updated 2022 ESC/ERS diagnostic criteria, this multicenter study identified a previously unrecognized subgroup of patients with cirrhosis and early-stage PoPH, defined by mildly elevated pulmonary vascular resistance and mean pulmonary artery pressure. Despite their subtle hemodynamic changes, these patients showed significantly reduced survival, independent of liver disease severity. These results highlight the prognostic relevance of early PoPH and suggest that applying the new criteria may help refine risk stratification and guide closer follow-up or earlier consideration of targeted interventions in selected patients.

Background & Aims: Current knowledge of the natural history of patients with porto-sinusoidal vascular disorder (PSVD) is derived from small studies. The aim of the present study was to determine the natural history of PSVD and prognostic factors in a large multicenter cohort of patients. Methods: We performed a retrospective study on patients with PSVD and signs of portal hypertension (PH) prospectively registered in 27 centers. Results: A total of 587 patients were included, median age of 47 years and 38% were women. Four-hundred and one patients had an associated condition, which was graded as severe in 157. Median follow-up was 68 months. At diagnosis, 64% of patients were asymptomatic while 36% had a PH-related complication: PH-related bleeding in 112 patients, ascites in 117, and hepatic encephalopathy in 11. In those not presenting with bleeding, the incidence of first bleeding was 15% at 5 years, with a 5-year rebleeding rate of 18%. The 5-year cumulative incidence of new or worsening ascites was 18% and of developing portal vein thrombosis was 16%. Fifty (8.5%) patients received a liver transplantation and 109 (19%) died, including 55 non-liver-related deaths. Transplant-free survival was 97% and 83% at 1 and 5 years, respectively. Variables independently associated with transplant-free survival were age, ascites, serum bilirubin, albumin and creatinine levels at diagnosis and severe associated conditions. This allowed for the creation of a nomogram that accurately predicted prognosis. Conclusions: The prognosis of PSVD is strongly determined by the severity of the associated underlying conditions and parameters of liver and renal function. (c) 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND & AIMS:Previous studies suggest that anticoagulation may reduce the risk of portal hypertension (PHT)-related complications and improve survival in patients with cirrhosis. This study aimed to evaluate the efficacy and safety of the direct oral anticoagulant rivaroxaban in patients with cirrhosis. METHODS:This was a randomized, double-blind, placebo-controlled, multicenter trial involving patients with cirrhosis, PHT, and moderate liver dysfunction (Child-Pugh score 7-10). Participants received either rivaroxaban 10 mg daily or placebo for 24 months. The primary composite endpoint was the development of a PHT-related complication or death/liver transplantation, whichever occurred first. Analyses were conducted using both modified intention-to-treat and per-protocol approaches. RESULTS:A total of 90 patients were enrolled (49 placebo, 41 rivaroxaban). After a median follow-up of 10.1 months, 34 patients reached the primary endpoint: 23 (46.9%) in the placebo group vs. 11 (26.8%) in the rivaroxaban group. The cumulative probability of survival free from the primary endpoint at 1 and 2 years was 54.4% and 43.0% in the placebo group, compared to 78.7% and 67.1% in the rivaroxaban group (log-rank p = 0.058). In a post hoc analysis of patients with Child-Pugh B7 scores (n = 55), rivaroxaban showed a potentially beneficial effect (hazard ratio 0.258; 95% CI 0.074-0.900). In the per-protocol analysis (41 placebo, 37 rivaroxaban), the primary event occurred in 19 patients (46.3%) in the placebo group vs. 9 (24.3%) in the rivaroxaban group (hazard ratio 0.463; 95% CI 0.209-1.024). Non-PHT-related bleeding events were more frequent in the rivaroxaban group (36.6% vs. 14.3%; relative risk 2.56; 95% CI 1.16-5.67). However, there were no significant differences in major bleeding events. CONCLUSIONS:In patients with cirrhosis and moderate liver dysfunction, rivaroxaban may improve PHT complication-free survival without significantly increasing the risk of major bleeding. IMPACT AND IMPLICATIONS:This study provides novel evidence supporting the potential use of rivaroxaban to prevent liver decompensation in patients with cirrhosis and portal hypertension. The observed reduction in decompensation events is consistent with previous findings on the benefits of anticoagulation in cirrhosis, suggesting a possible therapeutic role for rivaroxaban in this population. Although the reduction in the primary endpoint did not reach statistical significance in the overall cohort, a potential benefit was observed in a post hoc analysis of patients with Child-Pugh B cirrhosis. However, these findings should be interpreted with caution given the exploratory nature of the subgroup analyses. Non-portal hypertension-related bleeding events were more frequent in patients receiving rivaroxaban, though severe bleeding events were not increased. These results highlight the need for further studies to determine optimal dosing strategies that balance efficacy with bleeding risk. CLINICALTRIALS:GOV: NCT02643212. EUDRACT NUMBER:2014-005523-27.

BACKGROUND & AIMS:The NICER (liver and spleen stiffness by vibration-controlled transient elastography, platelet count, and BMI) and the ANTICIPATE±NASH models predict clinically significant portal hypertension (CSPH) in compensated advanced chronic liver disease (cACLD). This study reports follow-up data from the NICER cohort, comparing the prognostic utility of non-invasive tests for CSPH (CSPH-NITs) and hepatic venous pressure gradient (HVPG). METHODS:Patients with Child-Turcotte-Pugh A cACLD (liver stiffness ≥10 kPa and/or F3/4) from 16 European centres undergoing paired HVPG and CSPH-NIT assessment between 2020-2023 were included and followed until incident hepatic decompensation, hepatocellular carcinoma, death, or last visit. RESULTS:Three hundred and fifty-eight patients with cACLD were included (MASLD: 40.7%; MetALD/ALD: 32.1%; viral: 16.2%), with a CSPH prevalence of 62.0%. The cumulative 1-year and 2-year incidences of decompensation were 7.3 (95% CI 5.9-8.7%) and 12.6 (10.3-14.9%). Albumin levels were a key predictor of decompensation (subdistribution hazard ratio [sHR] 0.836; 95% CI 0.779-0.897), alongside HVPG (albumin-adjusted SHR 1.126; 95% CI 1.059-1.198), NICER (albumin-adjusted SHR 1.207; 95% CI 1.043-1.397), or ANTICIPATE±NASH (albumin-adjusted SHR 1.174; 95% CI 1.003-1.374). Models incorporating albumin alongside HVPG or CSPH-NIT achieved high C-indices for decompensation (0.772-0.806). Stratifying patients by a predicted 1-year decompensation-free survival probability of ≥95% or <95% identified approximately 60% of patients as being at negligible 1-year risk (1.4-2.1%), while the remaining patients were at high risk of decompensation (14.3-16.0%). CONCLUSION:In our multicentre study of contemporary European patients with cACLD, non-invasively estimated CSPH risk was as predictive for decompensation as HVPG. Models comprising indicators of portal hypertension and albumin discriminated between patients at negligible decompensation risk and those with a 1-year risk of approximately 15%, i.e. the potential target population for preventive strategies. IMPACT AND IMPLICATIONS:Non-invasive tests (NITs) facilitate the early diagnosis and management of clinically significant portal hypertension in patients with compensated advanced chronic liver disease (cACLD). In our contemporary cohort of patients with cACLD, mainly steatotic liver disease, recruited at 16 European expert centres, the hepatic venous pressure gradient and NITs were similarly predictive of decompensation within 1 to 2 years of follow-up. Serum albumin levels were identified as the second main predictor of decompensation after hepatic venous pressure gradient or NITs for clinically significant portal hypertension. Novel models were developed that could accurately predict the risk of decompensation, thereby refining point-of-care risk stratification and informing clinical trial design for patients with CTP-A cACLD.

Background The Omicron variant of SARS-CoV-2 emerged as a new variant of concern, characterized by high transmissibility and lower severity compared with previous variants, and became the majority variant in the sixth wave in Spain. This study aims to assess the impact of SARS-CoV-2 infection on liver transplant recipients (LTRs) during 2023 in the population of Cantabria. Methods The study included 295 LTRs undergoing follow-up at the Liver Transplant Unit of the Marqués de Valdecilla University Hospital. Data on patient characteristics, comorbidities, and vaccination schedules were collected. Humoral response to mRNA vaccines was evaluated using IgG antibodies against the S protein and an adequate response was defined as antibody titers of >260 BAU/mL 1 month after the third vaccine dose. Results In Cantabria, 0.75% of the general population and 7.10% of LTRs were infected with SARS-CoV-2. Most LTRs were men with comorbidities, mainly cardiovascular disease and hypertension. Of the LTRs, 95.2% were fully vaccinated and received 3 doses of the Moderna mRNA vaccine, and all had an adequate response after 4 to 5 doses. Most infections in LTRs were asymptomatic or mild, with lower hospitalization rates. No LTRs required intensive care admission or died owing to SARS-CoV-2 infection. Conclusions LTRs are targets for SARS-CoV-2 vaccination. The Omicron variant has shown greater transmissibility but causes milder disease in vaccinated LTRs. All vaccinated LTRs showed an adequate response after 4 to 5 doses. Therefore, vaccination protects against severe disease and mortality in LTRs, and booster vaccinations with variant-adapted vaccines are recommended.